EA040500B1 - IMPROVED METHOD FOR OBTAINING R-6-HYDROXY-8-[1-HYDROXY-2-[2-(4-METHOXYPHENYL)-1,1-DIMETHYLAMINEETHYL]-2H-1,4-BENZOXAZINE-3(4H)-ONE - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to an improved process for the preparation of olodaterol or its pharmaceutically acceptable salt, preferably the hydrochloride, in high chemical and enantiomeric purity and in high yield using 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate, 1,1 maleate -dimethyl-2-(4-methoxyphenyl)ethylamine and/or camphorsulfonate salt of intermediate (4). The present invention also relates to said salts, to a process for their preparation and to their use in the preparation of olodaterol or a pharmaceutically acceptable salt thereof.

State of the art (R)-6-Hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin3(4H)-one, compound formula (1), also known as the R-enantiomer of olodaterol, is a long-acting β ₂ -adrenergic agonist (LABA) sold as its hydrochloride under the trade name Striverdi® Respimat® for the once-daily treatment of chronic obstructive pulmonary disease (COPD). ).

WO 2004/045618 A2 discloses for the first time the preparation of racemic olodaterol by the reaction of the intermediate glyoxal hydrate with 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine in the presence of a hydride source. After hydrogenation, racemic olodaterol is recrystallized and the R-enantiomer is isolated by chiral chromatography. This method is not suitable for industrial applications because the preparation of the target R-enantiomer of olodaterol is carried out using chiral chromatographic techniques, which are usually expensive, environmentally harmful and time consuming. In addition, the preparation and purity of the intermediate 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine are not disclosed.

WO 2005/111005 A1 discloses the preparation of the R-enantiomer of olodaterol hydrochloride, a compound of formula (1) HCl shown in Scheme 1. it (2) is reacted with 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine in isopropanol under microwave heating at 135°C to give a new intermediate (4) which is purified by column chromatography and then recrystallized . The R-enantiomer of olodaterol hydrochloride is obtained after hydrogenation and subsequent reaction with hydrochloric acid. The new intermediate (4) is obtained in only 63% yield and the purity is not disclosed. This method has various disadvantages. For industrial applications, it is not easy to use not only a technique involving microwave radiation, but also the purification of the new intermediate (4) using chromatographic techniques. In addition, the preparation and purity of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine is not disclosed.

Scheme 1

WO 2007/020227 A1 discloses the preparation of the R-enantiomer of olodaterol hydrochloride as shown in Scheme 2. In particular, (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one (2 ) is reacted with 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (3) in 1,4-dioxane at 97° C. and then treated with hydrochloric acid to give the hydrochloride of the new intermediate (4), which is then hydrogenated . Intermediate (4) HCl is obtained with a purity of 89.5-99.5%.

- 1 040500

Scheme 2

WO 2007/020227 A1 also discloses the preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (3) from 4-methoxyphenylacetone (5) in three reactions using the steps shown in Scheme 3, with purity

94-96% (HPLC method) with an overall yield of 34-43% (calculated in WO 2007/020227 A1).

according to the data for examples, priScheme 3

WO 2008/090193 A2 discloses the preparation of the R-enantiomer of olodaterol hydrochloride as shown in Scheme 4. (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one (2) is introduced into reaction with 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (3) in toluene at reflux. Then treatment with hydrochloric acid gives the intermediate product (4) HCl with a purity of 9599.5%, then the hydrogenation step gives the R-enantiomer of olodaterol hydrochloride. In addition, WO 2008/090193 A2 discloses the preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride from 4-methoxyphenylacetone as in Scheme 3 above in >99.5% purity (HPLC method) in overall yield , equal to 41-54% (calculated from the data for the examples given in WO 2008/090193 A2).

Scheme 4

The above prior art documents WO 2007/020227 A1 and WO 2008/090193 A2 disclose the preparation of intermediate 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as base or as its hydrochloride in low yields, which means an increase in costs in the final process for obtaining olodaterol and pharmaceutical compositions containing it, which always leads to expensive drugs.

A known process for the preparation of amines as key intermediates in the synthesis

- 2,040,500 new β-sympathomimetics (olodaterol not disclosed), described in Archiv der Pharmazie (Weinheim, Germany), 1983, 316(3), pp. 193-2011. In particular, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride is prepared as shown in Scheme 5 in 66% overall yield from 4-(2-methyl-2nitropropyl)phenol in three synthetic steps. 4-(2-Methyl-2-nitropropyl)phenol, a compound of formula (6), is methylated to give an intermediate nitro compound (7), which is then recrystallized. The nitro group is then reduced by hydrogenation and the resulting amine is treated with hydrochloric acid to give 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride. Purity is not disclosed.

Scheme 5

Therefore, it is necessary to develop suitable methods for producing olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, in high purity and high yield.

The essence of the invention

The present inventors have surprisingly found that purification of intermediate (4) used in the process for producing olodaterol by forming a camphorsulfonate salt, preferably (R)-(-)-camphorsulfonate salt, increases the chemical and enantiomeric purity of the final olodaterol or its salt, preferably The R-enantiomer of olodaterol hydrochloride.

The present inventors have also surprisingly found that 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate is useful for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, in high chemical and enantiomeric purity and high yield. In particular, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is obtained in high purity and high yield in a reliable and reproducible manner. In addition, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is non-hygroscopic, unlike prior art hydrochloride.

In addition, the present inventors have surprisingly found that 1,1-dimethyl-2-(4methoxyphenyl)ethylamine maleate is useful for reducing or even removing impurities in a process for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Thus, the first object of the present invention is the camphorsulfonate salt of intermediate (4), where PG is a hydroxy protecting group, and its solid forms.

The second aspect of the present invention is a process for preparing the camphorsulfonate salt of intermediate (4) as defined in the first aspect.

A third aspect of the present invention is a process for the preparation of olodaterol, preferably the R-enantiomer of olodaterol hydrochloride, which uses the camphorsulfonate salt of intermediate (4) as defined in the first aspect.

The fourth object of the present invention is L-tartrate of methoxyphenyl)ethylamine, in which the ratio of the number of mol

1,1-dimethyl-2-(41,1-dimethyl-2-(4methoxyphenyl)ethylamine to the amount of moles of L-tartaric acid is 1:1, and its solid forms.

Meo

HE

COOH nh ₂ noos he (3) <- tartaric acid

A fifth aspect of the present invention is a process for producing 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate as defined in the fourth aspect.

The sixth object of the present invention is 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate and its solid forms.

- 3 040500

(3) maleic acid

The seventh aspect of the present invention is a process for the production of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine maleate as defined in the sixth aspect.

Other objects of the present invention are the use of the camphorsulfonate salt of the intermediate (4) defined in the first and second objects, the use of 1,1dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate corresponding to the first and fifth objects, and the use of maleate 1,1 -dimethyl-2-(4-methoxyphenyl)ethylamine as defined in the first and sixth aspects, to obtain olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Brief description of the drawings

Examples of the present invention are illustrated in the following drawings.

In FIG. 1 shows the results of a DSC analysis of 1,1-dimethyl-2(4-methoxyphenyl)ethylamine L-tartrate prepared in Example 2.

In FIG. 2 shows the results of a TG analysis of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate prepared in Example 2.

In FIG. 3 shows the results of an IR analysis of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate prepared in Example 2.

In FIG. 4 shows the results of the IR analysis of the (R)-(-)-camphorsulfonate salt of intermediate (4) in which PG is benzyl obtained in Example 6.

Definitions

When describing the compounds and methods of the present invention, the following terms have the following meanings, unless otherwise indicated.

The term olodaterol means 6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3(4H)-one.

When used in the present invention, the term organic solvent means an organic molecule capable of dissolving other substances (ie, a solute). Organic solvents may be liquid at room temperature. Examples of organic solvents that can be used in the present invention include, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane, decahydronaphthalene, etc. ), which also includes aromatic hydrocarbon solvents (for example, benzene, toluene, o-xylene, m-xylene and p-xylene), halogenated hydrocarbon solvents (for example, carbon tetrachloride, 1,2-dichloroethane, dichloromethane, chloroform, etc. .), ester solvents (e.g. ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, etc.), ketone solvents (e.g. acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, etc. .p.), ether solvents (e.g. diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl phenyl ether or anisole, etc.), amine solvents (for example, propylamine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (for example, methanol, ethanol, isopropanol, 1-propanol, 2-methyl1-propanol, 1- butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerin, ethylene glycol, propylene glycol, m-cresol, etc.), acidic solvents (e.g. acetic acid, hexanoic acid, etc.), nitrobenzene, K,K-dimethylformamide, K,K-dimethylacetamide, dimethyl sulfoxide, K-methyl-2-pyrrolidone, acetonitrile, propionitrile, butyronitrile, silicone solvents ( e.g. silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the implementation of the organic solvent may be formed by a combination of two or more organic solvents.

