KR100986734B1 - Novel Synthetic Method of Intermediate for Mosapride - Google Patents

Abstract

The present invention relates to a method for preparing an intermediate for preparing mosaprid, specifically, a) a compound of formula (V) containing triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and Intramolecular cyclization in the presence of a dialkylazodicarboxylate to prepare a compound of formula VI; b) reacting the compound of formula VI with formula VII to prepare a compound of formula VIII; And c) reacting the compound of formula (VIII) with methylamine. The present invention relates to a method for preparing an intermediate for preparing mosapride, which is represented by formula (II) while eliminating the use of sulfuric acid.

[Formula II]

[Formula V]

[Formula VI]

[Formula VII]

(VIII)

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t -butyl group.

Mosaprid, intermediate, triphenylphosphine, dialkylazodicarboxylate, dehydration

Description

Method for producing intermediate for producing mosapride {Novel Synthetic Method of Intermediate for Mosapride}

The present invention relates to a method for preparing an intermediate for preparing mosapride, specifically, to 2-aminoethyl-4- (4-fluorobenzyl) -morpholine, which is used as a key intermediate for preparing mosapride. It relates to a manufacturing method.

Mosapride is represented by Formula I below and is a selective stimulant for the 5-Hydroxytryptamine 4 (5-HT4) receptor and exhibits digestive tract hyperactivity as a drug currently being used clinically in patients with functional dyspepsia.

[Formula I]

[Formula II]

2-Aminoethyl-4- (4-fluorobenzyl) -morpholine (2-aminoethyl-4- (4-fluo-robenzyl)-represented by Chemical Formula II as an intermediate for the preparation of the mosaprid morpholine) or a method for preparing morpholine derivatives capable of preparing the same, is similar to the method shown in Scheme 1 below, in Korean Patent Publication Nos. 1995- 8530, International Patent WO 03/106440 and J. Med. Chem. 33 (1990), pp. 1406-1413 and J. Med. Chem. 34 (1991), pp 616-624.

Scheme 1

Representative conventional methods for the preparation of morpholine cyclic compounds used a method of forming intramolecular cyclization by removing water at high temperature using a diol compound as shown in Scheme 1 as a concentrated sulfuric acid as a dehydrating agent. .

As shown in Scheme 1, the key step was to convert the diol compound into a morpholine ring compound, using an excess (3-7 equivalents) of concentrated sulfuric acid as a dehydrating agent at an extremely high reaction temperature. The use of excess concentrated sulfuric acid not only causes severe chemical burns on skin contact, but also entails many limitations such as corrosion of the synthesis apparatus. In addition, waste sulfuric acid requires a large amount of caustic soda and water, there are also environmental and economic problems for waste treatment.

On the other hand, Heterocycles 38, 5 (1994), pp. Asymmetric synthesis of 2-aminomethyl-4- (4-fluorobenzyl) morpholine isomers has been proposed in 1033-1040. However, the synthesis method is a study of the isomers of the compound and thus is not related to optical synthesis in the present invention.

SUMMARY OF THE INVENTION In order to solve the above problems, an object of the present invention is to provide a method for preparing an intermediate for preparing mosapride, which is environmentally safe and efficient while eliminating the use of sulfuric acid to prepare a morpholine ring compound, which is an intermediate for producing mosapride. There is.

In order to achieve the above object, the present invention provides a compound of formula (V) containing triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and dialkylazodicarboxylate of formula XII. Intramolecular cyclization under to prepare a compound of formula VI; b) reacting the compound of formula VI with formula VII to produce a compound of formula VIII; And c) reacting the compound of Formula (VIII) with methylamine. It provides a method for preparing an intermediate for preparing mosapride of Formula (II).

[Formula II]

[Formula V]

[Formula VI]

[Formula VII]

(VIII)

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t -butyl group.

In addition, the present invention provides a process for preparing a compound of formula X in the presence of the triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and the dialkylazodicarboxylate of formula XII. Cyclization within to prepare a compound of Formula VIII; And e) reacting the compound of Formula (VIII) with methylamine. It provides a method for preparing an intermediate for preparing mosapride of Formula (II).

