Method for producing substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives

Abstract

This invention relates to a novel method for producing substituted 2-[2-(phenyl)ethylamino]alkanoamide derivatives of formula (I), particularly 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide, with high yield and extremely high chemical purity. This invention also relates to a method for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof:

Description

[0001] The present invention relates to a novel process for producing substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives, in particular 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide, in high yield and very high chemical purity. Background of the Invention

[0003] The substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives disclosed in WO 2008 / 151702 are sodium and / or calcium channel modulators and can therefore be used to prevent, alleviate and treat a variety of conditions in which the mechanisms described play a pathological role, such as neurological diseases, cognitive diseases, psychiatric diseases, inflammatory diseases, urogenital and gastrointestinal diseases. It is also described that these compounds have essentially no monoamine oxidase (MAO) inhibitory effect.

[0004] WO 2013 / 000651 discloses a new class of fluorinated arylalkylaminocarboxamide derivatives that are highly effective as sodium and / or calcium channel modulators.

[0005] WO 2008 / 151702 discloses in the examples the synthesis of 2-[2-(3-butoxyphenyl)ethylamino]-N,N-dimethylacetamide hydrochloride as outlined in the following Scheme 1:

[0006]

[0007] Process 1

[0008] The disclosed method has a number of disadvantages that prevent it from being scaled up to industrial level:

[0009] Starting materials that are not commercially available, such as 3-methoxyphenylethylamine, whose preparation from commercially available reagents involves several steps;

[0010] The intermediate is an oil, so purification is difficult;

[0011] Use of large excesses of toxic reagents, such as 1-bromobutane and 2-chloro-N,N-dimethylacetamide, which may be genotoxic;

[0012] Use of non-standard equipment (NaH / DMF is a potentially explosive compound because H2 is produced during the reaction);

[0013] The conditions for producing the final hydrochloride salt are impractical and potentially very hazardous due to the use of ether solvents, which readily form peroxides in the presence of air;

[0014] Low overall yield (about 13%);

[0015] The purity of the final product is unknown. Summary of the invention

[0016] The present invention relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0017]

[0018] Where R is (C3-C 10 )alkyl or ω-trifluoro(C3-C 10 )alkyl;

[0019] R1 and R2 are independently hydrogen, hydroxy, (C1-C8) alkoxy, (C1-C8) alkylthio, halogen, trifluoromethyl or 2,2,2-trifluoroethyl; or one of R1 and R2 is in the ortho position of the RO- group and together with the same RO- represents A group wherein R0 is a (C2-C9)alkyl group;

[0020] R3 and R4 are independently hydrogen or (C1-C6) alkyl; or together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocyclic ring, which optionally contains an additional heteroatom selected from -O-, -S- and -NR7-, wherein R7 is hydrogen or (C1-C6) alkyl;

[0021] R5 is hydrogen or (C1-C6) alkyl;

[0022] and wherein optionally, one or more hydrogen atoms in the groups R, R1, R2, R3, R4 and R5, preferably in the R groups, may be replaced by deuterium atoms;

[0023] The method comprises the following steps:

[0024] i) making a compound of formula (II) or a salt thereof

[0025]

[0026] Wherein R, R1, R2 are as defined above, and react with the compound of formula (III) under reducing conditions:

[0027]

[0028] wherein R3, R4 and R5 are as defined above, thereby obtaining a compound of formula (I) as defined above, and

[0029] ii) optionally salifying the obtained compound of formula (I).

[0030] Preferably, the compound of formula (II) is in the form of a salt with an acid selected from the group consisting of hydrochloric acid, benzenesulfonic acid, hydrobromic acid, camphorsulfonic acid, methanesulfonic acid, ethanesulfonic acid, fumaric acid, lactic acid, maleic acid, mandelic acid, sulfuric acid, tartaric acid, succinic acid, p-toluenesulfonic acid and 2-naphthalenesulfonic acid.

[0031] A preferred method of the present invention is the aforementioned method for obtaining the compound of formula (I'):

[0032]

[0033] wherein R, R1, R2, R3, R4 and R5 are as defined above, and

[0034] The compound of formula (II) has the following formula (II'):

[0035]

[0036] In a particular embodiment, the present invention relates to the hydrochloride salt of a substituted arylethylamino compound, wherein the compound has formula (I) or (I').

