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 the Chinese invention patent application with application date of October 17, 2014, application number 202210366235.7, and invention name “Method for preparing PDE4 inhibitors”. Technical Field

[0002] The present invention relates to a method for preparing a compound of formula (I) having phosphodiesterase (PDE4) inhibitory activity. The present invention also relates to a method for isolating compound (I) by crystallization 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 crystalline 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] The compounds having the chemical names (S)-3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester and (S)-3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester can be used for prophylactic purposes or for symptomatic relief of a wide range of conditions, including respiratory disorders such as chronic bronchitis, chronic obstructive pulmonary disease (COPD), all types of asthma, and allergic disease states such as atopic dermatitis and allergic rhinitis.

[0006] Said compounds are disclosed in WO 2010 / 089107 as potent PDE4 inhibitors with excellent LPDE4 selectivity.

[0007] Also disclosed in WO 2010 / 089107 are methods for preparing compounds of formula (I) wherein n is 0 or 1 and analogs thereof. Summary of the Invention

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

[0009] In particular, the present invention relates to a process for the preparation of compounds of formula (I), wherein n is 0 or 1, and the chiral carbon atom marked with an asterisk in the following formula exhibits the (S) configuration.

[0010]

[0011] The compounds are therapeutically useful because of their action as PDE4 inhibitors, making pharmaceutical compositions containing them useful 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; reperfusion injury of the myocardium and brain; cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, febrile illness, diabetes, pneumoconiosis, toxic and allergic contact eczema; systemic lupus erythematosus, follicular and generalized pyoderma, intrinsic and extrinsic 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 efficient process for preparing compounds of formula (I) which is an alternative to the processes disclosed in the above-cited prior art documents.

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

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

[0015] The process according to the invention makes it possible to obtain a thermodynamically stable crystalline form of the compound of formula (I) (wherein 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] As described in detail below, Form A of the present invention can be selectively produced by crystallization using appropriate solvents and operating conditions, giving it its characteristic peaks in the X-ray powder diffraction (XRPD) pattern and melting point range.

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

[0018] Since the crystalline form A can be used for preventive or therapeutic purposes, the present invention also includes the use of the crystalline form A of the compound of formula (I) (wherein n is 1) in the preparation of a medicament for preventing and / or treating 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 administering an effective amount of Form A by inhalation.

[0020] By working up with appropriate solvents, solvates of compounds of formula (I) wherein n is 1 are also obtained.

[0021] Therefore, the present invention also relates to a process for the preparation of said solvates.

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

[0023] definition

[0024] Unless defined otherwise, 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 crystalline form wherein the total amount of readily detectable impurities as determined by standard analytical methods such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) is less than 5%, advantageously 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 crystalline form wherein 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) thermotrace of an ethanol solvate of a compound of formula (I) wherein n is 1.

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

[0029] Figure 3 is the 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) thermotrace of Form A from ethyl acetate / n-heptane.

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

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

[0033] Figure 7 is the XRPD pattern of Form A from isopropyl acetate. Detailed Description of the Invention

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

[0036]

[0037] The method comprises:

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

[0039]

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

[0041]

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

[0043]

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

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

[0046]

[0047] in which n is 0 or 1, and reacting it with methanesulfonyl halide to obtain the compound of formula (I) in which 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 the alternative steps (c1) or (c2) or (c3):

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

[0050]

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

[0052]

[0053] in which n is 0 or 1, and which is subsequently enantioselectively reduced to give the compound of formula (II) in which n has the meaning reported above; or

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

[0055]

[0056] where n has the meaning reported above;

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

[0058] c3) making an intermediate of formula B"

[0059]

[0060] Reaction with the intermediate of formula D

[0061]

[0062] in which R is linear or branched (C1-C6)alkyl or arylalkyl and n has the meaning reported above, to directly obtain the compound of formula (VII) and subsequently enantioselectively reduce it to obtain the compound of formula (II), in which n has the meaning reported above;

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

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

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

[0066] The term straight-chain or branched (C1-C6) 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 (C1-C6)arylalkyl refers to a (C1-C6)alkyl group further substituted by an aryl group.

[0068] The term straight-chain or branched (C1-C6)alkoxy refers to any alkyl-oxy chain, wherein 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-pentoxy, n-hexoxy, etc., preferably methoxy.

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

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

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

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

[0073] In a preferred embodiment, the present invention provides a process for preparing a compound of formula (I) (wherein n is 0 or 1), which comprises, 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 NHSO2Me and Z has the meaning reported above).

[0074] According to an alternative preferred embodiment, the present invention provides a process for preparing a compound of formula (I) (wherein n is 0 or 1), which comprises, 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 -NO2 and Z has the meaning reported above).

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

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

[0077] Even more preferably, according to this latter embodiment, the present invention provides a process for the preparation of compounds of formula (I) (wherein n is 0 or 1), which process comprises reacting the compound of formula (II) obtained according to step (c2) by chromatographic separation of the compound of formula (VI) to obtain a compound of formula (II) and a compound of formula (VIII), wherein n has the meaning reported above, and then oxidizing the compound of formula (VIII) to the corresponding compound of formula (VII), which is subsequently reduced to the compound of formula (VI) which 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), said method comprising reacting the compound of formula (II) obtained according to step (c3) by reacting an intermediate of formula B″

[0079]

[0080] Reaction with the intermediate of formula D

[0081]

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

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

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

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

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

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

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

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

[0090] More specifically, when a compound of formula (III) wherein Z is -OH is used, the reaction is carried out in the presence of a coupling agent selected from the group consisting of 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 the presence of a coupling agent selected from the group consisting of dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, dimethylbenzene, methyl benzoate ... The reaction is carried out in a solvent selected from the group consisting of 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof.

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

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

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

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

[0095] Preferably, the reducing step is carried out with a reducing agent selected from the group consisting of hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, tin dichloride, 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 the reaction is carried out with hydrogen, cyclohexadiene, ammonium formate and formic acid, the reaction is carried out in the presence of a catalyst selected from a catalyst based on palladium, platinum or nickel, 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, dimethylbenzene, methyl ether, ethyl acetate, ethyl acetate, acetonitrile, and mixtures thereof.

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

[0100] The subsequent 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, dimethylbenzene, The reaction is carried out in the presence of 2-(4-(2-nitro-2-oxo-1-oxo-2-nitropropene)-2-nitropropene (e.g., 2-(2-nitro-2-oxo-1-oxo-2-nitropropene)-2-nitropropene (e.g., 2-nitro-2-oxo-1-oxo-2-nitropropene), 2-nitro-2-oxo-1-oxo-2-nitropropene), 2-nitro-2-oxo-1-oxo-2-nitropropene), 2-nitro-2-oxo-1-oxo-2-nitropropene, ...

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

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

[0103] Preferably, the reaction mixture is stirred at room temperature in the presence of an oxidizing agent (selected from metal oxides such as MnO2, supervalent iodine such as 2-iodoxybenzoic acid (IBX) or Dess-Martin periodinane, dimethyl sulfoxide-based oxidizing agents (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, dimethicone, methyl benzoate ... alkanes and their mixtures).

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

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

[0106]

[0107] and an intermediate of formula D (wherein n=0)

[0108]

[0109] Preparation of compounds of formula (VI).

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

[0111]

[0112] Converted into the intermediate of formula B

[0113]

[0114] In methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, with or without other solvents, react with thionyl chloride, hydrochloric acid, sulfuric acid; or in a suitable solvent (such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dimethicone) The method comprises reacting the alkyl halide with the relevant alkyl halide in the presence of 2-(4-(2-methyl-1-oxane, 2-ethylhexane, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and mixtures thereof) and a base, wherein 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), and pyridine.

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

[0116] By using a suitable solvent such as water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dimethicone, In the presence of alkane, 2-methoxyethyl ether, isopropyl acetate, acetonitrile, and mixtures thereof, a mixture of hydrogen peroxide, an organic peracid such as peracetic acid or meta-chloroperbenzoic acid, or an inorganic peracid such as persulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4) oxidizing intermediate B can obtain intermediate B'. More preferably, The above reaction was carried out in methanol.

