Method for preparing substituted 2-[2-(phenyl)ethylamino]alkanamide derivatives

Abstract

The present invention relates to a compound represented by the following formula (I): TIFF2022529916000036.tif42161 The present invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is an integer from 1 to 3;

Description

[Technical field]

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

[0002] The substituted 2-[2-(phenyl)ethylamino]alkanamide derivatives disclosed in WO 2008 / 151702 are sodium and / or calcium channel modulators and are therefore useful for preventing, alleviating and treating a wide range of pathologies in which said mechanisms play a pathological role, such as neurological, cognitive, psychiatric, inflammatory, genitourinary and gastrointestinal disorders. It is also disclosed that these compounds are substantially free of monoamine oxidase (MAO) inhibitory activity.

[0003] A novel class of fluorinated arylalkylaminocarboxamide derivatives with high potency as sodium and / or calcium channel modulators are disclosed in WO 2013 / 000651.

[0004] WO 2008 / 151702 describes the following scheme: [ka] As summarized in the Examples, the synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride is disclosed in the Examples.

[0005] The disclosed process has a number of drawbacks that make it impossible to scale up at an industrial level: · Commercially unavailable starting materials, such as 3-methoxyphenylethyl amine, whose preparation is carried out in two steps from commercially available reagents; · Difficult purification due to intermediates being oily; Use of large excesses of toxic reagents such as 1-bromobutane and 2-chloro-N,N-dimethylacetamide, which are potentially genotoxic; Use of non-standard equipment (NAH / DMF is a potentially explosive compound due to the generation of H2 during the reaction); Impractical and potentially very hazardous manufacturing conditions for the final hydrochloride salt due to the use of ethereal solvents that readily generate peroxides in the presence of air; · Low overall yield (about 13%); · Unknown final product purity. bear the burden.

[0006] Description of the invention The present invention relates to a compound of formula (I): [ka] (Wherein, 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, halo, trifluoromethyl, or 2,2,2-trifluoroethyl; or one of R1 and R2 is ortho to the RO- group and together with the RO-, R0 is (C2-C9)alkyl; [ka] Represents the group; R3 and R4 are independently hydrogen or (C1-C6) alkyl; or together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocycle, optionally containing one additional heteroatom selected from -O-, -S-, and -NR7- (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, preferably in the R group, can be replaced by a deuterium atom, or a pharma- ceutically acceptable salt thereof; i) Formula (II): [ka] (wherein R, R1, and R2 are as defined above) or a salt thereof, [ka] (wherein R3, R4 and R5 are as defined above). under reducing conditions to obtain a compound of formula (I) as defined above; and ii) optionally salifying the compound of formula (I) obtained. The present invention relates to a method comprising the steps of:

[0007] Preferably, the compound of formula (II) is in the form of a salt with an acid 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, paratoluenesulfonic acid and 2-naphthalenesulfonic acid.

[0008] A preferred method of the present invention comprises the steps of: [ka] wherein R, R1, R2, R3, R4 and R5 are as defined above, and the compound of formula (II) is represented by the following formula (II'): [ka] has.

[0009] In certain embodiments, the present invention relates to the hydrochloride salt of a substituted arylethylamino compound, wherein said compound has the formula (I) or (I').

[0010] A preferred method of the present invention comprises the steps of: R is (C4-C6)alkyl or CD3-CD2-(C3-C4)alkyl; R1 and R2 are independently hydrogen or halo, preferably fluoro; R3 and R4 are independently hydrogen or (C1-C3) alkyl; The above process for obtaining a compound of formula (I) or (I'), wherein R5 is hydrogen or (C1-C3) alkyl.

[0011] The most preferred process of the present invention is the process as defined above for obtaining a compound of formula (I) or formula (I') as defined above, wherein R is n-butyl or CD3-CD2-CH2-CH2- and R1, R2, R3, R4 and R5 are hydrogen.

[0012] Step i) may be carried out under catalytic hydrogenation conditions by using a heterogeneous catalyst selected from the group consisting of catalysts comprising at least one metal from the list of Pd, Pt, Ir, Ni and Ru catalysts, such as a palladium or platinum catalyst, on an inert support in a solvent at pH 9.0-10.5.

[0013] The solvent is selected from the group consisting of water, alcohols, and ethers.