[Formula II]

(VIII)

[Formula X]

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t -butyl group.

In addition, the present invention provides a composition for the preparation of a) a compound of formula V in the presence of a triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and a dialkylazodicarboxylate To prepare a compound of formula VI; b) reacting the compound of formula VI with formula VII to produce a compound of formula VIII; c) reacting the compound of Formula VIII with methylamine to prepare a compound of Formula II; And g) reacting with the mosapride intermediate, triphenyl phosphite, imidazole and the compound of formula (XI) of the compound of formula (II).

[Formula I]

[Formula II]

[Formula V]

[Formula VI]

[Formula VII]

(VIII)

(XI)

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t -butyl group.

In addition, the present invention provides a method for preparing a compound of formula (X) in the presence of the above triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and a dialkylazodicarboxylate of formula Cyclization to prepare a compound of Formula VIII; e) reacting the compound of Formula VIII with methylamine to prepare a compound of Formula II; And h) reacting the mosapride intermediate, triphenyl phosphite, imidazole, and the compound of formula (XI) with the compound of formula (II).

[Formula I]

[Formula II]

(VIII)

[Formula X]

(XI)

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t -butyl group.

Hereinafter, the present invention will be described in detail. In describing the present invention, detailed descriptions of related well-known functions or configurations are omitted in order not to obscure the subject matter of the present invention.

The terms "about "," substantially ", etc. used to the extent that they are used herein are intended to be taken to mean an approximation of, or approximation to, the numerical values of manufacturing and material tolerances inherent in the meanings mentioned, Accurate or absolute numbers are used to help prevent unauthorized exploitation by unauthorized intruders of the referenced disclosure.

A mosafride prepared via 2-aminomethyl-4- (4-fluorobenzyl) morpholine, which is an intermediate of the mosafride of the present invention, is added to Scheme 2 below. Indicated.

Scheme 2

The method for preparing the morpholine intermediate of Formula II in Scheme 2 includes the steps of (1), (2), (4) and (6), and (3), (5) and (6). The fermentation can proceed as a reaction.

First, in the reactions of steps (1), (2), (4), and (6), the step (1) is a condensation of epichlorohydrin (III) and (IV) to diol of formula V Compounds can be readily prepared and are common methods known to those skilled in the art.

In step (2) through step (1), the step of preparing the morpholine intermediate formula VI which is the core of the present invention is carried out by an intramolecular cyclization reaction by dehydration reaction. The dehydration reaction can be either a method of dehydration using a Mitsunobu reaction or a Dean-Stark apparatus.

The Michinobu reaction (reaction A) is a process in which the compound of formula V is converted to triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) in the presence of a dialkylazodicarboxylate of formula XII. The cyclocyclization reaction affords the compound of formula VI.

The michinobu reaction is the presence of triphenylphosphine (Triphenyl posphine; PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and a dialkylazodicarboxylate represented by the following formula (XII). Step (2) is carried out by intramolecular cyclization reaction of the formula (X).

(XII)

Wherein R 'is a linear or nonlinear alkyl group and is a methyl, ethyl, propyl, isopropyl or t -butyl group.

As the condensing agent, the dialkyl azodicarboxylate of formula (XII) is dimethyl azo dicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate or diisopropylazodicarboxylate. t -butyl azodicarboxylate may be used, and 1.0 to 3.0 equivalents, preferably 1.2 equivalents, are used for Formula V. Triphenylphosphine also uses 1.0 to 3.0 equivalents, preferably 1.2 equivalents relative to formula (V).

In the reaction, tetrahydrofuran (THF), Dioxane, Acetonitrile, Dimethylformamide, Dichloromethane, Chloroform, 1, 2-dichloroethane (1,2-dichloroethane), xylene (Xylene), toluene (Touene), acetone (Acetone) and the like can be used, the reaction temperature can be carried out at 0 ℃ ~ 100 ℃.

