WO2007009405A1

WO2007009405A1 - A method for the preparation of (r)-n-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride (atomoxetine)

Info

Publication number: WO2007009405A1
Application number: PCT/CZ2005/000091
Authority: WO
Inventors: Ludek Ridvan; Petr Hruby; Stanislav Radl; Monika Zatopkova; Lukas Placek
Original assignee: Zentiva, A.S.
Priority date: 2005-07-21
Filing date: 2005-12-01
Publication date: 2007-01-25
Also published as: CZ2005473A3; CZ296345B6

Abstract

Racemic N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylproρylamine (VIII) is an intermediate for obtaining atomoxetine. Racemic N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine (VIII) further reacts in a solution of an organic solvent with an optically active acid producing a mixture of diastereoisomers, which are subsequently resolved by crystallization and converted to the respective (R) and (S) enantiomers of N-benzyl-N-methyl- 3-(2-methylphenoxy)-3-phenylpropylamine by treatment with an organic or inorganic base. The (R)-enantiomer of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine ((R)-VIII) is further subjected to debenzylation by means of an alkyl or aryl chloro formate yielding an alkyl/aryl (R)-3-(2-methylphenoxy)-3-phenylpropylmethylcarbamate ((R)-IX), which is then hydrolyzed in the basic environment yielding the base of (R)-N-methyl-3-(2-methylphenoxy)- 3-phenylpropaneamine, which is finally converted to (R)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine hydrochloride ((R)-I) by treatment with hydrochloric acid.

Description

A METHOD FOR THE PREPARATION OF (i?)-N-METHYL-3-(2- METHYLPHEΝOXY)-3-PHEΝYLPROPYLAMIΝE HYDROCHLORIDE (ATOMOXETINE)

Technical Field

The invention concerns a new method for the preparation of (i?)-JV-methyl-3-(2- methylphenoxy)-3-phenylpropylamine hydrochloride of formula (R)-I

known under a generic name atomoxetine.

Background Art

Atomoxetine, formerly called tomoxetine, is a therapeutically useful substance with influence on central nervous system. The molecule of the substance is chiral; the (i?)-(-)-enantiomer is more effective as an anti-depressant or for treatment of ADHD (EP 0 052 492 Al).

Preparation of atomoxetine and its intermediate products is described for example in patents

US 4,018,895, EP 0 052 492 Al, US 6,541,668 Bl.

One of the possible methods of preparation of atomoxetine is presented in Scheme 1.

Scheme 1

If the intermediate product is a dimethylamino derivative of formula II, wherein R = Me, the necessary steps for preparation of the substance include demethylation, which is well described in literature, e.g. EP 0 052 492 Al. In this patent, resolution of racemic atomoxetine by means of (<S)-(+)-mandelic acid is also described, hi US patent 4,777,291, racemization of the (+)-enantiomer of atomoxetine with a strong base, such as for example n-butyllithium, is described. Use of organometals (e.g. n-butyllithium) for racemization of the undesirable enantiomer of atomoxetine is not suitable for industrial production because they have usually to be used in an inert atmosphere, and further these strong bases react violently with water or alcohols. The atomoxetine molecule contains a relatively acidic hydrogen (NH); for racemization (elimination of the hydrogen on the asymmetric carbon), more than 1 equivalent of the base is necessary. The organometallic bases are also disadvantageous due to their relatively high price.

Partial racemization was described for reactions of enantiomer-enriched substance of formula II with aryl halides (Tetrahedron Lett. 35, 1339-1342, 1994; Synth. Commun., 25, 1231-1238, 1995). If the enantiomer-enriched substance of formula II, wherein X = OH, is used for preparation of the substance of formula IV or of atomoxetine, it is necessary to expect either racemization when strong bases such as sodium hydride are used (quantitative conversion of the substance of formula II to an alcoholate) or long reaction times and side reactions when weaker bases are used (carbonates, hydroxides). If the enantiomer-enriched substance of formula II, wherein X = Cl, TsO, etc. (i.e. a leaving group in the sense of nucleophilic substitution), is used for preparation of the substance of formula IV or of atomoxetine, it is possible to use a weaker base for formation of the o-cresolate, but the reaction occurs directly on the asymmetric carbon and therefore racemization can again take place.

A method of preparation of atomoxetine, which is summed up in Scheme 2, according to this invention eliminates the above-mentioned disadvantages.

