MXPA06011239A - Chemical process and new crystalline form - Google Patents

Abstract

The present invention relates to the preparation of a ?2 adrenergic agonist in crystalline salt form. In particular the invention relates to preparation of a crystalline salt of compound (I):in particular a crystalline monohydrochloride salt. The invention also relates to a new crystalline form (polymorph) of the monohydrochloride salt of compound (Ia) and a process for preparing it.

Description

CHEMICAL PROCESS AND NEW CRYSTAL FORM The present invention relates to the preparation of a β2 adrenergic combatant in the form of a crystalline salt. In particular, the invention relates to the preparation of a crystalline salt of the compound (I) defined below. More particularly, the invention relates to a process for preparing a crystalline monohydrochloride salt of the defined compound (a) below. The invention also relates to a new crystalline (polymorph) form of the monohydrochloride salt of the compound (la). The β2 adrenergic receptor fighters are recognized as effective drugs for the treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema). F2 adrenergic receptor fighters are also recognized as useful for the treatment of premature labor, and are potentially useful for treating neurological disorders and cardiac disorders. International Patent Application WO 01/42193 and U.S. Pat. No. 6,576,793 describe, among other things, a new compound of the formula (I): m where the stereochemistry in * C and ** C may be among others (R) and (R). This compound can be represented in particular by the formula (la): The compound (la) can be referred to by the chemical names? / -. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (f?) - 2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine; N- [3 - [(1 f?) - 1 -hydroxy-2 - [[2- [4 - [((2f?) - 2-hydroxy-2-phenylethyl) amino] phenyI] etl] amino] ethyl-6-hydroxyphenyl] -formamide and alcohol (af?) -3-formamido-4-hydroxy- (a - [[[p - (? - ((2R) -hydroxy-phenethyl)) -amino-phenethyl] amino ] methylbenzyl In CAS the compound (la) is designated:? - [2-hydroxy-5 - [(1 R) -1-hydroxy-2 - [[2-4 - [[(2R) -2-hydroxy] -2-phenylethyl] amino] phenyI] ethyl] amino] ethyl] phenyl] -formamide, WO 01/42193 and U.S. Patent No. 6,576,793 describe Compound (Ia) as a combatant of β2 adrenergic receptor. 01/42193 and US Patent 6,576,793 describe the preparation of compound (la) as a mixture of stereoisomers, that is, where the stereochemistry at * C is (RS) and the stereochemistry at ** C is (RS) , according to the following reaction scheme: Scheme 1 nn Bn represents a benzyl protecting group. The US patent application No. 10 / 627,555 and the corresponding published international application WO 04/01 1416 describe the crystalline dihydrochloride salt of the compound (la) and methods for preparing said salt. In said applications, the compound (Ia) is prepared according to the following reaction scheme 2: Scheme 2 * m In Scheme 2, the abbreviations used have the following meanings: NaH MDS: hexamethyldisilazane sodium THF: tetrahydrofuran DMPU: 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1 H) pyrim dinone TBD MSC I: tert-butyldimethylsilylchloride DMF: dimethylformamide DMSO: dimethylsulfoxide TREAT HF: triethylamine trihydrofluoride The numbering of the compounds in Scheme 2 follows that in WO 04/01 1416, but it will be appreciated that the compound 1_ in the Scheme 2 is equivalent to the compound (la) in the present. According to WO 04/01 1416, the dihydrochloride salt of compound 1_ is prepared by dissolving the compound? _ In a polar solvent to form a first solution and adding hydrochloric acid to form a second solution from which the salt is formed. dihydrochloride by crystallization. WO 2004/106279 (claiming the priority of the Application for U.S. Patent Serial No. 60 / 473,423) describes a crystalline form of N- monohydrochloride. { 2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (/ c?) - 2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine. WO 2004/106279 describes, among other things, the following methods for preparing the crystalline monohydrochloride salt of compound V. i) adding between about 0.9 and about 1 molar equivalent of aqueous hydrochloric acid to active compound 1. dissolved in a polar solvent, such as isopropanol or water; ii) adding a molar excess of an aqueous solution of an inorganic chloride at a pH of between about 5 and about 6 to the active compound 1_ dissolved in a polar solvent, soluble in water. A suitable source of chloride ions is ammonium chloride and a suitable polar solvent is isopropanol.

For example, the monoHCl crystalline salt can be formed by dissolving compound 1_ in isopropanol, adding aqueous ammonium chloride, and allowing the solution to stand overnight at room temperature. The crystalline product can be isolated by filtration and dried, iii) a water mixture of the corresponding dihydrochloride salt, which mixture can be formed by the addition of water is added to the diHCl salt of compound 1. iv) recrystallization of a salt of hydrochloride of compound 1_ having between 1 and 2 equivalents of chlorine per mole of compound 1_. We have found an improved method for preparing a nonhydrochloride salt of the compound (I), in particular a monohydrochloride salt of the compound (la) and more preferably a crystalline monohydrochloride salt of the compound (la). It will be appreciated from the foregoing that the compound of the formula (I) includes two asymmetric centers, mainly at the carbon atoms designated in the formula (I) as * C and ** C. References herein to the compounds of the formula (I) include both (S) and (R) enantiomers either in substantially pure form or mixed in any of the proportions, both in * C and ** C. In this way, the stereochemistry in * C and ** C can be (RS) and (RS), (R) and (R), (R) and (S), (S) and (R), or (S) ) and (S). Hereinafter, references to compound (1) should be read as including in particular compound (a) unless otherwise specified. Thus, in a first aspect the present invention provides a process (A) for preparing a monohydrochloride salt (I) whose process comprises the steps: Aa) contacting a protected form of the compound (I), or compound (a) of hereinafter composed (ll) and (Ha) respectively): &) wherein P1 represents a hydroxyl protecting group, and P2 and P3 each independently represents hydrogen or a hydroxyl protecting group; with a weak acid, to carry out the selective protonation; Ab) contact the product of (a) with a source of chloride ions to effect the exchange of anions; Ac) deprotect the product of (b) to remove P1, and where P2 and P3 are necessary; Ad) isolation of compound (I) or (la) as a monohydrochloride salt; and optionally Ae) crystallization or recrystallization of compound (I) or (la). In a preferred embodiment, the invention provides said process for the preparation of a monohydrochloride salt of the compound (a), in particular, for the preparation of a crystalline monohydrochloride of the compound (la). The hydroxyl protecting groups P1, P2 and P3 can be selected from the wide range of known protecting groups using principles well known in the art. Examples of the hydroxyl protecting group P1 include arylalkyl, for example, benzyl. Where either or both of P2 and P3 represent protecting groups, these may be groups that can be removed selectively under conditions that also do not remove P1. In this way, each of P2 or P3 can be, for example, a silyl group; for example, a trialkyl silyl group such as silyl tert-butyldimethyl. In one embodiment of this invention, P1 represents a protecting group and P2 and P3 both represent hydrogen. If to use a protective group and if so the choice of the protective group is the referral of the expert in the field and can be achieved without due experimentation. It will be appreciated by those skilled in the art that compounds (I) and (a) contain two basic nitrogen atoms and thus have the potential to form the salts or both. In order to obtain a monohydrochloride directly, that is, by reaction of the compound (II) or (Ii) with hydrochloric acid, the reaction must be carefully controlled to achieve the correct stoichiometry, and to avoid the formation of, for example, a dihydrochloride salt . We have found that performing the initial protonation with a weak acid such as acetic acid results in the selective probing of only one nitrogen atom (the most basic nitrogen atom) and, following the exchange of anions, the formation of a stereometrically exact monohydrochloride salt. The process of the present invention also has the advantage that the hydrochloride salt can be prepared without the use of strong acid. It is desirable to avoid the use of a strong acid as this can lead to deformylation of the main compound.

