KR101149821B1 - Novel synthetic method of diphenylacetate derivatives - Google Patents

Abstract

The present invention provides a safe and efficient method for preparing propiberine hydrochloride of formula (I), which is an agent for the prevention and treatment of urinary incontinence and urinary incontinence caused by irritable bladder diseases such as neurological bladder disease, neuroanguria disease, unstable bladder disease, chronic cystitis and chronic prostatitis. In more detail, 2-halo-2, 2-diphenylacetate derivatives are prepared from commercially available diphenylacetate derivatives, and substituted with 1-propanol to produce diphenylpropoxy acetic acid esters. After the transesterification reaction with 4-hydroxy-N-methylpiperidine to provide a high-purity propiberine hydrochloride to provide a novel production method that is safer than the existing method and low production cost.
[Formula 1]

Description

Novel synthetic method of diphenylacetate derivatives

The present invention relates to a method for preparing propiberine hydrochloride, and in particular, to provide a novel production method that is completely different from the existing synthetic method using a diphenyl acetate derivative as a starting material.

Profiberine hydrochloride has anticholinergic and calcium antagonistic effects and is used for the prevention and treatment of urinary incontinence, urinary incontinence, neurogenic bladder, neurouria, unstable bladder, chronic cystitis due to bladder irritation and chronic prostatitis.

In addition, as a beta-adrenergic agonists, there is a study to treat hyperactive bladder by stimulating it because of the presence of beta-sympathetic receptor in the detrusor muscle, and as a cardiocyclic antidepressants, children with nocturnal enuresis and urinary incontinence It has been used to increase bladder volume and urethral resistance in patients. The exact pharmacological mechanisms are controversial, but they have alpha-sympathetic stimulation effects by sedative and antihistamine effects and by inhibiting reuptake of norepinephrine and serotonin into the sympathetic nerve endings. Alpha sympathetic blocker is used as a drug to treat the blockage of prostatic hyperplasia and has a good effect on urinary incontinence. In particular, when the bladder is decentralized due to nerve damage, the beta-sympathetic nerve receptor in the bladder is gradually converted into alpha-sympathetic nerve receptor, which reduces the elasticity of the bladder and increases the pressure in the bladder, resulting in urge incontinence. Reduces the risk of improvement and kidney damage.

Conventionally, as a drug which suppresses reflex bladder contraction, oxyvtinine hydrochloride, bamicamide, toterodine, and Japanese Unexamined Patent Publication No. 2-262548, Japanese Unexamined Patent Publication No. 6-92921, Japan Japanese Patent Laid-Open No. 6-135958, Japanese Patent Laid-Open No. 7-258250, Japanese Patent Laid-Open No. 8-291141, Japanese Patent Laid-Open No. 9-71563, WO93 / 16048, WO95 / 06635, WO96 / 33973, WO97 / 13766, The chemicals described in WO97 / 45414 are reported.

On the other hand, patents relating to the manufacturing method for propiberine hydrochloride are disclosed in German Patent 106643 (1974), Chinese Patent 1285348 (2001), Korean Patent Registration 10-0500760 and Korean Patent Publication 10-2005-0103610. . However, there are many problems in the method for preparing propiberine hydrochloride.

That is, the following preparation method specified in the German patent is carried out through the methoxycarbonylation reaction, transesterification reaction of benzylic acid as shown in Scheme 1, the hydroxy diphenyl acetate 1-methyl-piperidine-4 Profiberine hydrochloride is prepared by producing a -yl ester, treating thionyl chloride and then reacting 1-propanol. However, this method is difficult in industrial production due to the low yield in the transesterification reaction and the risk of fire and explosion by using metal sodium as a catalyst. In addition, the use of thionyl chloride (SOCl ₂ ) emits a large amount of sulfurous acid gas and hydrochloric acid gas, there are many restrictions on use in terms of environment.

