KR100772244B1 - Method for the preparation of milnacipran hydrogen chloride salt - Google Patents

Abstract

The present invention relates to a method for preparing milnacipran hydrochloride useful as a therapeutic agent for depression. The preparation method according to the present invention comprises the steps of a) reacting a compound of formula 4 with a sulfonyl halide in the presence of a base to obtain a compound of formula 3, b) reacting a compound of formula with hexamethylenetetraamine, Obtaining (Z) -1-phenyl-1-diethylaminocarbonyl-2-hexamethylenetetraammoniummethyl-cyclopropane salt, and c) treating the obtained compound with hydrochloric acid to obtain milnacifur hydrochloride having the formula (1). Obtaining step. The reaction process of the manufacturing method according to the present invention is the same as in Scheme 4. The preparation method according to the invention provides the effect of efficiently preparing milnacipran hydrochloride by a short synthesis step and carrying out the synthesis step in a mild and improved environment.

Scheme 4

In Scheme 4, Z is sulfonate.

Description

METHOD FOR THE PREPARATION OF MILNACIPRAN HYDROGEN CHLORIDE SALT}

The present invention relates to a method for producing (Z) -1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane hydrochloride (hereinafter, milnacipran hydrochloride). The present invention also relates to intermediates useful for the preparation of milnacipran hydrochloride.

Milnacifur (IUPAC NAME: (Z) -1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane) is a compound useful as an antidepressant (US Pat. No. 4,478,836 and the corresponding Japanese Patent Registration) 1,477,542). In particular, preparations containing milnacipran hydrochloride are usefully used as antidepressants.

According to US Pat. No. 4,478,836, milnacipran hydrochloride is prepared from a 2-step process from 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane. The specific reaction process is shown in Scheme 1 below.

The reaction process has a problem that the yield of the step of reacting 1-phenyl-2-aminomethylcyclopropane chloride with diethylamine is significantly low. Specifically, to introduce a diethylamine group, 1-phenyl-2-aminomethylcyclopropane chloride produced by activation of 1-phenyl-2-aminomethylcyclopropanoic acid undergoes an intramolecular cyclization reaction to 1 -Phenyl-2-oxo-3-azabicyclo [3.1.0] hexane. This side reaction leads to a decrease in reaction yield and difficulty in purification. In addition, the yield of the process for producing 1-phenyl-2-aminomethylcyclopropanoic acid from 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane is low, and is suitable for practical industrial production. There is a problem of using a material (SOCl ₂ or SOBr ₂ ) difficult to apply. In addition, the synthesis process of milnacipran hydrochloride has a long, low overall yield.

According to US Pat. No. 5,034,541 (corresponding to Japanese Patent No. 2,964,041), a method for preparing (Z) -1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl-cyclopropane is proposed. Specifically, the preparation method is a method of reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane with diethylamine in the presence of Lewis acid (Z) -1-phenyl-1-diethyl Obtaining aminocarbonyl-2-hydroxymethyl-cyclopropane; reacting the obtained compound with a chlorination reagent (typically SOCl ₂ ) to give (Z) -1-phenyl-1-diethylaminocarbonyl-2 -Obtaining chloromethyl-cyclopropane, the compound obtained by reacting with a phthalimide salt to prepare (Z) -1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl-cyclopropane do. (Z) -1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl-cyclopropane produced through the above process is reacted with alkylamine or hydroxyamine and hydrochlorination with concentrated hydrochloric acid ( hydrochlorination, which ultimately provides milnacipran hydrochloride. The specific reaction process is shown in Scheme 2 below.

The method uses phthalimide groups to introduce amine groups. This, unlike the conventional method, provides the advantage of preventing the production of lactam compounds through intramolecular cyclization. However, this process has the disadvantage that the step of converting phthalimide groups to amine groups is difficult. Specifically, an aqueous methanol amine solution and / or ethanol amine is used in the process of converting the phthalimide group to the amine group, which is not easy to remove. Moreover, the whole process consists of five steps, and the yield of the desired milnaciran hydrochloride falls. In addition, chlorinating agents (eg SOCl ₂ ) used to convert hydroxy groups to chloro groups are harmful to the human body.