In step (Aa) of the current process, a compound of formula (II) or (Na) can be contacted with a weak acid. Conveniently, this step can be carried out in an organic solvent, for example, a ketone such as 2-butanone (methyl ethyl ketone) or diethyl ketone, or a water immiscible alcohol such as 1-pentanol. The weak acids that can be used include, for example, acetic acid, 2-methoxybenzoic acid or 4-methoxybenzoic acid, preferably acetic acid. The weak acid can for example have a pKa in the range 4-5. This step can be conveniently carried out at a slightly elevated temperature, for example, at a temperature in the range of about 25 ° C to about 50 ° C. The Step (Ab) can be conveniently carried out without the isolation of the product of step (Aa). In this way, for example, the solution obtained from step (Aa) can be contacted with a source of chloride ions, using, for example, aqueous sodium chloride. This step can also be conveniently carried out at a temperature in the range of about 25 ° C to about 50 ° C. In this step, the intermediate product can be isolated using conventional methods to provide the monohydrochloride salt of the compound (I I) or (Ia). This product can be obtained in crystalline form. If necessary, crystallization can be facilitated by standard methods, such as agitation, cooling, excoriation or germination.

The deprotection of (I I) or (Na) according to step (Ac) can be carried out by conventional methods. Thus, where one or both P2 and P3 represents a silyl group, this can be removed, for example, using cesium fluoride, in an organic solvent such as methanol, optionally in admixture with an additional solvent such as diethylketone, methyl ethyl ketone or n-butylacetate. , or triethylamine trifluoride in a solvent such as tetrahydrofuran. A protecting group P1 can be removed for example by hydrogenation using a palladium or platinum catalyst for example, Pd / C, conveniently in an organic solvent such as N-methylpyrrolidone. The monohydrochloride salt of the compound (I) or (Ia) prepared according to the present invention can be isolated by conventional means. Advantageously said monohydrochloride salt of the compound (la) can be obtained in crystalline form, by precipitation of an aqueous organic solution. In a particular embodiment, the crystalline monohydrochloride (la) can be obtained from an organic solution comprising a mixture of N-methylpyrrolidone and isopropyl alcohol (preferably 1: 1), by heating said solution to a temperature in the range of about 60 ° C. at about 80 ° C, adding water and then contacting the resulting aqueous solution with additional isopropyl alcohol. During the addition of additional isopropyl alcohol the temperature is cooled, initially in the range of about 15 ° C to about 25 ° C and consequently in the range of about 0 ° C to about 10 °. Recrystallization of the monohydrochloride salt of the compound (Ia) can be effected upon suspending or dissolving said compound in a suitable solvent, for example, industrial methylated spirits or methanol, in admixture with water. The resulting suspension or solution may, if necessary, be heated, for example, to a temperature in the range of about 60 ° C to about 80 ° C. Crystallization can be initiated in conventional manner, for example, with cooling and / or germination. In initial experiments we found that the crystalline compound (monohydrochloride) was obtained not only in the same crystalline form as described and characterized in WO 2004/106279 (hereinafter Form 1), but also in a new crystalline form, referred to in the present as Form 2. We also find that the crystals of Form 2 are a more thermodynamically stable form than the crystals of Form 1. further, we find that a mixture of the Form 1 and Form 2 crystals of the monohydrochloride compound can be converted to substantially pure Form 2 crystals by mixing, for example, by suspending a mixture of the Form 1 and Form 2 crystals in a solvent such as methylated aqueous industrial spirit or methanol and by stirring at a temperature in the range of about 10 ° C to about 50 ° C, for an extended period, for example, up to 10 days, or by a process that includes recrystallization with temperature cycling . Such methods can be used to provide the seeds of the material Form 2. In this way, in a particular embodiment of the process A: recrystallization of the monohydrochloride salt, obtained can be carried out by subjecting a suspension of monohydrochloride (la) to repeated heating cycles and cooling. The heating can be carried out at a temperature in the range of about 50 ° C to about 60 ° C and cooling in the range of about 15 ° C to 25 ° C. The solution or suspension may age after each heating and / or cooling phase. The heating and cooling steps may be repeated for several cycles, for example, 2-5 cycles. Form 1 and Form 2 of crystalline monohydrochloride (la) can be distinguished using Differential Scanning Calorimetry analysis, X-ray diffraction, and / or infrared spectroscopy as described hereinafter. The crystalline monohydrochloride Form 2 has been found to be more thermodynamically stable than Form 1. The present invention thus also provides crystalline monohydrochloride (la) (mainly, N-. {2- [4 - ((f ?) - 2-hydroxy-2-phenylethylamine) phenol] ethyl] - (R) -2-hydroxy-2- (3-formamdo-4-hydroxyphenyl) ethylamine monohydrochloride) in one form (Form 2) which is characterized by a sign of differential scanning calorimetry showing an absence of discernable endothermic characteristics below about 125 ° C, two or more lower endothermic cases between about 130 ° C and about 180 ° C and an onset of significant endothermic heat flow at approximately 229 ° C. For example, said lower endothermic events may occur at about 133 ° C and at about 151 ° C, in addition an additional lower endothermic case may occur at about 170 ° C. The crystalline monohydrochloride (la) can also be characterized by infrared spectroscopy. In this way, when the infrared absorption spectrum was recorded over the wave number range 4000 to 650 cm "1 using a Perkin Elmer Spectrum One FT-I R spectrometer equipped with a PerkinElmer Universal ATR sampling accessory (attenuated total reflex) crystalline monohydrochloride (la) Form 2 gave an infrared absorption spectrum with significant absorption bands at approximately 663, 698, 747, 764, 788, 809, 827, 875, 969, 995, 1024, 1056, 1081, 101, 1212, 1294, 1371, 1440, 1520, 1543, 1596, 1659, 3371 and 3552. The crystalline monohydrochloride Form 2 can also be characterized by X-ray powder diffraction, for example, as in Figures 1 and 2. hereafter, still in a further embodiment, the present invention provides crystalline monohydrochloride (la) Form 2 in substantially pure form. As used herein, the term "substantially pure" means crystalline monohydrochloride (la) wherein more than 50% by weight in Form 2, suitably at least 75% by weight is Form 2, for example, at least 80%, suitably at least 85%, preferably at least 90% by weight. The crystalline monohydrochloride form (2) can be obtained in substantially pure form by controlling the crystallization or recrystallization of the monohydrochloride, for example, in step (e) of the process of the present invention. In general, it is desirable to effect the crystallization of the temperature cycling as described above. In this way, in a further aspect the present invention also provides a process (B) for obtaining crystalline monohydrochloride (Ia) Form 2 (as defined herein) comprising: Ba) Form a mixture of N-. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (/:) - 2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohyd rochloride in an aqueous organic solvent, upon contacting said monohydrochloride with said solvent and heating in a range of about 60 ° C to about 70 ° C, for example, approximately 65 ° C; Bb) Adjust the temperature of said mixture in the range of about 52 ° C to about 58 ° C, for example, about 55 ° C; Be) Germinate said mixture with Form 2 crystals; Bd) Cooling said mixture to a temperature in the range of about 1 5 ° C to 25 ° C; Be) Heating said mixture to a temperature in the range of about 47 ° C to about 52 ° C, for example, about 50 ° C; Bf) Repeat steps Bd) and Be) to obtain the desired Form 2. In step Ba) of the above process, the aqueous organic solvent may be, for example, an aqueous alcohol such as aqueous methanol or aqueous industrial methylated spirits. In the heating in the specified temperature range the mixture should form a solution in the organic solvent. If necessary or desired at this stage the solution can be clarified, for example, by filtration to remove impurities. In step Be) the germination can be carried out with crystalline material prepared as described above. After germination a suspension is formed. The mixture may age after each heating and / or cooling phase. The aging period may be, for example, from about 0.25 hours to about 3.00 hours. The heating and cooling steps Bd) and Be) can be repeated for several cycles, for example, 2-5 cycles. Thus, for example, the solution or suspension of monohydrochloride (la) can be initially heated to a temperature in the range of about 60 ° C to about 70 ° C, for example, 65 + 2 ° C, cooled to a temperature in the range 50 ° C to 60 ° C, for example, 55 + 2 ° C, germinate, age for about 30 minutes, then cool for a period of about 2 hours to about 20 ° C. In subsequent cycles, the solution or suspension can be heated to about 50 ° C and cooled to about 10 ° C. The n-. { 2- [4 - ((f?) - 2-hydroxy-2-phenylethylamino) phenyl] etiI} - (R) -2- hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride used as a raw material for the preparation of Form a2 can be prepared for example by process A above or as described in WO 04 / 01 1416. The compound of the formula (II) or (Ha) wherein P2 and P3 both represent hydrogen, can be obtained from a corresponding compound of the formula (III). wherein P1 and P3 are as defined for the compound (I I) and P2 is a hydroxyl protecting group. P2 can be selected from the hydroxyl protecting groups known in the art, for example, a silyl group such as tert-butyldimethylsilyl. It will be appreciated that P1, P2 and P3 should be selected such that P2 and P3 can be removed under conditions that will also not remove P1. When P2 represents a tert-butyldimethylsilyl group this can be conveniently removed using cesium fluoride, in an organic solvent such as methanol, optionally in admixture with an additional solvent such as diethyl ketone, methyl ethyl ketone or n-butylacetate. It will be understood that when it is desired to obtain a compound (a) the suitable chiral intermediate is desirably employed in this step and in the steps described below. The structures (III) (IV) and (V) should therefore be interpreted as representing the individual chiral forms as well as mixtures thereof. A compound (11) can be obtained by reacting a compound (IV): wherein Hal is an halo leaving group, eg, bromine, and P2 'is as defined for formula (I 1) with a compound (V): or a salt thereof, for example, a hydrobromide salt, wherein P3 is as defined for the formula (11). The reaction of (IV) and (V) can be conveniently carried out in the presence of a base, such as potassium carbonate and in a solvent such as N, N-dimethylacetamide or N-methylpyrrolidinone. The compounds (IV) and (V) can be coupled, in a solvent such as N, N-dimethylacetamide or dimethylsulfoxide, by adding potassium carbonate and sodium hydroxide or sodium iodide and by heating to a temperature in the range of about 90. ° C at about 140 ° C to form a compound (III), which can also react with the insulation. The compound (V) can be obtained by coupling 2- (4-aminophenyl) ethylamine and styrene oxide.