[0117] Alternatively, the reaction can be carried out by using the corresponding alkyl alcohol as solvent. Intermediate B can be directly prepared from intermediate B by oxidation.

[0118] Alternatively, intermediate B" can be prepared by converting intermediate C' to intermediate C" via Pinner reaction with sulfuric acid in the corresponding alkyl alcohol as solvent.

[0119]

[0120] Then, in a suitable solvent (such as toluene, benzene, xylene, tetrahydrofuran, Cyclopropyl bromide is alkylated in the presence of 2-(4-(2-nitro-2-oxo-1-oxo-4-oxo-1-oxo-2-oxo-1-oxo-2-oxo-2-oxo-2-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-4-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-oxo-3-oxo-2-

[0121] The intermediate B" is then converted to the corresponding ketone derivative of formula (VII) by reacting the mixture in the presence of a suitable solvent such as toluene, benzene, xylene, tetrahydrofuran, methyl-tetrahydrofuran, dimethylbenzene, The method comprises the following steps: reacting the intermediate D in the presence of alkyl, 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether and a mixture thereof, in the presence of a base, wherein the base is preferably selected from lithium diisopropylamide (LDA), butyllithium, hexyllithium, pentyllithium, lithium bis(trimethylsilyl)amide (LHMDS), sodium bis(trimethylsilyl)amide and potassium tert-butoxide.

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

[0123] The subsequent enantioselective reduction step is preferably carried out in the presence of a preformed or in situ formed heavy metal chiral complex using a reducing agent selected from hydrogen. The in situ formation can occur by reacting a Ru-, Rh- or Ir-complex such as RuCl2(PPh3)3, [Ru(p-cymene)Cl2]2, [RhCl2(Cp*)]2 or [IrCl2(Cp*)]2 with a chiral ligand such as SL-N004-1 ((S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl] Oxazoline), SL-N003-1((R)-4-isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl] The reaction was carried out using (1S,2S)-(-)-N-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), and (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, sodium C1-C4 alcoholate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium C1-C4 alcoholate, potassium bicarbonate, lithium hydroxide, lithium carbonate, lithium C1-C4 alcoholate, 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 aqueous sodium hydroxide solution using a complex formed in situ by reacting RuCl2(PPh3)3 with the chiral ligand SL-N004-1.

[0126] Alternatively, compounds of formula (II) and (VIII) can be separated by preparative chiral chromatography; a batch operation can be employed: a chiral column is loaded with a solution of the racemate (VI) in several cycles and the eluted fractions of the separated enantiomers are collected. Simulated moving bed (SMB) operation should be considered for separating large quantities 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, etc. The reaction is carried out in the presence of 2-dimethylformamide, ...

[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 of alkane, ethyl acetate, isopropyl acetate, acetonitrile, acetic acid and mixtures thereof is selected from hydrogen peroxide, organic peracid such as peracetic acid or m-chloroperbenzoic acid or inorganic peracid such as persulfuric acid or All compounds of the present invention (wherein n is 0) can be converted into corresponding compounds (wherein n is 1) by oxidation with an oxidizing agent such as (KHSO5*1 / 2KHSO4*1 / 2K2SO4).

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

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

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

[0133]

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

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

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

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

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

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

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

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

[0142] Likewise, the preparation of compounds of formula (III) wherein Z is other than -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 process for preparing further compounds of formula (IX) which, relative to the above compounds of formula (I), carry further R1 and R2 groups in place of the cyclopropylmethyl and difluoromethyl groups of formula (I).

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

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

[0146]

[0147] Where n is 0 or 1;

[0148] and R1 and R2 are independently selected from H, a linear or branched (C1-C6) alkyl group, the (C1-C6) alkyl group being optionally substituted by one or more substituents selected from a halogen atom, a (C3-C7) cycloalkyl group, a (C5-C7) cycloalkenyl group, a linear or branched (C2-C6) alkenyl group, an aryl (C2-C6) alkenyl group, and a linear or branched (C2-C6) alkynyl group, the method comprising:

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

[0150]

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

[0152]

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

[0154]

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

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

[0157]

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

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

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

[0161]

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

[0163]

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

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

[0166]

[0167] where 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 chromatographic separation method described below;

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

[0170] From all the above it is evident that the operating conditions of the preceding steps of the process for the preparation of compounds of formula (I) are equally applicable to the preparation of compounds of formula (XI).

[0171] The intermediate compounds of formula (XII) and (XIII) (and wherein n is 0 or 1) are novel and therefore represent a further object of the present invention.

[0172]

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

[0174] In another even more preferred embodiment, when compound (I) (wherein n is 0 or 1) is obtained, it can be purified by crystallization or fragmentation 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, dimethylbenzene, methyl ethyl ketone, methyl isobutyl ketone, methyl ethyl ... alkyl, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, an aliphatic or aromatic hydrocarbon, preferably selected from pentane, hexane, heptane, cyclohexane and methylcyclohexane or a mixture 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 the isolation of compound (I) by crystallization 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 process for the preparation of Form 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 crystalline form 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), which comprises administering an effective amount of crystalline form A by inhalation.

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

[0181] In another preferred embodiment, the present invention relates to a process for the preparation of 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] By mixing the compound (wherein n is 0 or 1) of formula (I) prepared according to the present invention and one or more pharmaceutically acceptable excipients, pharmaceutical compositions can be prepared.Depending on the nature of the medical disease to be treated or the type of the disease and the patient, the pharmaceutical composition can be configured to be delivered by any suitable route, including oral, intravenous, parenteral, suction, intranasal, local, subcutaneous, intramuscular, rectal, vaginal routes.Suitable dosage forms include known preparations such as tablets, capsules, powders, sustained release formulations, ointments, gels, creams, suppositories, eye drops, transdermal patches, syrups, solutions, suspensions, aerosols, solutions for sprayers, nasal sprays, etc. In a preferred embodiment, the composition is configured to be delivered by suction or intranasal route, for example, in aerosol solutions or suspensions, as dry powder for inhalation, or in nasal sprays.

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

[0184] The dosage of the compounds of the 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, toxicological properties, and pharmacokinetic properties of the compound.

[0185] Advantageously, the compound of formula (I) (wherein n is 0 or 1) may be administered, for example, at a dosage comprised 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) obtained according to the present invention (wherein n is 0 or 1) can be used for prophylactic purposes or for symptomatic relief of a wide range of conditions, including respiratory disorders such as chronic bronchitis, chronic obstructive pulmonary disease (COPD) and all types of asthma. However, the compounds of formula (I) (wherein n is 0 or 1) can be administered for the prevention and / or treatment of any disease or disease state mediated by PDE4 activity (e.g., disease states in which PDE4 is overexpressed or overactive) in which the activity of the PDE4 receptor is implicated and in which it is desired to inhibit the activity of the PDE4 receptor. Examples of such diseases include allergic disease states such as atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, chronic glomerulonephritis, endotoxic shock, cystic fibrosis, arterial restenosis, atherosclerosis, keratosis, rheumatoid spondylitis , osteoarthritis, fever, diabetes, pneumoconiosis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, simple lichen, sunburn, itching of the anal and genital areas, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and extensive area pyoderma, intrinsic and exogenous acne, rosacea, Behcet'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 according to any process of 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 according to any method of the present invention, wherein n is 0 or 1.

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

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] DETAILED DESCRIPTION

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

[0198] Route A - The intermediate (VI) (wherein n is 0 or 1) obtained according to the procedure described in Example 1 of WO 2010 / 089107 is oxidized to (VII) (wherein n is 0 or 1) in the presence of an oxidant selected from metal oxides such as MnO2, hypervalent iodine such as 2-iodoacylbenzoic acid (IBX) or Dess-Martin periodinane, dimethyl sulfoxide-based oxidants (Swern) such as sulfur trioxide pyridine complex. The synthesis is preferably carried out in an oxidizing agent 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), ... The reaction is preferably carried out with MnO2 in toluene or with Swern's oxidant in DMSO.

