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

Abstract

The present invention relates to a new method for producing a substituted 2-[2-(phenyl)ethylamino]alkanamide derivative of the following formula (I), specifically 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide, in high yield with very high chemical purity. The present invention relates to a method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof:.

Description

Technology Field

[0001] The present invention relates to a new method for producing substituted 2-[2-(phenyl)ethylamino]alkanamide derivatives, specifically 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide, with very high chemical purity and high yield. Background Technology

[0002] 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 the mechanism plays a pathological role, such as neurological, cognitive, psychiatric, inflammatory, genitourinary, and gastrointestinal diseases. These compounds are also described as having substantially no monoamine oxidase (MAO) inhibitory effect.

[0003] A new class of fluorinated arylalkylaminocarboxamide derivatives with excellent efficacy as sodium and / or calcium channel modulators is disclosed in WO 2013 / 000651.

[0004] WO 2008 / 151702 disclosed the synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride as summarized in Reaction Scheme 1 below in the examples:

[0005]

[0006] The method disclosed above has many drawbacks that prevent it from being scaled up to an industrial level:

[0007] Starting materials that are not commercially available, such as 3-methoxyphenylethylamine, and their preparation from commercially available reagents involves several steps;

[0008] Refining intermediates is difficult because they are oils;

[0009] Use of potentially genotoxic, large amounts of toxic reagents, e.g., 1-bromobutane and 2-chloro-N,N-dimethylacetamide;

[0010] Use of non-standard equipment (NaH / DMF is a potentially explosive compound as H2 is generated during the reaction);

[0011] Impractical and potentially very dangerous conditions for producing the final hydrochloride due to the use of etheric solvents that readily form peroxides in the presence of air;

[0012] Low overall yield (approx. 13%);

[0013] The purity of the final product is unknown.

[0014] The present invention relates to a method for preparing a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0015]

[0016] From the above

[0017] R is (C3-C 10 )alkyl, or ω-trifluoro(C3-C 10 )alkyl and;

[0018] R1 and R2 is independently hydrogen, hydroxy, (C1-C8)alkoxy, (C1-C8)alkylthio, halo, trifluoromethyl or 2,2,2-trifluoroethyl; or R1 and One of the R2s is in an ortho position relative to the RO-, and together with the same RO- Represents a group, where R0 is a (C2-C9)alkyl;

[0019] R3 and R4 are independently hydrogen or (C1-C6)alkyl; or together with an adjacent nitrogen atom, forming a 5-6 member monocyclic saturated heterocycle containing one additional heteroatom selected from -O-, -S- and -NR7- (where R7 is hydrogen or (C1-C6)alkyl);

[0020] R5 is hydrogen or (C1-C6)alkyl;

[0021] Optionally R, R1, One or more hydrogen atoms in the R2, R3, R4, and R5 groups, preferably in the R group, can be substituted with deuterium atoms;

[0022] The above method includes the following steps:

[0023] i) a step of reacting a compound of formula (II) or a salt thereof with a compound of formula (III) under reducing conditions to obtain a compound of formula (I) as defined above:

[0024]

[0025] Here, R, R1, and R2 are as defined above:

[0026]

[0027] Here, R3, R4, and R5 are as defined above; and

[0028] ii) Optionally, a step of salifying the compound of the obtained formula (I).

[0029] Preferably, the compound of formula (II) is in the form of a salt with an acid selected from hydrochloric acid, benzenesulfonic acid, hydrobromide, camphosulfonic 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.

[0030] A preferred method of the present invention is the method described above for obtaining a compound of the following formula (I'):

[0031]

[0032] In the above, R, R1, R2, R3, R4, and R5 are as defined above, and

[0033] The compound of the above chemical formula (II) has the following chemical formula (II'):

[0034] .

[0035] In a specific embodiment, the present invention relates to a hydrochloride salt of a substituted arylethylamino compound, said compound having the formula (I) or (I').

[0036] A preferred method of the present invention is the method described above for obtaining a compound of formula (I) or (I'), wherein:

[0037] R is a (C4-C6)alkyl or CD3-CD2-(C3-C4)alkyl;

[0038] R1 and R2 are independently hydrogen or halo, preferably fluoro;

[0039] R3 and R4 are independently hydrogen or (C1-C3)alkyl;

[0040] R5 is hydrogen or (C1-C3)alkyl.