It will be appreciated that to prepare a compound (la), the correct chiral form of the compound (V) should be employed. This can be prepared by using (R) -styrene oxide in the above reaction. The amine, which is optionally provided as a salt, can first react with between about 1 and about 1.2 equivalents of a base having a pKa value greater than about 18, in terms of substantially deprotonating the 4-amino group and the oxide (R) -styrene added to the product of the amine reaction. Useful basic compounds include sodium bis (trimethylsilyl) amide, alternatively known as sodium hexamethyldisilizone (NaHMDS), lithium diisopropyl amide, and n-butyl lithium. The reaction is preferably conducted in a solvent system including a polar aprotic solvent, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidinone (DM PU). Additional examples of polar aprotic solvents include dimethyl sulfoxide, N-methyl pyrrolidinone, N, N-dimethyl acetamide, tetramethylethylenediamine, and hexamethylphosphoramide. After the aqueous extraction, the product of the coupling reaction can be crystallized as a salt, for example, the hydrochloride salt or hydrobromide, from a solvent such as isopropanol, by the addition of aqueous hydrochloric or aqueous hydrobromic acid. The crystallization process efficiently separates the desired product from the by-products formed during the reaction. The hydrochloride salt can be redissolved with 10N aqueous sodium hydroxide to give 2- [4 - (((R) -2-hydroxy-2-phenylethylamino) phenyl] tilamine (compound (V)). however, it can be used directly in the next stage.The corresponding stereoisomer (S), 2- [4 - ((S) -2-hydroxy-2-phenylethylamino) phenyl] ethylamine, can be prepared by replacing (S) -styrene oxide for (R) -styrene oxide in the above process for the synthesis of the compound (V) The compounds of the formula (IV) can be prepared by methods known in the art In this way, for example, a compound of the formula IV) wherein P2 is hydrogen can be prepared as described in U.S. Patent No. 6,268,533 B1, and in R. Hett et al., Organic Process REearch and Development, 1998, 2, 96-99, or using procedures similar to those described by Hong et al., Tetrahedron Ltt., 1994, 35, 6631, or similar to those described s in U.S. Pat. No. 5,495,054. A protecting group P2 can be introduced by standard methods, for example, by the addition of tert-butyldimethylsilylchloride (TBDMS-CI) and dissolving in a suitable solvent such as dichloromethane. In a further aspect, the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a β2-adrenoreceptor fighter is indicated, comprising the administration of a therapeutically effective amount of Crystalline monohydrochloride (la) Form 2. In particular, the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible airway obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In the alternative, a crystalline monohydrochloride (Form) 2 is also provided for use in medical therapy, particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a combatant is indicated β2-adrenoreceptor. In particular, crystalline monohydrochloride (la) Form 2 is provided for the prophylaxis or treatment of a disease associated with the obstruction of. reversible airways such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. The present invention also provides the use of crystalline monohydrochloride (la) Form 2 in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a β2-adrenoreceptor fighter is indicated., for example, a disease associated with reversible airway obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. The amount of crystalline monohydrochloride (Form) 2 that is required to achieve a therapeutic effect will, of course, vary with the route of administration, the subject under treatment, and the particular disorder or disease being treated. The compound of the invention can be administered by inhalation at a dose of from 0.005 mg to 1 mg, preferably 0.001 mg to 0.1 mg, for example, 0.005 mg to 0.05 mg. The dose range for human adults is generally from 0.0005 mg to 0.5 mg per day, for example, from 0.0005 to 0.1 mg per day, conveniently 0.001 mg to 0.05 mg per day, for example, 0.005 mg to 0.05 mg. While it is possible for crystalline monohydrochloride (the) Form2 administered alone, it is preferable that it be presented as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation comprising crystalline monohydrochloride Form 2 and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. Figure 2 shows a powder diffraction pattern of rays X of N-. { 2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (f?) - 2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride crystalline Form 2 corresponding to Example 3. Figure 3 shows a DSC indication for N-. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (< c?) - 2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine crystalline monohydrochloride Form 2, corresponding to Example 3. A series of minor endothermic cases are previously observed at about 125 ° C.