Scheme 2

(i?)-Atomoxetin R = Me₁Et₁Ph, etc. Disclosure of Invention

The invention is based on the preparation of racemic N-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylρropylamine of formula VIII as an intermediate for production of atomoxetine. Starting from this intermediate, the preparation of atomoxetine according to the invention continues with resolution, wherein racemic iV-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylpropylamine of formula VIII reacts in a solution of an organic solvent with an optically active acid producing a mixture of diastereoisomers, which are subsequently separated via crystallization and converted to respective (R) and (S) enantiomers of N-benzyl-N-methyl-3 -(2-methylphenoxy)-3 -phenylpropylamine by treatment with an organic or inorganic base.

The (i?)-enantiomer of Λ/-benzyl-Λ/-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula (R)-VIII is further subjected to debenzylation using an alkyl or aryl chloroformate producing an alkyl/aryl (i?)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX, which is then hydrolyzed in a basic environment, yielding the base of (i?)-JV-methyl-3- (2-methyphenoxy)-3-phenlypropane amine, which is finally converted, by means of hydrochloric acid, to (i?)-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine hydrochloride of formula (R)-I.

The undesirable (ιS)-enantiomer of N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine of formula (S)-VIII can be returned to the process of preparation after its racemization using an inorganic or organic base in an organic solvent environment.

A more detailed description of the invention follows:

The starting 3-benzylmethylamino-l-phenyl-l-propanone hydrochloride of formula V is preferably prepared by reaction of acetophenone, paraformaldehyde and iV-methylbenzylamine (so-called Mannich reaction) in an appropriate solvent and in the presence of an acid. Suitable solvents include C₁ through C₄ alcohols and water or a mixture of these solvents; hydrochloric acid or sulfuric acid turned out to be suitable acids. Use of slight excesses of formaldehyde and N-methylbenzylamine (10 to 50 %), optimally 30 %, and of a high-boiling alcohol, e.g. 2- propanol, has also turned out to be preferable. Using such an alcohol allows for azeotropic distilling off the water contained in the reaction mixture. The reaction is best performed at a temperature of 50 to 100 °C for 3 to 30 hours. The crystalline product can be obtained by cooling down the reaction mixture. The Mannich reaction of acetophenone with paraformaldehyde and methylbenzylamine in ethanol is described in Chem. Pharm. Bull. 43, 748-753, 1995 with the yield of only 50 %. In our make-up of the reaction according to Example 1 a 90 % yield has been achieved.

N-Benzyl-Λ/-methyl-3-hydroxy-3-phenylpropane amine hydrochloride of formula VI can be prepared from 3 -benzylmethylamino-1 -phenyl- 1-propanone hydrochloride of formula V by conventional reduction with a suitable reduction agent such as for example LiAlH₄, NaBH₄ or diborane, in a suitable solvent, e.g. tetrahydrofuran, methanol, ethanol, water or a mixture of these solvents. It proved advantageous to use 0.5 to 1 equivalent of sodium tetrahydroborate dissolved in a mixture water/methanol. The reaction time at a temperature from 0 to 50 °C is roughly 2 to 24 hours.

N-Benzyl-iV-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII can be prepared by reaction of the compound of formula VI with 2-fluorotoluene. However, reactivity of 2-fluorotoluene is relatively low for this nucleophilic aromatic substitution; for obtaining at least a satisfactory yield (above 50 %) it is necessary to use long reaction times, high temperatures and/or strong bases for quantitative formation of the anion of the compound of formula VI. However, it proved more advantageous to convert the compound of formula VI to a derivative of N-benzyl-N-methyl-3-chloro-3-phenylpropane amine hydrochloride of formula VII, wherein X represents a suitable leaving group, e.g. a halogen or an alkanesulfoxy group R_aSO₃, wherein R_a represents a Cl through C5 aliphatic saturated hydrocarbon residue, or a C6 through C12 aromatic or alkylaromatic hydrocarbon residue. The compound of formula VII then, by reaction with o-cresol in a suitable solvent such as acetone, acetonitril, dimethylsulfoxide, using a base such as potassium tert-butanolate, potassium carbonate, sodium methanolate, yields N-benzyl-iV-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII in a high total yield (roughly 90 %). The reaction time at a temperature of 20 through 80 °C is roughly 2 to 24 hours. 7V-Benzyl-iV-methyl-3-(2-methylphenoxy)-3- phenylpropane amine of formula VIII was identified by the ¹H ΝMR method. Racemic N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII is subjected to reaction with an optically active acid selected from the group including tartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid and their sodium, potassium and lithium salts, mandelic acid and camphorsulfonic acid, preferably with mandelic acid, resulting in a mixture of diastereoisomeric salts. It has turned out that by crystallizing from an organic solvent from the group of alcohols (e.g. 2-propanol), ethers (e.g. diethylether, tert-butylmethylether), esters (e.g. ethylacetate) or their mixtures it is possible to obtain a salt of high enantiomeric purity. Crystallization from tert-butylmethylether according to Example 6 yielded (i?)-N-benzyl-N- methyl-3-(2-methylphenoxy)-3-phenylpropaneamine-(iS)-mandelate with enantiomeric purity of 99.5 % ee. The individual salts were identified using ¹H NMR.