The term polar solvent as used in the present invention means a solvent having a dielectric constant of at least 3, said dielectric constant being the ratio of the capacitance of a capacitor filled with solvent to the capacitance of an evacuated capacitor at 20-25°C. Dielectric constant values for solvents are given in Vogel's Textbook of Practical Organic Chemistry 5 ^th Edition, Appendix 5. Examples of polar solvents are dichloromethane, tetrahydrofuran, ester solvents (e.g. ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, etc.), ketone solvents (e.g. , acetone, methyl ethyl ketone or 2-butanone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), amine solvents (e.g. propylamine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (e.g. methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-octanol, benzyl

- 4 040500 alcohol, phenol, trifluoroethanol, glycerin, ethylene glycol, propylene glycol, m-cresol, etc.), acidic solvents (for example, acetic acid, hexanoic acid, etc.), nitrobenzene, K,K-dimethylformamide,

K,K-dimethylacetamide, dimethylsulfoxide, K-methyl-2-pyrrolidone, acetonitrile propionitrile, butyronitrile, and silicone solvents (eg silicone oils, polysiloxanes, cyclosilicones).

The term alcohol means a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by a —OH group, known as a hydroxy group. Suitable alcohols for the present invention include linear, cyclic or branched C ₁ -C 6 alkyl alcohols and any mixtures thereof. They also include commercially available alcohols. Examples of alcohols are methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-pentanol, 3-methyl-1-butanol, t-butanol, 1octanol, benzyl alcohol and phenol.

The term room temperature in the context of the present invention means a temperature of 10°C to 40°C, preferably 15°C to 30°C, more preferably 20°C to 25°C.

The term conventional purification techniques as used in the present invention means a technique by which a product can be obtained in high purity, which can be carried out on an industrial scale, such as solvent extraction, filtration, distillation, suspension, washing, phase separation, evaporation, centrifugation, isolation, or crystallization.

When used in the present invention, the term liquid extraction means a technique for separating the components of a mixture by using a solvent that has a greater affinity for one component and therefore can separate said one component from at least a second component that is less miscible with said solvent than said one component. .

The term filtration refers to the process of removing solid particles larger than a predetermined size from a feed containing a mixture of solid particles and liquid. The term filtrate means a mixture of solid particles smaller than those removed by the filtration technique. It should be understood that this mixture may contain solid particles that are smaller than a predetermined size. The term "filter cake" refers to the solid material left on the feed side of the filter element.

When used in the present invention, the term suspension means any technique in which a solvent is used to wash or suspend the crude product.

When used in the present invention, the term flushing means a technique for cleaning a solid mass (eg, crystals) by passing a liquid over and/or through the solid mass to remove solute. The technique involves passing a solvent, such as distilled water, over and/or through the precipitate resulting from filtration, decantation, or a combination thereof. For example, in one embodiment of the present invention, washing comprises contacting the solids with a solvent or mixture of solvents with vigorous agitation (eg, for 2 hours) and filtration. The solvent may be water, may be an aqueous solvent system, or may be an organic solvent system. In addition, washing can be carried out with a solvent having any suitable temperature. For example, washing can be carried out with a solvent having a temperature between about 0°C and about 100°C.

The term phase separation refers to a solution or mixture having at least two physically separate regions.

The term crystallization means any technique known to those skilled in the art, such as crystallization from a single solvent or a combination of solvents by dissolving the compound, optionally at an elevated temperature, and precipitating the compound by cooling the solution, or removing the solvent from the solution, or both. It further includes techniques such as solvent/anti-solvent or precipitation.

The terms polymorph or polymorph means crystalline forms of the same pure compound in which the molecules are arranged differently and/or have different conformations. Therefore, polymorphic solids have different unit cells and therefore different physical characteristics, including packing characteristics and different thermodynamic, spectroscopic, interfacial and mechanical characteristics.

The term solvate refers to solid molecular compounds which contain in their lattice an incorporated crystallizing solvent molecule. If the solvent included in the solvate is water, then the solvate is called a hydrate. All solvates are formed at stoichiometric or non-stoichiometric ratios of compound and crystallizing solvent. Solvates may have polymorphism, i.e. they may exist in more than one polymorphic form.

The term solid form includes all solids, polymorphs, solvates (including hydrates), amorphous solids, salts, and co-crystals.

The term purification and/or purification as used in the present invention means a procedure by which a purified drug substance can be obtained, preferably having a purity of more than 80%, more preferably more than 85%, more than

- 5 040500 preferably more than 90%, more preferably more than 95%, more preferably more than 99%, more preferably more than 99.5%, even more preferably more than 99.9%. The term industrial purification means purifications that can be carried out on an industrial scale, such as solvent extraction, filtration, suspension, washing, phase separation, evaporation, centrifugation or crystallization.

The term olodaterol or a pharmaceutically acceptable salt thereof, preferably olodaterol hydrochloride, of high chemical purity means HPLC purity of at least 99%, preferably at least 99.5%, most preferably at least 99.9%, even more preferably not less than 99.95% and most preferably equal to 100%.

The term olodaterol or a pharmaceutically acceptable salt thereof, preferably olodaterol hydrochloride, of high enantiomeric purity means an enantiomeric purity of the R-enantiomer, as determined by chiral HPLC, of at least 99.85%, more preferably at least 99.90%, even more preferably not less than less than 99.95%, even more preferably 100.00%.

The term pharmaceutically acceptable salt when describing salts of olodaterol means a salt derived from a base or its corresponding conjugate acids that are acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically acceptable inorganic or organic acids, which include, but are not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, camphorsulfonic, 1,5-naphthalenedisulfonic, formic , acetic, benzoic, malonic, malic, citric, fumaric, gluconic, glycolic, glutamic, lactic, maleic, L-tartaric, oxalic, almond, mucoid, pantothenic, succinic, xinafoic (1-hydroxy-2-naphthoic acid) and cinnamon acid. Preferably the pharmaceutically acceptable acid is hydrochloric acid.

The term (R)-camphorsulfonic acid means either (R)-(-)-camphorsulfonic acid or (1R)-(-)-10-camphorsulfonic acid. The term (S)-camphorsulfonic acid means either (S)-(+)camphorsulfonic acid or (1S)-(+)-10-camphorsulfonic acid.

Detailed description of the invention

Camphorsulfonate salt of intermediate (4).

The present inventors have found that the epoxide opening reaction of a compound of formula (2) with an amine (3) disclosed in prior art documents WO 2005/111005 A1, WO 2007/020227 A1 and WO 2008/090193 A2 gives the desired new intermediate ( 4) in the form of a free base or hydrochloride (shown above in schemes 1, 2 and 4), but always with a significant amount of impurities that are difficult to remove from the final olodaterol. These impurities are compounds of formula IMP-1, IMP-2, IMP-3 and IMP-4 below.

The most significant is the dimer impurity (IMP-1), which is a consequence of the second addition of the product, originally obtained with another epoxide (2), as well as the formation of another isomer (IMP-2), which is the result of the addition of the amine (3) to the secondary carbon atom epoxide (2). The present inventors have surprisingly found that the purification of the intermediate (4) obtained from the epoxide opening reaction by forming the camphorsulfonate salt significantly reduces the content of impurities in a reproducible manner, and thus provides

- 6 040500 obtaining the final olodaterol or its salt, preferably the R-enantiomer of olodaterol hydrochloride, in high chemical and enantiomeric purity and in high yield.

Thus, the first object of the present invention is the camphorsulfonate salt of intermediate (4), the compound of formula (4) -camphorsulfonic acid, and its solid forms, where PG is a hydroxy protecting group as defined above, preferably an arylalkyl group, more preferably C ₁ -C ₁₀ -αkyl substituted with a C ₆ -C ₁₀ aryl group, more preferably benzyl or p-methoxybenzyl, even more preferably benzyl. The camphorsulfonate salt of intermediate (4) is obtained in high chemical and enantiomeric purity and high yield, and it has high stability.

O-PG(4)-camphorsulfonic acid

The camphorsulfonic acid forming the salt of the present invention may be (R)-camphorsulfonic acid, (S)-camphorsulfonic acid, or mixtures thereof. In a preferred embodiment, the salt is the (R)-camphorsulfonate salt of intermediate (4). In another embodiment, the salt is the (S)-camphorsulfonate salt of intermediate (4). In a more preferred embodiment, the salt is the (R) camphor sulfonate salt of intermediate (4) wherein PG is benzyl, the structure of which is shown below.

OVp (DNA camphor sulfonic acid

In one embodiment, the ratio of moles of intermediate (4) to moles of camphorsulfonic acid is 1:1.

In a preferred embodiment, the camphorsulfonate salt of intermediate (4) is in solid form. Preferably, the camphorsulfonate salt of intermediate (4) is in crystalline solid form. In an alternative embodiment, the camphor sulfonate salt of intermediate (4) is in a non-crystalline (ie, amorphous) solid form. More preferably, the camphorsulfonate salt of intermediate (4), which is the (R)-camphorsulfonate salt, in which PG is benzyl, is in crystalline solid form. More preferably, the (R)-camphorsulfonate salt of intermediate (4) in which PG is benzyl is in an anhydrous solid form. In yet another embodiment, the (R)-camphor sulfonate salt of intermediate (4) wherein PG is benzyl includes solvates (including hydrates).