There are endothermic with starts of 135.7 ° C (case 1) 149.3IC (case 2) and 170.3 ° C (case 3). This is followed by a long endotherm with a start of 227.2 ° C. For a better understanding of the invention, the following Examples are given by way of illustration. Analytical Methods The XRPD analysis shown in Figure 1 was performed on a Bruker Model D8 Advance X-ray powder diffractometer, serial number ROE 2357. The method runs from 2 to 40 degrees 2-Theta with a stage size 2-Theta 0.0145 degrees and a collection time of 1 second in each stage. X-ray powder diffraction analysis (XRPD) of the Example 3 (shown in Figure 2) was carried out on an X'Pert Pro PA powder analyzer, model PW3040 / 60, serial number DY1850 using an X'Celerator detector. The acquisition conditions were: radiation: Cu Ka, generated voltage: 40 kV, generator current 45 mA, starting angle: 3.0 ° 2T, stage size 0.017 ° 2T, time per stage: 9205 seconds. The sample was prepared using a capillary glass with an external diameter of 0.5 mm. The characteristic XRPD angles and d-divisions are recorded in Table 1. The infrared absorption spectrum was recorded over the wave number range 4000 to 650 cm "1 using a Perkin Elmer Uno FT-IR spectrometer equipped with a Perkin Elmer Universal ATR sampling accessory (full attenuated reflex) .1 H NMR spectra were acquired in a 400 MHz Bruker DPX400 spectrometer in 300 K. The sample was dissolved in CDCI3 or dmso-D6 and chemical adjustments were reported in ppm in relation to the TMS signal at 0 ppm, henceforth the term "active ingredient". means crystalline monohydrochloride Form 2 or a form of the compound derived from said crystalline form Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) administration, inhalation (including fine particle powders or mists that can be generated from various types of metered dose pressurized aerosols, nebulizers or insufflators), rectal and local (including going dermal, buccal, sublingual and intraocular) although the most appropriate route may depend on, for example, the condition and disorder of the recipient. The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the pharmaceutical field. All methods include the step of bringing active reinforcement in association with the vehicle that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ing network with liquid carriers or finely divided solid carriers or both and thus, if necessary, shaping the product into the desired formulation. Powdered dry compositions for local delivery to the lung by inhalation, for example, can be presented in capsules and cartridges of eg gelatin, or ampoules of eg laminated aluminum tinsel., for use in an inhaler or insufflator. Powdered mixed formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (vehicle substance / diluent / excipient) such as mono-, di or pol-saccharides (eg, lactose or starch). The use of lactose is preferred. The powder-mixed formulations may also contain a ternary agent such as a sugar ester, for example, cellobiose octaacetate, or a stearate such as magnesium stearate or calcium stearate. Each capsule or cartridge can generally contain between 20 μg-10 mg of the active ingredient optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention can be presented without excipients. Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation can be pre-measured (e.g., as in Diskus, see GB 2242134, U.S. Patent Nos. 6,632,666, 5,860,419, 5,873,360 and 5,590,654 or Diskhaler, see GB 2178965, 2129691 and 2169265, U.S. Patent Nos. 4,778,054, 4,81 1, 731, 5,035,237) or measured in use (e.g., as in Turbuhaler, see EP 69715 or in the devices described in U.S. Pat. No. 6,321, 747). An example of a unit dose device is Rotahaler (see GB 2064336 and U.S. Patent No. 4,353,656). The Diskus inhalation device comprises an elongated strip formed from a base sheet having a plurality of cavities spaced apart along its length and a sheet cap hermetically sealed but debonable to it to define a plurality of containers, each container having therein an inhalable formulation containing active ingredient preferably combined with lactose. Preferably, the band is flexible enough to be wound on a roll. The lid sheet and the base sheet will preferably have guide end portions that do not seal together and at least one of said guide end portions is constructed to be attached to a winding means. Also, preferably, the hermetic seal between the base and lid sheets extends over its total width. The cover sheet can preferably be detached from the sheet ase in a longitudinal direction of a first end of the base sheet. Alternatively, the formulation can be presented if desired together with one or more therapeutic agents in an inhalation device where the individual therapeutic agents are administered simultaneously but stored separately (or stored separately completely or partially for triple combinations), by example, in separate pharmaceutical compositions, for example, as described in WO 03/061743. Spray compositions for local delivery to the lung by inhalation, for example, may be formulated as aqueous solutions or suspensions or as aerosols derived from pressurized containers, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation may be either a suspension or a solution and generally contain the active ingredient optionally in combination with another therapeutically active ingredient and a suitable propellant such as fluorocarbon or chlorofluorocarbon containing hydrogen or mixtures thereof, particularly hydrofluoroalkanes, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1, 1,2-tetrafluoroethane, 1,1,1,3,3,3-heptafluoro-n-propane or a mixture thereof . Carbon dioxide or another suitable gas can also be used as a propellant. The aerosol composition may be free excipient or may optionally contain additional formulation excipients well known in the art such as surfactants, for example, oleic acid or lecithin and cosolvents, for example, ethanol. Pressurized formulations will generally be retained in a container (e.g., an aluminum container) closed with a valve (e.g., a metering valve) and fitted in an actuator provided with a mouthpiece. Medications for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation in the bronchial system is usually 1-10 μm, preferably 2-5 μm. Particles that are larger than 20 μm are usually too large when inhaled to reach small airways. To achieve these particle sizes, the particles of the active ingredient as produced can be reduced in size by conventional means, for example, by micronization. The desired fraction can be separated by air classification or screening. Preferably, the particles will be crystalline. When an excipient such as lactose is employed, generally, the particle size of the excipient will be much larger than the inhaled medicament within the present invention. When the excipient is lactose it will typically be presented as crushed lactose, where no more than 85% of lactose particles will have a MMD of 60-90μm and not less than 15% will have a MMD of less than 15μm. The intranasal sprinklers can be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, regulatory or acid salts or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants. Solutions for inhalation by nebulization can be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, regulatory salts, isotonicity adjusting agents or antimicrobials. They can be sterilized by filtration or heating in an autoclave, or presented as a non-sterile product. Preferred unit dose formulations are those which contain an effective dose, as noted above, or a suitable fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art, having according to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents. The compound and pharmaceutical formulations according to the invention can be used in combination with or include one or more other therapeutic agents, for example, selected from anti-inflammatory agents, anti-cholinergic agents (particularly an M1 receptor fighter).; M2, M? / M2 or M3), other ß2-adrenoceptor combatants, anti-infective agents (eg, antibiotics, antivirals), or antihistamines. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride (Ia) Form 2 together with one or more other therapeutically active agents, for example, selected from an anti-inflammatory agent (eg, a corticosteroid or an NSAI D), an anticholinergic agent, another β2-adrenoceptor combatant, an anti-infective agent (eg, an antibiotic or an antiviral), or an anhistamine. Preferred are combinations comprising crystalline monohydrochloride (la) Form 2 together with a corticosteroid, and / or an anticholinergic, and / or a PDE-4 inhibitor. Preferred combinations are those comprising one or two other therapeutic agents. It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient (s) can be used in the form of salts, (eg, alkali metal or salts). amine or as acid addition salts), or prodrugs, or as esters (eg, lower alkyl esters), or as solvates (eg, hydrates) to optimize activity and / or stability and / or physical characteristics (e.g. , solubility) of the therapeutic ingredient. It will be clear that when appropriate, the therapeutic ingredients can be used in optically pure form. Anti-inflammatory agents include corticosteroids. Preferred corticosteroids include fluticasone propionate, S-fluoromethyl ester of 6a, 9a-difluoro-1β-hydroxy-16a-methyI-17a - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1, 4-diene-17β-carbothioic acid and S-fluoromethyl ester of 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -1 1 ß-h id roxy- 16a-methyl-3-oxo-and rosta-1,4-diene-17β-carbothioic, more preferably S-fluoromethyl ester of 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -1 1ß- hydroxy-16a-methyl-3-oxo-and rosta-1,4-diene-17β-carbothioic acid. Anti-inflammatory agents also include nonsteroidal anti-inflammatory drugs (NSAID's). NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase inhibitors (PDE) (eg, theophylline, PDE4 inhibitors or PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (eg, montelukast), NOS inhibitors, inhibitors triptase and elastase, beta-2 integrin antagonists and adenosine receptor antagonists and combatants (eg, 2a adenosine fighters), cytokine antagonists (eg, chemokine antagonists, such as CCR3 antagonist) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors. A specific PDE4 inhibitor can be any compound that is known to inhibit the PDE4 enzyme or that is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, or compounds that inhibit other members of the PDE family, such as PDE3 and PDE5 , as well as PDE4. Compounds of interest include c / s-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid. 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-di-fluoro-methoxyphenyl) -cyclohexane-1-one and c / s- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan- 1 -ol]. Another compound of interest is c / s-4-cyano-4- [3- (cyclopen-t-Ioxy) -4-methoxife or i] cyclohexane-1-carboxylic acid (also known as cilomilast) and its salts, esters, pro -drugs or physical forms, which is described in U.S. Pat. 5,552,438. Additional compounds of interest are described in published international patent application WO 04/024728 (Glaxo Group Ltd), PCT / EP2003 / 014867 (Glaxo Group Ltd) and PCT / EP2004 / 005494 (Glaxo Group Ltd.). Anticholinergic agents of interest are those compounds that act as antagonists at muscarinic receptors, dual antagonists of the M? / M3 or M2 / M3 receptors, receptors or antagonists of M1 / M2 / M3 receptors.

Exemplary compounds for administration by inhalation include ipratropium (e.g., as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286-75-0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva).

The anti-histamines of interest (also referred to as H 1 receptor antagonists) include any one or more of the numerous known antagonists that inhibit H 1 receptors, and are safe for human use. First generation antagonists include ethanolamine, ethylene diamine, and alkaline derivatives, such as diphenylhydramine, pyrilamine, clemastinechlorpheniramine. Secondary generation antagonists, which are not sedatives, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine, fexofenadine and cetirizine. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a PDE4 inhibitor. Preferably, the invention provides a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a preferred P DE4 inhibitor as described above, eg, c / s-4-cyano-4- [3- (cyclopentyloxy) - 4-methoxy in 1] cyclohexan or-1-carboxylic acid. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a corticosteroid.