N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine of formula VIII, which has not been described in literature so far, has an advantage compared to JV,iV-dimethyl-3-(2- methylphenoxy)-3-phenylpropane amine in its ability to crystallize with chiral, enantiomer- enriched acids such that a salt is obtained that contains only one enantiomer of JV-benzyl-JV- methyl-3-(2-methylphenoxy)-3-phenylpropane amine, m attempts at crystallization of N₁N- dimethyl-3-(2-methylphenoxy)-3-phenylpropanamine with chiral, enantiomer-enriched acids only a crystalline salt containing the two enantiomers of iV,7V-dimethyl-3-(2-methylphenoxy)- 3-phenylpropaneamine in the ratio 1:1 was obtained.

Another aspect of the invention is a reaction of (i?)-N-benzyl-iV-methyl-3-(2-methylphenoxy)- 3-phenylpropylamine of formula (R)-VIII with an alkylchloro formate of formula ClCOOR, wherein R is selected from the group OfC₁-C₅ alkyls or C₆-C₁₂ aryls or alkylaryls, particularly with phenyl, ethyl or methylchloroformate, in a suitable solvent, such as for example toluene, yielding an alkyl/aryl (i?)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX. According to literature, alkylchloroformates are known as agents suitable for N- demethylation of iV,N-dimethylalkylamines, e.g. EP 0 052 492 Al. According to this invention, alkylchloroformates have surprisingly turned out to be suitable also for selective removal of the benzyl group during reaction with N-benzyl-iV-methyl-3-(2-methylphenoxy)-3- phenylpropylamine. N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula VIII can be converted to N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine also by other debenzylation methods, e.g. by catalytic hydrogenolysis, but with lower yields because side reactions occur. The alkyl/aryl (i?)-3-(2-memylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX is then first hydrolyzed with an alkali metal (K, Na₅ Li) hydroxide in a solvent environment, preferably DMSO, producing the base of (i?)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine, and then converted to (i?)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine hydrochloride of formula (R)-I using hydrochloric acid. By the above- described procedure, followed by crystallization from a suitable solvent, such as for example ethylmethylketone, toluene or ethylacetate, a product having high purity can be obtained. The procedure according to Example 10, wherein ethylmethylketone was used, yielded a product with chemical purity 99.7% and optical purity 99.8%. Using differential scanning calorimetry DSC, a peak of the phase change was determined at the temperature 167.1 °C (onset at the temperature 164.8 °C) at the heating rate 10 °C/min. The record of DSC analysis is given in Fig. 2. The XRPD diffraction pattern of the crystalline form of atomoxetine prepared according to Example 10 is depicted in Fig. 1. The most intensive reflections in the X-ray diffraction pattern (XRPD) are: 7.92; 11.53; 12.29; 14.41; 15.01; 17.21; 19.84; 19.98; 21.32; 21.55; 22.54; 23.03; 23.65; 24.60; 24.73; 27.53; 28.51; 28.75; 31.24 (± 0.2) °2Θ, using the CuKa (λ=1.5402 A) radiation.