[0037] A preferred method of the present invention is the aforementioned method for obtaining a compound of formula (I) or (I'), wherein:

[0038] R is (C4-C6)alkyl or CD3-CD2-(C3-C4)alkyl;

[0039] R1 and R2 are independently hydrogen or halogen, preferably fluorine;

[0040] R3 and R4 are independently hydrogen or (C1-C3) alkyl;

[0041] R5 is hydrogen or (C1-C3) alkyl.

[0042] A most preferred process of the present invention is the aforementioned process for obtaining compounds of formula (I) or (I') as defined above, wherein R is n-butyl or CD3-CD2-CH2-CH2- and R1, R2, R3, R4 and R5 are hydrogen.

[0043] Step i) can be carried out under catalytic hydrogenation conditions by using a heterogeneous catalyst selected from a catalyst comprising at least one metal selected from Pd, Pt, Ir, Ni and Ru on an inert support, such as a palladium or platinum catalyst in a solvent at a pH of 9.0 to 10.5.

[0044] The solvent is selected from water, alcohol and ether.

[0045] Preferably, the catalyst is 5% Pt / C (50% H2O) wet or 10% Pd / C (50% H2O) wet, preferably 10% Pd / C (50% H2O) wet.

[0046] The process is carried out under a hydrogen pressure between 1 and 4 atmospheres, preferably between 2.5 and 3.5 atmospheres, at a temperature between 0°C and 10°C, preferably between 0°C and 5°C.

[0047] Step ii) (salt formation) can be carried out by reacting a compound of formula (I) or (I') with an acid in a suitable solvent. Preferably, the acid is selected from hydrochloric acid, benzenesulfonic acid, hydrobromic acid, camphorsulfonic acid, methanesulfonic acid, ethanesulfonic acid, fumaric acid, lactic acid, maleic acid, mandelic acid, sulfuric acid, tartaric acid, succinic acid, p-toluenesulfonic acid and 2-naphthalenesulfonic acid.

[0048] Most preferably, the acid is hydrochloric acid.

[0049] Suitable solvents may be methanol, ethanol, isopropanol, acetone, methyl ethyl ketone and methyl isobutyl ketone, preferably methyl isobutyl ketone.

[0050] The compound of formula (III) can be obtained in situ by hydrolysis of the compound of formula (VII):

[0051]

[0052] wherein R3, R4 and R5 are as defined above and R6 is (C1-C4)alkyl, preferably methyl, ethyl, isopropyl.

[0053] The hydrolysis reaction is preferably carried out in water in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid at a temperature ranging from 25°C to 70°C.

[0054] The compound of formula (II) (wherein R, R1 and R2 are as defined above) can be obtained by a process comprising the following steps:

[0055] i') reacting a compound of formula (IV) with MCN:

[0056]

[0057] wherein R, R1, R2 are as defined above, and M is an alkali metal selected from Li, Na and K, to obtain a compound of formula (V):

[0058]

[0059] wherein R, R1 and R2 are as defined above, and

[0060] ii') reducing the obtained compound of formula (V) to obtain the compound of formula (II) as defined above, and

[0061] iii') optionally salifying the obtained compound of formula (II).

[0062] The salt of the compound of formula (II) can be isolated by crystallization or used directly in step i) above.

[0063] Step i') is preferably carried out in a two-phase system consisting of water and an organic solvent in the presence of an acid at a temperature ranging from 0°C to 10°C, preferably from 0°C to 5°C.

[0064] The organic solvent is selected from tert-butyl methyl ether, 2-methyltetrahydrofuran, and toluene, and the acid is selected from hydrochloric acid, sulfuric acid, and phosphoric acid.

[0065] The reduction step ii') is preferably catalytic hydrogenation, which is preferably carried out by using a heterogeneous catalyst selected from nickel, rhodium, platinum and palladium catalysts on an inert support in a solvent selected from lower aliphatic (C1-C5) alkanols such as methanol, ethanol and isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, toluene and heptane in the presence of an acid such as hydrochloric acid, sulfuric acid and phosphoric acid. In the present invention, the reduction in methanol catalyzed by sulfuric acid is preferred.

[0066] The heterogeneous catalyst is preferably a palladium or platinum catalyst, such as wet 5% Pt / C (50% H2O) or wet 10% Pd / C (50% H2O), most preferably wet 10% Pd / C (50% H2O).