[0014] Preferably, the catalyst is hydrous 5% Pt / C (50% H2O) or hydrous 10% Pd / C (50% H2O), preferably hydrous 10% Pd / C (50% H2O).

[0015] The process is carried out at a hydrogen pressure comprised between 1 and 4 atmospheres, preferably between 2.5 and 3.5 atmospheres, and at a temperature comprised between 0°C and 10°C, preferably between 0°C and 5°C.

[0016] Step ii) (salt formation) can be carried out by reacting the compound of formula (I) or (I') with an acid in a suitable solvent, preferably 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, paratoluenesulfonic acid and 2-naphthalenesulfonic acid.

[0017] Most preferably, the acid is hydrochloric acid.

[0018] Suitable solvents can be methanol, ethanol, isopropanol, acetone, methyl ethyl ketone and methyl isobutyl ketone, with methyl isobutyl ketone being preferred.

[0019] The compound of formula (III) is represented by the formula (VII) [ka] (wherein R3, R4 and R5 are as defined above, and R6 is (C1-C4) alkyl, preferably methyl, ethyl, isopropyl). It may also be obtained in situ by hydrolysis of the compound of formula (I).

[0020] 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 range of 25°C to 70°C.

[0021] The compound of formula (II) (wherein R, R1 and R2 are as defined above) can be prepared by the following process: i') Formula (IV) [ka] wherein R, R1, R2 are as defined above, are reacted with MCN, wherein M is an alkali metal selected from Li, Na and K, to obtain a compound of formula (V): [ka] obtaining a compound of the formula: ii') reducing the compound of formula (V) obtained to obtain a compound of formula (II) as defined above; and iii') optionally salifying the compound of formula (II) obtained. It may be obtained by a method comprising:

[0022] The salt of the compound of formula (II) may be isolated by crystallization or may be used directly in step i) above.

[0023] Step i') is preferably carried out in the presence of an acid at a temperature range of 0°C to 10°C, preferably 0°C to 5°C, in a two-phase system consisting of water and an organic solvent.

[0024] The organic solvent is selected from the group consisting of tert-butyl methyl ether, 2-methyltetrahydrofuran, toluene, and the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid.

[0025] The reduction step ii') is preferably a catalytic hydrogenation carried out using a heterogeneous catalyst selected from the group consisting of 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, and in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. In the present invention, the reduction in methanol catalyzed by sulfuric acid is preferred.

[0026] The heterogeneous catalyst is preferably a palladium or platinum catalyst such as wet 5% Pt / C (50% HO) or wet 10% Pd / C (50% HO), most preferably wet 10% Pd / C (50% HO).

[0027] Step ii') is preferably carried out at a hydrogen pressure comprised between 0.5 and 4 atmospheres, preferably between 2.5 and 3.5 atmospheres, and at a temperature comprised between 30°C and 90°C, preferably between 40°C and 80°C.

[0028] The compound of formula (IV) defined above may be represented by the formula (VI): [ka] The compound of formula RX, wherein R and R are as defined above, may be obtained by alkylation with a compound of formula RX, wherein R is as defined above and X is a leaving group selected from the group consisting of Cl, Br, I or mesylate, tosylate and brosylate.

[0029] The alkylation reaction is preferably carried out in an aprotic polar solvent such as acetonitrile, DMF, DMAC, DMSO, acetates 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, and at a temperature range of 15° C. to 120° C. Among various combinations of solvent, base, and temperature, potassium carbonate in DMF at 110° C. to 120° C. is preferred. Alternatively, a preferred method of alkylation is to carry out the reaction in a biphasic system consisting of an organic solvent and an aqueous phase in the presence of a buffer and a phase transfer catalyst.

[0030] The process according to the invention is amenable to industrial scale-up without risk concerns. The overall molar yield is high at 51%. The crystalline intermediate compound of formula (II) as the hydrochloride salt allows for recrystallization (if required) ensuring high quality intermediate is used in the manufacture of active pharmaceutical ingredients (API).