European Patent No. 200,638 (corresponding Japanese Patent No. 1,854,206 and Korean Patent No. 81,785) reacts 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane with phthalimide (Z ) -1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropanoic acid, a step of sequentially amidating the obtained compound with a chlorinating agent and diethylamide, and obtaining (Z)- The reaction of 1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropane with alkylamine or hydroxyamine and hydrochlorination with concentrated hydrochloric acid finally provides milnacipran hydrochloride. do. The specific reaction process is shown in Scheme 3 below.

However, the method also uses phthalimide groups to introduce amine groups. As mentioned above, the process of converting a phthalimide group to an amine group is difficult to purify a product, which lowers the purity of the product. Thionyl chloride (SOCl ₂ ), also used as a chlorinating agent (or acid chloride), is harmful to the human body.

It is an object of the present invention to provide an efficient process for the preparation of milnacipran hydrochloride. The production method of the present invention efficiently prepares milnacipran through a short synthesis step. This produces Milnacifran with economical, improved yield and high purity. The preparation method of the present invention may also exclude the use of thionyl chloride, which is a toxic substance. Therefore, the production method of the present invention improves the working environment for producing milnasifran hydrochloride.

The production method of the present invention also introduces amine groups present in the molecule of milnacipran using hexamethylenetetraamine rather than phthalimide salts. Hexamethylenetetraamine was easily converted to an amine group as compared with the existing phthalimide salt.

The present invention relates to a method for preparing milnacipran hydrochloride, which is useful as a therapeutic agent for depression, comprising the steps of: reacting a compound of formula 4 with a sulfonyl halide in the presence of a base to obtain a compound of formula 3; Reacting with methylenetetraamine to obtain (Z) -1-phenyl-1-diethylaminocarbonyl-2-hexamethylenetetraammoniummethyl-cyclopropane salt having the formula (2), and c) the obtained compound with hydrochloric acid. Treatment to obtain milnacipran hydrochloride having formula (I).

In Formulas 2 and 3, Z is a sulfonate.

The method for preparing milnacipran hydrochloride according to the present invention can be summarized in Scheme 4 below.

In Scheme 4, Z is sulfonate.

According to the present invention, hexamethylenetetramine (HMTA) is employed in order to easily introduce amine groups into molecules of milnacipran. The compound having the formula (3) is reacted with hexamethylenetetraamine under mild conditions to give (Z) -1-phenyl-1-diethylaminocarbonyl-2-hexamethylenetetraammoniummethyl-cyclo having the formula (2) in high yield. Provide propane salt. Examples of the organic solvent that can be used in the reaction is not particularly limited, and organic solvents commonly used in the art may be widely used. For example, chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide, dimethylformamide, acetonitrile, benzene, xylene and the like can be used as the organic solvent. The temperature of the reaction is carried out in the range of 0 ° C-40 ° C. According to a preferred embodiment of the present invention, the substitution with hexamethylenetetraamine was achieved in high yield by stirring for about 24 hours at room temperature.

The hexamethylenetetraammonium introduced by the substitution reaction is converted into an amine group by hydrochloric acid treatment, and the compound of formula 2 produces milnacifran. At the same time, the produced milnacipran reacts with excess hydrochloric acid present in the reaction solution to produce milnacipran hydrochloride. That is, the conversion of the hexamethylenetetraammonium group to the amine group (which results in the production of milnacipran) and the formation of a salt by combining the resulting milnacipran and hydrochloric acid are simultaneously performed in one reaction, and consequently the milnasifran hydrochloride Create The reaction is preferably carried out in a polar solvent. Preferred examples may include C ₁ to C ₄ alcohols. Usually, methanol, ethanol, propanol, isopropanol, butanol and the like are used. In consideration of environmental friendliness, working environment and the like, anhydrous ethanol is preferable. In the course of the reaction, no aqueous methanol amine solution and / or ethanol amine is used. Therefore, the purification process is easily performed. The purification process can be carried out by solidification of milnacipran hydrochloride by the addition of a nonpolar solvent such as ether and filtration of the resulting solid.