[0041] The most preferred method of the present invention is the method defined above for obtaining a compound of the formula (I) or (I') defined above, wherein R is n-butyl or CD3-CD2-CH2-CH2-, and R1, R2, R3, R4 and R5 is hydrogen.

[0042] Step i) can be carried out under conditions of catalytic hydrogenation using a heterogeneous catalyst selected from the group consisting of, for example, palladium or platinum catalysts, a catalyst comprising at least one metal from the list of Pd, Pt, Ir, Ni and Ru catalysts on an inert support in a solvent at pH 9.0 to 10.5.

[0043] The above solvent is selected from the group consisting of water, alcohol, and ether.

[0044] Preferably, the catalyst is wet 5% Pt / C (50% H2O) or wet 10% Pd / C (50% H2O), preferably wet 10% Pd / C (50% H2O).

[0045] The above method is carried out at a hydrogen pressure of 1 to 4 Atm, preferably 2.5 to 3.5 Atm, and a temperature of 0 to 10°C, preferably 0 to 5°C.

[0046] 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, hydrobromide, camphosulfonic 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.

[0047] Most preferably, the acid is hydrochloric acid.

[0048] Suitable solvents may be methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, and methyl isobutyl ketone, and methyl isobutyl ketone is preferred.

[0049] The compound of the above formula (III) can be obtained in situ by hydrolysis of the compound of the following formula (VII):

[0050]

[0051] Here, R3, R4 and R5 are as defined above, and R6 is (C1-C4)alkyl, preferably methyl, ethyl, iso-propyl.

[0052] The above hydrolysis reaction is preferably carried out in water in the presence of an acid such as hydrochloric acid, hydrobromide, sulfuric acid, and phosphoric acid at a temperature in the range of 25°C to 70°C.

[0053] A compound of formula (II) in which R, R1 and R2 are defined as above can be obtained by a method comprising the following steps:

[0054] i') A step of reacting the compound of formula (IV) with MCN (where M is an alkali metal selected from Li, Na, and K) to obtain the compound of formula (V):

[0055]

[0056] Here, R, R1, and R2 are as defined above.

[0057]

[0058] Here, R, R1, and R2 are as defined above;

[0059] ii') a step of reducing the compound of formula (V) obtained above to obtain the compound of formula (II) defined above; and

[0060] iii') Optionally, a step of chlorinating the compound of the obtained formula (II).

[0061] The salt of the compound of the above formula (II) can be isolated by crystallization or used directly in step i) described above.

[0062] Step i') is preferably carried out in a two-phase system (biphasic system) consisting of water and an organic solvent in the presence of an acid at a temperature in the range of 0°C to 10°C, preferably 0°C to 5°C.

[0063] The above organic solvent is tert - Selected from the group consisting of butyl methyl ether, 2-methyltetrahydrofuran, and toluene, and the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid.

[0064] The above reduction step ii') is preferably a catalytic hydrogenation preferably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, and phosphoric acid, 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. In the present invention, reduction in methanol catalyzed by sulfuric acid is preferred.

[0065] The above 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).

[0066] Step ii') is preferably performed at a hydrogen pressure of 0.5 to 4 Atm, preferably 2.5 to 3.5 Atm, and at a temperature of 30°C to 90°C, preferably 40°C to 80°C.

[0067] The compound of formula (IV) defined above can be obtained by alkylating the compound of formula (VI) below with the compound of formula RX:

[0068]

[0069] Here, R1 and R2 are as defined above, and

[0070] In the above chemical formula RX, R is as defined above, and X is a leaving group selected from the group consisting of Cl, Br, I, or mesylate, tosylate, and broxylate.

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

[0072] The method according to the present invention is scalable to an industrial level without risk issues. The overall molar yield is as high as 51%. The crystal intermediate compound of formula (II) as a hydrochloride is recrystallized (if necessary) so that a high-quality intermediate is used in the manufacture of API.