In addition, another method for preparing the morpholine intermediate formula VI is possible by using a Dean-Stark device, which is well known in the art and detailed description thereof is omitted. The production process using the Dean-Stark apparatus requires an acid catalyst, and in the present invention, hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, methanesulfonic acid, and the like can be used, and the amount of the catalyst is 0.05 to 1.0 equivalents based on the diol compound of Formula V. . An important consideration in using this device is also the choice of solvent, which must be a solvent that is incompatible with water because it must be able to remove water by forming azeotropic with water produced during the reaction. Toluene, xylene, dichloromethane, 1,2-dichloromethane, hexane, octane, heptane and the like may be used as the solvent of the present invention.

In the step (4) after the step (2), the compound of formula (VI) is reacted with formula (VII) in the presence of dimethylformamide (Dimehylformamide) to obtain a compound of formula (VIII).

Through step (4) and in step (6), the compound of formula (VIII) obtained through step (4) is reacted with methylamine to form 2-aminomethyl-4- (4-fluorobenzyl) -moran of formula (II). By obtaining a poly (2-Aminomethyl-4- (4-fluorobenzyl) -morpholine), the mosaprid intermediate of the present invention can be prepared.

Here, steps (4) and (6) are also common methods known to those skilled in the art.

On the other hand, in the reaction passing through the steps (3), (5) and (6), the step (3) is a reaction of the general formula III and the general formula IX can be easily prepared a diol compound of the general formula (X), which It is a known universal method.

In the step (3) to (5), the compound of formula (X) obtained through the step (3) is carried out by an intramolecular cyclization reaction in the A reaction, or the dehydration reaction is carried out using a Dean-Stark apparatus To obtain a compound of formula VIII.

In the present invention, the Mitsunobu reaction represented by the A reaction may be performed.

In the reaction A, the compound of formula (X) obtained through step (3) is converted to triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and dialkylazodicarboxylate of formula XII. In the presence of step (5) to obtain the compound of the formula (VIII) by intramolecular cyclization reaction through the dehydration reaction.

Through step (5) and step (6), the compound of formula (VIII) obtained through step (5) is reacted with methylamine to form 2-aminomethyl-4- (4-fluorobenzyl) -moran of formula (II). By obtaining a poly (2-Aminomethyl-4- (4-fluorobenzyl) -morpholine), the mosaprid intermediate of the present invention can be prepared.

It has a mosapride intermediate that is 2-aminomethyl-4- (4-fluorobenzyl) -morpholine of formula II prepared through step (6). In the presence of Triphenyl phophite (PhO) ₃ P and imidazole, condensation with the reaction of formula XI can produce the mosapride of formula I, which is also known to those skilled in the art. It is a universal way.

As described above, the method for preparing the intermediate for preparing mosapride of the present invention does not use a strong acid during dehydration to provide stability of the reaction and has an environmentally harmless effect for waste treatment.

In addition, the reaction is easy, and since the reaction proceeds continuously until the end without separately separating the intermediate step, there is an effect of providing an efficient and high yield.

Through the following examples will be described in more detail.

Example 1

1.1-chloro-3- [4-fluoro-benzyl) -2- (hydroxy-ethyl) -amino] -propan-2-ol (1-chloro-3- [4-fluoro-benzyl) -2- ( hydroxy-ethyl-amino] -propan-2-ol; Formula V)

(Stage 1

2- (4-fluorobenzylamino) -ethanol [2- (4-fluorobenzyl amino) -ethanol, Formula III] (4.54 g, 26.8 mmol) and epichlorohydrin (IV) (2.61 g, 28.2 mmol) was stirred at 40 to 45 ° C. for 3 hours to prepare 1-chloro-3- [4-fluoro-benzyl) -2- (hydroxy-ethyl) -amino] -propan-2-ol (Formula V). ) Is obtained quantitatively. As a result of HPLC analysis, the product was used for the next reaction without purification with a purity of 90% or more.