Another aspect of the invention is racemization of the undesired (5)-iV-benzyl-N-methyl-3-(2- methylphenoxy)-3-phenylpropylamine of formula (S)-VIII, thanks to which it is possible to obtain significantly higher yield of the process. The base of (ιS)-iV-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylpropylamine is obtained after separation of the salt of the (R)- enantiomer of 7V-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine with mandelic acid and evaporation of the mother liquors, by means of an aqueous solution of an inorganic or organic base, extraction with an organic solvent and evaporation of the volatile fractions. Subsequently, racemization is performed using an inorganic or organic base, such as for example alkali metal (K, Na, Li) hydroxides or alcoholates (e.g. potassium tert-butanolate), in a solvent environment. These bases, as compared to those mentioned in US 4,777,291 for racemization of atomoxetine, are advantageous in their low prices and safety in handling. The bases set froth herein (alkali metal hydroxides) do not react explosively with water, are not sensitive to the presence of water in the organic solvent, and hence do not require any special treatment. Advantageous solvents for racemization are especially polar high-boiling solvents such as for example dimethylsulfoxide. Racemization takes place also in less polar or low- boiling solvents with addition of a phase transfer catalyst from the group of crown ethers, polyethyleneglycols and quaternary ammonium or phosphonium salts, particularly tetrabutylammoniumbromide or 18-crown-6.

Brief Description of Drawings

Figure 1 presents an XRPD diffraction pattern of the crystalline form of atomoxetine prepared according to Example 10. Figure 2 presents a recording of DSC analysis.

Examples

The invention is further elucidated in the following examples. The examples have purely illustrative character and do not limit the scope of the invention in any respect.

Example 1

3-Benzylmethylamino-l-phenyl-l-propanone hydrochloride (V)

Aqueous concentrated HCl is added dropwise to a solution of benzylmethylamine (129.1 ml) in 2-propanol (600 ml). Then, paraformaldehyde (39.64 g) and acetophenone (116.7 ml) are added. The mixture is refluxed for 6 hours. After gradual cooling down to 0 ⁰C, the mixture is stirred for 1 hour. Precipitated crystals are sucked off and washed with 2-propanol. The yield was 261 g (90 %) of substance V.

Example 2

N-Benzyl-N-methyl-S-hydroxy-S-phenylpropaneamine hydrochloride (VI) 4M NaOH (110 ml) is added dropwise to a stirred mixture of 3-benzylmethylamino-l-phenyl-

1-propanone hydrochloride (V) (290 g) (prepared according to Example 1) in methanol (1,200 ml) at 0 to 5 ⁰C over 10 min. Then, NaBH₄ in a mixture water/methanol is added portionwise.

The mixture is stirred at 0 up to 10 °C for 4 hours, then under gradual heating up to the room temperature for another 4 hours and further at the room temperature for another 8 hours. Methanol is evaporated at reduced pressure; the mixture is mixed with toluene (400 ml) and water (100 ml). The organic phase is separated, shaken up with 100 ml water and evaporated.

The evaporation residue is dissolved in 2-propanol (400 ml) and aqueous coned. HCl (82 ml) is added dropwise while the mixture is being stirred. Subsequently, the solution is evaporated. The yield was 268 g (92 %) of substance VI.

Example 3 N-Benzyl-iV-methyl-S-chloro-S-phenylpropaneamine hydrochloride (VII)

N-Benzyl-N-methyl-3-hydroxy-3-phenylpropaneamine hydrochloride VI (292 g), prepared according to Example 2, is partially dissolved in CHCl₃ (600 ml). SOCl₂ (117 ml) is added dropwise at such a rate that the mixture refluxes. The solution is then refluxed for 3 hours. Subsequently, the mixture is cooled with ice and the first fraction of crystals is sucked off. The mother liquors are evaporated at reduced pressure and the evaporation residue is stirred up with acetone. Crystals are sucked off and washed with acetone. The total yield was 292 g (94 %) of substance of formula VII.

Example 4 N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine (VIII)

N-Benzyl-N-methyl-3-chloro-3-phenylpropaneamine hydrochloride VII (310 g), prepared according to Example 3, is mixed in DMSO (800 ml) and o-cresol (103 ml) and K₂CO₃ (414 g) are added to the resulting mixture. The mixture is stirred vigorously at the room temperature for 24 hours. After the reaction is complete, toluene (400 ml) and then water (1,600 ml) are added to the stirred mixture. The organic layer is separated; the aqueous one is shaken up with toluene (100 ml). The combined organic fractions are shaken up with water (2x 100 ml) and evaporated. The yield was 307 g (89 %) of substance VIII. ¹H NMR (250 MHz, DMSO): 2.06 (2H, m), 2.13 (3H, s), 2.15 (3H, s), 2.46 (2H, m), 3.45 (2H, m), 5.38 (IH, m), 6.60-7.45 (14H, m).