Preferably, the invention provides a combination comprising crystalline monohydrochloride (la) Form 2 together with a preferred corticosteroid as described above, for example, fluticasone propionate, S-fluoromethyl acid ester 6a, 9a-difluoro-1 1 ß-hydroxy-1 6a-methylo-7a - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3oxo-androsta-1,4-diene 1 7ß-carbothioic acid and S-fluoroemethyl ester of 6a, 9a-difluoro-1 7 - [(2-furanylcarbonyl) oxy] -1 1 ß-h id roxy-16a-methyl-3-oxo-and rosta-1, 4-diene-1 7ß-carbothioic acid. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride Form 2 together with an anticholinergic. Preferably, the invention provides a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a preferred anticholinergic as described above, eg, ipatropium, oxitropium or tiotropium. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride (la) Form 2 together with an antihistamine. Preferably, the invention provides a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a preferred antihistamine as described above. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a PDE4 inhibitor and a corticosteroid. Preferably, the invention provides a combination comprising crystalline monohydrochloride (Ia) Form 2 with a preferred antihistamine and a preferred corticosteroid as described above. The invention thus provides, in a further aspect, a combination comprising crystalline monohydrochloride (la) Form 2 together with a PDE4 inhibitor. Preferably, the invention provides a combination comprising crystalline monohydrochloride (Ia) Form 2 together with a preferred PDE4 inhibitor and a preferred anticholinergic as described above. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with physiologically stable carrier or diluent represent a further aspect of the invention. The individual compounds of such combinations can be administered either sequentially or simultaneously in combined or separate pharmaceutical formulations. Suitable doses of the known therapeutic agents will be readily appreciated by those skilled in the art.

Brief Description of the Drawings Figure 1 shows a powder diffraction pattern of rays X of N-. { 2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (f?) - 2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine crystalline monohydrochloride Form 2 (monohydrochloride compound (la)) corresponding to Example 1 (iv). The differential scanning calorimetry analysis for Example 1 (iv) is obtained with a Perkin Elmer instrument model Pyris 1. The samples are weighed in a 50 microliter aluminum mortar, an aluminum cap placed on top of the sample and compressed with a brass rod. An aluminum cover is placed on top of the mortar and sealed using a universal press. An empty mortar, lid and cover serving as a reference. The samples are equilibrated at 30 ° C and heated at 10 ° C per minute at a temperature of 300 ° C. The instrument is calibrated using indium, tin and lead standards. The DSC indicator of the product of Example 3 is shown in Figure 3 and is obtained using a calorimeter TA Instruments Q 1000. The sample is weighed in an aluminum mortar, a mortar cap placed on top and narrowed slightly without sealing the mortar. The experiment is conducted using a heating rate of 10 ° C min "1. Abbreviations TBDMS-CI: tert-buti Id imethylsilyl chloride DCM: dichloromethane DMA: N, N-dimethylacetamide MEK: 2-Butanone (methylethyl ketone) NMP: N -methylpyrrolidone IPA: Isopropylalcohol IMS: industrial methylated spirit (in the following examples composition of I MS was Ethanol-96%, methanol 4%) Reference Examples (preparation of crystalline monohydrochloride (la) as per WO2004 / 106279) a) Synthesis of 2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethylamine (2) To a 3-neck flask of 1000 mL is added 10 g (74 mmol) of 2- (4-aminophenyl) ethylamine and 15 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2. (1 -) pirimdinone (DMPU). The reaction flask is adjusted with a top stirrer, a 125 mL addition funnel and a thermometer. The reaction flask is purged with nitrogen and placed in a cold water bath. The addition funnel is charged with 83 mL (83 mmol) of 1.0 M bis (trimethylsilyl) amide sodium in tetrahydrofuran. The solution of sodium bis (trimethylsilyl) amide is added dropwise during 30 min with vigorous stirring. The addition funnel is removed and replaced with a rubber septum, (ft) -styrene oxide (8.4 mL, 74 mmol) is added dropwise by syringe for 10 minutes. The rate of addition is controlled to maintain a temperature below 35 ° C. After 1 h, the reaction is quenched by dropwise addition of 88 mL of water. The reaction mixture is transferred to a separate funnel, diluted with 56 mL isopropyl acetate and rinsed with 84 mL saturated aqueous sodium chloride. The organic layer is rinsed a second time with a mixture of 84 mL water and 84 mL saturated aqueous sodium chloride and finally with 84 mL saturated aqueous sodium chloride. The organic layer is concentrated under vacuum. The residue is reconcentrated twice from isopropanol (55 mL portions) and then redissolved in isopropanol (235 mL) and heated to 70 ° C with stirring. Concentrated hydrochloric acid (13.2 mL, 160 mmol) is added for two minutes. The mixture is allowed to cool to room temperature and stir for 14 h. The precipitated product is isolated by filtration and rinsed with isopropanol and isopropyl acetate. The product is dried under vacuum for 3 h and then dissolved in 56 mL water and transferred to a separate funnel. Isopropyl acetate (56 mL) and 10 N aqueous sodium hydroxide (19 mL, 190 mmol) are added. The separated funnel is stirred and the phases are separated. The organic layer is dried over sodium sulfate and concentrated to give the product (2) as an orange-brown oil (11 g, 44 mmol, 59%). / z: [M + H +] cale for C 16 H 2 o N 2 O 257.2; found 257.2. b) Synthesis of 2-bromo- (R) -1-tert-butylmethylsiloxy-1 - (3-formamido-4-benzyloxyphenyl) ethane (4) (ft) -2-Bromo-1 - (3-formamide -4-benzyloxyphenyl) ethanol (intermediate 3) (9.9 g, 28 mmol) is dissolved in 36 mL dimethylformamide. Imidazole (2.3 g, 34 mmol) and t-butyldimethylsilylchloride (4.7 g, 31 mmol) are added. The solution is stirred under a nitrogen atmosphere for 72 h. Additional imidazole (0.39 g, 5.7 mmol) and t-butyldimethylsilylchloride (0.64 g, 4.3 mmol) are added and the reaction is stirred for an additional 20 h. The reaction is diluted with a mixture of isopropyl acetate (53 mL) and hexanes (27 mL) and transferred to a separate funnel. The organic layer is rinsed twice with a mixture of water (27 mL) and saturated aqueous sodium chloride (27 mL) followed by a final rinse with saturated aqueous sodium chloride (27 mL). The organic layer is dried over sodium sulfate. Silica gel (23.6 g) and hexanes (27 mL) are added and the suspension is stirred for 10 minutes. The solids are removed by filtration and the filtrate concentrated under vacuum. The residue is crystallized from hexanes (45 mL) to provide 8.85 g (19 mmol, 68%) of intermediate 4 as a white solid, m / z: [M + H +] for C22H3oNO3S¡Br 464.1, 466.1; found 464.2, 466.4. c) Synthesis of W-. { 2- [4 ((/?) - 2-hydroxy-2-phenylethylamino) phenyl] ethyl} (R) -2-iyer-butyldimethylsiloxy-2- (3-formamido-4-benzyl-phenyl) -ethylamine (5) Intermediate 4 (5.0 g, 11 mmol), intermediate 2 (3.5 g, 14 mmol), and dimethyl sulfoxide (10 mL) are combined in a 100 mL round bottom flask and shaken to form a homogeneous solution. Potassium carbonate (6.0 g, 43 mmol) and sodium iodide (1.7 g, 11 mmol) are added and the mixture reaction is heated to 140 ° C. The reaction mixture is maintained at 140 ° C for 10 min, then cooled to room temperature and diluted with water (24 mL) and isopropyl acetate (28 mL). The reaction is stirred until all the solids are dissolved and then transferred to a separate funnel. The organic layer is rinsed with water (17 mL) followed by acetate buffer (5% v / v acetic acid, 12% w / v sodium acetate trihydrate in water, 18 mL) followed by sodium bicarbonate solution (5 mL). % w / v in water, 17 mL) followed by saturated aqueous sodium chloride (17 mL). The organic layer is dried over sodium sulfate and concentrated to provide intermediate 5 as a brown gelatinous solid (7.0 g, 11 mmol,> 99%). m / z: [M + H +] for C 38 H 9 N 3 O 4 Si 640.4; found 640.6. d) Synthesis of? / -. { 2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-benzyloxyphenyl) ethylamine (6) Intermediate 5 (5.2 g, 8.1 mmol) is dissolved in tetrahydrofuran (26 mL) and triethylamine trihydrochloride (1.4 mL) , 8.6 mmol) is added.