Scheme 1

The following Chinese patent slightly improves the problem of the German patent, but as shown in Scheme 2, when the benzylic sodium salt is prepared with 5% caustic soda solution of benzylic acid, the reaction time is very long, and 4-chloro-1 Hydroxy-diphenyl acetic acid 1-methyl-piperidin-4-yl ester using -methylpiperidine, followed by chloro-diphenyl acetic acid 1-methyl-piperidine immediately using thionyl chloride without purification The yield is reduced overall by synthesizing the 4-yl ester. In addition, it is difficult to remove the remaining thionyl chloride after the reaction, and in particular, the production cost is high using expensive 4-chloro-1-methyl piperidine. As mentioned above, thionyl chloride has many limitations in use. .

Scheme 2

The following Korean Patent No. 10-0500760 is prepared by adding phosphorus pentachloride to benzylic acid and reacting with 1-propanol and caustic soda to obtain propylbenzylic acid, as shown in Scheme 3 below. Very difficult to do After reacting with 4-hydroxy-1-methylpiperidine, triphenylphosphine, and diezazodicarboxylate to obtain propiberine base, the use of expensive diezoazodicarboxylate is expensive. . In addition, 35% aqueous hydrochloric acid solution and acetone are used when converting to propiberine hydrochloride, and water remaining in the solvent causes a decrease in yield, resulting in a high manufacturing cost.

Scheme 3

 Korean Patent Publication No. 10-2005-0103610 discloses 2-chloro-2,2-diphenylacetylchloride by reacting benzylic acid with thionyl chloride added to toluene, as shown in Scheme 4 below. It must be obtained by crystallization and filtration, and it is difficult to recover by filtration in mass production because it has a property of being moistened in air. In addition, the use of thionyl chloride mentioned above has many limitations in terms of use.

Scheme 4

In order to solve the above problems, the present invention is to provide a method for producing propiberine hydrochloride which is low in production cost, environmentally and industrially safe and efficient while excluding thionyl chloride or phosphorus pentachloride which is not suitable for mass production.

In order to achieve the above object, the present invention provides a method for preparing propiberine hydrochloride, comprising the steps of: a) preparing a compound of formula 3 by halogenation by reacting a diphenylacetate derivative of formula 2 with a halogenating agent; b) preparing a diphenylpropoxy acetic acid ester of Formula 4 by reacting the compound of Formula 3 with 1-propanol; c) a process for preparing propiberine hydrochloride of Formula 1 by a transesterification reaction of the compound of Formula 4 with 4-hydroxy-N-methylpiperidine of Formula 5; to provide.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[In Formula 2 to Formula 4, R is (C1-C10) alkyl with or without substituent, (C6-C20) aryl, (C6-C20) ar (C1-C10) aryl, allyl with or without substituent And any functional group selected from vinyl groups, and X is any one selected from Br, Cl, and I.]

In Formulas 2 to 4, R is more specifically methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, amyl, hexyl, heptyl or phenyl.

In addition, a a halogenating agent may be used in the reaction step a), and in particular, any reagent may be used as long as it is a reagent capable of substituting halogen at an alpha position of a carbonyl group in the compound of Formula 2 with halogen. The halogenating agent that can be preferably used may be a chlorinating agent, a brominating agent or an iodinating agent, more preferably N-chlorosuccinimide (NCS) as the chlorinating agent or N-bromosuccinimide (NBS as the brominating agent ) Can be used.

In addition, in the reaction step a), a catalyst may be used to promote the halogenation reaction, and examples thereof include azobisisobutyronitrile, ammonium acetate, magnesium percronate, Amberlyst-15, NaHSO ₄ ㆍ SiO ₂ , and sulfonic acid. Any one or more selected from sulfonic acid functionalized silica may be used, and the choice of catalyst may be appropriately selected in consideration of the intensity and mildness of the reaction conditions of the user or according to the cost of the catalyst.

In addition, as the reaction conditions of step a), 1.0 to 3.0 equivalents of the halogenating agent may be used, and 0.01 to 0.05 equivalents of the catalyst may be used for 1.0 equivalent of the compound of the diphenyl acetate derivative (Formula 2). Solvents used are hexane, cyclohexane, toluene, benzene, methylene chloride, 1,2-dichloroethane, isopropyl ether, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, N, N-dimethyl Any one or more selected from the group consisting of formamide may be used, and the reaction may include the steps of preparing the compound of Chemical Formula 3 as an intermediate by stirring under a reaction solvent for 1 to 12 hours and then distilling off the solvent under reduced pressure; It may include.