[0199] Alternatively, the compound of formula (VII) can be obtained by reacting the precipitate with a suitable solvent (such as toluene, benzene, xylene, tetrahydrofuran, methyl-tetrahydrofuran, dimethylbenzene, ... In the presence of alkane, 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether and mixtures thereof, the intermediate of formula B" is reacted with

[0200]

[0201] Wherein R is a linear or branched (C1-C6) alkyl or arylalkyl group, reacting with the intermediate of formula D

[0202]

[0203] where n has the meaning reported above.

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

[0205] Compound B' can be obtained from compound B' as follows: 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 a suitable solvent such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dimethicone ... The present invention relates to a method for reacting the alkyl halide with the relevant alkyl halide in the presence of 2-naphthalene, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, and a mixture thereof and a base, wherein 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 base, diisopropylethylamine), NMM (N-methylmorpholine), pyridine.

[0206] More preferably, the above reaction is carried out using 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, dimethicone In the presence of alkane, 2-methoxyethyl ether, isopropyl acetate, acetonitrile, and mixtures thereof, a mixture selected from hydrogen peroxide, an organic peracid such as peracetic acid or m-chloroperbenzoic acid, or an inorganic peracid such as persulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4) oxidant can be used to obtain compound B' from compound B. More preferably, the above reaction is carried out with Performed in methanol.

[0208] Alternatively, the reaction mixture may be prepared by reacting the mixture 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, dimethicone, The intermediate of formula B" can be obtained from the intermediate of formula C" by alkylation with bromo-methylcyclopropane in alkane, 2-methoxyethyl ether, ethyl 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 base, diisopropylethylamine), NMM (N-methylmorpholine), pyridine, DBU, DBO, DMAP. More preferably, the above reaction is carried out with potassium carbonate in dimethylformamide.

[0209] The reaction is carried out by using or not a suitable solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, tetrahydrofuran, dimethylbenzene, etc. in the presence of an alcohol and a Lewis acid. Intermediate C' can be obtained by Pinner reaction with alkane, 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether and a mixture thereof. The Lewis acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, alkanesulfonic acid such as methanesulfonic acid, arylsulfonic acid 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 carried out with sulfuric acid in methanol.

[0210] Subsequent enantioselective reduction of (VII) (where n is 0 or 1) provides a 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 RuCl2(PPh3)3, [Ru(p-cymene)Cl2]2, [RhCl2(Cp*)]2 or [IrCl2(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] The reaction was carried out using (1S,2S)-(-)-N-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), and (1R,2S)-1-amino-2-indanol. The reaction is carried out in the presence of a base, preferably selected from sodium hydroxide, sodium carbonate, sodium C1-C4 alcoholate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium C1-C4 alcoholate, potassium bicarbonate, lithium hydroxide, lithium carbonate, lithium C1-C4 alcoholate, 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, dimethylbenzene, methyl ether, ethyl acetate, ethyl acetate, acetonitrile, and mixtures thereof.

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

[0214] Alternatively, (II) (wherein n is 1) is obtained by oxidizing (II) (wherein 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 persulfuric acid or (KHSO5*1 / 2KHSO4*1 / 2K2SO4). The reaction solvent is selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF ... Alkane, ethyl acetate, isopropyl acetate, acetonitrile, acetic acid and mixtures thereof. The reaction is preferably carried out with Performed in water and methanol.

[0215] Route B - Alternative route A, intermediates (II) and (VIII) (wherein n is 0 or 1) are obtained from intermediate (VI) (wherein n is 0 or 1) by preparative chiral HPLC separation of the enantiomers.

[0216] Batch operation can be employed: a chiral column is loaded with a solution of the racemate (VI) in several cycles and the eluted fractions of the separated enantiomers are collected. Simulated moving bed (SMB) operation should be considered for separations of large quantities of material.

[0217] Once the compounds of formula (II) and (VIII) have been separated by preparative chiral HPLC techniques, the compound of formula (VIII) can be conveniently reconverted to the compound of formula (VI) by oxidation to the corresponding derivative of formula (VII) and subsequent reduction and reprocessing in a chromatographic separation method as previously reported.

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

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

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

[0221] Intermediate (III) (wherein X is -NHSO2Me and Z is as defined above) is converted to (III) (wherein Z is -OH) by hydrolysis in a base, wherein 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 in admixture with methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, THF, dimethylbenzene, In a preferred embodiment, the reaction is carried out with NaOH in THF and water.

[0222] Route C - Compound (I) (wherein n is 0 or 1) is obtained by reacting a mixture 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-oxoethylidenaminooxy)dimethylamino-morpholino-carbonyl) The reaction mixture is stirred at room temperature for 2 hours in the presence of a coupling agent selected from the group consisting of dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, dimethicone, 1-hydroxybenzotriazole ... Intermediate (III) (wherein X is -NHSO2Me and Z is -OH) is condensed with intermediate (II) (wherein n is 0 or 1) in a solvent selected from the group consisting of 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof.

[0223] When the compound of formula (III) is an acid chloride or acid bromide or an 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 carried out with CDI and DBU in ethyl acetate.

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

[0226] By reducing (IV) (wherein n is 0 or 1) with a reducing agent selected from hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, tin dichloride, tin, nickel chloride, nickel, lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride and potassium borohydride, sodium dithionite, intermediate (V) (wherein n is 0 or 1) is obtained. In the case of using hydrogen, cyclohexadiene, ammonium formate and formic acid, the reaction is carried out in the presence of a catalyst, 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, dimethylbenzene, 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 platinum on carbon in ethyl acetate using hydrogen.

[0229] By in the presence of a solvent selected from the group consisting of toluene, benzene, xylene, tetrahydrofuran, (V) (wherein n is 0 or 1) is reacted with methanesulfonyl chloride in the presence of a suitable solvent selected from the group consisting of 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene and mixtures thereof, and a base to give compound (I) (wherein n is 0 or 1). The base is preferably selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, 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 pyridine in excess, 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) (wherein n is 0) to compound (II) (wherein n is 1), 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).

[0232] When compound (I) (wherein n is 0 or 1) is obtained, it can be purified by crystallization or crushing 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, dimethylbenzene, methyl ethyl ketone, methyl isobutyl ketone, methyl ethyl ... The reaction is preferably carried out in ethyl acetate with n-heptane, 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, an aliphatic or aromatic hydrocarbon, preferably selected from pentane, hexane, heptane, cyclohexane and methylcyclohexane or a mixture thereof.

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

[0234] The reaction can be carried out in a reactor wherein the compound of formula (I) is loaded 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) may be obtained.

[0236] Described reaction can be carried out from the compound of formula (I) in one or more solvents that are selected from pentane, hexane, heptane, cyclohexane, methylcyclohexane and methylene dichloride, thereby obtain solution, it can concentrate and then add together with ethanol.Solution can be concentrated, and the suspension obtained can be cooled and stirred 1-5 hour at the temperature between 0-10 ℃.Solid is filtered, washed with ethanol, and dried 10-30 hour at the temperature between 25-55 ℃.

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

[0238] Example 1

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

[0240]

[0241] Obtain (III) as described in WO 2010 / 08910, Example 18, wherein X is -NHSO Me and Z is -OMe. It (6.0kg) and 18L THF are loaded into the reactor. Separately, 6.6kg 35%w / w sodium hydroxide and 21L purified water are mixed and transferred into the reactor, and the mixture is heated to 65 ℃, while distilling out all THF. After the hydrolysis reaction finishes, the alkaline solution is slowly transferred into another reactor containing a solution of 24L purified water and 7.2kg 37%w / w hydrochloric acid, kept the temperature below 40 ℃ and stirred for 15 minutes. The solid obtained is filtered and washed with 24L water. Wet solid (III) (16.6kg wet weight) is reloaded into the reactor together with 60L ethyl acetate, then heated to reflux to distill out 30L solvent. 12.6L heptane is loaded into the reactor, and the mixture is kept under stirring for 15-30 minutes. It was then cooled to 5°C and maintained under stirring for 2 hours. The resulting solid was filtered, and the reactor and filter cake were washed with 12 L of heptane. The wet solid was dried under vacuum in a static tray drier. 6235 g of a white solid was obtained (93.9% yield).