[0031] The methods include commercially available materials. Experimental section

[0032] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide

[0033] 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide was reacted with 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide according to the following scheme 2: [ka] It was synthesized as reported. Example 1

[0034] Synthesis of 3-butoxybenzylaldehyde [ka]

[0035] A mixture containing 3.95 Kg (32.34 moles) of 3-hydroxybenzaldehyde, 4.49 Kg (48.52 moles) of 1-chlorobutane, and 6.26 Kg (45.28 moles) of potassium carbonate in 19.75 L of N,N-dimethylformamide was heated to 115-118°C and maintained at this temperature until the reaction was complete (approximately 0.1% area % of 3-hydroxybenzaldehyde). The reaction mixture was cooled to approximately 20°C. To the slurry was added a mixture of 32.4 L of tert-butyl methyl ether and 52.9 L of water and stirred for 15 minutes. The two-phase mixture was allowed to separate. The organic solution was washed with aqueous sodium chloride solution. The batch was concentrated under reduced pressure below 50°C to provide 5.57 Kg of oily product 3-butoxybenzaldehyde in a molar yield of 96.6%. Example 2

[0036] Synthesis of 3-butoxybenzaldehyde [ka]

[0037] A solution containing 25 Kg (204.7 moles) of 3-hydroxybenzaldehyde, 39.5 Kg (285.8 moles) of potassium carbonate, and 28.5 Kg (307.8 moles) 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 less than 1%). The mixture was cooled, diluted with 325 Kg of water, and then concentrated under vacuum 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 successively with dilute sodium chloride solution and then with water. The batch was concentrated under vacuum and the remaining methyl tert-butyl ether was replaced with tetrahydrofuran via a series of dilutions and concentrations under vacuum. 33.5 kg (188.0 mol) of 3-butoxybenzaldehyde was obtained (molar yield 91%, purity 99.7%). MS(M+1:179.1); 1 H-NMR is consistent with the given structure. Example 3

[0038] Synthesis of α-hydroxy-α-(3-butoxyphenyl)-acetonitrile [ka]

[0039] To a biphasic mixture consisting of a solution of 1.79 Kg (36.53 moles) of sodium cyanide in 4.18 L of water and a solution of 5.43 Kg (36.59 moles) of 3-butoxybenzaldehyde in 7.94 L of tert-butyl methyl ether (TBME), 4.34 Kg (38.11 moles) of 32% HCl was added over a period of 6 hours under stirring at 0-5° C. until the reaction was complete (residual 3-butoxybenzaldehyde 2-3 wt %, 1 H-NMR), the mixture was kept at 0-5° C. The mixture was warmed to 18-25° C. and then diluted with 11.5 L of tert-butyl methyl ether. The two phases were separated.

[0040] The organic solution was washed successively with water and then with saturated aqueous sodium chloride. 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 several cycles of dilution (with methanol) and the mixture was concentrated under reduced pressure below 50° C. to give 6.16 Kg (24.31 moles) of α-hydroxy-α-(3-butoxyphenyl)-acetonitrile as an oil in 97% molar yield. Example 4

[0041] Synthesis of 2-(3-butoxyphenyl)-ethylamine hydrochloride [ka]

[0042] A mixture containing 6.12 Kg (29.82 moles) of α-hydroxy-α-(3-butoxyphenyl)-acetonitrile, 0.31 Kg of 10% Pd / C; Evonik Type E196NN / W; water content up to 50% 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, diluted with 22.5 L of water and the catalyst was removed by filtration and washed with water. The combined filtrate was concentrated at atmospheric pressure until the solution temperature reached about 90°C (final volume up to 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 followed by washing with isopropyl acetate. The combined filtrate (consisting of two phases) was separated and the aqueous layer was discarded. The organic phase was washed successively with 3.4 L of 25% aqueous ammonium chloride and brine. The batch was azeotropically dried under reduced pressure up to 50°C, filtered on a cellulose filter pad and the pad was washed with 6.12 L of isopropyl acetate, then the solution was concentrated to about 31 L below 50°C. A solution of 5-6 M hydrochloric acid in 7.85 Kg of isopropanol was added. The suspension was filtered at 0-5°C with a rinse of cold isopropyl acetate (6.1 L). The wet product was dried under vacuum at 40° C. to give 4.5 kg of 2-(3-butoxyphenyl)-ethylamine hydrochloride in 65.5% yield. Spectroscopic data (LC / MS, 1 H-NMR was found to be consistent with the assigned structure of 2-(3-butoxyphenyl)-ethylamine hydrochloride.

[0043] LC / MS: [M-HCl+H] + =194.2 1H NMR (400 MHz, DMSO-d6); δ 8.17 (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).