[0073] The above method includes 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 Reaction Scheme 2 below:

[0077]

[0078] Example 1

[0079] Synthesis of 3-Butoxybenzylaldehyde

[0080]

[0081] A mixture containing 3.95 kg (32.34 mol) of 3-hydroxybenzaldehyde, 4.49 kg (48.52 mol) of 1-chlorobutane, and 6.26 kg (45.28 mol) of potassium carbonate in 19.75 L of N,N-dimethylformamide was heated to 115-118°C and maintained at the said temperature until the reaction was complete (approx. 0.1% area %) of 3-hydroxybenzaldehyde. The reaction mixture was cooled to approximately 20°C. The slurry tert It was added to a mixture of 32.4 L of butylmethyl ether and 52.9 L of water and stirred for 15 minutes. The mixture of the two phases was separated. The organic solution was washed with an aqueous sodium chloride solution. The batch was concentrated under reduced pressure at < 50°C to yield 5.57 kg of the oily product, 3-butoxybenzaldehyde, in a molar yield of 96.6%.

[0082] Example 2

[0083] Synthesis of 3-Butoxybenzaldehyde

[0084]

[0085] 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 (less than 1% of 3-hydroxybenzaldehyde). The mixture was cooled, diluted with 325 kg of water, and then concentrated to about 325 L under vacuum. The batch was diluted with 126 kg of water, and methyl tert 150 kg of γ-butyl ether was added at approximately 20°C. The aqueous layer was discarded, and the batch was washed sequentially with a dilute sodium chloride solution, followed by water. The batch was concentrated under vacuum, and the remaining methyl tert-Butyl ether was replaced with tetrahydrofuran through a series of dilutions and concentrated under vacuum. 33.5 kg (188.0 mol) of 3-butoxybenzaldehyde was obtained (91% molar yield, 99.7% purity).

[0086] MS (M +1: 179.1); 1 The H NMR matched the given structure.

[0087] Example 3

[0088] Synthesis of benzoacetonitrile, alpha-hydroxy-3-butoxy

[0089]

[0090] 4.34 kg (38.11 mol) of 32% HCl at 0-5℃, a solution of 1.79 kg (36.53 mol) of sodium cyanide in 4.18 L of water, and tert A solution of 5.43 kg (36.59 mol) of 3-butoxybenzaldehyde in 7.94 L of butylmethyl ether (TBME) was added to a two-phase mixture and stirred for 6 hours. The mixture was then added to the mixture upon completion of the reaction ( 1 The mixture was maintained at 0-5°C until the residual 3-butoxybenzaldehyde was 2-3 wt% as determined by H-NMR. After heating the mixture to 18-25°C, tert It was diluted with 11.5 L of butylmethyl ether. The two phases were separated.

[0091] The above organic solution was washed sequentially with water and then with a saturated aqueous sodium chloride solution. The above 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 dilution cycles, and the mixture was concentrated under reduced pressure at < 50°C to yield 6.16 kg (24.31 mol) of benzoacetonitrile, alpha-hydroxy-3-butoxy as oil in a 97% molar yield.

[0092] Example 4

[0093] Synthesis of Benzene Ethanolamine, 3-Butoxy Hydrochloride

[0094]

[0095] A mixture containing 6.12 kg (29.82 mol) of benzoacetonitrile, alpha-hydroxy-3-butoxy, 0.31 kg of 10% Pd / C; Evonik type E196 NN / W; ~50% wet water, 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, the catalyst was removed by filtration, and washed with water. The combined filtrate was concentrated at atmospheric pressure until the solution temperature reached approximately 90°C (final volume ~31 L). The above solution was extracted with a mixture of 6.12 L isopropyl acetate and 6.12 L heptane. The aqueous layer was diluted with 43 L isopropyl acetate. 1.22 kg of Hyflo was added. The pH of the aqueous solution was adjusted to pH 12-13 with a 50% solution of approximately 3.64 kg of sodium hydroxide. The mixture was filtered through a cellulose filter pad and then washed with isopropyl acetate. The combined filtrate (composed of two phases) was separated, and the aqueous layer was discarded. The organic phase was sequentially washed with 3.4 L of 25% aqueous ammonium chloride and brine. The batch was azeotropically dried under reduced pressure at up to 50°C, filtered on a cellulose filter pad, and the pad washed with 6.12 L isopropyl acetate, after which the solution was concentrated to approximately 31 L at < 50°C. A 5-6 M solution of hydrochloric acid was added to 7.85 kg of isopropanol. The suspension was rinsed with cold isopropyl acetate (6.1 L) and filtered at 0-5°C. The wet product was dried under vacuum at 40°C to yield 4.5 kg of benzeneethanolamine, 3-butoxyhydrochloride in 65.5% yield. Spectroscopic data (LC / MS, 1It was found from 1H NMR that it matches the assigned structure of benzeneethanolamine, 3-butoxyhydrochloride.