[0242] 1 H NMR(400MHz,DMSO-d6)δppm 12.85(br.s.,1H),9.03(s,1H),7.40-7.71(m,2H),7.35(d,J=8.16Hz,1H),3.91(d,J =6.84Hz,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 preparative procedure described in WO 2010 / 089107, Example 1, intermediate (VI) was obtained, wherein n is 0.

[0246]

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

[0248] Operations using MnO2

[0249] 5 kg of (VI) (wherein n is 0) is dissolved in 30 L of toluene in a reactor; 3.15 kg of activated MnO2 is added to the organic mixture, and the suspension is heated to reflux for 3 hours. The mixture is cooled to 50 ° C, and the MnO2 is filtered off on a diatomaceous earth pad. The organic solution is loaded into the reactor, and toluene is distilled off until 3 residual volumes. 20 L of 2-propanol is added to the reactor and concentrated again until 2 residual volumes in order to remove the entire amount of toluene. Another 20 L of 2-propanol is loaded, and the solvent is partially distilled to have 4 residual volumes in the reactor. The suspension is cooled and kept at 10 ° C overnight with stirring. The solid is filtered, and the wet solid is dried 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] Operating Swern

[0252] Triethylamine (4.5 mL, 32 mmol) was added dropwise to a solution of alcohol (VI) (wherein n is 0) (5.0 g, 12.4 mmol) in DMSO (15 mL) with stirring at 25°C. Pyridine.SO3 complex (5.0 g, 31 mmol) was added portionwise over approximately 1 hour, such that the internal batch temperature did not rise above 35°C. The reaction mixture was stirred at 25°C for 4 hours and then quenched with water (60 mL) and 10% aqueous H2SO4 solution (10 mL). The resulting mixture was stirred at 25°C, and the solid was filtered off and dried under reduced pressure at 50°C to give 4.6 g (92% yield) of pure ketone (VII) as a colorless solid.

[0253] Operations using IBX

[0254] (VI) (wherein n is 0) (1.0 g, 2.5 mmol) was added in one portion to a suspension of 2-iodoacylbenzoic acid (IBX) (0.9 g, 3.2 mmol) prepared according to the literature (JOC 1999, p. 4537) in DMSO (5 mL), and the resulting mixture was stirred at 25° C. for 1 hour and then heated to 50° C. for 2 hours. After cooling to 25° C., the reaction was quenched with 10% aqueous potassium carbonate (40 mL), and the solid was filtered off to give ketone (VII) in quantitative yield.

[0255] use Operation

[0256] Commercially available ("Stabilized IBX", a white powder preparation of IBX consisting of a mixture of benzoic acid (22%), isophthalic acid (29%) and o-iodooxybenzoic acid (49%), obtained from SIMAFEX) (2.0 g, 3.2 mmol) was added in one portion to a solution of (VI) (wherein n is 0) (1.0 g, 2.5 mmol) in acetone (15 mL). The resulting mixture was refluxed for 2.5 h, cooled at 25° C., and then quenched with 10% aqueous sodium sulfite (10 mL) and 10% aqueous potassium carbonate (40 mL). The mixture was stirred at 25° C. for 0.5 h and the solid was filtered off to give ketone (VII) (wherein n is 0) in quantitative yield.

[0257] Operations using DMP

[0258] Dess-Martin periodinane (DMP) (1.3 g, 0.31 mmol) was added in one portion to a solution of alcohol (VI) (wherein n is 0) (1.0 g, 2.5 mmol) in acetone (5 mL). The reaction mixture was stirred at 25-30 ° C for 1 hour 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 hours and the solid was filtered off to obtain (VII) (wherein n is 0) in quantitative yield.

[0259] Example 2A

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

[0261]

[0262] 3,5-Dichloro-4-methyl-pyridine (0.5 g, 3.08 mmol) and The product (1.5 g, 4.62 mmol) was suspended in a 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 hours. The solvent was removed under reduced pressure, and the resulting crude solid was suspended in hot toluene (80 ° C) with stirring for 20 minutes. The heterogeneous hot solution was then filtered and the mother liquor was cooled to room temperature to obtain a solid precipitate. After stirring at 0-5 ° C for 30 minutes and filtering, the pure product (0.43 g, 78% yield) was obtained as a white solid.

[0263] Example 2B

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

[0265]

[0266] In a three-necked 50ml flask, intermediate A (0.4g, 2.25mmol) and intermediate B (0.78g, 3.22mmol) were added under a nitrogen atmosphere and dissolved in anhydrous THF (5ml). The stirred solution was cooled to -35°C. Potassium tert-butoxide (0.3g, 2.67mmol) was added portionwise to the solution over 10 minutes. After reacting at -35°C for 60 minutes, the solution was quenched with a 25% NH4Cl aqueous solution (10ml). EtOAc (8ml) and water (8ml) were added to the suspension and stirred, the phases were separated, and the organic phase was extracted and washed with a 5% NaCl aqueous solution (10ml). The organic solvent was then dried over Na2SO4 and removed under reduced pressure to obtain a crude white solid. It was crystallized from hot toluene to obtain a white solid (0.40g, 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(PPh3)3 were placed in a 2 L Schlenk bulb and dried, and degassed toluene (1.2 L) was added. The mixture was heated to 80°C for 1 hour and then allowed to reach room temperature (RT). The catalyst solution and 298 mL of degassed 0.5 M NaOH aqueous solution were then added to the reactor. The reactor was sealed, degassed with nitrogen, and set under 10 bar of hydrogen. The mixture was heated to 35°C under a constant pressure of 10 bar. After a total reaction time of 19 hours, the heater was turned off. The reactor was cooled to room temperature and the aqueous layer was removed. The organic phase was washed twice with 0.5 L of water; the aqueous phase was stripped with 1 L of toluene added to the organic phase. 240 g of decolorizing carbon (Norit CAP Super) was added to the toluene solution, and the mixture was stirred at room temperature overnight. The carbon was filtered out and the filter cake was rinsed with 1.5 L of ethyl acetate. The slightly yellow solution was concentrated to dryness under reduced pressure to produce 2.38 kg of crude wet material. This was dissolved in 1.5 L of isopropyl acetate at 60 ° C with stirring, 9 L of preheated heptane (50 ° C) was added, and the mixture was stirred at 60 ° C. Seeded crystals were added to the solution and slowly cooled to room temperature with stirring. Stirring was continued at room temperature overnight, and then the mixture was cooled to 0 ° C and held for 1 hour. The solid was filtered and dried. The yield was 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] Use ChiralpakIC 20 μ m-250*76mm post and dichloromethane / ethanol 95 / 5 (v / v) as mobile phase, 3000g (VI) (wherein n is 0) is carried out chromatographic separation in batches.The solution of racemate (VI) is loaded on the top of chiral column in several rounds, and the elution fraction of the separated enantiomer collected at column bottom is merged. Make (II) from the concentrated DCM / EtOH elution mixture crystallization enriched in ethanol.Obtain 1440g (48% yield) desired enantiomer (II) (wherein n is 0), it has>99.5% HPLC purity and>99.5% HPLC chiral purity.Also obtain 1470g (49% yield) other enantiomer (VIII) (wherein n is 0), it has>99% HPLC purity and>99% HPLC chiral purity.

[0275] Example 4A

[0276] Separation of (R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanol and (S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanol (Intermediates (VIII) and (II), n=1)

[0277]

[0278] Similar to Example 4, a solution of the racemate (VI) (wherein n is 1) can be chromatographed using a Chiralpak IC 20 μm-250*76 mm column and methanol as the mobile phase to obtain the desired enantiomer (II) (wherein n is 1) with high HPLC purity and HPLC chiral purity. The other enantiomer (VIII) (wherein n is 1) can also be obtained with high HPLC purity and HPLC chiral purity.

[0279] Example 5

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

[0281]

[0282] 75 g of (III) (wherein X is -NHSO2Me and Z is -OH) are suspended in 750 ml of DCM; 42.5 g of N,N-carbonyldiimidazole are added portionwise and the resulting solution is stirred at room temperature for 30 min. 375 ml of toluene is added, followed by 85 g of (II) (wherein n is 0), and the mixture is heated to reflux. The DCM is removed by distillation, and the suspension is then stirred at 100 ° C overnight. The resulting solution is cooled to 40 ° C, 500 ml of ethyl acetate is added, and washed with NaHCO3 solution and brine. The product is isolated by crystallization from ethyl acetate / heptane and recrystallized from the same solvent mixture to obtain a white solid (129 g recovered, 73% yield).