The compound of formula 4 is obtained by reacting 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane having formula (5) with diethylamine in the presence of Lewis acid, the compound having formula (4) obtained Is converted to a compound of formula 3 by reaction with a sulfonyl halide in the presence of a base. If necessary, the obtained compound of formula 3 may be further converted to the compound represented by formula 3a by substitution with halide ions.

상기 반응공정은 아래의 반응식 5에 요약되어 있다.

The reaction process is summarized in Scheme 5 below.

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In Scheme 5, Z ₁ is a sulfonate and Z ₂ is a halide.

As shown in Scheme 5, 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane having Formula 5 is reacted with diethylamine in the presence of Lewis acid to have Formula 4 (Z ) -1-phenyl-1-diethylaminocarbonyl-2-hydroxymethyl-cyclopropane. At this time, a preferable example of Lewis acid is aluminum chloride. If desired, further tertiary amines may be added which form complexes with Lewis acids. See US Pat. No. 5,034,541 mentioned in the prior art for specific conditions of the reaction. Preferred organic solvents are chlorinated hydrocarbons. Such examples include ClCH ₂ CH ₂ Cl. Preparation of 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane having the formula (5) can be prepared by a conventional general method. According to an embodiment of the present invention, phenylacetonitrile was prepared by reacting with epichlorohydrin in the presence of sodium amide (NaNH ₂ ), and then sequentially treating with inorganic base and hydrochloric acid.

The resulting compound of formula 4 is reacted with sulfonyl halide to produce a compound of formula 3 wherein Z is a sulfonate (represented by compound 3a in Scheme 5). The reaction is carried out in the presence of a base and tertiary amines are used. Examples of tertiary amines that can be used include trimethylamine, triethylamine, diisopropylethylamine, N, N-diethylaniline, N, N-dimethylbenzylamine. A catalytic amount of pyridine may further be added. Examples of the organic solvent that can be used in the reaction is not particularly limited, and organic solvents commonly used in the art may be widely used. For example, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide, dimethylformamide, acetonitrile, benzene, xylene and the like can be used as the organic solvent. Examples of sulfonyl halides that can be used include methanesulfonyl chloride (simply MsCl), p-toluenesulfonyl chloride (simply TsCl), benzenesulfonyl chloride, trifluoromethanesulfonyl chloride (simply TfCl) or nitrobenzene Sulfonyl chloride. The sulfonyl halides and the compound of formula 4 react to yield the corresponding sulfonate of formula 3a. According to an embodiment of the invention, methanesulfonyl chloride provided the highest yield. The sulfonate of formula (3a) obtained reacts with hexamethylene tetraamine, where (Z) -1-phenyl-1-diethylaminocarbonyl-2-hexamethylenetetraammoniummethyl-cyclopropane sulfo in which Z is sulfonate in formula (2) It provides a salt of nate. On the other hand, the production of the compound having Formula 3a may be achieved by converting the hydroxy group present in the compound of Formula 4 into a chloride group using thionyl chloride (SOCl ₂ ), and reacting it with hexamethylenetetraamine. However, this reaction, with the deterioration of the working environment, showed a significantly lower yield. Therefore, the use of thionyl chloride (SOCl ₂ ) should be ruled out whenever possible.

According to another embodiment of the present invention, the sulfonate of formula 3a may be converted to the corresponding halide compound represented by formula 3b by substitution with a halide ion. At this time, the sulfonate compound can be directly applied to the substitution reaction by halide ions without undergoing a purification step. As a source of halide ions, metal halides are preferable. Examples of the metal halides include alkali metal halides or alkaline earth metal halides. Examples include NaI, NaBr, NaCl, KI, KBr, KCl, CuI ₂ , MgI ₂ , and the like. Examples of halide ions include iodide ion (I ⁻ ), bromide ion (Br ⁻ ) and chloride ion (Cl ⁻ ). According to a preferred embodiment of the present invention, iodide ions (I ⁻ ) provided the highest yields. Substitution of the sulfonate group by halide ions is preferably carried out in the presence of a polar organic solvent (eg, acetone, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide and acetonitrile). The obtained halide compound of formula (3b) is reacted with hexamethylenetetraamine and (Z) -1-phenyl-1-diethylaminocarbonyl-2-hexamethylenetetraammoniummethyl-cyclopropane halide salt wherein Z is a halide in formula (2). To provide.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are presented for the understanding of the present invention, and the scope of the present invention should not be construed as being limited by these examples.