In the reaction of step b), one or more bases selected from the group consisting of N-methylmorpholine, potassium carbonate, triethylamine, tributylamine and sodium hydroxide may be used, and the reaction conditions of b) may be 1 to 6 equivalents of 1-propanol to 1.0 equivalent of a compound in the presence of 1.0 to 3.0 equivalents of base, for 12 to 20 hours in one or more solvents selected from the group consisting of toluene, benzene, methylene chloride and xylene After the reaction by stirring, the solvent may be removed by distillation under reduced pressure to prepare a compound of formula (4) as an intermediate.

The transesterification reaction which is the reaction of step c) may be carried out under an acid or base catalyst and a neutral catalyst other than an acid or base catalyst may be used, and preferred base catalysts are potassium carbonate, sodium carbonate, potassium tert-butoxide, Sodium tert-butoxide, sodium and sodium hydroxide, potassium hydroxide.

In addition, the transesterification reaction of step c) is used in the amount of 0.1 to 3.0 equivalents of the base catalyst with respect to 1.0 equivalent of the compound of formula 4, by distilling the solvent after the reaction in a solvent selected from the group consisting of benzene, hexane, toluene and xylene It may include the step of removing.

Hereinafter, the present invention will be described in more detail.

As described above, the present invention comprises the steps of: a) preparing a compound of formula 3 by halogenation by reacting a commercially useful diphenylacetate derivative (Formula 2) with a halogenating agent; b) preparing diphenylpropoxy acetic acid ester (Formula 4) by reacting the compound of Formula 3 with 1-propanol; c) transesterification by the reaction of the compound of Formula 4 with 4-hydroxy-N-methylpiperidine (Formula 5), and then simple purification to be safer and lower production cost and higher than conventional methods. It provides a method for preparing propiberine hydrochloride (Formula 1) having a purity.

The method for preparing propiberine hydrochloride according to the present invention is shown in Scheme 5, in order to solve the problems of the conventional method, the method for producing propiberine hydrochloride according to the present invention is a halogenated reaction using diphenylacetate derivative as a starting material. After preparing Chemical Formula 3, a substitution reaction with 1-propanol is performed to prepare diphenylpropoxy acetic acid ester. Thereafter, transesterification is carried out in the presence of 4-hydroxy-N-methylpiperidine and a base catalyst to obtain high-purity propibel hydrochloride. This manufacturing method is not only simple and environmentally friendly, but also has a high yield, which has a very low production cost.

Scheme 5

a. Halogenation reaction

In the halogenation step, the compound of Formula 2 is reacted with a halogenating agent to obtain a compound of Formula 3, and the yield is 80 to 100% depending on the reaction conditions. Specifically, the halogenating agent may be any kind as long as it is a reagent capable of substituting halogen at the alpha position of the carbonyl group in the compound of [Formula 2] with halogen. The halogenating agent that can be preferably used may be a chlorinating agent, a brominating agent or an iodinating agent, more preferably N-chlorosuccinimide (NCS) as the chlorinating agent or N-bromosuccinimide (NBS as the brominating agent ) Can be used.

In this case, N-bromosuccinimide or N-chlorosuccinimide may be used in 1 to 10 equivalents, preferably 1 to 3 equivalents, more preferably based on 1.0 equivalent of the compound of Formula 2 It is suitable to use 1.2 equivalents.

The use of a catalyst is preferred in order to increase the reaction rate in this reaction. The catalyst is irradiated with ultraviolet rays or azobisisobutyronitrile (AIBN), ammonium acetate, magnesium perchlorate, Amberlyst-15, NaHSO 4 · SiO 2, sulfonic acid Sulfuric acid functionalized silica may be used, and the choice of catalyst to be used may be appropriately selected in consideration of the intensity and mildness of the reaction conditions of the user or according to the cost of the catalyst.

The amount of catalyst used may be 0.001 to 0.2 equivalents based on Formula 2, preferably using 0.01 to 0.05 equivalents, more preferably 0.02 equivalents.