[0044] 4.42 Kg (19.24 moles) of 2-(3-butoxyphenyl)-ethylamine hydrochloride was further recrystallized from 13.3 L of isopropanol as above to provide 3.99 Kg of high purity 2-(3-butoxyphenyl)-ethylamine hydrochloride in 90.3% yield. Example 5

[0045] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide [ka]

[0046] 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 moles)) was added over 2 minutes to the acidic solution, which was then held at 58-61°C under stirring for 60 minutes (5.6% area % DEDMA). The mixture was cooled to about 20°C and 20% aqueous sodium hydroxide (about 5.48 Kg) was added until the pH was 8.8 and concentrated under vacuum at less than 45°C to a residual volume of about 29 L.

[0047] The solution was added to 3.95 Kg (17.19 moles) of solid 2-(3-butoxyphenyl)-ethylamine hydrochloride and adjusted to PH 9.9 with about 4.19 Kg of 20% aqueous sodium hydroxide at 19-20°C. 0.18 Kg of hydrous (1:1=water:Pd / C) 5% Pd / C was added to the mixture under stirring, then hydrogenated with H2 (3 bar) at 0-5°C until the reaction was complete (area of ​​2-(3-butoxyphenyl)-ethylamine hydrochloride less than 0.2%). The mixture was diluted with water (approximately 10 L) and neutralized with aqueous hydrochloric acid. The batch was filtered at 5-10°C, 20.5 L of tert-butyl methyl ether was added under stirring, and the phases were separated. The aqueous layer was diluted with 22.1 Kg of methyl isobutyl ketone and adjusted to PH 9.8 with about 2.0 Kg of 50% aqueous sodium hydroxide. The phases were separated and the aqueous phase was extracted with 11.0 Kg of methyl isobutyl ketone. To the combined organic phases was added 8.18 Kg of saturated aqueous sodium chloride solution and the mixture was stirred for 5 minutes. After adding 3.20 Kg of water, the phases were separated. Example 6

[0048] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride [ka]

[0049] 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 by repeated cycles of dilution with methyl isobutyl ketone and then concentrated under vacuum at less than 45° C. to a residual volume of about 27 L. The precipitated solid was filtered and washed successively with 10.95 Kg of methyl isobutyl ketone and 18.70 Kg of heptane. The wet product was dried at 40° C. to give 4.91 Kg of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride as a white solid in 90.7% yield. Spectroscopic data of the solid (1 H-NMR) is consistent with the assigned structure of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. The identity of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride was confirmed by elemental analysis: (theoretical vs. observed: C 61.04% vs. 61.3±0.2 wt%; H 8.64% vs. 8.7±0.1 wt%; N 8.90% vs. 8.9±0.1 wt%; O 10.16% vs. 10.17±0.1 wt%; Cl 11.26% vs. 10.2±0.5 wt%) (MS(M+1:279.0) and 300 MHz in DMSO on a BRUKER AVANCE 300 at 20°C). 1 Confirmed by H-NMR spectrum: [ka] [Table 1] BRUKER AVANCE 300 in DMSO at 20°C 13 C-NMR spectrum [ka] [Table 2] Example 7

[0050] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0051] 8.10 g (1 equiv.) of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide free base was dissolved in 15 mL of diethyl ether. 46 mL (2 mmol) of HCl in ether solvent was added to the solution and stirred vigorously. The resulting residue was stirred at 0° C. to give 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-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride (6.66 g, 72% yield). Example 8

[0052] Synthesis of 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride [ka]

[0053] 8.25 g (1 equiv.) 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. 46 mL (2 mmol) of HCl in ether solvent was added to the solution and stirred vigorously. The resulting gummy residue was stirred at 0° C. to give a white precipitate of crude 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride. This precipitate was further purified by trituration in 40 mL of ethyl acetate. The resulting precipitate was filtered and dried under nitrogen to give 6.77 g of pure 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride in 72% yield. [Brief description of the drawings]

[0054] [Figure 1] The 1H-NMR spectrum is reported in Figure 1; LC-MS: [Table 3]

[0055] 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide free base can be obtained by the methods described in Examples 2, 3, 4 and 5 starting from 3-hydroxybenzaldehyde and using butane-1,1,1,2,2-d5-4-chloro instead of 1-chlorobutane.