[0067] Step ii') is preferably carried out at a hydrogen pressure between 0.5 and 4 atmospheres, preferably between 2.5 and 3.5 atmospheres, at a temperature between 30°C and 90°C, preferably between 40°C and 80°C.

[0068] The compound of formula (IV) as defined above can be obtained by alkylating a compound of formula (VI) with a compound of formula RX:

[0069]

[0070] wherein R1 and R2 are as defined above, wherein R is as defined above and X is Cl, Br, I or a leaving group selected from mesylate, tosylate and bromobenzenesulfonate.

[0071] The alkylation reaction is preferably carried out in an aprotic polar solvent such as acetonitrile, DMF, DMAC, DMSO, an acetate such as ethyl acetate, isopropyl acetate and n-butyl acetate, in the presence of an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, at a temperature ranging from 15° C. to 120° C. Among various combinations of solvent, base and temperature, DMF, potassium carbonate and 110-120° C. are preferred. In another preferred alkylation method, the reaction is carried out in a two-phase system consisting of an organic solvent and an aqueous phase in the presence of a buffer and a phase transfer catalyst.

[0072] The process according to the invention can be scaled up at an industrial level without risk concerns. The overall molar yield is as high as 51%. The crystalline intermediate compound of formula (II) in the form of a hydrochloride salt allows recrystallization (if necessary), thereby ensuring the use of high-quality intermediates to produce API.

[0073] The method involves commercially available materials.

[0074] Experimental Section

[0075] Synthesis of 2-[2-(3-Butoxyphenyl)-ethylamino]-N,N-dimethylacetamide

[0076] 2-[2-(3-Butoxyphenyl)-ethylamino]-N,N-dimethylacetamide was synthesized as reported in Scheme 2 below:

[0077]

[0078] Process 2

[0079] Example 1

[0080] Synthesis of 3-Butoxybenzaldehyde

[0081]

[0082] A mixture containing 3-hydroxybenzaldehyde 3.95 kg (32.34 mol), 1-chlorobutane 4.49 kg (48.52 mol) and potassium carbonate 6.26 kg (45.28 mol) in N,N-dimethylformamide 19.75 L was heated to 115-118° C. and maintained at this temperature until the reaction was complete (3-hydroxybenzaldehyde about 0.1% area %). The reaction mixture was cooled to about 20° C. A mixture of tert-butyl methyl ether 32.4 L and water 52.9 L was added to the slurry and stirred for 15 minutes. The two phase mixture was separated. The organic solution was washed with aqueous sodium chloride solution. The batch was concentrated under reduced pressure at <50° C. to give 5.57 kg of 3-butoxybenzaldehyde as an oily product in 96.6% molar yield.

[0083] Example 2

[0084] Synthesis of 3-Butoxybenzaldehyde

[0085]

[0086] A solution containing 25 kg (204.7 mol) of 3-hydroxybenzaldehyde, 39.5 kg (285.8 mol) of potassium carbonate and 28.5 kg (307.8 mol) of 1-chlorobutane in 120 kg of N,N-dimethylformamide was heated to 115°C and maintained at this temperature until the reaction was complete (3-hydroxybenzaldehyde was less than 1%). The mixture was cooled, diluted with 325 kg of water and then concentrated in vacuo to about 325 L. The batch was diluted with 126 kg of water and 150 kg of methyl tert-butyl ether was added at about 20°C. The aqueous layer was discarded and the batch was washed first with dilute sodium chloride solution and then with water. The batch was concentrated in vacuo and the residual methyl tert-butyl ether was replaced with tetrahydrofuran by a series of dilutions and vacuum concentrations. 33.5 kg (188.0 mol) of 3-butoxybenzaldehyde (91% molar yield, purity 99.7%) was obtained.

[0087] MS (M+1:179.1); 1 H NMR was consistent with the given structure.

[0088] Example 3

[0089] Synthesis of α-Hydroxy-3-Butoxyphenylacetonitrile

[0090]

[0091] 4.34 kg (38.11 mol) of 32% HCl was added to a two-phase mixture consisting of a solution of 1.79 kg (36.53 mol) of sodium cyanide in 4.18 L of water and a solution of 5.43 kg (36.59 mol) of 3-butoxybenzaldehyde in 7.94 L of tert-butyl methyl ether (TBME) under stirring at 0-5°C over 6 hours. The mixture was maintained at 0-5°C until the reaction was complete ( 1 H-NMR showed residual 3-butoxybenzaldehyde (2-3 wt%). The mixture was heated to 18-25° C. and then diluted with tert-butyl methyl ether (11.5 L). The two phases were separated.

