KR102351052B1 - Method of Manufacturing Pyrrolizidine Compound And Method of Manufacturing Pyrrolizidine Hydrochloride Hemihydrate - Google Patents

Abstract

The invention comprises a pyrrolidine compound jidin preparation and pyrrolidine jidin hydrochloride 1/2 hydrate relates to a manufacturing method, according to the present invention, the phosphoryl chloride (Phosphoryl chloride, POCl ₃₎ and pyridine, and further reaction with the aniline intermediate Accordingly, while lowering the manufacturing cost of the pyrrolizidine compound and the pyrrolizidine hydrochloride 1/2 hydrate, it provides the effect of increasing the manufacturing yield while solving the manufacturing environmental problem.

Description

Pyrrolizidine compound manufacturing method and pyrrolizidine hydrochloride 1/2 hydrate manufacturing method {Method of Manufacturing Pyrrolizidine Compound And Method of Manufacturing Pyrrolizidine Hydrochloride Hemihydrate}

The present invention relates to a method for preparing a pyrrolizidine compound and a method for preparing pyrrolizidine hydrochloride 1/2 hydrate, and more particularly, to a method for preparing a pyrrolizidine compound, comprising the step of performing a reaction with _{phosphoryl chloride (POCl 3 ) and pyridine, furthermore, an aniline intermediate} It relates to a method for preparing a pyrrolizidine compound and a method for preparing pyrrolizidine hydrochloride 1/2 hydrate.

Atrial fibrillation, a disease that shows irregular ventricular contraction due to loss of atrial contraction, is the most common arrhythmia, which can be seen in about 0.4 to 2.0% of the general population and about 10% in the elderly over 60 years of age. Atrial fibrillation is an important risk factor for stroke.

In order to treat atrial fibrillation, antiarrhythmic drugs that convert the pulse to a normal sinus rhythm are being used and developed. Pilsicainide, N-(2,6-dimethylphenyl)-8-pyrrolizidinyl Acetamide, N-(2,6-dimethylphenyl)-8-pyrrolizidinyl acet, which is an antiarrhythmic drug Amide) is a drug capable of rapid sinus rhythm conversion and constant sinus rhythm maintenance through rapid and strong drug absorption, and a recent study reported that it is effective in sinus rhythm conversion from atrial fibrillation in patients with no deterioration in left ventricular function.

With respect to this method for producing pilcicainide, Patent Document 1 (EP 0089061 B1) uses thionyl chloride (SOCl ₂ ), but there is a problem that the yield is only 52% (95%). confidence interval of ).

In addition, non-patent document 1 (Seiji Miyano et al, 1985, "New antiarrhythmic agents. N-Aryl-8-pyrrolizidinealkanamides", J. Med. Chem. , 28, pp. 714 with respect to such a method for producing pilcicainide) -717.), as in the following [Scheme 1], various routes of a pilcicainide preparation method from compound (3) to compound (6) and a pilcicainide preparation method from compound (3) to compound (9) describes the reaction of

[Scheme 1]

However, in the latter route, the yield is only 74%, and in the former route, when oxalyl chloride (COCl) ₂ ) is used, the yield is 80%, and sodium hydride (NaH) is used. In this case, the yield is only 83%, so there is an urgent need to develop a method for producing pilsicainide, which still has a high production yield.

European Patent Publication No. EP 0089061 B1 (published December 16, 1987)

Seiji Miyano et al, 1985, "New antiarrhythmic agents. N-Aryl-8-pyrrolizidinealkanamides", J. Med. Chem., 28, pp. 714-717.

The present invention has been filed to solve the above problems, and an object of the present invention is to solve the problems of the manufacturing environment while lowering the manufacturing cost, and at the same time, a pyrrolizidine compound manufacturing method and pyrrolizidine hydrochloride 1/ To provide a method for preparing a dihydrate.

In order to achieve the above object of the present invention, an aspect of the present invention provides a method for preparing a pyrrolizidine compound of the following [Formula 4], comprising the following steps.

_{a) performing a reaction with phosphoryl chloride (POCl 3} ) and pyridine (Pyridine) with respect to the hydrochloride compound of the following [Formula 1], a hydrate or a solvate thereof to generate an intermediate of the following [Formula 2]; and

a') Using the intermediate of [Formula 2] and the aniline intermediate of the following [Formula 2] produced by step a), producing a pyrrolizidine hydrochloride compound of the following [Formula 3], a hydrate or a solvate thereof.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

However, in the above formula, R ¹ to R ³ are each independently a hydrogen atom, a halogen atom, a C ₁ to C ₆ straight-chain or branched alkyl group, a C ₁ to C ₆ straight-chain or branched alkoxy group, or an amino group. All of R ¹ to R ³ may be hydrogen atoms; In terms of use as an antiarrhythmic drug, any one is a halogen atom, a C ₁ -C ₆ linear or branched alkyl group, a C ₁ -C ₆ linear or branched alkoxy group, or an amino group, and the other two are preferably a hydrogen atom; It is more preferable that one is a hydrogen atom and the other two are a halogen atom, a C ₁ -C ₆ linear or branched alkyl group, a C ₁ -C ₆ linear or branched alkoxy group or an amino group.