2. Preparation of Chloromethyl-4- (4-fluorobenzyl) -morpholine (Formula VI)

(2) step

1-Chloro-3- [4-fluoro-benzyl) -2- (hydroxy-ethyl) -amino] -propan-2-ol (Formula V) prepared in step (1) (6.80 g, 26 mmol) Is dissolved in dichloromethane (100 ml). Triphenylphosphine (7.50 g, 28.6 mmol) is added and cooled to 10 ° C. Diisopropyl azodicarboxylate (5.78 g, 28.6 mmol) was added dropwise for 2 hours. Thereafter, after stirring for 1 hour at room temperature, diluted hydrochloric acid is added to make the aqueous layer reach pH 1-2. The aqueous layer is taken, adjusted to pH 9-10 with dilute caustic soda solution, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield 2-chloromethyl-4- (4-fluorobenzyl) -morpholine (Formula VI) (5.07 g, 80%).

¹ H-NMR (CDCl ₃ ) δ7.32 (t, 2H), 7.04 (t, 2H), 3.95 (d, 2H), 3.54-3.85 (m, 4H), 3.53 (s, 2H), 2.83 (d , 1H), 2.68 (d, 1H), 2.24 (t, 1H), 2.03 (t, 1H).

3.2- [4- (4-fluorobenzyl) -morpholin-2-yl-methyl] isoindole-1,3-dione (2- [4- (fluorobenzyl) -morpholine-2-yl-methyl] isoindol- 1,3-dion, Formula VIII)

(4) step

2-Chloromethyl-4- (4-fluorobenzyl) -morpholine (Formula VI) (6.8 g, 27.9 mmol) and potassium phthalimide (Formula VII) (6.7 g, 36.2 mmol) prepared above To DMF (30 ml) and stirred under reflux for 3.5 hours. After adding water, the precipitated solid was filtered and washed with water to give 2.2- [4- (4-fluorobenzyl) -morpholin-2-yl-methyl] isoindole-1,3-dione as a pale yellow solid. VIII) (8.8 g, 90%).

mp.148-150 ℃

¹ H-NMR (CDCl ₃ ) δ 7.86 (m, 2H, ar), 7.73 (m, 2H, ar), 7.31 (t, 2H, ar), 7.02 (t, 2H, ar), 3.8-4.1 ( m, 3H), 3.4-3.7 (m, 4H), 2.81 (m, 1H), 2.62 (m, 1H), 2.43 (m, 1H), 2.09 (m, 1H).

4.2 Preparation of 2-aminomethyl-4- (4-fluorobenzyl) morpholine (2-aminomethyl-4- (4-fluorobenzyl) morpholine (Formula II)

(6) step

The prepared 2- [4- (4-fluorobenzyl) -morpholin-2-yl-methyl] isoindole-1,3-dione (Formula VIII) (1.54 g, 4.3 mmol) was prepared in 40% -MeNH _2. It is added to (5.1g) and stirred under reflux for 1 hour. After cooling to room temperature, water (7 ml) was added, adjusted to pH 1-2 with 6N-HCl, and extracted with dichloromethane (10 ml, twice). The aqueous layer is taken, basified with 2N-NaOH solution, and extracted with dichloromethane (10 ml, 5 times). Each of the extracted organic layers was combined, dried over K ₂ CO ₃ and dried under reduced pressure to obtain 2-aminomethyl-4- (4-fluorobenzyl) morpholine (Formula II) (0.90 g, 93%) as an oil.

¹ H-NMR (DMSO-d6) δ 7.30 (m, 2H, ar), 7.11 (m, 2H, ar), 3.87 (d, 1H), 3.15-3.55 (m, 4H), 2.71 (d, 1H) , 2.35-2.60 (m, 4H), 1.97 (t, 1H), 1.70 (t, 1H), 1.40 (br, 2H).

5.4-Amino-5-chloro-2-ethoxy-N-{[4- (4-fluorobenzyl) -2-morpholinyl] -methyl} -benzamide (4-amino-5-chloro-2- Preparation of ethoxy-N-{[4- (4-fluorobenzyl) -2-morpholinyl] -methyl} -benzamide (Formula I)

(7) step

2-Aminomethyl-4- (4-fluorobenzyl) morpholine (Formula II) prepared above (0.49 g, 2.18 mmol, 4-amino-5-chloro-2-ethoxybenzoic acid (4-amino-5- Chloro-2-ethoxy benzoic acid, 0.47 g, 2.18 mmol), triphenylphosphite ((PhO) ₃ P) (0.41 g, 3.2 mmol) and imidazole (0.22 g, 3.2 mmol) were acetonitrile (6 ml ) And stirred for 1 day at room temperature After stirring, the precipitated solid is filtered and washed with acetonitrile to give 4-amino-5-chloro-2-ethoxy-N-{[4- (4 -Fluorobenzyl) -2-morpholinyl] -methyl} -benzamide (Formula I) (0.74 g, 80%) is obtained.