In one embodiment, the crystalline solid form of the camphor sulfonate salt of intermediate (4) wherein PG is benzyl is characterized by at least one of the following:

a) a DSC thermogram showing an endothermic peak starting at 163-166°C, or

b) IR spectrum having the following bands at 2955, 1745, 1702, 1617, 1513, 1470, 1369, 1329, 1250, 1162, 1051, 1038, 852, 746, 700 cm ¹ .

In another embodiment, the (R)-camphor sulfonate salt of intermediate (4) wherein PG is benzyl has a DSC thermogram having an endothermic peak starting at 163-166°C.

In another embodiment, the (R)-camphor sulfonate salt of intermediate (4) wherein PG is benzyl has an IR spectrum having the following bands at 2955, 1745, 1702, 1617, 1513, 1470, 1369, 1329, 1250, 1162, 1051, 1038, 852, 746, 700 cm ^-1 .

In another embodiment, the (R)-camphor sulfonate salt of intermediate (4), wherein PG is benzyl, is characterized in that it has an IR spectrum substantially as shown in FIG. 4.

In an alternative embodiment, the salt is the (S)-camphorsulfonate salt of intermediate (4) wherein PG is benzyl.

The second aspect of the present invention is a process for preparing the camphorsulfonate salt of intermediate (4) as defined in the first aspect, comprising the steps of:

a) treating an intermediate of formula (4) wherein PG is a hydroxy protecting group as defined above with camphorsulfonic acid in the presence of a solvent or mixture of solvents

preferably PG is an arylalkyl group, more preferably C ₁ -C ₁ o-alkyl substituted with a C ₆ -C ₁₀ aryl group, more preferably benzyl or p-methoxybenzyl, and

b) isolating the camphorsulfonate salt obtained in step a).

The molar ratio of camphorsulfonic acid to intermediate (4) used in step a) of the above process is preferably at least 1:1, preferably 1:1 to 2:1, even more preferably 1:1 to 1.1 :1.

Suitable solvents in step a) are organic solvents as defined above. Preferably, the solvent includes an organic solvent, water, or mixtures thereof. A suitable organic solvent is a polar solvent. Preferably, the solvent comprises a mixture of two polar solvents. Suitable polar solvents are ether and ester solvents. Suitable ethers are diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, t-butyl methyl ether, tetrahydrofuran and 1,4-dioxane, and mixtures thereof. Suitable esters are ethyl formate, methyl acetate, ethyl acetate, ethyl malonate and mixtures thereof. More preferably, the polar solvent comprises a mixture of an ether and an ester. More preferably, the organic solvent comprises a mixture of ester (preferably ethyl acetate) and tetrahydrofuran, preferably in a ratio of 15:1 to 1:15 (v/v). More preferably, the solvent comprises a mixture of ester (preferably ethyl acetate) and tetrahydrofuran in a ratio of 15:1 to 1:1 (v/v). Also more preferably an ester (preferably ethyl acetate) and tetrahydrofuran in a ratio of 15:1 to 10:1 (v/v) as the yield increases.

Step b) isolating the salt obtained in step a) can be carried out according to conventional techniques such as filtration, optionally followed by washing. Preferably, the washing is carried out with a mixture of ester (preferably ethyl acetate) and tetrahydrofuran, preferably in a ratio of 6:1 to 4:1 (v/v).

In a preferred embodiment, the camphor sulfonate salt can be purified by conventional purification techniques. In a preferred embodiment, the camphor sulfonate salt can be purified by crystallization. In an even more preferred embodiment, the (R) camphor sulfonate salt of intermediate (4), preferably wherein PG is benzyl, is purified by crystallization. In another preferred embodiment, the (S)camphorsulfonate salt of intermediate (4), preferably wherein PG is benzyl, is purified by crystallization.

The third object of the present invention is a process for the production of olodaterol or its pharmaceutical salt, preferably the R-enantiomer of olodaterol hydrochloride, comprising the steps:

a) obtaining camphorsulfonate salt of the compound (4) corresponding to the first object of the present invention;

b) optionally treating the camphorsulfonate salt of compound (4) with hydrochloric acid to give a compound of formula (4)-HX, in which HX is hydrochloric acid

c) removing the hydroxyl protecting group PG from the products of steps a) or b) by hydrogenation in the presence of a catalyst and an organic solvent to obtain olodaterol or a pharmaceutical salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, and optionally treating the olodaterol obtained in step d) pharmaceutically with an acceptable acid to give a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

- 8 040500

The present invention also includes a process for purifying olodaterol or a salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, said process comprising preparing the camphorsulfonate salt of intermediate (4) according to the first aspect of the present invention, preferably the (R)-camphorsulfonate salt, by the method of the second aspect and converting it to olodaterol or a salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

L-T arthrate of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

The inventors of the present invention have found that prior art 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride, after exposure to ambient conditions, rapidly absorbs up to 4% by weight of water and rapidly converts to a hemihydrate. This behavior leads not only to difficulties in use, but also to the fact that the absorbed water can react with the intermediate amine to form additional impurities. In addition, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride, prepared by a procedure replicating that of the prior art, contains at least two essential compounds of formula A and formula B, see Scheme 6. These impurities react as nucleophiles, similarly to how 1,1-dimethyl-2-(4methoxyphenyl)ethylamine (3) participates in the epoxide opening reaction with (R)-6-benzyloxy-8-oxiranyl4H-benzo[1,4]oxazin-3-one (2) to form impurity compounds (8) and (9) which are difficult to remove from the olodaterol intermediate (4) and from the final olodaterol product, resulting in a marked decrease in the yield of olodaterol.

Scheme 6

Purification of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride, Compound (3) HCl, by conventional purification procedures in different solvents was unsuccessful. See study example 1 in the experimental section. On the other hand, the present inventors surprisingly found that 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is obtained in high purity, low in impurities A and B, and in high yield in a reproducible manner. In addition, 1,1dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is non-hygroscopic and stable over time, so this intermediate is easy to handle in industrial scale production.

Thus, the fourth object of the present invention is 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate, a compound of formula (3)-L-tartaric acid, where the ratio of the number of moles of 1,1-dimethyl-2-(4- methoxyphenyl)ethylamine to the number of moles of L-tartaric acid is 1:1. Alternatively, the ratio of moles of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine to moles of Ltartaric acid is 2:1.

Meo

he soon nh ₂ noos he (3) tartaric acid

1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate corresponding to the fourth aspect is obtained in high chemical purity and high yield, and it has high stability. Advantageously, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate of the present invention is applicable to the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably olodaterol hydrochloride, in high purity and high yield in a reproducible manner, and having low concentrations of undesirable impurities of the formula (8) and (9).

In one embodiment of the fourth aspect, the present invention relates to solid forms of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate as defined in said fourth aspect.

- 9 040500

In another preferred embodiment of the fourth aspect, 1,1-dimethyl-2(4-methoxyphenyl)ethylamine L-tartrate is in crystalline solid form. In a more preferred embodiment, the crystalline solid form of L-tartrate is in an anhydrous form.

In an even more preferred embodiment of the fourth aspect, 1,1-dimethyl2-(4-methoxyphenyl)ethylamine L-tartrate is in a non-crystalline (amorphous) solid form.

In another embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is in the form of a solvate (including hydrates).

In another embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is characterized by a DSC thermogram having an endothermic peak starting at 209-211°C.

In another embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is characterized in that it has a DSC thermogram substantially as shown in FIG. 1.

In another embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is characterized in that it has a TG thermogram substantially as shown in FIG. 2.

In another embodiment of the fourth aspect, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate has an IR spectrum having the following bands at 3386, 3283, 3207, 2995, 2956, 2908, 1648, 1507, 1252, 1121 and 823 cm ^-1 .

In another embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate is characterized in that it has an IR spectrum substantially as shown in FIG. 3.

In another embodiment, the present invention includes 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate alone or admixed with other materials, such as other polymorphs, solvates, or remaining reaction solvents or by-products.

The fifth aspect of the present invention is a process for the preparation of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate as defined in the fourth aspect, which comprises the steps of:

a) treatment of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine, compound of formula (3), with L-tartaric acid in the presence of a solvent, preferably in the presence of a mixture of an organic solvent and water

b) isolating the L-tartrate obtained in step a).

The ratio of moles of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine to L-tartaric acid used in the above process is at least 1:1. Alternatively, the ratio of moles of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine to L-tartaric acid used in the above process is 2:1.

Suitable solvents in step a) are organic solvents as defined above. Preferably, the solvent includes an organic solvent, water, or mixtures thereof. A suitable organic solvent is a polar solvent. Preferably, the solvent comprises a mixture of a polar solvent and water. Suitable polar solvents are alcohol, ester and ketone solvents. More preferably, the solvent comprises a mixture of alcohol and water. Suitable alcohols are linear or branched C1-C6 alcohols such as methanol, ethanol, 1-propanol, isopropanol and mixtures thereof. Preferably, the solvent comprises a mixture of alcohol and water in a ratio of 10:1 to 1:10 (v/v). More preferably, the solvent comprises a mixture of alcohol and water in a ratio of 10:1 to 1:1 (v/v). It is also more preferred if the solvent comprises a mixture of alcohol and water in a ratio of 7:1 to 3:1 (v/v) as the yield increases.