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

[0284] Example 6

[0285] Preparation of (S)-3-cyclopropylmethoxy-4-methanesulfonylaminobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester (Compound (I), n=1)

[0286]

[0287] Operation using H2O2 / acetic acid

[0288] 73 g of (I) (wherein n is 0) was charged to a flask, followed by 150 ml of toluene, 290 ml of acetic acid, and 75 ml of 35% H2O2, and the mixture was heated to 80°C for 8 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% aqueous NaHCO3 to an alkaline pH, and the solvent was removed by distillation. The crude material was purified by crystallization from 375 ml of ethyl acetate and 225 ml of n-heptane and dried in a stationary tray dryer to give a white solid (65.1 g recovered, 87.1% yield).

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

[0290] Example 7

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

[0292]

[0293]

[0294] Operation using H2O2 / acetic acid

[0295] 490g (II) (wherein n is 0) is loaded into the reactor together with 1960ml glacial acetic acid. The mixture is heated to 50 ℃, then gradually added 980ml of 30-35% hydrogen peroxide solution in water, and the mixture is kept at the same temperature under stirring for 16 hours. 2000ml purified water is slowly added, and (II) (wherein n=1) is precipitated as a solid. The slurry is cooled to 10 ℃ and kept for 3 hours under stirring. The solid is then filtered out, and the solid obtained is washed with 1000ml water. The wet solid (II) (wherein n is 1) is resuspended in 2000ml water for 2 hours and resuspended in 2000ml diisopropyl ether for 3 hours. The wet solid is dried under vacuum. 433g white solid (85% yield) is obtained.

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

[0297] use Operation

[0298] 456g (KHSO5*1 / 2KHSO4*1 / 2K2SO4) and 1.2 L of water were added to the reactor, and the mixture was stirred at room temperature. 400 g of (II) (wherein n is 0) and 3.2 L of methanol were added, and the mixture was heated to 70°C for 3 hours. Another 50 g of After 1.5 hours, the reaction finished. Alcohol was distilled off and 4L water and 2L ethyl acetate were added at 50 ℃. The aqueous phase was discharged, and the organic phase was washed with 800ml water and concentrated to 1.5L under vacuum. 4L toluene was added and the mixture was concentrated to 2.5L under vacuum, and the product began to precipitate. The suspension was cooled to 10 ℃ and kept under stirring for 1.5 hours. The solid obtained was filtered and washed with 800ml toluene. The wet solid was dried in a static tray dryer under vacuum. 288g of white solid (72% yield) was obtained.

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

[0300] Example 8

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

[0302]

[0303] 100g (III) (wherein X is NHSO2Me and Z is -OH) and 1L ethyl acetate are loaded in a reactor. 57g carbonyldiimidazole is added portionwise at 40°C under stirring, and the mixture is then stirred for 60min. 123g (II) (wherein n=1) and 3.7ml 1,8-diazabicyclo[5.4.0]undec-7-ene are added, and the mixture is heated to 75°C for approximately 4 hours. The organic solution is washed with 500ml of 1M HCl aqueous solution, 500ml of 5% NaHCO3 aqueous solution, and 500ml of 10% NaCl aqueous solution. The organic mixture is heated to 70°C under vacuum and concentrated to 600ml. The mixture is cooled to 50°C and 300ml of n-heptane is added. Seed crystals are added to the solution, cooled to 5°C and kept under stirring for 1.5 hours. The resulting solid is filtered out and dried under vacuum. 168g of crude solid (82% yield) is obtained.

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

[0305] Example 9

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

[0307] A solution of crude compound (I) (wherein n is 1) is loaded into a 1L reactor. DCM (90ml) and EtOH (300ml) are added, the white suspension is stirred and warmed to reflux until completely dissolved. DCM is distilled off, and a white solid begins to precipitate. The ethanolic solution is further concentrated to 6-7 volumes, a portion of EtOH is distilled off, and then cooled to 0-5 ℃ and stirred for 120 minutes. The solid obtained is filtered, and washed with 30ml EtOH. The wet solid is dried in a static tray dryer under vacuum. 28.55g of white solid (95% yield) is obtained.

[0308] The compound of formula (I) (wherein n is 1) obtained as a solvate according to Example 9 was studied by differential scanning calorimetry (DSC) (determination of melting point), Raman spectroscopy (observation of vibrational modes, rotational modes and low frequency modes) and X-ray powder diffraction (XRPD) patterns.

[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] The X-ray powder diffraction pattern (Bruker D8 Advance with Xray Diffraction Tube Model KFL CuKa2) was 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) (wherein n is 1)

[0313] Operation from ethyl acetate / heptane

[0314] 5g of crude product (I) (wherein n is 1) is loaded into a reactor together with 30ml of ethyl acetate, and the suspension is stirred while being heated to 75°C until the solid is completely dissolved. 15ml of n-heptane is added and the solution is allowed to reach room temperature. The suspension is cooled to 5°C and kept for 2 hours, filtered and dried under vacuum. A white solid, so-called Form A (3.6g, 72% yield) is obtained.

[0315] The compound of formula (I) (wherein n is 1) obtained as Form A according to Example 10 was studied by differential scanning calorimetry (DSC) (determination of melting point), Raman spectroscopy (observation of vibrational modes, rotational modes and low frequency modes) and X-ray powder diffraction (XRPD) patterns.

[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] The X-ray powder diffraction pattern (Bruker D8 Advance with Xray Diffraction Tube Model KFL CuKa2) is 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] Operations from isopropyl acetate

[0319] 5 g of crude product (I) (wherein n is 1) was loaded into a flask along 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, i.e., Form A (81% yield), was obtained.

[0320] Product characterization is described in the Examples 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-oxy-pyridin-4-yl)ethanone (Intermediate (VII), n=1)

[0323]

[0324] Operation using H2O2 / acetic acid

[0325] 0.5g (VII) (wherein n is 0) is loaded in the 50ml flask together with 3ml glacial acetic acid.Use homogeneous solution to be heated to 50 ℃, then add the 30-35% aqueous hydrogen peroxide solution of 1ml gradually, and mixture is kept at the same temperature for 21 hours under agitation.Desolventize under reduced pressure then, and with crude solid on the column chromatography that uses gradient elution (hexane / EtOAc 85 / 15 to EtOAc 100%), produce the pure product (yield 50%) as white solid.

[0326] use Operation

[0327] 10 g of (VII) (wherein n is 0) and 11.44 g 80ml of methanol and 30ml of water are loaded into the flask together. The mixture is heated to 65°C and kept for 5 hours, and kept at room temperature for 48 hours. Alcohol is distilled out, and 50ml of water and 100ml of toluene are added. The mixture is heated until the solid is completely dissolved, the aqueous phase is discharged and the organic phase is concentrated to 70ml under vacuum. The suspension is cooled to 0°C and kept under stirring for 1.5 hours. The solid obtained is filtered out and dried in a static tray dryer under vacuum. 6.7g of white solid (60% yield) is obtained.

[0328] Operation using MCPBA

[0329] 0.5 g of (VII) (wherein 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 at room temperature overnight. HPLC control confirmed almost complete conversion. The solution was partitioned between 100 ml of ethyl acetate and 50 ml of a 5% aqueous potassium bicarbonate solution. The organic phase was washed with another 50 ml of alkaline solution and dried under vacuum. The crude product was purified on a silica gel pad using a mixture of ethyl acetate and dichloromethane as eluent. 0.22 g of (VII) was obtained, where n=1 (42% yield).