The solution is stirred for 20 h. The reaction is quenched by the addition of water (7.6 mL) followed by 10.0 N sodium hydroxide (3.8 mL, 38 mmol). After 3 min, the reaction is diluted with isopropyl acetate (20 mL) and transferred to a separate funnel. The mixture is stirred and the biphasic mixture is filtered through celite to remove undissolved solids. The filtrate is returned to a separate funnel and the phases are separated. The organic layer is rinsed with a mixture of 9 mL water and 9 mL saturated aqueous sodium chloride followed by 15 mL of saturated aqueous sodium chloride. The organic layer is dried over sodium sulfate and concentrated to give product 6 as a brown gelatinous solid (4.2 g, 8.0 mmol, 99%). m / z [M + H +] cale for C 32 H 35 N 3 O 4526.3; found 526.4. e) Synthesis of? / -. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) et-alamine (1_) Intermediate 6 (2.5 g, 4.8 mmol) is dissolved in 8.0 mL of ethanol and treated with activated charcoal, Darco G -60 (1.25 g). The suspension is stirred at 50 ° C for 20 min and then filtered to remove Darco. 10% palladium on activated carbon (250 mg) is added to the filtrate and the suspension is placed in a Parr shaker. The reaction is stirred for 10 h under 30 psi hydrogen gas. The reaction is filtered through celite and concentrated under vacuum to provide compound 1_ as a brown gelatinous solid (1.9 g, 4.3 mmol, 91%). 1HNMR (300 MHz, DMSO-d6) d 2.40-2.68 (m, 6H), 2.92-3.18 (m, 2H), 4.35-4.45 (m, 1H), 4.60-4.69 (m, 1H), 5.22-5.30 ( m, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 6.68-6.86 (m, 4H), 7.12-7.36 (m, 5H), 7.95 (d, 1H, J = 1.4 Hz), 8.19 (s, 1H), 9.49 (br s, 1H). m / z: [M + H +] cale for C 25 H 29 N 3 O 4436.2; found 436.4. f) Crystallization of? / -. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride In a 500 mL round flask, compound (5.2 g, 11.9 mmol) is dissolved in 187.9 mL isopropyl alcohol with stirring at 40 ° C. Complete dissolution is achieved in 10 minutes. The flask is then charged with a solution containing 1.0 N HCl (11.3 mL, 11.3 mmol, 0.95 eq.) And H2O (29.6 mL). The solution is stirred and the product crystallizes for several hours. After 6 h, the crystals are isolated by filtration and rinsed with 15 mL of 15% cold water in isopropyl alcohol solution followed by 15 mL of isopropyl alcohol. The crystals are dried under local vacuum for 12-16 h to provide the monohydrochloride salt of compound 1_. (3.92 g, 8.3 mmol, 70% or yield, 98.89%) purity by HPLC) as a white crystalline solid. 0.2% H2O, 1H NMR (300 MHz, DMSO-d6): d (ppm) 10.13 (s, 1H), 9.62 (m, 1H), 8.93 (br s, 1H), 8.66 (br s, 1H) , 8.27 (d, 1 H, J = 1.92), 8.13 (d, 1 H, J = 1.65), 7.21-7.40 (m, 5H), 6.86-6.94 (m, 4H), 6.57 (d, 2H, J = 8.52), 6.05 (d, 1H, J = 3.57), 5.45-5.55 (m, 2H), 4.80 (m, 1H), 4.70 (m, 1H), 2.70-3.24 (m, 8H). Elemental Analysis (% by weight) cale for C25H29N3O4.HCI: C, 63.62; H, 6.41; N, 8.90; Cl, 7.51. found: C, 63.47; H, 6.54; N, 8.81; Cl, 7.78. Example 1 f) 2-Bromo- (ff) -1-ferf-butyldimethylsiloxy-1- (3-formamido-4-benzyloxypheni Detane A solution of TBDMS-CI (40.1 g, 0.26 mol) in DCM (37.5 mL) is added to a paste of imidazole (21.86 g, 0.32 mol) and (R) -2-bromo-1- (3-formamido-4-benzyloxyphenyl) ethanol (74.54 g, 0.21 mol) in DCM (260 mL) for 8 minutes. The mixture is stirred for 22 hours, the reaction is quenched with water (190 mL) and the aqueous layer is extracted with DCM (37.5 mL) .The combined DCM layers are distilled at atmospheric pressure to a volume of ca. , spontaneous crystallization occurred Isooctane (750 mL) is added dropwise during 20 minutes.The paste is cooled to 0 ° C and the solids are collected by filtration then rinsed with 9: 1 v / v isooctane: DCM (3 x 75 mL) and stirred in vacuo to give the title compound as an uncoloured solid (89.65 g, 90% th) .1H NMR according to structure (400 MHz, CDCl 3) d (ppm): -0.06 (3H) s; 0.11 (3H) s; * 0.12 (3H) s; * 0.89 (9H) s; 0.90 (9H) s; * 3.38-3.4 9 (2H) m; 4.78-4.87 (1H) m; * 5.09 (2H) s; 5.1.0 (2H) s; 6.96 (1H) d, J = 8.6Hz; * 7.06 (1H) d of d, J = 8.3, 2.0Hz; 7.11 (1H) d of d, J = 8.3Hz, 2.0Hz; 7.25-7.27 (1H) m; 7.36-7.45 (5H) m; * 7.70 (1H) d, J = 11.0Hz; 7.79 (1H) s; 8.38 (1H) d, J = 2.0Hz; 8.42 (1H) d, J = 1.5 Hz; * 8.76 (1H) d, J = 11.8Hz. * Peaks are due to ca 25M% of the minor rotamer. ii)? -. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-benzloxyphenyl) ethylamine monohydrochloride 2- [4 - ((f?) -2-Hydroxy-2-phenylethylamino) phenyl] ethylamine (19.8 g, 60 mmol) is dissolved in water (80 mlL). Isopropyl acetate (100 mL) is added with stirring. 32% w / v aqueous sodium hydroxide solution (17.2 mL) is added with stirring for 8 minutes. The organic layer is rinsed with water (100 mL) then distilled at atmospheric pressure to a volume of ca. 70 mL. To this solution is added DMA (50 mL) followed by 2-bromo- (f?) - 1 -err-butyldimethylsiloxy-1- (3-formamido-4-benzyl-oxyphenyl) ethane (20 g, 43 mmol) and potassium carbonate (7.44 g, 54 mmol). The mixture is heated to 90 ° C (oil bath temperature) for 17 hours then cooled to 50 ° C. Water (150 mL) is added and the mixture is further cooled to room temperature. MEK (150 mL) is added and the layers separated. The organic layer is rinsed with 17: 40: 340 v / w / v acetic acid: sodium acetate: water (100 mL) followed by 29% w / v aqueous sodium chloride solution (100 mL). The organic layer is diluted with MEK (50 mL) and then distilled at atmospheric pressure to a volume of ca 150 mL, followed by addition of more MEK (50 mL). The mixture is heated to 37 ° C and a solution of cesium fluoride (8.1 g, 51.6 mmol) in methanol (100 mL) is added. Heating at 37 ° C is continued for 7.5 hours after the mixture is cooled to 30 ° C. The reaction is quenched with 44% w / v aqueous potassium carbonate solution (100 mL) and water (20 mL) is added. The organic layer is rinsed with 29% w / v aqueous sodium chloride solution (100 mL) then treated with acetic acid (3.7 mL, 64.6 mmol). The mixture is rinsed with 29% > p / v aqueous sodium chloride solution (100 mL) followed by 6% w / v aqueous sodium chloride solution (3 x 100 mL).