Example 5 iV-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine oxalate N-Benzyl-7V-methyl-3-hydroxy-3-phenylpropane amine VI (20 g), prepared according to Example 2, is mixed in DMSO (800 ml) and 2-flurotoluene (12.2 ml) and KOH (19 g) are added to the resulting mixture. The mixture is stirred vigorously at 100 °C for 48 hours. After cooling down to 25 °C, toluene (100 ml) and then water (200 ml) are added to the stirred mixture. The organic layer is separated; the aqueous one is shaken up with toluene (50 ml). The combined organic fractions are shaken up with water (2x 50 ml) and evaporated. The crude product is dissolved in acetone (20 ml) and oxalic acid (14 g) in acetone (100 ml) is added dropwise to the solution. The precipitated salt is sucked off and washed with acetone. The crude product is re-crystallized from methanol. The yield was 22 g (56 %) of iV-benzyl-iV- methyl-3-(2-methylphenoxy)-3-phenylpropaneamine oxalate. ¹H NMR (250 MHz, DMSO): 2.20 (3H, s), 2.42 (2H, m), 2.64 (3H, s), 3.22 (2H, m), 4.31 (2H, s), 5.51 (IH, m), 6.65-7.55 (14H, m), 10.06 (2H, br s).

Example 6 (i?)-N-Benzyl-7V-methyl-3-(2-methylρhenoxy)-3-phenylpropaneamine-(5)-mandelate N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine VIII (345 g), prepared according to Example 4, is dissolved in toluene (100 ml) under reflux and a solution of (S)- (+)-mandelic acid (76 g) in toluene (400 ml) is added. The solution is then evaporated. The evaporation residue is dissolved in tBuOMe (1,200 ml) under boiling, inoculated, and stirred at 45 ⁰C for 20 hours. Precipitated crystals are sucked off and re-crystallized from tBuOMe in a similar way. The yield was 131 g of (i?)-iV-benzyl-N-methyl-3-(2-methylphenoxy)-3- ρhenylpropaneamine-(6)-mandelate (31%). Optical purity was 99.5 % ee (CE). ¹H NMR (250 MHz, DMSO): 2.08 (2H, m), 2.13 (3H, s), 2.21 (3H, s), 2.60 (2H, m), 3.55 (2H, br s), 4.96 (IH, s), 5.38 (IH, m), 6.65-7.45 (19H, m).

Example 7

(i?)-N-Benzyl-iV-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine-(5)-mandelate N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine VIII (345 g) is dissolved in 2-propanol (100 ml) under reflux and a solution of (S)-(+)-mandelic acid (76 g) in 2-propanol (300 ml) is added. The solution is cooled down to 20 °C over 16 hours. The yield was 101 g of (i?)-N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamme-(<S)-mandelate (24 %). Optical purity was 94 % ee (CE).

Example 8 iV-Benzyl-N-methyl-3-(o-tolyloxy)-3-phenylpropanamine (VIII) Ground KOH (0.045 g) is added to a solution of (_IS)-N-benzyl-N-methyl-3-(2-methylphenoxy)- 3-phenylpropaneamine (S)-VIII (1.38 g) in DMSO (6 ml) and the mixture is stirred under heating at 100 °C for 1 hour. After cooling down to the room temperature, the mixture is diluted with water (10 ml) and the racemic product is extracted with toluene (10 ml). Evaporation after drying yielded 1.16 g (84 %) of (i?£)-N-benzyl-N-methyl-3-(2- methylphenoxy)-3-phenylpropane amine (VIII). Optical purity was 0 % ee (CE).

Example 9 iV-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropane amine (VIII) t-BuOK (0.3 g) is added to a solution of (£)-N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropane amine (S)-VIII (4.14 g) in DMSO (15 ml) and the mixture is stirred under heating at 90 °C for 1.5 hours. After cooling down to the room temperature, the mixture is diluted with water (30 ml) and the racemic product is extracted with toluene (30 ml). Evaporation of the solution yielded 3.25 g (78 %) of (i?6)-7V-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylpropane amine VIII. Optical purity was 0 % ee (CE).