[0092] The organic solution was first washed with water and then with a saturated sodium chloride aqueous solution. The organic solution was added to a solution of 0.027 kg of oxalic acid in 11.7 L of methanol. The solvent was replaced with methanol by a cycle of diluting (with methanol) several times and concentrating the mixture under reduced pressure at <50°C to obtain 6.16 kg (24.31 mol) of oily α-hydroxy-3-butoxybenzeneacetonitrile in a 97% molar yield.

[0093] Example 4

[0094] Synthesis of 3-Butoxyphenylethylamine Hydrochloride

[0095]

[0096] A mixture containing 6.12 kg (29.82 mol) of α-hydroxy-3-butoxybenzeneacetonitrile, 0.31 kg of 10% Pd / C (Evonik E196 NN / W type; ~50% water wetness) and 3.73 kg of 96% sulfuric acid in 51.5 L of methanol was stirred at 0-5° C. under 0.5 bar of hydrogen. The reaction mixture was then stirred at 40° C. under 2 bar of hydrogen and then at 80° C. under 3 bar of hydrogen. The mixture was cooled to 20-25° C., purged with N2 and diluted with 22.5 L of water, the catalyst was removed by filtration and washed with water. The combined filtrates were concentrated at atmospheric pressure until the solution temperature reached about 90° C. (final volume ~31 L). The solution was extracted with a mixture of 6.12 L of isopropyl acetate and 6.12 L of heptane. The aqueous layer was diluted with 43 L of isopropyl acetate. 1.22 kg of Hyflo was added. The pH of the aqueous solution was adjusted to pH 12-13 with about 3.64 kg of 50% sodium hydroxide solution. The mixture was filtered through a cellulose filter pad and subsequently washed with isopropyl acetate. The combined filtrate (consisting of two phases) was separated and the aqueous layer was discarded. The organic phase was washed with 3.4 L of 25% aqueous ammonium chloride solution and brine in sequence. The batch was azeotropically dried under reduced pressure at a maximum of 50°C, filtered through a cellulose filter pad and the filter pad was washed with 6.12 L of isopropyl acetate, and then the solution was concentrated to about 31 L at <50°C. 7.85 kg of 5-6M hydrochloric acid in isopropanol was added. The suspension was filtered at 0-5°C and rinsed with cold isopropyl acetate (6.1 L). The wet product was dried in vacuo at 40°C to give 4.5 kg of 3-butoxyphenethylamine hydrochloride in a yield of 65.5%. Its spectral data (LC / MS, 1 H NMR) was consistent with the assigned structure of 3-butoxyphenethylamine hydrochloride.

[0097] LC / MS: [M-HCl+H] + =194.2

[0098] 1 H NMR (400MHz, DMSO-d6); δ8.17(s,3H),7.24-7.20(m,1H),6.83-6.79(m,3H),3.97-3.94(t,2H), 3.04-2.99(m,2H),2.89-2.85(m,2H),1.72-1.65(m,2H),1.48-1.39(m,2H),0.95-0.92(t,3H).

[0099] As described above, 4.42 kg (19.24 mol) of 3-butoxyphenethylamine hydrochloride was further recrystallized with 13.3 L of isopropanol to obtain 3.99 kg of high-purity 3-butoxyphenethylamine hydrochloride with a yield of 90.3%.

[0100] Example 5

[0101] Synthesis of 2-[2-(3-Butoxyphenyl)-ethylamino]-N,N-dimethylacetamide

[0102]

[0103] A solution of 2.93 kg of 32% aqueous hydrochloric acid in 23.16 kg of water was heated to 57°C; 2,2-diethoxy-N,N-dimethylacetamide (DEDMA; 5.12 kg (29.23 mol)) was added to the acidic solution over two minutes, which was then maintained at 58-61°C for 60 minutes with stirring (DEMDA 5.6% area %). The mixture was cooled to about 20°C, 20% aqueous sodium hydroxide solution (about 5.48 kg) was added until pH 8.8, and then concentrated in vacuo at <45°C to a residual volume of about 29 L.