Example

Example 1: Preparation of 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane

42.9 g of sodium amide were suspended in 190 mL of benzene, then 58.6 g of phenylacetonitrile dissolved in 95 mL of benzene was slowly added to the suspension. The resulting reaction solution was stirred at room temperature for 3 hours and then cooled to 0 ° C. To the solution was slowly added a solution of 41.6 g of epichlorohydrin in 95 mL of benzene. The reaction temperature was then raised to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, and 95 mL of ethanol and 50 mL of 1N-KOH were added to the concentrate, followed by stirring under reflux. The reaction mixture was cooled to 0 ° C. and acidified (pH = 1) with 12N HCl. The solvent was removed under reduced pressure, 1000 mL of ethyl acetate was added to the resulting concentrate, followed by stirring for 30 minutes, and then the precipitate was removed by filtration. The filtered organic layer was washed sequentially with saturated aqueous NaHCO ₃ solution and brine, dried over anhydrous sodium sulfate, and the resulting solution was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (hexane: ethyl acetate = 4: 1) to give 50.4 g of the target compound 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane (yield: 58%) .

¹ H NMR (400 MHz, CDCl ₃ ): 1.28 (1H, t, J = 4.8 Hz), 1.58 (1H, dd, J = 4.8, 7.6 Hz), 2.50 (1H, m), 4.20 (1H, d, J = 9.2 Hz), 4.38 (1H, dd, J = 4.8, 9.2 Hz), 7.32 (5H, m, phenyl)

Example 2: Preparation of (Z) -1-phenyl-1-diethylcarbonyl-2-hydroxymethylcyclopropane

26.6 g of 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane were dissolved in 266 mL of dichloroethane and 22.0 g of AlCl ₃ were added. The reaction temperature was cooled to 0 ° C. and stirred for 10 minutes. At the same temperature, a solution of 32.6 mL of diethylamine in 50 mL of dichloroethane was slowly added to the mixture. The reaction temperature was raised to room temperature and then stirred for 2 hours. To the solution, 1.0 L of cold water was added to terminate the reaction, and further stirred for 10 minutes. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and the resulting solution was concentrated under reduced pressure. The residue was subjected to tube chromatography (hexane: ethyl acetate = 2: 1) to give 31.90 g of the target compound (yield: 86%).

¹ H NMR (400 MHz, CDCl ₃ ): 0.90 (3H, t, J = 7.2 Hz), 1.08 (1H, m), 1.14 (3H, t, J = 7.2 Hz), 1.55 (1H, m), 1.65 (1H, dd, J = 5.2, 9.2 Hz), 3.17 (1H, m), 3.32-3.55 (4H, m), 4.04 (1H, m), 4.74 (1H, br), 7.19-7.35 (5H, m )

Example 3: Preparation of (Z) -1-phenyl-1-diethylcarbonyl-2-hexamethylenetetraammoniummethylcyclopropane-methanesulfonate salt

10.0 g of (Z) -1-phenyl-1-diethylcarbonyl-2-hydroxymethylcyclopropane was dissolved in 30 mL of methylene chloride, and the resulting solution was cooled to 0 ° C. To this solution, 6.7 mL of triethylamine and 3.25 mL of methanesulfonyl chloride were slowly added sequentially. The reaction solution was stirred at room temperature for 30 minutes and 20 mL of water was added to terminate the reaction. The organic layer was collected, washed three times with 20 mL of water and then with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 100 mL of chloroform and 5.04 g of hexamethylenetetraamine were added to the concentrate, followed by stirring at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain an oil phase, to which 200 mL of ethyl acetate was added and stirred for 3 hours. The resulting solid was filtered, washed with ethyl acetate and dried to obtain 10.50 g of the target compound (yield: 56%).