Step b) isolating the salt obtained in step a) can be carried out according to conventional techniques such as filtration, optionally followed by washing.

In another embodiment, L-tartrate can be purified by conventional purification techniques. In a preferred embodiment, L-tartrate can be purified by crystallization.

In one embodiment of the method of the fifth object, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine of formula (3) is obtained using the steps:

a) treatment of the compound of formula (6) with a methylating reagent in the presence of a base and an organic solvent

- 10 040500 ^HO 'FF (6) to obtain a compound of formula (7)

Ύ Ί y (7) .

b) converting the compound of formula (7) obtained in step a) into an amine of formula (3) by hydrogenation in the presence of a catalyst and an organic solvent.

Advantageously, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate according to the fourth aspect of the present invention, obtained by the method of the fifth aspect, contains less than 0.1% (w/w) of an impurity of formula (A) and/or less than 0.1% (w/w) of an impurity of formula (B), based on the amount of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L tartrate, as determined by HPLC. Preferably, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate according to the present invention contains less than 0.05% (w/w) of an impurity of formula (A) and/or less than 0, 05% (w/w) of an impurity of formula (B), based on the amount of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate determined by HPLC.

1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine maleate.

As shown for 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate, the use of hydrochloride in the synthesis of olodaterol leads to some difficulties due to its hygroscopicity, including poor purification from impurities such as compounds of formula (A) and (B ) indicated in Scheme 6, and also other impurities (C), the chemical nature of which has not been established. The present inventors have surprisingly found that the use of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate can reduce or even remove the above impurity. Thus, the use of this salt is useful in the preparation of olodaterol or its pharmaceutically acceptable salts with low levels of impurities.

Thus, a sixth aspect of the present invention is 1,1-dimethyl-2-(4methoxyphenyl)ethylamine maleate, a compound of formula (3)-maleic acid, and solid forms thereof.

(3) maleic acid

The 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate according to the sixth aspect of the present invention is obtained in high chemical purity and high yield, and it has high stability.

In one embodiment, the ratio of moles of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine to moles of maleic acid is 2:1. Alternatively, the ratio of moles of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine to moles of maleic acid is 1:1.

In a preferred embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate is in solid form. Preferably, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate is in crystalline solid form. In an alternative embodiment, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate is in a non-crystalline (ie, amorphous) solid form.

The seventh aspect of the present invention is a process for producing maleate as defined in the sixth aspect, which includes the steps of:

a) treatment of the amine of formula (3) with maleic acid in the presence of a solvent

b) isolating the maleate obtained in step a).

The ratio of moles of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine to moles of maleic acid used in step a) of the above process is preferably at least 1:1, more preferably 1:1 to 2:1 , even more preferably from 1:1 to 1.5:1, more

- 11 040500 more preferably from 1:1 to 1.1:1.

Suitable solvents in step a) are organic solvents as defined above. Preferably, the solvent includes an organic solvent, water, or mixtures thereof. A suitable organic solvent is a polar solvent. Preferably, the solvent includes an organic solvent, water, or mixtures thereof. Suitable polar solvents are alcohol, ester, ether and solvents. Preferably, the polar solvents are esters and ethers. Suitable esters can be ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and ethyl malonate and mixtures thereof. Suitable ethers can be diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran and 1,4dioxane and mixtures thereof. More preferably, the solvent used in step a) is an ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and mixtures thereof, since the yield is increased.

Step b) isolating the salt obtained in step a) can be carried out according to conventional techniques such as filtration, optionally followed by washing.

In a preferred embodiment, the maleate can be purified by conventional purification techniques. In a preferred embodiment, the maleate can be purified by crystallization.

In one embodiment of the method of the fifth object, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine of formula (3) is obtained using the steps:

IVeCk,^

Ί y (3)

a) treating a compound of formula (6) with a methylating agent in the presence of a base and an organic solvent

Ή Y (6) to obtain a compound of formula (7) (7) .

b) converting the compound of formula (7) obtained in step a) into an amine of formula (3) by hydrogenation in the presence of a catalyst and an organic solvent.

The process for preparing a pharmaceutically acceptable salt of olodaterol includes 1,1-dimethyl2-(4-methoxyphenyl)ethylamine L-tartrate, 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate and/or camphorsulfonate salt of intermediate (4).

Another embodiment of the third aspect of the present invention relates to a process for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, comprising at least the steps of:

a1) treatment of L-tartrate, compound of formula (3)-E-tartaric acid, or as defined in the fourth aspect, which can be obtained by the process of the fifth aspect

base in the presence of a mixture of an organic solvent and water to obtain an amine of formula (3) MeO

_NH2 or

- 12 040500 a2) treatment of maleate, compound of formula (3) maleic acid as defined in the sixth aspect, which can be obtained by the method of the seventh aspect

MeO^tx f^COOH

I 1 U COOH (3) maleic acid with a base in the presence of a mixture of an organic solvent and water to obtain an amine of formula (3) MeO

νη ₂ (3)

b) reacting the amine of formula (3) obtained in step a1) or a2) with an epoxide of formula (2), where PG is a hydroxy protecting group, in the presence of an organic solvent

to obtain a compound of formula (4)

c) optionally treating the compound of formula (4) obtained in step b) with a pharmaceutically acceptable acid HX, preferably in which the acid HX is camphorsulfonic acid or hydrochloric acid, most preferably camphorsulfonic acid, to obtain a compound of formula (4) ΗΧ, where PG means a hydroxy protecting group as defined above

d) removing the hydroxy protecting group PG from the products obtained in step b) or c), if present, by hydrogenation in the presence of a catalyst and an organic solvent to obtain olodaterol or its pharmaceutical salt, preferably olodaterol hydrochloride,

e) optionally treating the olodaterol obtained in step d) with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt thereof.

In one embodiment, the method comprises step a1), preferably step a1), and wherein HX in step c) is hydrochloric acid. In an alternative embodiment, the method comprises step a2), preferably step a2), and wherein HX in step c) is hydrochloric acid.

Suitable bases for step a1) and step a2) may be inorganic bases selected from the group consisting of hydroxides, carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and cesium and mixtures thereof. The ratio of moles of base used to moles of L-tartrate may be at least 1:1, preferably 1:1 to 10:1, more preferably 1:1 to 5:1, even more preferably 1:1 to 2 .5:1. The ratio of moles of base used to moles of maleate may be at least 1:1, preferably at least 2:1, more preferably 1:1 to 10:1, more preferably 1:1 to 5:1, even more preferably from 1:1 to 2.5:1.

PG means a hydroxy protecting group commonly known in the art for protecting phenolic groups. Examples of their introduction and removal are discussed in T. W. Greene and G. M. Wuts, Protecting groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

- 13 040500 hydroxy groups are those that are stable in an alkaline environment. More preferably, the hydroxy protecting group can be removed by hydrogenation, such as arylalkyl groups and heteroarylalkyl groups, and the like.

Alkyl means having a linear or branched chain hydrocarbon chain radical, not containing multiple bonds, containing from 1 to 10 carbon atoms, described by the formula C ₁ -C ₁₀ -alkyl. Such alkyl groups may be selected from the group consisting of methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, linear or branched pentyl, linear or branched hexyl, linear or branched heptyl, linear or branched nonyl. or linear or branched decile. Preferably the alkyl group is C ₁ -C 4 alkyl.

Aryl means an aromatic hydrocarbon radical containing from 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl radical may optionally be substituted with one or more substituents such as OH, SH, halogen, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, acyl as defined in the present invention.

Arylalkyl means C ₁ -C ₁₀ alkyl as defined above, substituted with C ₆ -C ₁₀ aryl as defined above. Preferably the arylalkyl group is a C1- _C4 alkyl group substituted with a _C6 - _C10 aryl group such as phenyl, tolyl, xylyl and naphthyl. C ₆ -C ₁₀ aryl groups may also be substituted on the ring with one or more substituents. Suitable substituents are selected from the group consisting of alkyl, alkoxy, halogen as defined in the present invention, and nitro. Preferred substituents are alkyl and alkoxy. Preferred arylalkyl groups are 4-methylbenzyl, 2-methylbenzyl, 4-methoxybenzyl or p-methoxybenzyl, 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-nitrobenzyl, 2-nitrobenzyl or o-nitrobenzyl, 2,4-dinitrobenzyl, 4-chlorobenzyl and 2-chlorobenzyl. More preferably, the arylalkyl is benzyl or p-methoxybenzyl. Even more preferably, the arylalkyl is benzyl.

Heteroarylalkyl means straight or branched arylalkyl as defined above, which may include one of the C ₆ -C ₁₀ aryl, C ₁ -C ₁₀ alkyl groups noted above in the present invention, substituted with one or more heterocyclic groups. Preferably the arylalkyl group is C ₆ -C ₁₀ aryl, C 1 -C ₄ alkyl substituted with one or more heterocyclic groups.