Example 10

(i?)-iV-Methyl-3-(2-methylphenoxy)-3-phenylpropaneamine hydrochloride (R)-I (i?)-N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropaneamine-(iS)-mandelate (20 g), prepared according to Example 6, is stirred up in 2M NaOH (40 ml) and toluene (110 ml) and the mixture is stirred at he room temperature for 30 minutes. The phases are then separated; the aqueous one is extracted with 25 ml of toluene. The combined organic fractions are washed with water (100 ml) and dried with Na₂SO₄. The desiccant is filtered off. Phenylchloro formate (6 ml) is added dropwise to the solution at 80 °C over 10 minutes. The solution is then stirred at 80 °C for 30 min. After cooling down to 50 °C, methanol (6 ml) is added dropwise. After cooling down to the room temperature, the solution of alkyl/aryl (R)-3- (2-methylphenoxy)-3-phenylpropylmethyl carbamate (R)-IX is evaporated. Crude alkyl/aryl (R)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate (R)-IX is dissolved in DMSO (85 ml) and 5M KOH (50 ml) is added dropwise at 50 °C over 10 minutes. The solution is then heated at 100 °C for 30 minutes. After cooling down to the room temperature, toluene (100 ml) and water (100 ml) are added. The organic layer is separated and the aqueous one is shaken up with toluene (50 ml). The combined organic fractions are shaken up with water and evaporated. The crude base of the product is dissolved in 5 ml of tert-butylmethylether, atomoxetine seeds are added and aqueous coned. HCl (3 ml) is added dropwise at 0 ⁰C. Precipitated crystals are sucked off and then re-crystallized from ethylmethylketone. The yield was 7.4 g (63 %) of (/?)-(-)-atomoxetine hydrochloride, optical purity 99.8 % ee (CE), chemical purity 99.7 % (HPLC). The XRPD diffraction pattern of the crystalline form of atomoxetine hydrochloride is presented in Fig. 1, the recording from DSC analysis is in Fig. 2.

Survey of the employed analytical methods

X-Ray powder diffraction TXRPDI

Diffraction pattern was obtained using the X'PERT PRO MPD PANalytical diffractometer under the following experimental conditions: Radiation: CuKa (λ=1.5402 A) Monochromator: graphite

Excitation voltage: 45 kV

Anodic current: 40 mA

Measured range: 4 - 40° 2Θ

Step size: 0.008° 29

Flat sample with area/thickness 10/0.5 mm

The XRPD diffraction pattern of crystalline form of atomoxetine hydrochloride prepared according to Example 10 is presented in Figure 1; the values of characteristic diffraction angles are presented in Table 1.

Table 1: Values of diffraction angles 2Θ, interplanar distances d and relative intensities of characteristic peaks of crystalline form of atomoxetine hydrochloride.

Differential scanning calorimetry CDSC)

A record from DSC analysis of crystalline product of formula (R)-I prepared according to Example 10 is presented in the annex, Fig. 2. Analysis was performed at the heating rate 10 °C/min (within the range of from 50 to 300 ⁰C).

Capillary electrophoresis (^"CE^*)

Optical purity of (i?)-(-)-atomoxetine and of the racemate and individual (R) and (S) enantiomers ofN-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropanamine was determined using capillary electrophoresis .

Nuclear magnetic resonance (NMIO

¹H NMR analysis in liquid phase was performed using the Bruker 250 DPX device. DMSOd₆ was used as the solvent. The chemical shifts of recorded signals of hydrogens for the compound of formula VIII, for N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropaneamine oxalate and (i?)-N-benzyl-iV-methyl-3-(2-methylphenoxy)-3- phenylpropaneamine -(iS)-mandelate are presented in respective examples in the Examples section.

Claims

C L A I M S

1. A method for the preparation of (i?)-N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine hydrochloride of formula (R)-I

characterized in that

a) iV-benzyl-iV-methyl-S-chloro-S-phenylpropaneamine hydrochloride of formula VII

wherein X represents the leaving group halogen or R₈SO₃, wherein R_a stands for a C₁- C₅ aliphatic saturated hydrocarbon residue or a C₆-C₁₂ aromatic or alkylaromatic hydrocarbon residue, is reacted with o-cresol, or

N-benzyl-7V-methyl-3-hydroxy-3-phenylpropanamine of formula VI

is reacted with 2-fluorotoluene producing N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula VIII

b) iV-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula VIII is reacted with an optically active acid selected from the group including tartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid and their sodium, potassium and lithium salts, mandelic acid and camphorsulfonic acid, .