As the reaction solvent, hexane, cyclohexane, toluene, benzene, methylene chloride, 1,2-dichloroethane, isopropyl ether, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, N, N-dimethylform Amide and the like are possible, the reaction temperature can be carried out at 20 to 200 ℃ but it is usually carried out at 40 to 150 ℃. The reaction may be prepared by stirring the solvent for 7 to 12 hours under a reaction solvent and then distilling off the solvent under reduced pressure to obtain the compound of Chemical Formula 3 as an intermediate.

b. Substitution reaction step

The next reaction is a substitution step using a compound of Formula 3 and one or more bases selected from the group consisting of 1-propanol and N-methylmorpholine, potassium carbonate, triethylamine, tributylamine and sodium hydroxide In this case, the yield of Formula 4 produced at this time is 80 to 100% depending on the reaction conditions. Reaction solvents include hexane, cyclohexane, toluene, benzene, methylene chloride, 1,2-dichloroethane, isopropyl ether, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, N, N-dimethylform Amide or chlorobenzene and the like are possible.

Substitution reaction conditions may include reacting by stirring in the solvent for 12 to 20 hours, the solvent is distilled off under reduced pressure to prepare a compound of formula (4) as an intermediate, 1-propanol used is It is suitable to use 1 to 10 equivalents, preferably 3 to 6 equivalents, and more preferably 4.5 equivalents to the compound of formula 3 above.

c. Transesterification step

The transesterification reaction may be carried out under an acid or base catalyst and a neutral catalyst other than an acid or base catalyst may be used, and as the catalyst used, sulfuric acid, hydrochloric acid or phosphoric acid may be used, and sodium methoxide or Potassium tert-butoxide is used, 4-dimethylaminopyridine or DBU / LiBr as amine catalyst, Al (OiPr) ₃ , NaOiPr, Ti (OiPr) ₄ , Al ₂ as Lewis acid and metal alkoxide catalyst O ₃ can also be used.

In the present invention, a base catalyst is used as the preferred catalyst, but the type of catalyst used may be differently selected according to the price and reaction conditions of the catalyst, and the scope of the present invention is not limited to the base catalyst.

The transesterification reaction is suitably used in an amount of 0.5 to 5 equivalents, preferably 1.0 to 3.0 equivalents, and more preferably 1.1 equivalents based on 1.0 equivalent of the compound of formula (4). It is suitable to use 0.1 to 2.0 equivalents, preferably 0.3 to 1.0 equivalents, more preferably 0.4 equivalents of the catalyst. Solvents used are hexane, cyclohexane, toluene, benzene, methylene chloride, 1,2-dichloroethane, isopropyl ether, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, N, N- Dimethylformamide, xylene and the like.

Further, 4-hydroxy-N-methylpiperidine (Formula 5) used in the reaction is used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents based on 1.0 equivalent of the compound of Formula 4, and more preferably It is appropriate to use 1.1 equivalents.

In the transesterification step, the compound of Formula 4 is warmed in the presence of the catalyst, the solvent is concentrated under reduced pressure, methylene chloride and an aqueous hydrochloric acid solution are added thereto, the mixture is stirred for 1 hour, and then the aqueous layer is removed. After drying with magnesium, the residue obtained by concentrating the filtrate can be crystallized with acetone to obtain propiberine hydrochloride as a compound of Chemical Formula 1 as a target compound. The yield of Formula 1 produced at this time may vary depending on the reaction conditions, but may be obtained in a yield of 60 to 90%.

The method for preparing propiberine hydrochloride, the urinary incontinence treatment agent according to the present invention, is safer and has less risk than the conventional manufacturing method, the purification method is simple, the production process is simple, the production cost is low, and the high purity product can be produced. have.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Example 1 Preparation of methyl 2-bromo-2,2-diphenyl acetate

100 g of methyl diphenyl acetate, 87 g of N-bromosuccinimide (NBS) and 3 g of azobisisobutyronitrile (AIBN) were stirred at 500-85 ° C. under 500 ml of 1,2-dichloroethane for 7 hours. Cool to 20 ° C. and wash with 4% aqueous sodium hyposulfite solution. 20 g of anhydrous magnesium sulfate is added to an organic layer, and it stirred for 30 minutes. Filtration and concentration under reduced pressure gave 135 g of methyl 2-bromo-2,2-diphenyl acetate (yield: 100%).