In one embodiment, PG hydroxy protecting groups are those that can be removed by hydrogenation, such as 4-methylbenzyl, 2-methylbenzyl, 4-methoxybenzyl, 2methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl , 4-nitrobenzyl, 2-nitrobenzyl, 2,4-dinitrobenzyl, 4-chlorobenzyl and 2-chlorobenzyl. Preferably, the protecting group of the hydroxy group PG is benzyl and 4-methoxybenzyl. More preferably, the protecting group of the hydroxy group of PG is benzyl.

The intermediate compound of formula (2) is known in the art. Preferably, if the compound of formula (2), in which the protecting group of the hydroxy group of PG is benzyl, (R)-6benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one, is obtained in accordance with the document of the prior art WO 2008/090193 A2.

The organic solvent for step b) is as defined above. Preferably the organic solvent is selected from the group consisting of an ether solvent (e.g. diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, t-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methylphenyl ether or anisole), aromatic hydrocarbon solvent (for example, benzene, toluene, o-xylene, mxylene and p-xylene), alcohol solvents (for example, methanol, ethanol, isopropanol, 1-propanol, 2methyl-1-propanol, 1-butanol, 2-butanol, 1 -pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerin, ethylene glycol, propylene glycol, m-cresol), ketone solvents (for example, acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone), ester solvents (e.g. ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate) and Ν,Ν-dimethylformamide, N,N, dimethylacetamide, dimethyl sulfoxide and acetonitrile, propionitrile and butyronitrile. More preferably, the organic solvent for step b) is selected from the group consisting of 2-methyltetrahydrofuran, 1,4-dioxane, anisole, toluene, ethylene glycol and acetonitrile.

In another embodiment, step b) can be carried out without the presence of an organic solvent.

A suitable pharmaceutically acceptable HX acid for step c) is selected from the group consisting of hydrochloric, hydrobromic, sulfuric, methanesulfonic, ethanesulfonic, ptoluenesulfonic, camphorsulfonic, formic, acetic, malic, succinic, fumaric, glycolic, citric, fumaric, benzoic, malonic, maleic, L-tartaric, D-tartaric, ditoluyl-L-tartaric, ditoluyl-D-tartaric, dibenzoyl-L-tartaric, dibenzoyl-D-tartaric, oxalic, mandelic and 1-hydroxy-2-naphthoic acid. Preferably, if the pharmaceutically acceptable acid

- 14 040500 for stage c) is hydrochloric acid, camphorsulfonic, fumaric, benzoic, maleic, L-tartaric, D-tartaric, ditoluyl-B-tartaric and ditoluyl-6-tartaric, oxalic and mandelic acids.

More preferably, the pharmaceutically acceptable HX acid for step c) is hydrochloric acid or camphorsulfonic acid, even more preferably hydrochloric acid, even more preferably camphorsulfonic acid.

In a preferred embodiment, the pharmaceutically acceptable salt of olodaterol is the hydrochloride obtained by the method of the present invention, which can be further purified. More preferably, the pharmaceutically acceptable salt of olodaterol, preferably olodaterol hydrochloride, can be purified by recrystallization.

In another preferred embodiment, step c) is carried out and the HC acid is camphorsulfonic acid, and the camphorsulfonate salt of intermediate (4) as defined in the first aspect is obtained. Preferably, step c) further comprises converting the camphorsulfonate salt of intermediate (4) (i.e., HX is camphorsulfonic acid) to the hydrochloride of intermediate (4) (i.e., HX is hydrochloric acid). This includes treating the camphorsulfonate salt of compound (4), where PG is the hydroxy protecting group as defined above, with hydrochloric acid (which may be present as a gas or as an aqueous solution, or generated in situ, for example, from an alkylsilyl halide in the presence of a protic solvent (such as an alcohol; i.e. methanol, ethanol, isopropanol, 1-propanol and 1-butanol) in the presence of a suitable organic solvent or mixture of solvents Suitable organic solvents can be selected from the group consisting of alcohols, ethers, esters, chlorinated hydrocarbons and mixtures thereof or aqueous mixtures thereof Preferably the organic solvent is selected from the group consisting of alcohols, ethers and esters In a more preferred embodiment the camphorsulfonate salt of intermediate (4) is converted to the free base (i.e. the compound of formula (4 )), for example, by treating with a suitable base (which may be inorganic bases selected from the group consisting of hydroxides, carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and cesium and mixtures thereof), preferably in the presence of a suitable organic solvent as defined above, preferably a polar solvent such as an ester and an ether or mixtures thereof. The compound of formula (4) in free base form is then reacted with hydrochloric acid (which may be present as a gas or as an aqueous solution or produced in situ, for example from an alkylsilyl halide in the presence of a protic solvent (such as an alcohol; i.e. methanol , ethanol, isopropanol, 1-propanol and 1-butanol) in the presence of an organic solvent as defined above to give the corresponding salt of intermediate (4). More preferably, the salt of intermediate (4) is isolated, for example, by filtration, optionally followed washing (such as washing with an ester, preferably ethyl acetate).

The hydrogenation step d) is carried out in the presence of a catalyst and an organic solvent. Suitable catalysts are selected from the group consisting of Pd, Pt, Rh, Ru, Ni, Fe, Zn and Ir catalyst.

Preferably, the suitable catalyst is selected from the group consisting of (0) (Pd(0)), palladium hydroxide (Pd(OH) ₂ ), palladium on activated carbon (Pd/C), palladium on alumina, palladium on powdered carbon, platinum, activated carbon platinum and Raney nickel™. It is also possible to use a combination of catalysts. Most preferably, the catalyst is palladium on activated carbon and palladium hydroxide (Pd(OH) ₂ ). The amount of catalyst is not critical and may be equal to or less than 10% by weight, based on the amount of the compound of formula (4). In addition, hydrogenation occurs at a hydrogen pressure in the range from 0.5 to 10 atm. Most preferably, if the hydrogen pressure is from 0.5 to 5 atm, because less impurities are formed.

In a preferred embodiment of the third aspect of the present invention, the process for producing the R-enantiomer of olodaterol hydrochloride comprises at least the steps of:

al) treatment of L-tartrate, the compound of formula (3) L-tartaric acid defined in the fourth aspect, which can be obtained by the method of the fifth aspect

OH (3)-L-tartaric acid with a base in the presence of a mixture of an organic solvent and water to obtain an amine of formula (3)

- 15 040500

or a2) treatment of a maleate compound of formula (3)-maleic acid as defined in the sixth aspect, which can be obtained by the process of the seventh aspect

M X^COOH

XV ^co ° ⁿ (3) maleic acid with a base in the presence of a mixture of an organic solvent and water to obtain an amine of formula (3) MeO

NH ₂ (3)

b) reacting the amine of formula (3) obtained in step al) or a2) with an epoxide of formula (2), where PG is a hydroxy protecting group, in the presence of an organic solvent

to obtain a compound of formula (4)

c) treating the compound of formula (4) obtained in step b) with a pharmaceutically acceptable acid HX, preferably wherein the HX acid is hydrochloric acid, camphorsulfonic, fumaric, benzoic, maleic, L-tartaric, D-tartaric, ditoluyl-B-tartaric and ditoluyl-O-tartaric, oxalic and mandelic acid to give a compound of formula (4)-HX, where PG is a hydroxy protecting group as defined above

d) removing the hydroxyl protecting group PG from the resulting product in step c) by hydrogenation in the presence of a catalyst and an organic solvent to obtain olodaterol or a pharmaceutical salt thereof, a compound of formula (1)-HX, preferably olodaterol hydrochloride

e) converting the pharmaceutical salt of olodaterol obtained in step d), in which HX is not hydrochloric acid, into olodaterol hydrochloride.

In one embodiment, the method includes step al). In an alternative embodiment, the method includes step a2).

- 16 040500

Another embodiment of the third aspect of the present invention relates to a process for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, comprising at least the steps of:

a) reaction of an amine of formula (3), with an epoxide of formula (2), where PG is a hydroxy protecting group, in the presence of an organic solvent

to obtain a compound of formula (4)

b) treating the compound of formula (4) obtained in step a) with camphorsulfonic acid, preferably (R)-camphorsulfonic acid, to give the camphorsulfonate salt of intermediate (4) wherein PG is a hydroxy protecting group as defined above

c) optionally treating the camphorsulfonate salt of compound (4) with hydrochloric acid to give a compound of formula (4)-HX, wherein HX is hydrochloric acid

d) removing the hydroxy protecting group PG from the products obtained in step b) or c) by hydrogenation in the presence of a catalyst and an organic solvent to obtain olodaterol or its pharmaceutical salt, preferably the R-enantiomer of olodaterol hydrochloride,

e) optionally treating the olodaterol obtained in step d) with a pharmaceutically acceptable acid to obtain a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

In particular, camphorsulfonic acid, preferably (R)-camphorsulfonic acid, is excellent for purifying the new intermediate (4) from impurities IMP-1, IMP-2, IMP-3 and IMP-4 and thus obtaining the final olodaterol or its salts, preferably the R-enantiomer of olodaterol hydrochloride, in high chemical and enantiomeric purity.