¹ H-NMR (CDCl ₃ ) δ 8.25 (t, 1H, NH), 8.10 (s, 1H, ar), 7.29 (m, 2H, ar), 7.02 (m, 2H, ar), 6.30 (s, 1H , ar), 4.39 (s, 2H), 4.06 (q, 2H), 3.89 (m, 1H), 3.60-3.80 (m, 3H), 3.49 (s, 2H), 3.34 (m, 1H), 2.78 ( d, 1H), 2.67 (d, 1H), 2.18 (t, 1H), 2.01 (t, 1H), 1.49 (t, 3H).

Example 2

1. 2- {3- [fluorobenzyl)-(2-hydroxy-ethyl) -amino] -2-hydroxy-propyl} -isoindole-1,3-dione (2- {3- [fluorobenzyl) Preparation of-(2-hydroxy-ethyl) -amino]-2-hydroxy-propyl} -isoindol-1,3-dion;

(3) step

2- (4-fluorobenzylamino) -ethanol [2- (4-fluorobenzyl amino) -ethanol, Formula III] (4.54 g, 26.8 mmol) and N- (2,3-epoxypropyl) -O-phthal Imide [N- (2,3-epoxypropyl) -O-phthalimide, Formula IX] (51.4 g, 0.25 mol) is suspended in toluene (330 ml). The reaction solution is stirred at 120 ° C. for 4 hours and then cooled to 100 ° C. As a result of HPLC analysis, the purity was over 90% and used for the next reaction without any other treatment.

2.2- [4- (4-fluorobenzyl) -morpholine-2-methyl] isoindole-1,3-dione (2- [4- (fluorobenzyl) -morpholine-2-yl-methyl] isoindol-1, Preparation of 3-dion, Formula VIII)

(5) step

Triphenyl phosphine (Triphenyl phosphine, Formula XII) (75.4 g, 0.28 mol) was added to the reaction solution in which Formula X was dissolved, and after cooling to 10 ° C., Diisopropyl azodicarboxylate, 58.1 g , 0.29 mol) is added dropwise for 2 hours. Thereafter, the mixture was warmed to 50 ° C., stirred for 1 hour, 500 ml of ethanol was added thereto, stirred at 80 ° C. for 1 hour, cooled to 20 ° C., and stirred for 4 hours to filter the resulting crystals. It was washed with 100 ml of ethanol and dried to give 2- [4- (4-fluorobenzyl) -morpholin-2-yl-methyl] isoindole-1,3-dione (Formula VIII) of white crystals (81 g, 88%). Get)

mp.148-150 ℃

¹ H-NMR (CDCl ₃ ) δ 7.86 (m, 2H, ar), 7.73 (m, 2H, ar), 7.31 (t, 2H, ar), 7.02 (t, 2H, ar), 3.8-4.1 ( m, 3H), 3.4-3.7 (m, 4H), 2.81 (m, 1H), 2.62 (m, 1H), 2.43 (m, 1H), 2.09 (m, 1H).

Preparation of 2-aminomethyl-4- (4-fluorobenzyl) morpholine (Formula II)

(6) step

2- [4- (4-fluorobenzyl) -morpholin-2-yl-methyl] isoindole-1,3-dione (chemical formula VIII) prepared in the same manner as in step (6) of Example 1 Proceeding to prepare 2-aminomethyl-4- (4-fluorobenzyl) morpholine (Formula II).