[0096] LC / MS: [M-HCl + H] + =194.2

[0097] 1 H 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).

[0098] 4.42 kg (19.24 mol) of benzeneethanolamine, 3-butoxyhydrochloride was further recrystallized from 13.3 L of isopropanol as described above to provide 3.99 kg of high-purity benzeneethanolamine, 3-butoxyhydrochloride in a yield of 90.3%.

[0099] Example 5

[0100] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide

[0101]

[0102] 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 within 2 minutes, and then maintained at 58-61°C for 60 minutes while stirring (DEDMA 5.6% area%). The mixture was cooled to about 20°C, 20% aqueous sodium hydroxide (about 5.48 kg) was added to a maximum pH of 8.8, and concentrated to a residual volume of about 29 L under vacuum at < 45°C.

[0103] The above solution was added to 3.95 kg (17.19 mol) of solid benzenethanamine, 3-butoxyhydrochloride, and the pH was adjusted to 9.9 using approximately 4.19 kg of 20% aqueous sodium hydroxide at 19-20°C. 0.18 kg of wet (1:1 = water:Pd / C) 5% Pd / C was added to the mixture under stirring, and then hydrogenated with H2 (3 bar) at 0-5°C until the reaction was complete (benzenethanamine, 3-butoxyhydrochloride < 0.2% area). The mixture was diluted with water (approx. 10 L) and neutralized with aqueous hydrochloric acid. The batch was filtered at 5-10°C, and tert - Added to 20.5 L of butylmethyl ether while stirring, and the phases were separated. The aqueous layer was diluted with 22.1 kg of methyl isobutyl ketone, and the pH was adjusted to 9.8 using approximately 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. 8.18 kg of saturated aqueous sodium chloride solution was added to the combined organic phase, and the mixture was stirred for 5 minutes. After adding 3.20 kg of water, the phases were separated.

[0104] Example 6

[0105] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0106]

[0107] 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 dilution cycles with methyl isobutyl ketone, and then concentrated to a residual volume of about 27 L under vacuum at < 45°C. The precipitated solid was filtered and washed sequentially with 10.95 kg of methyl isobutyl ketone and 18.70 kg of heptane. The wet product was dried at 40°C to provide 4.91 kg of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride as a white solid in a yield of 90.7%. Spectral data of the solid ( 1 H NMR matched 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. found: 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). 1 1H NMR Spectrum (DMSO) Bruker Avance 300, 20℃:

[0108]

[0109] Bruker Avance 300 in DMSO at 20℃ 13 C-NMR spectrum

[0110]

[0111] Example 7

[0112] Synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0113] 8.10 g (1 equivalent) 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 the ether solvent was added to the solution and vigorously stirred. The resulting 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 grinding in ethyl acetate (40 mL) to obtain 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride (6.66 g, 72% yield).

[0114] Example 8

[0115] 2-[2-(3-butoxy-3,3,4,4,4-d 5 Synthesis of -phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride

[0116]

[0117] 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. 46 mL (2 mmol) of HCl in the ether solvent was added to the solution and vigorously stirred. The formed gummy residue 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 grinding in 40 mL of ethyl acetate. The obtained precipitate was filtered and dried under nitrogen to obtain 6.77 g of pure 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide hydrochloride in a 72% yield.