Amine (3) can be obtained by any of the methods described above.

In the process described above, PG is preferably benzyl.

Step b) is preferably carried out as described in the second aspect of the present invention.

Step c) is optional. Thus, in one embodiment, step c) is carried out. In an alternative embodiment, step c) is omitted. This step includes treating the camphorsulfonate salt of compound (4), where PG is a hydroxy protecting group as defined above, with hydrochloric acid (i.e., HX is hydrochloric acid). In a preferred embodiment, the camphorsulfonate salt of intermediate (4) is converted to the free base (i.e. compound (4)), for example by treatment with a suitable base such as aqueous sodium hydroxide, preferably in the presence of a suitable organic solvent as defined above, such as an ester, preferably ethyl acetate. Compound (4) in free base form is then converted to the hydrochloride by treatment

- 17 040500 hydrochloric acid (ie HX means hydrochloric acid), preferably in the presence of a suitable organic solvent as defined above, such as an ester, preferably ethyl acetate. More preferably, the hydrochloride is isolated, for example, by filtration, optionally followed by washing (such as washing with ester, preferably ethyl acetate).

Steps d) and e) can be carried out as described above in the present invention.

An even more preferred embodiment of the third aspect of the present invention relates to a process for the production of the R-enantiomer of olodaterol hydrochloride, comprising at least the steps of:

a) reaction of an amine of formula (3), with an epoxide of formula (2), where PG is a hydroxy protecting group, in the presence of an organic solvent

to obtain a compound of formula (4)

b) treating the compound of formula (4) obtained in step a), with (R)-camphorsulfonic acid to give the (R)-camphorsulfonate salt of intermediate (4) wherein PG is a hydroxy protecting group as defined above

c) treating the (R)-camphorsulfonate salt of compound (4) with hydrochloric acid to give a compound of formula (4)-HX, where PG is a hydroxy protecting group as defined above and HX is hydrochloric acid

d) removing the hydroxy protecting group PG from the resulting product in step c) by hydrogenation in the presence of a catalyst and an organic solvent to obtain the R-enantiomer of olodaterol hydrochloride. Amine (3) can be obtained by any of the methods described above.

In the process described above, PG is preferably benzyl.

Steps a), b) c) and d) can be carried out as described above in the present invention.

Another aspect of the present invention is the use of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine L-tartrate as defined in the fourth and fifth aspects for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Another object of the present invention is the use of 1,1-dimethyl-2-(4methoxyphenyl)ethylamine maleate as defined in the first and sixth aspects for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Another aspect of the present invention is the use of the camphorsulfonate salt of the intermediate (4) defined in the first and second aspects for the preparation of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Below, the present invention is further illustrated by examples. They should in no way be interpreted as imposing limitations on the scope of the present invention, defined

- 18 040500 included in the claims.

Experimental section

General methods.

Proton nuclear magnetic resonance (1H NMR) analyzes were performed in deuterated solvent (d ₆ -DMSO) on a Varian Gemini 200 Fourier-Transform (FT) NMR spectrometer and chemical shifts are given in parts per million (ppm) downfield from the residual solvent peak used as an internal standard. The spin-spin coupling constants are given in hertz (Hz). Spectra were taken from 5-10 mg of sample dissolved in 0.7 ml of deuterated solvent.

Differential scanning calorimetry (DSC) analyzes were performed on a Mettler Toledo DSC822e calorimeter. Experimental conditions: alumina crucibles 40 µl; dry nitrogen atmosphere at a flow rate of 50 ml/min; heating rate 10°C/min from 30 to 300°C. Data collection and processing was carried out using the STARe software.

Thermogravimetric analyzes (TG) were performed using a Mettler Toledo SDTA851e thermobalance. Experimental conditions: aluminum oxide crucibles 40 µl; dry nitrogen atmosphere at flow rate ml/min; heating rate 10°C/min from 30 to 300°C. Data collection and processing was carried out using the STARe software.

Infrared spectroscopy (IR) analyzes were performed on a Perkin Elmer FT-IR spectrum One appliance using Perkin Elmer ATR accessories.

Karl Fischer (KF) analyzes were performed on a Metrohm 701 KF Titrino equipped with a Metrohm 6.0338.100 electrode and a 684/737 coulometer (diaphragm cell) using AQUAMETRIC Composite 5 as a reagent.

Examples

Example 1 1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride.

To a suspension of 4-(2-methyl-2-nitropropyl)phenol (50.0 g, 256.1 mmol), K ₂ CO ₃ (38.9 g, 281.7 mmol, 1.1 eq.) in acetone ( 200 ml) at room temperature in an inert atmosphere was carefully added dropwise dimethyl sulfate (26.7 ml, 35.5 g, 281.7 mmol, 1.1 eq.). The resulting mixture was stirred at 58° C. for 4 hours under an inert atmosphere and cooled to room temperature. A 1M NaOH aqueous solution (120 ml) was added and the resulting mixture was stirred for 90 minutes at room temperature. Then toluene (150 ml) was added and the phases were separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The solvent of the organic phase was distilled off under reduced pressure at a maximum temperature of 45°C. Then ethanol (150 ml) was added and distilled off at a maximum temperature of 45°C. The resulting brown oil was mixed with ethanol (400 ml) and hydrogenated under a hydrogen pressure of 15 atm over Raney Ni (10.0 g) at 50° C. for 5 hours. The resulting mixture was filtered through a pad of celite and washed with ethanol. The filtrate was distilled off under reduced pressure at a maximum temperature of 45°C. Then ethyl acetate (250 ml) was added and partially distilled off at atmospheric pressure. The resulting mixture was then cooled to 70° C. and a 4 M solution of hydrochloric acid in ethyl acetate (71.5 ml) was added over 5 minutes. The resulting mixture was cooled to room temperature over 2 hours and further stirred for 2 hours. The resulting white solid was filtered off and washed with ethyl acetate.

Yield: 41.3 g (72%).

KF: 3.7-4%.

DSC (10°C/min): first broad endothermic peak starting at 86°C due to water evaporation, second narrow endothermic peak starting at 170°C due to melting.

TG (10°C/min): weight loss equal to 3.9 wt.%, from 30°C to 100°C due to water evaporation and additional weight loss starting at 180°C due to decomposition.

Purity (HPLC): 98.0%.

Significant impurities: 0.05% (Compound A), 1.03% (Compound B), 0.84% (Compound C not characterized).

Study Example 1 Effect of purification of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride.

The hydrochloride obtained in example 1 was treated with different solvents to exclude the presence of significant impurities (compounds A and B). The results obtained are shown in the table below and indicate poor results in the purification of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride.

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No. Solvent Type Purity (HPLC) Significant impurities A IN WITH 1 Example 1 Solid N.A. 98.0% 0.05% 1.03% 0.84% 2 Acetone Suspension 99.4% N.D. 0.23% 0.26% 3 Methyl ethyl ketone Solution 98.0% 0.04% 0.98% 0.75% 4 ethyl acetate Suspension 98.0% 0.05% 0.99% 0.79% 5 Isopropanol Solution 98.5% N.D. 0.88% 0.62% 6 Acetonitrile Solution 98.2% N.D. 0.96% 0.83% 7 Acetone and water (10:0.2) Solution 98.9% N.D. 0.73% 0.38%

N.A.: not applicable

N.D.: not researched

Impurity C has not been characterized.

General suspension procedure: 1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride (5.0 g) was suspended in 50 ml of solvent, heated to the reflux temperature of the solvent, and stirred for 45 minutes. The resulting suspension was then cooled to room temperature and stirred for 2 hours. The resulting solid was filtered off, washed with solvent and dried at 45°C at atmospheric pressure.

General crystallization procedure: 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride (5.0 g) was dissolved in a minimum amount of solvent and heated at the boiling temperature of the solvent until a solution was formed. The resulting solution was then cooled to room temperature and stirred for 2 hours. The resulting solid was filtered off, washed with solvent and dried at 45° C. under atmospheric pressure.

Example 2 1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine L-Tartrate.

To a suspension of 4-(2-methyl-2-nitropropyl)phenol (10.0 g, 51.2 mmol), K ₂ CO ₃ (7.8 g, 56.3 mmol, 1.1 eq.) in acetone ( 40 ml) at room temperature in an inert atmosphere was carefully added dropwise dimethyl sulfate (5.3 ml, 7.1 g, 56.3 mmol, 1.1 eq.). The resulting mixture was stirred at 58° C. for 4 hours under an inert atmosphere and cooled to room temperature. A 1M NaOH aqueous solution (24 ml) was added and the resulting mixture was stirred for 90 minutes at room temperature. Then toluene (30 ml) was added and the phases were separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The solvent of the organic phase was distilled off under reduced pressure at a maximum temperature of 45°C. Then ethanol (30 ml) was added and distilled off at a maximum temperature of 45°C. The resulting brown oil was mixed with ethanol (80 ml) and hydrogenated under a hydrogen pressure of 15 atm over Raney Ni (2.0 g) at 50°C for 5 hours. The resulting suspension was filtered through a pad of celite, washed with ethanol and distilled off under reduced pressure at a maximum temperature of 45°C. The resulting brown oil was then dissolved in ethanol (50 ml) at 50° C. and a solution of L-tartaric acid (7.7 g, 1.0 eq.) in water (10 ml) was added dropwise. The resulting white suspension was stirred at 40-45° C. for 1 h, cooled to room temperature over 1 h, and further stirred for 1 h. The resulting crystals were filtered off and washed with a mixture of ethanol and water (5:1; v/v. ).