¹ H NMR (300 MHz, DMSO): 0.69 (3H, t, J = 6.9 Hz), 1.04 (3H, t, J = 6.9 Hz), 1.46 (1H, t, J = 6.0 Hz), 1.63 (1H, m), 1.89 (1H, m), 2.30 (3H, s), 3.04-3.17 (4H, m), 3.30-3.45 (2H, m), 7.25-7.38 (5H, m)

Example 4: Preparation of (Z) -1-phenyl-1-diethylcarbonyl-2-hexamethylenetetraammoniummethylcyclopropane-p-toluenesulfonate salt

The reaction was carried out in the same manner as described in Example 3, except that the same equivalent of p-toluenesulfonyl chloride was used instead of methanesulfonyl chloride to give the target compound (yield: 38%).

¹ H NMR (300 MHz, DMSO): 0.69 (3H, t, J = 6.9 Hz), 1.04 (3H, t, J = 6.9 Hz), 1.46 (1H, t, J = 6.0 Hz), 1.63 (1H, m), 1.89 (1H, m), 2.35 (3H, s), 3.04-3.17 (4H, m), 3.30-3.45 (2H, m), 7.25-8.02 (10H, m)

Example 5: Preparation of (Z) -1-phenyl-1-diethylcarbonyl-2-hexamethylenetetraammoniummethylcyclopropane iodide salt

10.0 g of (Z) -1-phenyl-1-diethylcarbonyl-2-hydroxymethylcyclopropane was dissolved in 30 mL of methylene chloride, and the resulting solution was cooled to 0 ° C. To the solution, 6.7 mL of triethylamine was added and stirred for 5 minutes. 3.25 mL of methanesulfonyl chloride was slowly added to the mixture and stirred for an additional 30 minutes. After the reaction was completed, the mixture was washed three times with water and once with brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the concentrate was dissolved in 100 mL of acetone, and then 6.06 g of sodium iodide (NaI) were added and stirred under reflux for 2 hours. Acetone was removed under reduced pressure, and the resulting concentrate was dissolved in 100 mL of chloroform. A solution of 5.04 g of hexamethylenetetraamine in 30 mL of chloroform was slowly added to the solution, and stirred at room temperature for 24 hours. After the reaction was completed, chloroform was concentrated to obtain an oil phase, and 200 mL of ethyl acetate was added thereto, followed by stirring for 3 hours. The resulting solid was filtered to yield 7.5 g of the target compound (yield: 40%).

¹ H NMR (400 MHz, CDCl ₃ ): 0.80 (3H, t, J = 8.0 Hz), 1.14 (3H, t, J = 8.0 Hz), 1.56 (1H, t, J = 4.0 Hz), 1.74 (1H , m), 2.03 (1H, m), 3.21-3.30 (3H, m), 3.36-3.45 (2H, m), 3.53-3.56 (1H, m), 4.50-4.80 (6H, m), 5.48-5.65 (6H, m), 7.22-7.46 (5H, m)

Example 6: Preparation of (Z) -1-phenyl-1-diethylcarbonyl-2-hexamethylenetetraammoniummethylcyclopropane bromide salt

The reaction was carried out in the same manner as described in Example 5, except that the same amount of sodium bromide (NaBr) was used instead of sodium iodide (NaI) (yield: 37% ).

¹ H NMR (300 MHz, DMSO): 0.69 (3H, t, J = 7.2 Hz), 1.04 (3H, t, J = 7.2 Hz), 1.46 (1H, t, J = 5.7 Hz), 1.63 (1H, m), 1.88 (1H, m), 3.11-3.45 (6H, m), 4.43-4.65 (6H, m), 5.16-5.27 (6H, m), 7.25-7.39 (5H, m)

Example 7: Preparation of Milnacifranine Hydrochloride

After dissolving 4.0 g of (Z) -1-phenyl-1-diethylcarbonyl-2-methanesulfonatomethylcyclopropane completely in 10 mL of ethanol, the mixture was stirred under reflux for 2 hours while flowing HCl (g) at room temperature. It was. After the reaction was completed, the reaction temperature was cooled to 0 ° C. and further stirred for 30 minutes. The precipitate was filtered off, and the solvent was concentrated in half under reduced pressure, and 10 mL of ether was added thereto to precipitate a solid. The obtained solid was filtered and dried to obtain 2.13 g of milnacipran hydrochloride (yield: 88%).