[0104] The above solution was added to solid 3-butoxyphenethylamine hydrochloride 3.95 kg (17.19 mol) and the pH was adjusted to pH 9.9 with 20% aqueous sodium hydroxide solution (about 4.19 kg) at 19-20° C. Wet (1:1=water:Pd / C) 5% Pd / C 0.18 kg was added to the mixture under stirring and then hydrogenated with H2 (3 bar) at 0-5° C. until the reaction was complete (3-butoxyphenethylamine hydrochloride <0.2% area). The mixture was diluted with water (about 10 L) and neutralized with aqueous hydrochloric acid. The batch was filtered at 5-10° C., tert-butyl methyl ether 20.5 L was added under stirring and the phases were separated. The aqueous layer was diluted with methyl isobutyl ketone 22.1 kg and the pH was adjusted to pH 9.8 with 50% aqueous sodium hydroxide solution (about 2.0 kg). The phases were separated and the aqueous phase was extracted with methyl isobutyl ketone 11.0 kg. 8.18 kg of saturated aqueous sodium chloride solution was added to the combined organic phases and the mixture was stirred for 5 minutes. 3.20 kg of water was added and the phases were separated.

[0105] Example 6

[0106] Synthesis of 2-[2-(3-Butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0107]

[0108] A solution of 5.4 Kg of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base in 35 L of methyl isobutyl ketone solution was added to 2.03 kg of 37% hydrochloric acid. The mixture was azeotropically dried to a residual volume of about 27 L by repeating a cycle of dilution with methyl isobutyl ketone and then vacuum concentration at <45°C. The precipitated solid was filtered and washed with 10.95 kg of methyl isobutyl ketone and 18.70 kg of heptane in sequence. The wet product was dried at 40°C to obtain 4.91 kg of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride as a white solid with a yield of 90.7%. The spectral data of the solid ( 1 H NMR) was consistent with the assigned structure of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. The entity of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride was confirmed by elemental analysis (theoretical value relative to found value: C 61.04% relative to 61.3±0.2wt%; H 8.64% relative to 8.7±0.1wt%; N 8.90% relative to 8.9±0.1wt%; O 10.16% relative to 10.17±0.1wt%; Cl 11.26% relative to 10.2±0.5wt%) (MS (M+1: 279.0), and 300MHz 1 H NMR spectrum (DMSO, Bruker Avance 300, 20°C):

[0109]

[0110]

[0111] Bruker Avance 300 13 C-NMR spectrum, DMSO, 20 °C

[0112]

[0113]

[0114]

[0115] Example 7

[0116] Synthesis of 2-[2-(3-Butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0117] 8.10 g (1 equivalent) of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base was dissolved in 15 mL of diethyl ether. To the solution was added HCl (2 mmol) in 46 mL of ether solvent and stirred vigorously. The formed residue was scraped off at 0°C to produce a white precipitate of crude 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. The precipitate was further purified by trituration in ethyl acetate (40 mL) to give 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride (6.66 g, 72% yield).

[0118] Example 8

[0119] Synthesis of 2-[2-(3-Butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0120]

[0121] 8.25 g (1 equivalent) of 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide free base was dissolved in 15 mL of diethyl ether. To the solution was added HCl (2 mmol) in 46 mL of ether solvent and stirred vigorously. The sticky residue formed was scraped off at 0°C to produce a white precipitate of crude 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. The precipitate was further purified by trituration in 40 mL of ethyl acetate. The resulting precipitate was filtered and dried under nitrogen to give pure 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride (6.77 g, 72% yield).

[0122] 1 H NMR-spectra reported on Figure 1 middle;

[0123] LC-MS:

[0124] m / z Abundance 283.30 4.5 284.30 100.0 285.30 12.7 286.30 1.8 305.80 0.5 306.25 7.1 307.25 0.8

[0125] 2-[2-(3-Butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide free base can be obtained according to the methods described in Examples 2, 3, 4 and 5 starting from 3-hydroxybenzaldehyde and replacing 1-chlorobutane with butane-1,1,1,2,2-d5-4-chloro.