c) the mixture of diastereoisomers is resolved by crystallization from a solution of an organic solvent and the individual diastereoisomers are converted to the respective (R) and (S) enantiomers of iV-benzyl-iV-methyl-3-(2-methylphenoxy)-3-phenylpropylamine by treatment with an organic or inorganic base,

d) (i?)-N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula (R)- VIII

(W-VIII)

is debenzylated by reaction with alkyl or aryl chloroformate of formula ClCOOR, wherein R is selected from the group including C₁-C₅ alkyls and C₆-Ci₂ aryls or alkylaryls,

e) the resulting alkyl/aryl (i?)-3-(2-methylphenoxy)-3-phenylpropylmethyl carbamate of formula (R)-IX

is reacted with an alkali metal hydroxide producing the atomoxetine base, which is subsequently converted to (i?)-N-methyl-3-(2-methylphenoxy)-3-ρhenylρropaneamine hydrochloride of formula (R)-I by treatment with hydrochloric acid,

f) the resulting (i?)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride of formula (R)-I is crystallized from an organic solvent.

2. The method according to claim 1, characterized in that in step (a) the compound of formula VI

is used, which is prepared by reduction of the aminoketone of formula V

3. The method according to claim 1, characterized in that in step (a)

the compound of formula VII is used, which is prepared by reduction of the aminoketone of formula V and subsequent conversion of the -OH group to X = halogen or RaSO₃, wherein R_a is as defined above, by treatment with halogenating or sulfonating agent.

4. The method according to claims 2 or 3, characterized in using the compound of formula V prepared by reaction of acetophenone with a molar excess of formaldehyde and N-methylbenzylamine in the environment of a solvent or mixture of solvents selected from the group including water and Ci-C₄ alcohols in the presence of hydrochloric acid or sulfuric acid.

5. The method according to claim 4, characterized in that formaldehyde and N- methylbenzylamine are contained in a 30% excess with respect to acetophenone in the reaction mixture, that 2-propanol is used as the solvent and HCl as the acid and the reaction runs under reflux for several hours, optimally at least 4 hours.

6. The method according to claim 1, characterized in that mandelic acid is used as the optically active acid in step (b) and resolving of the mixture of diastereoisomers in step (c) is performed via crystallization of the salt of (i?)-N-benzyl-N-methyl-3-(2- methylphenoxy)-3-phenylpropaneamine-(5)-mandelate from a solution of an organic solvent selected from the group including alcohols, ethers and esters.

7. The method according to claim 6, characterized in that tert-butylmethylether is used as the organic solvent.

8. The method according to claim 1, characterized in that (iS)-iV-benzyl-N-methyl-3-(2- methylphenoxy)-3-phenylpropaneamine of formula (S)-VIII is subsequently converted to the racemic mixture by treatment with an organic or inorganic base.

9. The method according to claim 8, characterized in that (iS)-N-benzyl-iV-methyl-3-(2- methylphenoxy)-3-phenylpropaneamine of formula (S)-VIII is converted to the racemic mixture by treatment with an organic base from the group OfC₁-C₄ alkali metal alcoholates.

10. The method according to claim 9, characterized in that potassium tert-butanolate is used as the base.

11. The method according to claim 8, characterized in that (5)-iV-benzyl-7V-methyl-3-(2- methylphenoxy)-3-phenylpropaneamine of formula (S)-VIII is converted to the racemic mixture by treatment with an inorganic base from the group including alkali metal hydroxides.

12. The method according to claims 8 to 11, characterized in that (jS)-N-benzyl-7V-methyl- 3-(2-methylphenoxy)-3-phenylpropaneamine of formula (S)-VIII is converted to the racemic mixture by treatment with a base in the environment of an organic solvent, optionally in the presence of a phase transfer catalyst selected from crown ethers, polyethyleneglycols and quaternary ammonium and phosphonium salts.

13. The method according to the claim 12, characterized in that dimethylsulfoxide is used as the organic solvent.

14. N-Benzyl-N-methyl-3-(2-methylplienoxy)-3-phenylpropylamine including its (R) and (S) enantiomers.

15. Salts of (i?)-N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine of formula (R)-VIII with an optically active acid selected from the group including tartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid and their sodium, potassium and lithium salts, mandelic acid and camphorsulfonic acid.

16. (i?)-N-Benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylpropanamme-(5)-mandelate.

17. The method according to claim 1, characterized in that phenylchloro formate is used for debenzylation in step (d).

18. The method according to claim 1, characterized in that ethylmethylketone is used for crystallization of (i?)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride of formula (R)-I in step (f).