Yield: 14.0 g (83%).

KF: 0.5%.

Purity (HPLC): 98.8%.

Significant impurities: 0.14% (compound A), 0.11% (compound B), 0.04% (compound C not characterized).

Example 3 Recrystallization of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate.

1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate prepared in Example 2 (1 g) was suspended in ethanol (5 ml) and heated at the reflux temperature of the solvent. Water (2 ml) was then added dropwise while maintaining the boil. The resulting solution was seeded, cooled to room temperature for 14 and further stirred for 1 h and finally cooled to 0-5°C for 1 h. The resulting suspension was filtered and washed with a cold mixture of ethanol and water (5:2; v/v) to give 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate as an off-white solid.

Yield: 0.9 g (90%).

Purity (HPLC): 99.5%.

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Significant impurities: 0.02% (Compound A), 0.03% (Compound B).

DSC (10°C/min): narrow endothermic peak starting at 209-211°C.

TG (10°C/min): weight loss started at 180-190°C due to decomposition.

1H NMR (200 MHz, d ₆ -DMSO): δ/ppm. 8.00-7.00 (s, 6H, NH, OH), 7.14 (d, J 10 Hz, 2H, aromatic H), 6.90 (d, J 10 Hz, 2H, aromatic H), 3 .96 (s, 2H, CHOH), 3.73 (s, 3H, OCH3), 2.78 (s, 2H, CH), 1.17 (s, 6H, 2CH3).

Example 4 Preparation of (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1dimethylethylamino]ethyl]-4H-benzo[1,4]oxazine- hydrochloride 3-she.

1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate (1.66 g, 5 mmol) obtained in Example 3 was partitioned between toluene (10 ml) and 1M NaOH aqueous solution (11 ml, 2 .2 equiv.). The aqueous phase was extracted with toluene and the resulting organic phases were combined and washed with water. The organic phase solvent was distilled off under reduced pressure to give 1,1-dimethyl-2-(4methoxyphenyl)ethylamine as a brownish oil. Then (R)-6-benzyloxy-8-oxiranyl4H-benzo[1,4]oxazin-3-one (1.0 g, 3.4 mmol) and 1,4-dioxane (10 ml) were added and the resulting mixture was heated at 97°C for 17 hours Then the mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Then, 1,4-dioxane (2 ml) and ethanol (10 ml) were added to the resulting residue, and an aqueous hydrochloric acid solution of 37% w/v was added dropwise. (410 µl, 1.4 eq.). The resulting mixture was stirred at room temperature for 2 h, filtered, washed with ethanol and dried at 40-50° C. at atmospheric pressure.

Yield: 85-90%.

Purity (HPLC): 95.0-99.9%.

Enantiomeric purity (chiral HPLC): 97.0-99.9%.

Example 5 Preparation of (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazine-3(4H) hydrochloride -she.

(R)-6-(Benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-4H-benzo[1,4]oxazin-3-one hydrochloride mixture (600 mg, 1.2 mmol) obtained in example 4, palladium on charcoal 5% (40 mg) and methanol (40 ml) were hydrogenated under a hydrogen pressure of 3 atm at 40°C for 5 hours. The resulting suspension was filtered through a pad of celite. The filtrate was distilled off under reduced pressure, and the resulting residue was recrystallized from a mixture of methanol and isopropanol. The suspension was filtered, washed with cold ethanol and dried.

Yield: 85-90%.

Purity (HPLC): 95.0-99.9%.

Enantiomeric purity (chiral HPLC): 97.0-99.9%.

Example 6 Purification of (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-benzo[1,4]oxazine -3-she.

(R)-6-(Benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]4H-benzo[1,4]oxazin-3-one hydrochloride (5.6 g, 10.9 mmol; 95.0% pure; 98.3% enantiomeric purity) obtained in Example 4 was stirred with ethyl acetate (50 ml) and 1M aqueous sodium hydroxide solution (50 ml). The aqueous phase was extracted with ethyl acetate and the resulting organic phases were combined and washed with water. The organic phase solvent was distilled off under reduced pressure to give a brownish oil. To the resulting oil was added ethyl acetate (25 ml) and a suspension of (R)-(-)-10 camphorsulfonic acid (2.8 g, 12 mmol, 1.0 eq.) in ethyl acetate (5.6 ml) and THF (2. 8 ml). The resulting suspension was stirred at room temperature for 12 hours, filtered and washed with ethyl acetate/THF (5:1) to give the corresponding (R)-(-)-10-camphorsulfonate salt as an off-white solid.

Yield: 6.4 g.

Purity (HPLC): 99.3%.

Significant impurities: 0.10% (IMP-1), 0.20% (IMP-2) and 0.50% (IMP-4).

Enantiomeric purity (chiral HPLC): 100% (N.D. IMP-3).

The solid was recrystallized from a mixture of ethyl acetate and THF (13:4).

Yield: 93%.

Purity (HPLC): 99.8%.

Enantiomeric purity (chiral HPLC): 100%.

¹ H NMR (200 MHz, d ₆ -DMSO): δ/ppm. 9.21 (s, 1H), 9.03 (s, 1H), 7.93 (s, 1H), 7.31-7.26 (m, 5H, OCH ₂ Ph), 7.12 (d, J 10 Hz, 1H, aromatic H), b, 94 (d, J 4 Hz, 1H, aromatic H), 6.82 (d, J 10 Hz, 1H, aromatic H), 6.54 (d, J 4 Hz, 1H, aromatic H), 6.14 (s, 1H), 5.44 (s, 1H, CHOH), 4.90 (s, 2H, OCH2Ph), 4.42 (d, J 28 Hz, 1H , COCH _a H), 4.35 (d, J 28 Hz, 1H, COCHHb), 3.76 (s, 3H, OCH3), 3.45 (d, J 16 Hz, 1H, CHOHCHaHbNH), 2.92 (d, J 16 Hz, 1H, CHOHCHHbNH), 3.36-1.70 (m, 11H, 1.33 (s, 3H), 1.10 (s, 3H, CH3), 0.83 (s, 3H, CH3).

¹³ C NMR (50 MHz, d6-DMSO): δ/ppm. 216.65, 166.03, 158.92, 154.53, 126.95-137.05, 113.95, 107.03, 103.54, 70.53, 67.36, 64.57, 60, 94, 58.66, 55.33, 42.83-48.06, 27.14, 24.86, 22.94, 22.80, 20.17, 19.98.

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DSC (10°C/min): narrow endothermic peak starting at 163-167°C.

TG (10°C/min): weight loss started at 210°C due to decomposition.

IR (cm ^-1 ): 2955.7, 1745.4, 1702.1, 1617.9, 1513.7, 1470.4, 1369.7, 1329.5, 1250.0, 1162.2, 1051.5 ,

1038.3, 852.0, 746.7, 700.4.

Example 7 Preparation of purified (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-benzo[1,4] hydrochloride ]oxazin-3-one.

The (R)-(-)-10-Camphorsulfonate salt (1.4 g, 1.97 mmol) obtained in Example 6 was stirred with ethyl acetate (14 ml) and 1M aqueous sodium hydroxide solution (5 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with brine. 4 n. An aqueous solution of HCl in ethyl acetate was added until pH=1-2. The resulting suspension was stirred at room temperature for 30 min and at 0-5°C for another 30 min, filtered, washed with chilled ethyl acetate and dried.

Yield: 1.0 g.

Purity (HPLC): 99.3%.

Enantiomeric purity (chiral HPLC): 100%.

Example 8 Preparation of purified (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazine-3 (4H) hydrochloride -she.

A suspension of the hydrochloride (913 mg, 1.77 mmol) obtained in Example 7 and palladium on charcoal JM 452 (5%) in methanol (40 ml) was hydrogenated with H ₂ at a hydrogen pressure of 3 atm at 40 °C for 5 hours. The resulting suspension was filtered through a pad of celite. The filtrate was distilled off under reduced pressure, and the resulting residue was recrystallized from a mixture of methanol and isopropanol. The suspension was filtered, washed with cold ethanol and dried.

Yield: 85-90%.

Purity (HPLC): 99.0-99.9%.

Enantiomeric purity (chiral HPLC): 99.0-100%.

Example 9 Preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine maleate.