The solution is diluted with MEK (100 mL) then distilled at a volume of ca 120 mL. MEK (80 mL) is added and the mixture is seeded * with the title compound. The mixture is distilled again at a volume of ca. 140 mL. More MEK (60 mL) is added and the mixture is cooled to room temperature. The solids are collected by filtration, rinsed with MEK (3 x 20 mL) and dried in vacuo to give the title compound as a colorless solid (18.64 g, 77% th). 1 H NMR according to structure (400 MHz, DMSO-d6) d (ppm): 2.70-2.89 (2H) m; 2.95 (1 H) m; 3.01 -3.14 (4H) m; 3.14-3.23 (1 H) m; 4.71 (1 H) m; 4.81 (1 H) m; * 5.17 (1 H) s; 5.23 (1 H) s; 5.46 (1 H) d, J = 4.4 Hz; 5.50 (1 H) m; 6.10 (1 H) d, J = 3.2 Hz; 6.59 (2H) d, J = 8.3Hz; 6.94 (2H) d, J = 8.3Hz; 7.03 (1 H) d of d, J = 8.6, 2.0 Hz; 7.12 (1 H) d, J = 8.6 Hz; 7.25 (1 H) m; 7.30-7.36 (3H) m; 7.36-7.42 (4H) m; 7.50 (2H) d, J = 7.3 Hz; 8.26 (1 H) d, J = 2.0 Hz; 8.35 (1 H) d, J = 1 .7 Hz; * 8.54 (1 H) d, J = 1 1 .0Hz; 8.63 (2H) res broad; * 9.64 (1 H) m; 9.67 (1 H) s. * Peaks are due to ca 1 1 .5M% of the minor rotamer, "" sowings can be obtained using the methods described in the present above. iii) N-. { 2- [4 - ((R) -2-Hydroxy-2-phenylethylamine) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride A mixture of N-. { 2- [4 - ((/?) - 2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (ft) -2-hydroxy-2- (3-formamido-4-benzy! oxyphenyl) ethylamine monohydrochloride (40g) and 5% Pd / C catalyst (Englehard 167, 50% wet with water) (200mg) in? MP (120ml) is stirred under hydrogen at 22 ± 2 ° C. The mixture is filtered (Whatman GF / F filter) when analyzed, by hplc (detection at 220 nm), of the reaction mixture showed < 0.5% > (per area) of the initial material (product of Ex 1ii). The filter cake is rinsed with a mixture of NMP and IPA (1: 1) (80ml).

The combined filtrates are stirred and heated to 69 ± 3 ° C. Water (10ml) is added. IPA (100ml) is added at a rate that maintains the temperature at 69 ± 3 ° C. Sown crystals (0.8g) are added. IPA (50ml) is added for 15 minutes. The resulting mixture is stirred for approximately 0.75h. IPA (250ml) is then added for approximately 2.5h. The resulting paste is allowed to cool slowly to 20 ± 3 ° C and stir at this temperature for ca 16h. The resulting paste is cooled to 3 ± 3 ° C and stirred at this temperature for 4 h. The paste is filtered and the collected solid is successively rinsed with IPA / water (10: 1) (80ml) and IPA (160ml). The solid is dried under vacuum at ca 50 ° C to give the title compound as a white solid (29.7g). Production: 88%, 74% w / w NMR: (400 MHz, DMSO-d6) d (ppm): 2.73-2.89 (2H) m; 2.95 (1H) m; 3.01-3.14 (4H) m; 3.15-3.24 (1H) m; 4.72 (1H) m; 4.82 (1H) m; 5.46 (1H) d, J = 4.7 Hz; 5.48 (1H) m; 6.03 (1H) d, J = 3.4Hz; 6.59 (2H) d, J = 8.6Hz; 6.89 (1H) d, J = 8.1 Hz; 6.91-6.98 (3H) m; * 7.01 (1H) d, J = 8.6Hz; * 7.14 (1H) s; 7.25 (1H) t, J = 7.3Hz; 7.33 (2H) t, J = 7.3, 7.6Hz; 7.39 (2H) d, J = 7.6Hz; 8.13 (1H) d, J = 1.5Hz; 8.29 (1H) d, J = 1.7Hz; * 8.53 (1H) d, J = 11.0Hz; 8.57-9.08 (2H) broad res; * 9.36 (1H) d, J = 11.0Hz; 9.60 (1H) s; * 9.92 (1H) s; 10.10 (1H) s. * Peaks are due to ca 11 M% of the minor rotamer. iv) Recrystallization of / V-. { 2- [4 - ((R) -2-Hydroxy-2-phenylethylamine) phenyl] ethyl} - (R) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride The monohydrochloride of the compound (5g) is suspended in aqueous industrial methylated spirit (I MS) (2: 1 MS: water, 72.5ml) in a 1 00ml round bottom flask. The mixture is heated to 78 ° C to give a clear solution. This is filtered, rinsed with aqueous MS (2: 1 MS: water, 2.5 ml) and the stock solution is reheated to 78 ° C to redissolve the solid that precipitates during filtration. The temperature is adjusted to 65 ° C and seeding with monohydrochloride (1.0 mg). The mixture is maintained at 60-65 ° C for 2 hours and then cooled to 20-25 ° C and stirred at that temperature for 14 hours. The suspension is cooled to 0-5 ° C and maintained at that temperature for 3 hours. The product is collected by filtration, and rinsed with aqueous MS (2: 1 MS: water, 2 X 7.5ml) and then I MS (3 X 7.5ml) to give the title compound as a white solid, which is dried at 50 ° C under vacuum overnight (60.28g). Expected production: 80%, 80% p / p The XRPD pattern of this product is shown in Figure 1. The differential scanning calorimetry indicator for this product shows an absence of discernable endothermic characteristics below about 125 ° C, with lower endothermic events having starts at about 1 33 ° C, about 151 ° C and about 1 70 ° C. Example 2 Alternative preparation of / V-. { 2- [4 - ((R) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (R) -2-Hydroxy-2- (3-formamido-4-benzyloxyphenyl) ethylamine monohydrochloride 2-Bromo- (R) -1-err-butyldimethylsiloxy-1- (3-formamido-4-benzyloxyphenyl) ethane (100 g, 215 mmol), 2- [4 - (() -2-Hydroxy-2-phenylethylamino) phenyI] ethylamine bis-hydrobromide salt (99 g, 237 mmol) and potassium carbonate (1 19 g, 861 mmol ) are loaded in a reactor. NMP (500 mL) is added and the mixture is heated at 1 10 -1 15 ° C for 5 hours then cooled to 50 ° C. Water (900 mL) is added followed by 1-pentane (500 mL) and the mixture is further cooled to room temperature (<; 35 ° C) when the layers separate. The organic layer is rinsed with water (500 mL) followed by 2% w / v aqueous sodium chloride solution (500 mL). To the organic layer is added acetic acid (20 mL, 350 mmol) followed by a solution of cesium fluoride (39 g, 257 mmol) in methanol (500 mL). The mixture is heated at 55 ° C for 4 hours. The reaction is quenched with 37% w / v aqueous potassium carbonate solution (500 mL) then cooled to 30 ° C (= 35 ° C). The organic layer is rinsed with 10% > p / v aqueous sodium chloride solution (500 mL) then treated with acetic acid (18.5 mL, 324 mmol). The mixture is rinsed with 10% w / v aqueous sodium chloride solution (2 x 500 mL). The solution is diluted with 1-pentanol (1 L), seeded with the title compound (0.2 g) and ripe for 30 minutes. The mixture is distilled under vacuum at a volume of ca. 1.4 L and the mixture is cooled to room temperature. The solids are collected by filtration, rinsed with 1-pentanol (2 x 300 mL) followed by ethyl acetate (300 mL) and dried in vacuo to give the title compound as a colorless solid (86.09 g, 71%). 1 H NM R according to structure (400 MHz, DMSO-d6) d (ppm): 2.70-2.89 (2H) m; 2.95 (1 H) m; 3.01 - 3.14 (4H) m; 3.14-3.23 (1 H) m; 4.71 (1 H) m; 4.81 (1 H) m; * 5.17 (1 H) s; 5.23 (1 H) s; 5.46 (1 H) d, J = 4.4 Hz; 5.50 (1 H) m; 6.10 (1 H) d, J = 3.2 Hz; 6.59 (2H) d, J = 8.3Hz; 6.94 (2H) d, J = 8.3Hz; 7.03 (1 H) d of d, J = 8.6, 2.0 Hz; 7.12 (1 H) d, J = 8.6 Hz; 7.25 (1 H) m; 7.30-7.36 (3H) m; 7.36-7.42 (4H) m; 7.50 (2H) d, J = 7.3 Hz; 8.26 (1 H) d, J = 2.0 Hz; 8.35 (1 H) d, J = 1 .7 Hz; * 8.54 (1 H) d, J = 1 1 .0Hz; 8.63 (2H) res broad; * 9.64 (1 H) m; 9.67 (1 H) s. • Peaks are due to ca 1 1 .5M% of the minor rotamer. Example 3 Recrystallization from ?? - 2- [4 - ((R) -2-Hydroxy-2-phenylethylamino) phenyl] etiI} - (R) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride Mononhydrochloride (30 g) is suspended in aqueous methanol (2: 1 methanol, 600 ml) in a 1 L reactor. It is heated to 64 ° C to give a clear solution. This is filtered and the stock solution is reheated to redissolve the solid that precipitates during filtration. The temperature is adjusted to 56 ° C and seeding with the title compound * (0.6g). The mixture is maintained at 56 ° C for 30 minutes and then cooled to 20 ° C for 2 hours. The suspension is heated to 50 ° C for one hour and kept at 50 ° C for 1 hour. The mixture is cooled to 20 ° C for 2.5 hours. The suspension is heated to 50 ° C for one hour and kept at 50 ° C for 1 hour. The mixture is cooled to 10 ° C for 2.5 hours and kept at 10 ° C for 8 hours. The product is collected by filtration, and 5 rinsed with aqueous methanol (2: 1 methanol: water, 60ml) and then methanol (60ml) to give the title compound as a white solid, which is dried at 40 ° C under Empty during the night. Production: 76% IR (measured as described above) gave absorption bands at about 663, 698, 747, 764, 788, 809, 827, 875, 969, 995, 1024, 1056, 1081, 1101, 1212, 1294, 1371, 1440, 1520, 1543, 1596, 1659, 3371 and 3552 cm-1 X-ray powder diffraction analysis (XRPD) of the product is shown in Figure 2. Characteristic XRPD angles and 15 d spaces are recorded in Table 1. * sows can be obtained using the methods described above. Table 1 Peak angles XRPD characteristic and spaces d Two-space Theta (degree) * (A) 2 0u 46.0 ° 2142.83 8.0 11.1 10.0 8.9 12.0 7.4 16.0 5.5 16.8 5.3 17.0 5.2 17.4 5.1 17.7 5.0 18.1 4.9 25 00 h- O lO lO ^ | - C0 < CM -! - s) h- h- CD O O lO lO in - < t ^ l- C0 CM o LO EYE ? c or m or c (D? 't s) (or s) ^ -' í (D t- '? N CM' |! f oo \ c -5- t- t- - - CM CM CM (CM CM CM CM CM <CM CM \ CM CM CM M M; 0"or re • s re (0 re 0.