[0330] Example 12

[0331] Oxidation of Intermediate (VI), n=1 to 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanone (Intermediate (VII), n=1)

[0332]

[0333] Operations using DMP

[0334] Alcohol (VI) (wherein n is 1) (1.0 g, 2.38 mmol) was suspended in acetone (15 ml). The suspension was cooled in an ice bath at 0-5°C with stirring. Dess-Martin periodinane (1.4 g, 3.3 mmol) was then 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 a 10% aqueous sodium metabisulfite solution and 30 mL of a 15% aqueous potassium carbonate solution was added. The mixture was stirred at 25°C for 0.5 hours and the solid was filtered to give ketone (VII) (wherein n is 1) in quantitative yield.

[0335] Example 13

[0336] Preparation of 3-(cyclopropylmethoxy)-4-nitrobenzoic acid (Intermediate (III), X = -NO2 and Z = -OH)

[0337]

[0338] (III) is prepared according to the operation described in WO 2010 / 089107 Example 18, wherein X is-NO and Z is-OMe. 550g (III) (wherein X is-NO and Z is-OMe) is loaded into the reactor, and the 1M lithium hydroxide aqueous solution of 1.65L THF and 2.85L is loaded subsequently. The mixture is heated to 40°C and kept for 1.5 hours, then cooled to room temperature. 4.4L ethyl acetate is added, followed by 240ml of 37% HCl aqueous solution. Aqueous phase is discharged, and the organic phase is washed 2 times with 2.75L water, and then concentrated under vacuum at 50°C, 1.65L normal heptane is added at the same temperature, and the suspension is cooled to room temperature. Solid is filtered out and dried in a vacuum tray dryer to obtain 337g (III), wherein X is-NO and Z is-OH (73% yield).

[0339] Example 14

[0340] Preparation of (S)-3-cyclopropylmethoxy-4-nitrobenzoic acid-l-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-l-pyridin-4-yl)-ethyl ester (Intermediate (IV), n=0)

[0341]

[0342] Intermediate (III) (wherein X is -NO2 and Z is -OH) (80 g, 0.34 mol, ref.) and (II) (wherein n is 0) (109.1 g, 0.27 mol, 0.9 eq.), EDC.HCl (193.9 g, 1.01 mmol, 3 eq.), DMAP (20.6 g, 0.17 mol, 0.5 eq.) and DMF (400 ml, 5 vol.) were mixed together and heated to 75°C overnight. The solution was partitioned between water and ethyl acetate, and the organic phase was washed with acidic and basic aqueous solutions and concentrated under vacuum. The crude material was crystallized from EtOH (1200 ml) and acetone (100 ml). A white solid (101 g, 60% yield relative to (VIII)) was obtained.

[0343] 1H NMR(400MHz,DMSO-d6)δppm 8.60(s,2H),7.97(d,J=8.38Hz,1H),7.61-7.80(m,2H),7.18-7.32(m,2H) ,7.02-7.14(m,2H),6.27(dd,J=9.70,3.97Hz,1H),4.04-4.21(m,2H),3.8 9-4.02(m,2H),3.74(dd,J=14.11,9.70Hz,1H),3.45(dd,J=13.89,4.19Hz ,1H),1.10-1.30(m,2H),0.49-0.65(m,4H),0.36(qd,J=5.44,5.29Hz,4H).

[0344] Example 15

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

[0346]

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

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

[0349] Example 16

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

[0351]

[0352] Hydrogenation operation

[0353] The reactor was charged with 2.5 g of (IV) (wherein n is 0), 119 mg of Pd / C catalyst, and 25 ml of ethyl acetate. The reactor was then sealed and heated to an internal temperature of 40° C. under gentle stirring. 4 bar of hydrogen was introduced into the reactor. After 4 hours, the conversion was complete. The catalyst was removed by filtration, and the solvent was distilled under reduced pressure. 2.20 g of product (90% yield) was recovered.

[0354] 1 H NMR (400MHz, CDCl3) δppm 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] Operations using SnCl2

[0356] 2 g of (IV) (wherein n is 0) was dissolved in 20 ml of THF and 4.34 g of tin (II) chloride dihydrate was added. The solution was stirred at 80° C. overnight. The solution was partitioned between 100 ml of ethyl acetate and 100 ml of a 5% aqueous solution of KHCO 3 . The mixture was filtered to remove the precipitated salts and the aqueous phase was drained. The organic phase was washed with additional KHCO 3 and brine. The organic solvent was removed under vacuum and (V) (wherein n is 0) was isolated as a yellow oil (1.84 g, 97% yield).

[0357] Example 17

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

[0359]

[0360] Hydrogenation operation

[0361] The reactor was charged with 400 mg of (IV) (where n=1), 8 mg of 1% Pt / C catalyst and 4 ml of ethyl acetate, sealed and heated to 60° C. with gentle stirring, filled with 4 bar of hydrogen and stirred for 4 hours. The mixture was filtered to remove the catalyst and dried under vacuum.

[0362] Operations using SnCl2

[0363] 1 g of (IV) (where n=1) was dissolved in 10 ml of THF and 1.06 g of tin(II) chloride dihydrate was added. The solution was stirred at room temperature overnight. The solvent was evaporated under vacuum and 10 ml of ethyl acetate and 10 ml of a 1 M NaOH aqueous solution were added to the crude product. The aqueous phase was drained and the organic phase was washed with 10 ml of a 10% NaCl aqueous solution. The organic solvent was removed and the crude product was suspended in diethyl ether and stirred until a solid was obtained; it was filtered, washed with 4 ml of diethyl ether and dried in a stationary rack dryer. A white solid (0.68 g, 71.3%) was obtained.

[0364] 1H NMR(400MHz,DMSO-d6)δppm 8.55(s,2H),7.40(dd,J=8.38,1.76Hz,1H),7.28(d,J=1.76Hz,1H),7.15-7.21( m,2H),6.99-7.08(m,2H),6.64(d,J=8.38Hz,1H),6.14(dd,J=9.59,4.30Hz,1H) ,5.63(s,2H),3.88-3.96(m,2H),3.70-3.88(m,2H),3.55(dd,J=14.11,9.92Hz, 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] Preparation of (S)-3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid 1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester (Compound (I), n=0)

[0367]

[0368] 0.5 g of (V) (wherein n is 0) (0.84 mmol) was dissolved in DCM (7 ml) and TEA (0.17 ml, 1.26 mmol), and then methanesulfonyl chloride (0.11 g, 0.93 ml) was slowly added and the solution was stirred at room temperature for 20 hours. The reaction was then quenched with water (20 ml), extracted with an organic solvent, and washed with a 5% NaCl aqueous solution (10 ml). The solvent was removed and the crude product was purified on column chromatography with a gradient elution (hexane 100% to hexane / EtOAc 60 / 40) to produce the pure product (yield 30%) as a colorless oil.

[0369] Example 19

[0370] Oxidation of intermediate (IV) (where n is 0) to give (S)-3-cyclopropylmethoxy-4-nitrobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester (Intermediate (IV), n=1)

[0371]

[0372] Operation using H2O2 / acetic acid

[0373] 0.5 g of (IV) (wherein n is 0) is charged into a 50 ml flask containing 3 ml of glacial acetic acid. The solution is heated to 55° C., then 1 ml of hydrogen peroxide (35%) is gradually added, and the mixture is maintained at the same temperature under stirring for 48 hours. 5 ml of water is added, the product is extracted with ethyl acetate, and the organic solvent is removed under reduced pressure to produce the product as a yellow oil (yield 74%).

[0374] use Operation

[0375] 0.3 g of (IV) (wherein n is 0) was charged into a 50 ml flask, followed by 2.4 ml of methanol, 1 ml of water and 215 mg of The suspension was stirred at 55° C. for 48 h and at 40° C. for 72 h. Methanol was removed under reduced pressure and 5 ml of ethyl acetate was added. The aqueous phase was extracted with ethyl acetate (3×5 ml), the organic phase was dried over Na 2 SO 4 and the solvent was removed under reduced pressure to produce the product as a slightly yellow oil (yield 96%).

[0376] Operation using MCPBA

[0377] 0.5 g of (IV) (wherein n is 0) was dissolved in 10 ml of THF, 0.22 g of MCPBA (3-chloroperoxybenzoic acid, 77% assay) was added, and the mixture was stirred at room temperature overnight. HPLC control confirmed almost complete conversion. The solution was distributed between 100 ml of ethyl acetate and 50 ml of a 5% aqueous potassium bicarbonate solution. The organic phase was washed with another 50 ml of alkaline solution and dried under vacuum. The crude product was purified on a silica gel pad using a mixture of ethyl acetate and dichloromethane as eluent. 0.19 g of (VII) was obtained (37% yield).