T.L.C. (hexane: ethyl acetate / 10: 1) = 0.4

¹ H-NMR (CDCl ₃ ): 3.52 ~ 3.63 (s, 3H), 7.26 ~ 7.44 (m, 10H)

Example 2 Preparation of methyl 2-chloro-2,2-diphenyl acetate

100 g of methyl diphenyl acetate, 65 g of N-chlorosuccinimide (NCS), and 3 g of azobisisobutyronitrile (AIBN) were stirred at 80 to 85 ° C. under 500 ml of 1,2-dichloroethane for 12 hours. Cool to 20 ° C. and wash with 4% aqueous sodium hyposulfite solution. 20 g of anhydrous magnesium sulfate was added to the organic layer, stirred for 30 minutes, filtered and concentrated under reduced pressure to obtain 115 g of methyl 2-chloro-2,2-diphenyl acetate (yield: 100%).

T.L.C. (hexane: ethyl acetate / 10: 1) = 0.4

¹ H-NMR (CDCl ₃ ): 3.48 ~ 3.59 (s, 3H), 7.26 ~ 7.44 (m, 10H)

Example 3 Preparation of Diphenylpropoxy Acetate Methyl Ester

135 g of methyl 2-bromo-2,2-diphenylacetate is added to 121 g of 1-propanol and 49 g of triethylamine under 600 milliliters of 1,2-dichloroethane and stirred at 110 to 115 ° C for 12 hours. Cool to 20 ° C. and wash sequentially with 400 ml of purified water and 300 ml of 3N hydrochloric acid solution. 20 g of anhydrous magnesium sulfate is added to the organic layer, the mixture is stirred for 30 minutes, and the solvent is concentrated under reduced pressure to obtain 125 g of diphenylpropoxy methyl acetate (yield: 99%).

T.L.C. (hexane: ethyl acetate / 10: 1) = 0.9

¹ H-NMR (CDCl ₃ ): 0.91 to 0.98 (t, 3H), 1.51 to 1.58 (m, 2H), 3.32 to 3.41 (m, 2H), 3.52 to 3.61 (s, 3H), 7.21 to 7.42 (m , 10H)

Example 4 Preparation of Diphenylpropoxy Acetate Methyl Ester

100 g of methyl diphenyl acetate, 87 g of N-bromosuccinimide and 3 g of azobisisobutyronitrile (AIBN) were stirred at 500-85 ° C. under 500 ml of 1,2-dichloroethane for 7 hours. Cool to 20 ° C. and wash with 4% aqueous sodium hyposulfite solution. 20 g of anhydrous magnesium sulfate was added to the organic layer, stirred for 30 minutes, filtered and washed with 100 milliliters of 1,2-dichloroethane. 121 g of 1-propanol and 49 g of N-methylmorpholine were added to the filtrate, and the mixture was stirred at 110 to 115 ° C for 12 hours. Cool to 20 ° C. and wash sequentially with 400 ml of purified water and 300 ml of 3N hydrochloric acid solution. 20 g of anhydrous magnesium sulfate was added to the organic layer, the mixture was stirred for 30 minutes, and then washed with 100 ml of 1,2-dichloroethane. The filtrate was concentrated under reduced pressure at 80 ° C. to obtain 125 g of diphenylpropoxy methyl acetate (yield: 99%).

Example 5 Preparation of 1- Methyl -4 -piperidylphenylpropoxyacetate hydrochloride

56 g of 4-hydroxy-N-methylpiperidine is added with 22 g of potassium tert-butoxide under 60 ml of dimethylformamide and 1 L of toluene and stirred at 50 to 60 ° C for 1 hour. 125 g of diphenylpropoxy methyl acetate are added and 800 ml of toluene is distilled off at 110-115 degreeC. After cooling to 20 ° C. and washing with 300 L of purified water, 20 g of anhydrous magnesium sulfate was added to the organic layer, stirred for 30 minutes, filtered, and washed with 50 ml of toluene. The filtrate was concentrated under reduced pressure at 80 ° C., and 500 ml of dichloromethane and 250 ml of 3N hydrochloric acid solution were added to the residue, which was then stirred for 1 hour. The aqueous layer was removed, 20 g of anhydrous magnesium sulfate was added to the organic layer, the mixture was stirred for 30 minutes, filtered and washed with 50 ml of dichloromethane. 500 ml of acetone were added to the residue obtained by concentrating under reduced pressure, and stirred at 60 ° C for 2 hours, cooled to 5 ° C, and stirred for 1 hour. The resulting crystals were filtered and dried to give 114 g (80%) of 1-methyl-4-piperidylphenylpropoxyacetate hydrochloride.