4.4-amino-5-chloro-2-ethoxy-N-{[4- (4-fluorobenzyl) -2-morpholinyl] -methyl} -benzamide (4-amino-5-chloro-2- Preparation of ethoxy-N-{[4- (4-fluorobenzyl) -2-morpholinyl] -methyl} -benzamide (Formula I)

(7) step

In the same manner as in step (7) of Example 1 to 2-aminomethyl-4- (4-fluorobenzyl) morpholine (Formula II) prepared as above, 4-amino-5-chloro-2-ethoxy- N-{[4- (4-fluorobenzyl) -2-morpholinyl] -methyl} -benzamide (Formula I) was prepared.

Example 3

Preparation of Chloromethyl-4- (4-fluorobenzyl) -morpholine (Formula VI)

The reaction solution of 2- (4-fluorobenzylamino) -ethanol (4.54 g, 26.8 mmol) and epichlorohydrin (2.61 g, 28.2 mmol) is stirred at 40-45 ^° C. for 3 hours. Add xylene (30 ml) and add c-HCl (1 ml). Water is removed by reflux stirring for 3 hours using a Dean-Stark apparatus. After cooling to about 70 ^° C. sulfuric acid (1.3 g) is carefully added and stirred at reflux for 10 hours. Cool to about 100 ^o C and add 20 ml of water carefully. After cooling to room temperature, the pH was adjusted to about 9 with dilute NaOH solution and the layers were separated. The aqueous layer was extracted with dichloromethane (10 ml) and the combined organic layers were dried over MgSO ₄ and distilled under reduced pressure to give a nearly colorless 2-aminomethyl-4- (4-fluorobenzyl) morpholine (Formula VI) (5.6 g, 85%). ) Is obtained in the oil phase.

The 2-aminomethyl-4- (4-fluorobenzyl) morpholine prepared above proceeds with steps (4) and (6) of Example 1 to 2-aminomethyl-4- (4-fluorobenzyl ) Morpholine (Formula II) was prepared, and proceeded to step (7) to 4-amino-5-chloro-2-ethoxy-N-{[4- (4-fluorobenzyl) -2-morpholinyl ] -Methyl} -benzamide (Formula I) was prepared.

The present invention described above is not limited to the above-described embodiments, and various substitutions, modifications, and changes can be made without departing from the technical spirit of the present invention. It will be obvious to him.

Claims (7)

a) Intramolecular cyclization of a compound of Formula V by a Michinobu reaction in the presence of triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) with a dialkylazodicarboxylate of formula XII To prepare a compound of formula VI; b) reacting the compound of formula VI with formula VII to produce a compound of formula VIII; And c) reacting the compound of Formula VIII with methylamine; Method for producing an intermediate for preparing mosapride of formula II comprising a. [Formula II]

[Formula V]

[Formula VI]

[Formula VII]

(VIII)

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t-butyl group. d) an intramolecular ring of the compound of formula (X) in the presence of a Michinobu reaction in the presence of the triphenylphosphine (PPh ₃ ) or n-tributylphosphine (n-Bu ₃ P) and the dialkylazodicarboxylate of formula (XII) To prepare a compound of formula VIII; And e) reacting the compound of Formula VIII with methylamine; Method for producing an intermediate for preparing mosapride of formula II comprising a. [Formula II]

(VIII)

[Formula X]

(XII)

In formula (XII), R 'is a methyl, ethyl, propyl, isopropyl or t-butyl group. The method according to claim 1 or 2, The compound of formula XII of step a) or d) is dimethylazodicarboxylate. Diethyl azodicarboxylate, Diisopropylazodicarboxylate, or Di-t-butylazodicarboxylate Di-t-butylazodicarboxylate A method for producing an intermediate for preparing mosapride. The method according to claim 1 or 2, The compound of formula (XII) of step a) or d) is 1.0 to 3.0 equivalents to the formula (V) or formula (X) is used for the preparation of the intermediate for preparing mosapride. The method according to claim 1 or 2, As a reaction solvent of step a) or d), tetrahydrofuran (THF), dioxane, acetonitrile, dimethylformamide, dimethylformamide, dichloromethane, chloroform , 1,2-dichloroethane (1,2-dichloroethane), xylene (Xylene), toluene (Touene), acetone (Acetone) and a method for producing an intermediate for preparing a mosa fride selected from the group consisting of a mixture thereof. delete delete