[0378] Example 20

[0379] (V) (wherein n is 1) is mesylated to give (S)-3-cyclopropylmethoxy-4-methanesulfonylaminobenzoic acid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester (compound (I) where n is 1)

[0380]

[0381] 0.2g (V) (wherein n is 1) (0.33mmol) is dissolved in DCM (3ml) and TEA (0.05ml, 0.39mmol), then methanesulfonyl chloride (0.045g, 0.07ml) is slowly added, and the solution is stirred at room temperature for 20 hours. The reactant is then quenched with HCl 1N (10ml), organic solvent extracted, and washed with 5% NaCl aqueous solution (10ml). Remove solvent, and the crude product is purified on column chromatography with gradient elution (hexane / EtOAc 85 / 15 to EtOAc 100%) to obtain the pure product (yield 30%) as a colorless oil.

[0382] Example 21

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

[0384]

[0385] 100 g of 3-hydroxy-4-(difluoromethoxy)-benzaldehyde (0.53 mol) was dissolved in MeOH (600 ml) and solid was added portionwise over 1 hour. (325g, 1.06mol), and the solution was stirred and warmed to 50-55°C for 2 hours. The solvent was concentrated under vacuum to 200ml, and water (1L) was added. The resulting heterogeneous solution was stirred at 50-55°C, then toluene (500ml) was added, and the two-phase mixture was stirred vigorously. The aqueous phase was discharged, and the organic phase was washed with water (500ml). Activated carbon (10g) was added, and the organic solution was stirred for 20 minutes. It was filtered on a celite pad, the solvent was concentrated under vacuum to 2-3 volumes, and the resulting solution was warmed to 80-90°C. N-heptane (400ml) was slowly added. The mixture was cooled to 0°C, and the suspension was stirred at 0°C overnight. The solid was filtered on a Buchner funnel and washed with n-heptane (100ml). The resulting white solid was dried at room temperature under vacuum (yield 70%).

[0386] Example 22

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

[0388]

[0389] 873 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (3.61 mol) was dissolved in MeOH (4.4 L) and then the solid was added portionwise over 1 hour. (1.86 Kg, 6.06 mol), and the solution was stirred and warmed to 55-60 ° C for 2 hours. The solvent was concentrated under vacuum to 1.6 L and water (7 L) was added. The resulting heterogeneous solution was stirred at 50-55 ° C, then toluene (3 L) was added and the two-phase mixture was stirred vigorously. The aqueous phase was discharged and the organic phase was washed with water (3 L). The solvent was concentrated under vacuum to 2-3 volumes and the resulting solution was warmed to 80-90 ° C. N-heptane (5.5 L) was slowly added. The mixture was cooled to -10 ° C and the suspension was stirred at -10 ° C overnight. The solid was filtered on a Buchner funnel and washed with n-heptane (1 L). The resulting yellow solid was dried at room temperature under vacuum (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-methylpyridine (21.4 g, 0.13 mol) were charged to a 1 L reactor and dissolved in THF (120 ml). The homogeneous solution was cooled to -10°C with stirring. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (0.22 mol, 220 ml) was slowly added over 30 minutes. The mixture was stirred at low temperature for 15-30 minutes, then quenched with 10% aqueous HCl (250 ml) and allowed to warm to room temperature. Ethyl acetate (300 ml) was added, and the biphasic mixture was stirred vigorously for 15-20 minutes. The aqueous phase was re-extracted with ethyl acetate (150 ml). The recombined organic phase was concentrated to 2 volumes. Isopropyl alcohol (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 light yellow solid precipitate. After 3 hours, the solid was filtered on a Buchner funnel and washed with 1 volume of cold isopropanol. The resulting solid was dried under vacuum at room temperature (yield 90.5%).

[0394] Example 24

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

[0396]

[0397] Procedures using DMF and potassium carbonate

[0398] 3-Hydroxy-4-(difluoromethoxy)-benzoic acid methyl ester (5 g, 22.9 mmol), K2CO3 (4.75 g, 34.4 mmol), NaI (0.34 g, 2.3 mmol) and bromo-methylcyclopropane (3.7 g, 27.5 mmol) were dissolved in DMF (25 ml), and the heterogeneous mixture was stirred and warmed at 80°C for 2 hours. The suspension was cooled to room temperature and water (50 ml) was added under stirring. The heterogeneous mixture was cooled to 0-5°C for 60-90 minutes, and the solid was filtered on a Gucci funnel and washed with water (50 ml). An orange solid was obtained. It was dried under vacuum 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] 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (50 g, 193.6 mmol) and K2CO3 (28.1 g, 203.3 mmol) were suspended in DMA (400 ml) and the suspension was warmed to 75-85°C. A solution of MeI (32.97 gr, 232.0 mmol) in DMA (100 ml) was added via a dropping funnel over 1 hour. At the end of the addition, the suspension was cooled to 0-5°C and water (500 ml) was added with stirring. Precipitation of a white solid occurred. The cold, heterogeneous mixture was stirred for 60-90 minutes and the solid was filtered on a Gucci funnel and washed with water (50 ml). The product was obtained as a white solid. It was dried under vacuum 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% H2SO4 aqueous solution (1 ml) was slowly added dropwise 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 Gucci funnel. The product was obtained as a white solid (yield 78%).

[0408] Example 27

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

[0410]

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

[0412] This application also includes the following specific implementation plans:

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

[0414]

[0415] The method comprises:

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

[0417]

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

[0419]

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

[0421]

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

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

[0424]

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

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

[0427] c1) Oxidation of the compound of formula (VI)

[0428]

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

[0430]

[0431] in which n is 0 or 1, and which is subsequently reduced enantioselectively to give the compound of formula (II) in which n has the meaning reported above; or

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

[0433]

[0434] where n has the meaning reported above;

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

[0436] All compounds of formula (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 process according to embodiment 1, comprising reacting in step a) a compound of formula (II) with a compound of formula (III), wherein X is -NHSO2Me.

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

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

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

[0441] 6. The process according to embodiment 1, which comprises oxidizing a 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 to 3, comprising reacting a 5-nitropropene benzoate with a nitropropene benzoate in the presence of a coupling agent selected from the group consisting of DCC, CDI, HATU, HBTU, TBTU, DMTMM, COMU, and EDCI, with or without HOBt, with or without an organic base such as TEA, DIPEA, NMM, DBU, DBO, pyridine, and DMAP, in the presence of a coupling agent selected from the group consisting of dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, dimethicone, cyclopentane ... The compound of formula (II) is reacted with the compound of formula (III) wherein Z is -OH in a solvent selected from the group consisting of 2-methoxyethyl ether, ethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixtures thereof.

[0443] 8. The process according to embodiment 1 or 2, which is carried out with CDI and DBU in ethyl acetate.

[0444] 9. The method according to embodiment 1 or 3, carried out with EDCI and DMAP in DMF.

[0445] 10. The process according to embodiment 1 or 3, wherein the reduction of (IV) in step b) is carried out with a reducing agent selected from the group consisting of hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, tin dichloride, 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, wherein the catalyst is selected from a catalyst based on palladium, platinum or nickel, or selected from palladium on carbon, palladium sulfide on carbon, palladium on barium sulfate, palladium on calcium carbonate, and platinum on carbon.

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

[0448] 13. The process according to embodiment 10, carried out with hydrogen in 5% palladium on activated carbon powder, type 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, wherein the solvent is selected from toluene, benzene, xylene, tetrahydrofuran, dimethylbenzene, The base is preferably selected from the group consisting of alkane, 2-methoxyethyl ether, ethyl 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 the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA, DIPEA, NMM, DBO, pyridine and DMAP, and wherein in the case of using pyridine in excess, other solvents can be avoided.