WHAT

Claims (21)

1. CLAIMS 1. 1 . A process to prepare a monohydrochloride salt where * C and C ** indicate the asymmetric carbon atoms, whose process comprises the steps of: a) contacting a compound of the formula (I I): wherein P1 represents a hydroxyl protecting group, and P2 and P3 each independently represents hydrogen or a protecting group; with a weak acid, to carry out the selective protonation; b) contact the product of (a) with a source of chloride ions to effect the exchange of anions; c) deprotection to remove P1, and where P2 and p3 are necessary; d) isolation of compound (I) as monohydrochloride; and optionally e) crystallization or recrystallization of compound (I).
2. 2. A process according to claim 1, wherein the compound of the formula (I) is the compound (Ia): and the compound of the formula (I I) is the compound (I ia): wherein P1 is as defined in claim 1.
3. 3. A process according to claim 1 or claim 2 wherein the weak acid is acetic acid.
4. 4. A process according to any of claims 1 to 3 wherein the group P1 represents benzyl.
5. 5. A process according to any of claims 1 to 4 where the source of chloride ions is sodium chloride.
6. 6. A process according to any of claims 1 to 5 for the preparation of a crystalline monohydrochloride salt of the compound of the formula (la). A process according to claim 6, wherein the product of said process is characterized by an X-ray powder diffraction pattern in which the weak positions are substantially in accordance with the maximum positions of the pattern shown in Fig. 1 . 8. Crystalline monohydrochloride (la) which is characterized by a sign of differential scanning calorimetry showing an absence of discernible endothermic characteristics below about 125 ° C. 9. Crystalline monohydrochloride (la) according to claim 8 characterized by a sign of differential scanning calorimetry showing an absence of discernible endothermic characteristics below about 125 ° C, and an important endothermic heat flow start at about 229 ° C. 10. Crystalline monohydrochloride (la) according to claim 8 or claim 9 which is characterized by an indication of differential scanning calorimetry showing an absence of discernible endothermic characteristics below about 125 ° C, there are more endothermic cases less than about 130 ° C and approximately 180 ° C and an important endothermic heat flow start at approximately 229 ° C. eleven . Crystalline monohydrochloride (la) according to claim 10 wherein said lower endothermic cases occur at about 133 ° C, at about 151 ° C and at about 1 70 ° C. 12. Crystalline monohydrochloride (la) Form 2 in substantially pure form. 1 3. A process to obtain crystalline monohydrochloride (la) Form 2 in substantially pure form whose process comprises: Ba) Form a mixture of N-. { 2- [4 - ((f?) -2-hydroxy-2-phenylethylamino) phenyl] ethyl} - (/:) -2-hydroxy-2- (3-formamido-4-hydroxyphenyl) ethylamine monohydrochloride in an aqueous organic solvent, by contacting said monohydrochloride with said solvent and heating in a range of about 60 ° C to about 70 ° C, for example, approximately 65 ° C; Bb) Adjust the temperature of said mixture in the range of about 52 ° C to about 58 ° C, for example, about 55 ° C; Be) Germinate said mixture with Form 2 crystals; Bd) Cooling said mixture to a temperature in the range of about 1 5 ° C to 25 ° C; Be) Heating said mixture to a temperature in the range of about 47 ° C to about 52 ° C, for example, about 50 ° C; Bf) Repeat steps Bd) and Be) to obtain the desired Form 2. 14. A method for profoxylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective β2-ad renoreceptor fighter is indicated, which comprises the administration of a therapeutically effective amount of crystalline monohydrochloride (la) Form 2. 15. Crystalline monohydrochloride (LA) Form 2 to be used in medical therapy. 1 6. The use of crystalline monohydrochloride (la) Form 2 in the preparation of a drug for the prophylaxis or treatment of a clinical condition for which a β2-adrenoreceptor fighter is indicated. 1 7. A pharmaceutical formulation comprising crystalline monohydrochloride (Ia) Form 2 and a pharmaceutically acceptable excipient or carrier, and optionally one or more other therapeutic ingredients. 1 8. A combination comprising crystalline monohydrochloride (Ia) Form 2 and one or more other therapeutic ingredients. 9. A combination according to claim 17, wherein the other therapeutic ingredient is a PDE4 inhibitor or an anticholinergic or a corticosteroid. 20. A combination according to any of claims 1 7 or 1 8 comprising crystalline monohydrochloride (la) Form 2 and S-fluoromethyl ester of 6a, 9a-difluoro-1 7a - [(2-furanylcarbonyl) oxy] -1 1 ß-h id roxy-16a-methyl-3-oxo-and rosta-1,4-diene-7β-carbothioic acid. twenty-one . A combination according to any of claims 17 or 18 comprising crystalline monohydrochloride (la) Form 2 and S-fluoromethyl ester of 6a, 9a-difluoro-1 1 -β-hydroxy-16a-methyl-17a - [(4-methyl-1 , 3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1,4-diene-17β-carbothioic acid.