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof: Where R is C3-C 10 Alkyl or ω-trifluoro C3-C 10 alkyl; R1 and R2 are independently hydrogen, hydroxy, C1-C8 alkoxy, C1-C8 alkylthio, halogen, trifluoromethyl or 2,2,2-trifluoroethyl; R3 and R4 are independently hydrogen or C1-C6 alkyl; or R3 and R4 together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocyclic ring, which optionally contains an additional heteroatom selected from -O-, -S- and -NR7-, wherein R7 is hydrogen or C1-C6 alkyl; R5 is hydrogen or C1-C6 alkyl; and wherein optionally, one or more hydrogen atoms in the groups R, R1, R2, R3, R4 and R5 may be replaced by deuterium atoms; The method comprises the following steps: i) making a compound of formula (II) or a salt thereof Wherein R, R1, R2 are as defined above, and react with the compound of formula (III) under catalytic hydrogenation conditions: wherein R3, R4 and R5 are as defined above, thereby obtaining a compound of formula (I) as defined above, wherein the catalytic hydrogenation is carried out using a catalyst comprising at least one metal selected from Pd, Pt, Ir, Ni and Ru on an inert support, and ii) optionally salifying the obtained compound of formula (I); The compound of formula (II) is obtained by a method comprising the following steps: i') reacting a compound of formula (IV) with MCN: wherein R, R1, R2 are as defined above, and M is an alkali metal selected from Li, Na and K, to obtain a compound of formula (V): wherein R, R1 and R2 are as defined above, and ii') reducing the obtained compound of formula (V) by catalytic hydrogenation under a hydrogen pressure of 0.5 to 4 Atm to obtain a compound of formula (II) as defined above, and iii') optionally salifying the obtained compound of formula (II).

2. The method according to claim 1, wherein optionally, one or more hydrogen atoms in the group R can be replaced by a deuterium atom.

3. The method according to claim 1, which is used to obtain a compound of formula (I'): wherein R, R1, R2, R3, R4 and R5 are as defined in claim 1, and The compound of formula (II) has the following formula (II'):

4. A process according to claim 1 for obtaining a compound of formula (I) or a compound (I') as defined in claim 3, wherein R is n-butyl or CD3-CD2-CH2-CH2- and R1, R2, R3, R4 and R5 are hydrogen.

5. The method according to claim 1, which is used to obtain 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide.

6. The method according to claim 1, wherein: The compound of formula (II) is in the form of a salt with an acid selected from the group consisting of hydrochloric acid, benzenesulfonic acid, hydrobromic acid, camphorsulfonic acid, methanesulfonic acid, ethanesulfonic acid, fumaric acid, lactic acid, maleic acid, mandelic acid, sulfuric acid, tartaric acid, succinic acid, p-toluenesulfonic acid and 2-naphthalenesulfonic acid.

7. The method according to claim 1, wherein: Catalytic hydrogenation was performed where the catalyst was 5% Pt / C wet in 50% H2O or 10% Pd / C wet in 50% H2O.

8. The method according to claim 1, wherein: The compound of formula (III) is obtained in situ by hydrolyzing a compound of formula (VII): wherein R3, R4 and R5 are as defined in claim 1 and R6 is C1-C4 alkyl.

9. The method according to claim 8, wherein R6 is methyl, ethyl or isopropyl.

10. The method according to claim 1, wherein: The salt of the compound of formula (II) can be isolated by crystallization or used directly in step i) as defined in claim 1 .

11. The method according to claim 1, wherein: Step i') is carried out in a two-phase system consisting of water and an organic solvent in the presence of an acid at a temperature ranging from 0°C to 10°C.

12. The method according to claim 11, wherein: Step i') is carried out at a temperature ranging from 0°C to 5°C.

13. The method according to claim 1, wherein: The reduction step ii') is a catalytic hydrogenation which is carried out by using a heterogeneous catalyst selected from nickel, rhodium, platinum and palladium catalysts on an inert support.

14. The method according to claim 13, wherein: The heterogeneous catalyst was either 5% Pt / C wet in 50% H2O or 10% Pd / C wet in 50% H2O.

15. The method according to claim 1, wherein: The compound of formula (IV) as defined in claim 1 is obtained by alkylating a compound of formula (VI) with a compound of formula RX: wherein R1 and R2 are as defined in claim 1, R is as defined in claim 1 and X is Cl, Br, I or a leaving group selected from mesylate, tosylate and bromobenzenesulfonate.

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