[0450] 15. The method according to embodiment 1 or 4, wherein the oxidizing agent is in the presence of an oxidizing agent in an atmosphere selected from the group consisting of 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, dimethyl ether, Oxidation of (VI) to give (VII) is carried out in a solvent containing alkanes and mixtures thereof, wherein the oxidizing agent is selected from metal oxides such as MnO2, hypervalent iodine such as 2-iodoylbenzoic acid (IBX) or Dess-Martin periodinane, dimethyl sulfoxide-based oxidizing agents (Swern) such as sulfur trioxide pyridine complex.

[0451] 16. The process 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, wherein the in situ formation can take place by reacting a Ru-, Rh- or Ir-complex such as RuCl2(PPh3)3, [Ru(p-cymene)Cl2]2, [RhCl2(Cp*)]2 or [IrCl2(Cp*)]2 with a chiral ligand such as SL-N004-1((S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl] Oxazoline), SL-N003-1((R)-4-isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl] The reaction was carried out using (1S,2S)-(-)-N-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), and (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, sodium C1-C4 alcoholate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium C1-C4 alcoholate, potassium bicarbonate, lithium hydroxide, lithium carbonate, lithium C1-C4 alcoholate, 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 a borane chiral complex such as diisopinocampheylborane (e.g. allyl-diisopinocampheylborane, chloro-diisopinocampheylborane, diisopinocampheyl-methoxyborane) or Boridine (e.g. 2-methyl-CBS- Boridine, 2-butyl-CBS- Boridine, o-tolyl-CBS- Azoboridine, where CBS stands for Corey-Bakshi-Shibata oxazolidinone catalyst).

[0454] 19. The method according to embodiment 16, wherein the enantioselective reduction is carried out in an atmosphere selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, toluene, benzene, xylene, THF, dimethylbenzene, The reaction is carried out in a solvent selected from the group consisting of 2-methoxyethyl ether, ethyl 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 in the presence of aqueous sodium hydroxide solution by reacting RuCl2(PPh3)3 with a chiral ligand SL-N004-1 to form an in situ complex.

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

[0457]

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

[0459]

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

[0461]

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

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

[0464]

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

[0466]

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

[0468]

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

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

[0471]

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

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

[0474] c1) Oxidation of the compound of formula (XIV)

[0475]

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

[0477]

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

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

[0480]

[0481] where n has the meaning reported above;

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

[0483] 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 performed according to any one of the preceding embodiments.

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

[0486]

[0487] wherein n is 0 or 1, and R1 and R2 are independently selected from H, a linear or branched (C1-C6) alkyl group, the (C1-C6) alkyl group being optionally substituted with one or more substituents selected from a halogen atom, a (C3-C7) cycloalkyl group, a (C5-C7) cycloalkenyl group, a (C5-C7) cycloalkenyl group, a linear or branched (C2-C6) alkenyl group, an aryl (C2-C6) alkenyl group, and a linear or branched (C2-C6) alkynyl group.

[0488] 26. The method according to embodiment 1, wherein the method comprises crystallization or fragmentation 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, dimethyl ether ... alkyl, 2-methoxyethyl ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, an aliphatic or aromatic hydrocarbon, preferably selected from pentane, hexane, heptane, cyclohexane and methylcyclohexane or a mixture thereof.

[0489] 27. The method for preparing Form A according to embodiment 26, wherein the method is carried out using n-heptane in ethyl acetate.

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

[0491] 29. A crystalline 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 crystalline form according to embodiment 29, for use in 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), said method comprising administering by inhalation an effective amount of the crystalline form according to embodiment 29 or 30.

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

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

[0496]

[0497] The method comprises:

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

[0499]

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

[0501]

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

[0503]

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

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

[0506]

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

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

[0509] c3) making an intermediate of formula B"

[0510]

[0511]

[0512] Reaction with the intermediate of formula D

[0513]

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

[0515]

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

[0517] 34. The process according to embodiment 33, wherein the intermediate of formula B" is obtained by converting the intermediate of formula B':

[0518]

[0519] In the mixture selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dimethyl The method comprises reacting the alkyl group with thionyl chloride, hydrochloric acid or sulfuric acid in the presence of a solvent selected from the group consisting of thionyl chloride, hydrochloric acid or sulfuric acid, or with a relevant alkyl halide in the presence of a base selected from the group consisting of 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 process according to embodiment 34, wherein the intermediate of formula B″ is obtained by converting the intermediate of formula B′ in dimethylformamide or dimethylacetamide in the presence of potassium carbonate.

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

[0522]

[0523] The method comprises using a mixture selected from hydrogen peroxide, organic peracid, meta-chloroperbenzoic acid, persulfate or The oxidant (KHSO5*1 / 2KHSO4*1 / 2K2SO4) oxidizes intermediate B

[0524]

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

[0526]

[0527] wherein R is a linear or branched (C1-C6) alkyl or arylalkyl group, the method comprising: (KHSO5*1 / 2KHSO4*1 / 2K2SO4) oxidation intermediate B

[0528]

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

[0530]

[0531] wherein R is a linear or branched (C1-C6) alkyl or arylalkyl group, the method comprising reacting the intermediate C' by Pinner reaction with sulfuric acid in the corresponding alkyl alcohol as a solvent.

[0532]

[0533] Transformed into intermediate C",

[0534]

[0535] Then, in a mixture selected from the group consisting of toluene, benzene, xylene, tetrahydrofuran, The alkylation reaction is carried out by alkylating the alkylated ...

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

[0537]

[0538] wherein n is 1 and is 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 easily detectable impurities is less than 0.5% w / w.

[0543] 44. A method for preparing the crystalline form according to any one of embodiments 39-43, 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, dimethylbenzene, methyl ethyl ketone, methyl isobutyl ketone, methyl ethyl ... methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, aliphatic or aromatic hydrocarbons, pentane, hexane, heptane, cyclohexane and methylcyclohexane or mixtures thereof.

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

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

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

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

Claims

1. Intermediate compound of formula (III) wherein X is selected from -NHSO2Me and -NO2, and Z is selected from -OH, chlorine, bromine, linear or branched (C1-C6)alkoxy, aryloxy, arylalkoxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6)alkylcarbonyloxy, wherein the linear (C1-C6)alkoxy is selected from ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy.

2. An intermediate compound of formula (III) according to claim 1, wherein X is -NHSO2Me.

3. An intermediate compound of formula (III) according to claim 2, wherein X is -NHSO2Me and Z is -OH.

4. A method for preparing a compound of formula (III): wherein X is selected from -NHSO2Me, and Z is selected from -OH, chlorine, bromine, straight-chain or branched (C1-C6)alkoxy, aryloxy, arylalkoxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6)alkylcarbonyloxy, wherein the straight-chain (C1-C6)alkoxy is selected from ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, The process comprises reducing the corresponding derivatives wherein X is -NO2 to amino derivatives and subsequently reacting them with methanesulfonyl halide.

5. A method for preparing a compound of formula (III): wherein X is selected from -NHSO2Me and -NO2, and Z is -OH, The method comprises a hydrolysis reaction of the corresponding ester derivative.

6. The process according to claim 5, wherein the hydrolysis reaction of the corresponding ester derivative of the compound of formula (III) wherein Z is methoxy is 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 and in a solvent selected from water alone or in a mixture with methanol, ethanol, isopropanol, n-butanol, tert-butanol, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, THF, dimethicone, methylbenzene, methyl ether ... Alkanes and mixtures thereof.

7. The process according to claim 5, wherein the hydrolysis of the ester derivative to the free acid wherein Z is -OH is carried out using NaOH in THF and water.

8. A method for preparing a compound of formula (III): wherein X is selected from -NHSO2Me and -NO2, and Z is chlorine, bromine, straight-chain or branched (C1-C6)alkoxy, aryloxy, arylalkoxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy and aryl(C1-C6)alkylcarbonyloxy, wherein the straight-chain (C1-C6)alkoxy is selected from ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, The process is carried out by esterification or transesterification techniques or starting from the relevant esters of 3-hydroxy-4-nitrobenzoic acid.

9. A crystalline form of a compound of formula (I), Where n is 1, characterized in that 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).

10. The crystalline form according to claim 9, wherein the compound of formula (I) is prepared from an intermediate compound of formula (III).

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