T.L.C. (hexane: ethyl acetate / 10: 1) = 0.3

m.p: 213 ~ 216 ℃

Mass: 368.2

¹ H-NMR (CDCl ₃ ): 0.86 to 0.92 (t, 2H), 1.53 to 1.63 (m, 2H), 1.84 to 2.09 (m, 4H), 2.36 to 2.47 (m, 4H), 3.0 to 3.06 (d , 3H), 3.16-3.23 (t, 3H), 5.11 (m, 1H), 7.26-7.44 (m, 10H)

Claims (12)

a) reacting the diphenylacetate derivative of Formula 2 with a halogenating agent to prepare a compound of Formula 3 by halogenation;
b) preparing a diphenylpropoxy acetic acid ester of Formula 4 by reacting the compound of Formula 3 with 1-propanol; And
c) a process for preparing propiberine hydrochloride of Formula 1 by transesterification of the compound of Formula 4 with 4-hydroxy-N-methylpiperidine of Formula 5;
[Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[In Formulas 2 to 4, R is any one functional group selected from (C1-C10) alkyl, (C6-C20) aryl, (C6-C20) ar (C1-C10) aryl, allyl and vinyl groups, X is any one selected from Br, Cl and I.] The method of claim 1,
R is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, amyl, hexyl, heptyl or phenyl. The method of claim 1,
The halogenating agent used in step a) is chlorinating agent, brominating agent and iodide, characterized in that any one selected from, a method for producing propiberine hydrochloride. The method of claim 3,
Said halogenating agent is N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) The manufacturing method of the propibel hydrochloride characterized by the above-mentioned. The method of claim 1,
The reaction of step a) is any one selected from azobisisobutyronitrile, ammonium acetate, magnesium percronate, Amberlyst-15, NaHSO ₄ ㆍ SiO ₂ and sulfonic acid functionalized silica as a catalyst. The above method is used for the preparation of propiberine hydrochloride. 6. The method of claim 5,
The halogenating agent is used in 1.0 to 3.0 equivalents and the catalyst is used in 0.01 to 0.05 equivalents based on 1.0 equivalent of the diphenyl acetate compound of Formula 2 in step a). 6. The method of claim 5,
The reaction solvent of step a) is hexane, cyclohexane, toluene, benzene, methylene chloride, 1,2-dichloroethane, isopropyl ether, ethyl acetate, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and A process for producing propiline hydrochloride comprising one selected from the group consisting of N, N-dimethylformamide. The method of claim 1,
The reaction of step b) is propiberine hydrochloride, characterized in that at least one base selected from the group consisting of N-methyl morpholine, potassium carbonate, triethylamine, tributylamine and sodium hydroxide and potassium hydroxide is used. Manufacturing method. The method of claim 8,
The reaction conditions of step b) is 1,2-dichloroethane, toluene, benzene, methylene chloride and x, in the presence of 1.0 to 3.0 equivalents of base in the presence of 3 to 6 equivalents of 1-propanol relative to 1.0 equivalent of compound of Formula 3 After reacting by stirring in at least one solvent selected from the group consisting of styrene for 12 to 20 hours, the solvent is distilled off under reduced pressure to prepare the compound of formula (4) as an intermediate; Manufacturing method. The method of claim 1,
The transesterification reaction of step c) is characterized in that it is carried out under an acid or base catalyst, a method for producing propiberine hydrochloride. The method of claim 10,
Wherein said base catalyst is at least one selected from the group consisting of potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium and sodium hydroxide, potassium hydroxide. 12. The method of claim 11,
The transesterification is a method for preparing propiberine hydrochloride, characterized in that the base catalyst is used 0.1 to 3.0 equivalents to 1.0 equivalent of the compound of formula (4).