To a suspension of 4-(2-methyl-2-nitropropyl)phenol 100 g, 512 mmol), K ₂ CO ₃ (77.8 g, 563 mmol, 1.1 eq.) in acetone (300 ml) at room temperature in dimethyl sulfate (53.3 ml, 562 mmol, 1.1 eq.) was carefully added dropwise under an inert atmosphere. The device for adding dimethyl sulfate was washed with acetone (100 ml) and the washing solution was added to the reaction mixture. The resulting mixture was stirred at reflux for 4 hours and cooled to room temperature. Then 1M NaOH aqueous solution (240 ml) was added and the mixture was stirred for 90 minutes. Then toluene (300 ml) was added and the phases were separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The resulting brown oil (purity 97.8%) was dissolved in ethanol (800 ml). Half of the solution was hydrogenated under a hydrogen pressure of 15 atm over Raney Ni (10.0 g) at 50° C. for 12 hours. The resulting mixture was filtered through a pad of celite and 1/3 of the solution was used and distilled off. The resulting brown oil was mixed with maleic acid (9.9 g, 85.3 mmol, 1.0 eq.) and ethyl acetate (113 ml). The resulting suspension was heated to 50° C. and stirred until a solution formed, and cooled to room temperature over 12 hours. The resulting solid was filtered off and washed with ethyl acetate.

Yield: 17.5 g (74%).

Purity (HPLC): 99.2%.

Significant impurities: 0.04% (compound A), N.D. (Compound B), N.D. (compound C has not been characterized).

1H NMR (200 MHz, d ₆ -DMSO), δ/ppm 7.78 (s broad, 3H, NH, OH), 7.14 (d, J8 Hz, 2H, H aromatic), 6.92 (d, J 8 Hz, 2H, aromatic), 6.03 (s, 2H, CH=COOH), 3.74 (s, 3H, OCH ₃ ), 2.76 (s, 2H, CHPh), 1.18 (s, 6H, 2 CH ₃ ).

DSC (10°C/min): narrow endothermic peak starting at 96-99°C.

TG (10°C/min): weight loss started at 130°C due to decomposition.

Example 10 Preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hemimaleate.

The second half of the solution obtained in Example 9 was hydrogenated under a hydrogen pressure of 15 atm over Raney Ni (10.0 g) at 50° C. for 12 hours. The resulting mixture was filtered through a pad of celite and 1/2 of the solution was distilled off. The resulting brown oil was mixed with maleic acid (7.4 g, 63.8 mmol, 0.5 eq.) and ethyl acetate (125 ml). The resulting suspension was heated to 50° C. and stirred until a solution formed, and cooled to room temperature over 2 hours. The resulting solid was filtered off and washed with ethyl acetate.

Yield: 23 g (76%).

Purity (HPLC): 99.3%.

Significant impurities: 0.09% (compound A), N.D. (compound B), 0.05% (compound C not characterized).

1H NMR (200 MHz, d ₆ -DMSO), δ/ppm 7.11 (d, J 8 Hz, 2H, H aromatic), 6.88 (d, J 8 Hz, 2H, aro-

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Claims (17)

matic), 6.03 (s, 1H, CH=COOH), 4.5-4.0 (s broad, 3H, NH, OH), 3.73 (s, 3H, OCH ₃ ), 2.63 ( s, 2H, CH ₃ Ph), 1.07 (s, 6H, 2 CH3). Example 11 Preparation of 4-(2-methyl-2-nitropropyl)phenol A suspension of 4-hydroxybenzyl alcohol (1 kg, 8.06 mol), potassium hydroxide (0.23 kg, 4.03 mol, 0.5 eq.) and tetrabutylammonium bromide (TBAB) (0.01 kg, 1% wt./ vol.) in toluene (3.0 l) was heated at 8590°C for 48 hours. The resulting mixture was cooled to room temperature and 1 n. an aqueous solution of HCl was added to establish pH=6-7. The solvent was distilled off. Then, ethyl acetate and water were added to the resulting residue, and the phases were separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined and washed with water. The organic phases were distilled off to give 4-(2-methyl-2nitropropyl)phenol as a brown solid, which was recrystallized from a mixture of ethyl acetate and methylcyclohexane. Yield: 1.42 g (78%). Purity (HPLC): 97.0-98.0%. Example 12 Preparation of (R)-camphorsulfonate salt of (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-benzo[1 ,4]oxazin-3-one. 1,1-Dimethyl-2-(4-methoxyphenyl)ethylamine L-tartrate (4.9 g, 14.9 mmol) was partitioned between toluene (50 ml) and 1M NaOH aqueous solution (50 ml). The aqueous phase was extracted with toluene and the resulting organic phases were combined and washed with water and brine. The organic phase solvent was distilled off under reduced pressure to give 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a brownish oil. Then (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one (3.4 g, 11.4 mmol) and 1,4-dioxane (20 ml) were added and the resulting the mixture was heated at 97° C. for 16 hours under an inert atmosphere. The mixture was then cooled to room temperature, and the solvent was distilled off under reduced pressure to give a residue. Ethyl acetate (47 ml) and a solution of (R)camphorsulfonic acid (3.4 g, 15.0 mmol) in tetrahydrofuran (28 ml) were then added. The resulting solution was seeded, stirred at room temperature, filtered, washed with a mixture of ethyl acetate and tetrahydrofuran (5:1) and dried. Yield: 4.0 g (48%). Purity (HPLC): 99.5%. Enantiomeric purity (chiral HPLC): 99.9%. CLAIM 1. Camphorsulfonate salt of intermediate (4) wherein PG is C ₁ -C ₁₀ alkyl substituted with C ₆ -C ₁₀ aryl group 2. The camphor sulphonate salt of claim 1, wherein the camphor sulphonic acid is (R)-(-)-camphor sulphonic acid. 3. The camphor sulphonate salt of claim 1, wherein the camphor sulphonic acid is (S)-(+)-camphor sulphonic acid. 4. Camphorsulfonate salt according to any one of claims 1 to 3, wherein the molar ratio of intermediate (4) to camphorsulfonic acid is 1:1. 5. Camphorsulfonate salt according to any one of claims 1 to 4, wherein the PG group is benzyl or pmethoxybenzyl. 6. Camphorsulfonate salt according to any one of claims 1 to 5, wherein the PG group is benzyl. 7. Camphorsulfonate salt according to any one of claims 1 to 6, which is in crystalline solid form. 8. The crystalline solid form of the camphor sulfonate salt of claim 7, characterized by at least one of the following: a) a DSC thermogram showing an endothermic peak starting at 163-166°C, or b) IR spectrum having the following bands at 2955, 1745, 1702, 1617, 1513, 1470, 1369, 1329, 1250, 1162, 1051, 1038, 852, 746, 700 cm' ¹ . 9. Camphorsulfonate salt according to any one of claims 1 to 6, which is in non-crystalline solid form. 10. The method for producing camphorsulfonate salt according to any one of claims 1 to 9, including the steps: a) treating an intermediate of formula (4) wherein PG is as defined in claim 1, 5 or 6 with camphorsulfonic acid in the presence of a solvent or mixture of solvents - 23 040500 b) isolating the camphorsulfonate salt obtained in step a). 11. A method for producing olodaterol or a pharmaceutical salt thereof, comprising the steps: a) obtaining camphorsulfonate salt of the compound (4) according to any one of paragraphs.1-9; b) optionally treating the camphorsulfonate salt of compound (4) with hydrochloric acid to give a compound of formula (4)-HX, where PG is Ci-Ci-alkyl substituted with a C ₆ -C ₁₀ aryl group as defined in step a) and HX is hydrochloric acid c) removing the PG group from the products of steps a) or b) by hydrogenation in the presence of a catalyst and an organic solvent to obtain olodaterol or its pharmaceutical salt; d) optionally treating the olodaterol obtained in step d) with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt thereof. 12. The method according to claim 11, wherein in step d) the R-enantiomer of olodaterol hydrochloride is obtained by treating the R-enantiomer of olodaterol hydrochloride. 13. The method according to any one of claims 11 or 12, in which step b) is carried out and which includes additional steps: b1) converting the camphorsulfonate salt of the compound (4) according to any one of claims 1 to 9 to the free base in the presence of a base and a solvent, and b2) treating the free base obtained in step b1) with hydrochloric acid to obtain a compound of formula (4)-HX , in which HX means hydrochloric acid. 14. The method according to any one of claims 11 to 13, wherein the camphorsulfonate salt in step a) is (R)-(-)-camphorsulfonate. 15. The method according to any one of claims 11 to 14, wherein the camphorsulfonate salt of compound (4) is produced by a method comprising the steps of: a) reacting an amine of formula (3) or a salt thereof with an epoxide of formula (2), where PG is C ₁ -C ₁₀ alkyl substituted with a C ₆ -C ₁₀ aryl group as defined in any one of claims 1, 5 or 6, in the presence of an organic solvent to obtain a compound of formula (4) b) treatment of the compound of formula (4) obtained in step a) with camphorsulfonic acid in the presence of a solvent or mixture of solvents, where PG is C ₁ -C ₁₀ alkyl substituted with C ₆ -C ₁₀ aryl group as defined in step a) . 16. Use of the camphorsulfonate salt according to any one of claims 1 to 9 for the preparation of olodaterol or a pharmaceutically acceptable salt thereof. 17. Use according to claim 16 wherein olodaterol or a pharmaceutically acceptable salt thereof is the R-enantiomer of olodaterol hydrochloride and the camphorsulfonate salt is (R)-(-)camphorsulfonate salt. -