Claims

1. Formula (I): 【Chemical 22】 (Wherein, R is (C ３ -C １０ ) alkyl, or ω-trifluoro(C ３ -C １０ ) alkyl; R １ and R ２ are independently hydrogen, hydroxy, (C １ -C ８ ) alkoxy, (C １ -C ８ ) alkylthio, halo, trifluoromethyl, or 2,2,2-trifluoroethyl; or R １ and R ２ is in the ortho position relative to the R—O— group and, together with the R—O—, ０ But (C ２ -C ９ ) alkyl 【Chemistry 23】 represents a group; R ３ and R ４ are independently hydrogen or (C １ -C ６ ) alkyl; or together with the adjacent nitrogen atom, optionally —O—, —S—, and —NR ７ - (wherein, R ７ is hydrogen or (C １ -C ６ ) alkyl); R ５ is hydrogen or (C １ -C ６ ) alkyl; In addition, in the formula, optionally, the groups R, R １ , R ２ , R ３ , R ４ and R ５ one or more hydrogen atoms in which may be replaced by deuterium atoms) or a pharma- ceutically acceptable salt thereof, comprising: i') Formula (IV): 【Chemical Formula 29】 wherein R, R 1 , R 2 are as defined above, are reacted with MCN, wherein M is an alkali metal selected from Li, Na and K, to give a compound of formula (V): 【Chemistry 30】 obtaining a compound of formula: ii') The resulting compound of formula (V) is reduced by catalytic hydrogenation at a hydrogen pressure comprised between 0.5 and 4 atmospheres to give the compound of formula (II): 【Chemistry 24】 obtaining a compound of formula: iii') optionally salifying the compound of formula (II) obtained; and i) reacting a compound of formula (II) as defined above or a salt thereof with a compound of formula (III): 【Chemistry 25】 (In the formula, R ３ , R ４ and R ５ is as defined above) under reducing conditions to obtain a compound of formula (I) as defined above; and ii) optionally salifying the compound of formula (I) obtained. The method includes:

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

3. Formula (I'): 【Chemistry 26】 (In the formula, R, R １ , R ２ , R ３ , R ４ and R ５ A process according to claim 1 for obtaining a compound of formula (II) having the following formula (II'): 【Chemical 27】 The method comprising:

4. Formula (I) or (I′) (wherein R is n-butyl or CD ３ - CD ２ -CH ２ -CH ２ - and R １ , R ２ , R ３ , R ４ and R ５ 2. The method of claim 1 for obtaining a compound of the formula:

5. The process according to claim 1 for obtaining the compound of formula (I'), wherein the compound of formula (I') is 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide.

6. 2. The process of claim 1, wherein the compound of formula (II) is in the form of a salt with an acid 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, paratoluenesulfonic acid and 2-naphthalenesulfonic acid.

7. 2. The process of claim 1, wherein step i) is carried out under catalytic hydrogenation conditions.

8. 8. The process according to claim 7, wherein the catalytic hydrogenation is carried out by using a catalyst comprising at least one metal selected from Pd, Pt, Ir, Ni and Ru on an inert support.

9. The catalyst is 5% Pt / C (50% H ２ O) or hydrous 10% Pd / C (50% H ２ 9. The process according to claim 8, wherein catalytic hydrogenation is carried out.

10. The compound of formula (III) may be represented by the formula (VII): 【Chemistry 28】 (In the formula, R ３ , R ４ and R ５ is as defined above, and R ６ (C １ -C ４ ) alkyl 2. The process according to claim 1, wherein the compound is obtained in situ by hydrolysis of the formula:

11. R ６ The method of claim 10, wherein is methyl, ethyl, or isopropyl.

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

13. 2. The process 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 range of 0°C to 10°C.

14. The process of claim 13, wherein step i') is carried out at a temperature range of 0°C to 5°C.

15. 2. The process according to claim 1, wherein the reduction step ii') is a catalytic hydrogenation carried out by using a heterogeneous catalyst selected from the group consisting of nickel, rhodium, platinum and palladium catalysts on an inert support.

16. The heterogeneous catalyst is a hydrous 5% Pt / C (50% H ２ O) or hydrous 10% Pd / C (50% H ２ 16. The method of claim 15, wherein

17. The compound of formula (IV) defined in claim 1 is Formula (VI): 【Chemistry 31】 (In the formula, R １ and R ２ is as defined in claim 1, with a compound of formula RX, where R is as defined in claim 1 and X is a leaving group selected from the group consisting of Cl, Br, I or mesylate, tosylate and brosylate.

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