Melting Point = 169 ℃-172 ℃

¹ H NMR (300 MHz, CDCl ₃ ): 0.91 (3H, t, J = 7.2 Hz), 1.11-1.15 (4H, m), 1.74 (1H, m), 1.86 (1H, m), 2.47 (1H, m), 3.25-3.47 (4H, m), 3.76 (1H, m), 7.17-7.30 (5H, m)

Reference Example : (Z) -1- Phenyl -One- Diethylcarbonyl -2- Hexamethylenetetraammoniummethylcyclopropane Chloride salt  Produce

6.3 g of (Z) -1-phenyl-1-diethylcarbonyl-2-hydroxymethylcyclopropane are dissolved in 41 mL of methylene chloride, the resulting solution is cooled to 0 ° C., and then 2 mL of SOCl ₂ is slowly added. It was. The reaction solution was stirred at room temperature for 15 minutes, diluted with 41 mL of methylene chloride, and washed with saturated aqueous NaHCO ₃ solution and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The concentrate was dissolved in 70 mL of chloroform, 3.21 g of hexamethylenetetraamine were added and stirred at room temperature for 24 hours. When the reaction was completed, the solvent was concentrated under reduced pressure, 100 mL of ethyl acetate was added and stirred for 3 hours. The resulting solid was filtered and dried to give 2.80 g of the target compound (yield: 27%).

The method for preparing milnacipran hydrochloride according to the present invention provides the following effects.

First, milnacipran hydrochloride is prepared by a short synthetic step. Starting from 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane of the formula (5) as raw material, milnasperan hydrochloride can be efficiently produced in only three steps. This makes it possible to economically prepare milnacipran hydrochloride.

Second, the method for preparing milnacipran hydrochloride according to the present invention may exclude the use of thionyl chloride, which is a toxic substance. This improves the working environment for producing milnacipran hydrochloride and enables to prepare milnacipran hydrochloride under mild conditions.

Third, the method for producing milnacipran hydrochloride according to the present invention introduces an amine group present in the molecule of milnacipran using hexamethylenetetraamine, not phthalimide salt. The use of hexamethylenetetraamine allows for easy introduction of amine groups into the molecules of milnacipran, and conversion to the amine group and the production of milnacipran hydrochloride are achieved simultaneously. This simplifies the manufacturing process of milnacipran hydrochloride and enables efficient preparation of milnacipran hydrochloride.

Claims (8)

a) reacting a compound of formula 4 with a sulfonyl halide in the presence of a base to obtain a compound of formula 3, b) reacting the compound of Formula 3 with hexamethylenetetraamine to obtain (Z) -1-phenyl-1-diethylaminocarbonyl-2-hexamethylenetetraammoniummethyl-cyclopropane salt having formula (2) , c) A process for preparing milnacipran hydrochloride comprising the step of treating the obtained compound with hydrochloric acid to obtain milnasifranal hydrochloride having formula (I). Formula 1

Formula 2

Formula 3

Formula 4

In Formulas 2 and 3, Z is a sulfonate. The method of claim 1 wherein Z is methanesulfonate, p-toluenesulfonate, benzenesulfonate, trifluoromethanesulfonate or nitrobenzenesulfonate. The compound of claim 1, wherein the compound having Formula 4 is reacted with diethylamine in the presence of Lewis acid in 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane Obtained. Formula 5

The method of claim 3, wherein 2-oxo-1-phenyl-3-oxabicyclo [3.1.0] hexane having the formula (5) reacts phenylacetonitrile with epichlorohydrin in the presence of sodium amide, Obtained by sequentially treating with inorganic base and hydrochloric acid. delete delete delete delete