[0118] 1 The H NMR spectrum is shown in Fig. 1;

[0119] LC-MS:

[0120]

[0121] The 2-[2-(3-butoxy-3,3,4,4,4-d5-phenyl)-ethylamino]-N,N-dimethylacetamide free base can be obtained starting from 3-hydroxybenzaldehyde and using butane-1,1,1,2,2-d5-4-chloro instead of 1-chlorobutane according to the method described in Examples 2, 3, 4, and 5.

Claims

Claim 1 A method for preparing a compound of the following chemical formula (I') or a pharmaceutically acceptable salt thereof, In the above, R is (C3-C 10 )alkyl or ω-trifluoro(C3-C 10 )alkyl and; R1 and R2 is independently hydrogen or a halo; R3 and R4 are independently (C1-C6)alkyl; or form a 5-6 member monocyclic saturated heterocycle with an adjacent nitrogen atom; R5 is hydrogen or (C1-C6)alkyl; optionally R, R1, One or more hydrogen atoms in the R2, R3, R4 and R5 groups may be substituted with deuterium atoms; and the method comprises: i) reacting a compound of formula (II') or a salt thereof with a compound of formula (III) under reducing conditions to obtain a compound of formula (I') as defined above: Here, R, R1, and R2 are as defined above: Herein, R3, R4 and R5 are as defined above; and ii) optionally, a method comprising the step of salifying the compound of the obtained formula (I'). Claim 2 A method according to claim 1 for obtaining a compound of the formula (I'), wherein R is n-butyl or CD3-CD2-CH2-CH2- and R1, R2, and R5 are hydrogen. Claim 3 A method according to claim 1 or 2, wherein the compound of formula (II') is in the form of a salt with an acid selected from hydrochloric acid, benzenesulfonic acid, hydrobromide, camphosulfonic 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. Claim 4 A method according to claim 1 or 2, wherein step i) is performed under catalytic hydrogenation conditions. Claim 5 A method according to claim 4, wherein the catalytic hydrogenation is performed using a catalyst comprising at least one metal selected from Pd, Pt, Ir, Ni, and Ru on an inert support. Claim 6 A method according to claim 5, wherein the catalytic hydrogenation is performed, wherein the catalyst is a wet 5% Pt / C (50% H2O) or a wet 10% Pd / C (50% H2O). Claim 7 In claim 1 or 2, the compound of formula (III) is obtained in situ by hydrolysis of the compound of formula (VII) below: A method in which R3, R4, and R5 are as defined above, and R6 is a (C1-C4)alkyl. Claim 8 The method of claim 7, wherein R6 is methyl, ethyl, or isopropyl. Claim 9 In claim 1, the compound of formula (II') defined in claim 1 comprises: i') reacting the compound of formula (IV') with MCN (wherein M is an alkali metal selected from Li, Na, and K) to obtain the compound of formula (V'); (IV') Here, R, R1, and R2 are as defined above (V') where R, R1 and R2 are as defined above; ii') a step of reducing the obtained compound of formula (V') to obtain the compound of formula (II') defined above; and iii') optionally, a step of chlorinating the obtained compound of formula (II') to obtain a method obtained by a method comprising the steps of: (V') where R, R1 and R2 are as defined above; ii') a step of reducing the obtained compound of formula (II') above. Claim 10 A method according to claim 9, wherein the salt of the compound of formula (II') is isolated by crystallization or can be used directly in step i) defined in claim 1. Claim 11 A method according to claim 9, wherein step i') is performed in a biphasic system composed of water and an organic solvent in the presence of an acid at a temperature in the range of 0°C to 10°C or 0°C to 5°C. Claim 12 A method according to claim 9, wherein the reduction step ii') is catalytic hydrogenation performed using a heterogeneous catalyst selected from the group consisting of nickel, rhodium, platinum, and palladium catalysts on an inert support. Claim 13 The method of claim 12, wherein the heterogeneous catalyst is wet 5% Pt / C (50% H2O) or wet 10% Pd / C (50% H2O). Claim 14 A method according to claim 9, wherein the compound of formula (IV') defined in claim 9 is obtained by alkylating the compound of formula (VI') below with the compound of formula RX: (VI') Here, R1 and R2 are as defined in Claim 1, and in the formula RX, 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 broxylate.

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