First, the step a) will be described. The reaction performed in step a) is the hydrochloride salt of [Formula 1] (tetrahydro-1H-pyrrolizidine-7a(5H)-acetic acid hydrochloride, Tetrahydro-1H-pyrrolizine-7a(5H)-acetic acid hydrochloride, CMOH) For the compound, its hydrate or its solvate, phosphoryl chloride (POCl ₃ ) and pyridine are used. As described above, _{when using thionyl chloride (SOCl 2} ) as in Patent Document 1, there is a problem that the yield is remarkably low, and when using oxalyl chloride ((COCl) ₂ ) as in Non-Patent Document 1, the yield is still There is a problem that has not been improved, and phosphoryl chloride (POCl ₃ ) There is a problem that is not suitable for mass production because the cost is higher than that of phosphoryl chloride (POCl 3 ).

Accordingly, the present inventors have completed a method for preparing a pyrrolizidine compound in high yield according to a novel route, and specifically, the present invention _{performs a reaction with phosphoryl chloride (POCl 3} ) and pyridine, the [Formula 2] Provided is a process for preparing a novel pyrrolizidine compound comprising the step of preparing an intermediate. By using phosphoryl chloride (POCl ₃ ) and pyridine, a novel intermediate of the above [Formula 2] is generated, and the reaction proceeds according to a novel mechanism resulting therefrom, thereby ultimately producing a pyrrolizidine compound with improved production yield do.

Step a) is carried out in a chlorinated hydrocarbon organic solvent. Specifically, dichloromethane (Dichloromethane, DCM), chloroform (Chloroform, CF), chlorobenzene (Chlorobenzene, CB), dichlorobenzene (Dichlorobenzene, DCB), dichloroethane (Dichloroethane), trichloroethane (Trichloroethane), trichloroethylene (Trichloroethylene, TCE), tetrachloroethane (Tetrachloroethane), and tetrachloroethylene (Tetrachloroethylene) is carried out in one or more organic solvents selected from the group consisting of. In terms of production yield, it is preferably carried out in chloroform (CF) or dichloromethane (DCM), or more preferably carried out in dichloromethane (DCM).

The molar ratio of the hydrochloride salt of [Formula 1] and the pyridine may have various values, but is preferably 1:1 to 5 in terms of production yield. In addition, when using chloroform (Chloroform, CF) as the organic solvent, it is preferably 1:1 to 4, more preferably 1:1 to 2. When using dichloromethane (DCM) as an organic solvent, it is preferably 1:1 to 4, and more preferably 1:1 to 2.4.

Next, the step a') will be described. In the step a'), the pyrrolizidine hydrochloride compound of Formula 3, its hydrate or its solvate is produced using the intermediate of [Formula 2] and the aniline intermediate produced by the step a). to be.

In this case, step a') may be performed after completing step a), or may be performed simultaneously while step a) is in progress. When proceeding simultaneously, phosphoryl chloride (POCl ₃ ), pyridine and aniline intermediates are simultaneously added to the hydrochloride compound of [Formula 1] to proceed with the reaction. In the present invention, step a) and step a') can be carried out at the same time as described above, so that not only the cost but also the reaction time can be shortened.

The aniline intermediate used in the present invention may include arylamines, and the arylamine intermediate may include intermediates in which R ¹ to R ³ constituting an aryl group are defined above. Specifically, 2,6-dimethylaniline (2,6-Dimethylaniline, 2,6-DMA), 2,3-dimethylaniline (2,3-Dimethylaniline), 2-methylaniline (2-Methylaniline), 4-methyl Aniline (4-Methylaniline), 2,4-dichloroaniline (2,4-Dichloroaniline), 3,4-dichloroaniline (3,4-Dichloroaniline), 2,5-dichloroaniline (2,5-Dichloroaniline), 2 -Chloroaniline (2-Chloroaniline), 3-chloroaniline (3-Chloroaniline), 2,6-difluoroaniline (2,6-Difluoroaniline), 2,5-difluoroaniline (2,5-Difluoroaniline) , 3,4-difluoroaniline (3,4-Difluoroaniline), 2-fluoroaniline (2-Fluoroaniline), 4-fluoroaniline (4-Fluoroaniline), 3-fluoroaniline (3-Fluoroaniline), 2-fluoro-6-chloroaniline (2-Fluoro-6-chloroaniline), 4-fluoro-3-chloroaniline (4-Fluoro-3-chloroaniline), 4-acetoxyaniline (4-Acetoxyaniline); can Among them, it is most preferable to use 2,6-dimethylaniline (2,6-DMA) to achieve the object of the present invention.

The reaction of step a') is carried out at -10 °C to 20 °C, preferably at 0 °C to 20 °C, more preferably at 0 °C to 10 °C.

In one embodiment of the present invention, the step of adding a crystallization solvent to the pyrrolizidine hydrochloride compound of Formula 3, its hydrate or its solvate produced by step a) or step a') is further added. may include

Step b) above will be described. Before proceeding to step b), the method may further include a step of adjusting the pH through a hydroxide compound such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) and separating.

In step b), a crystallization solvent is added to the pyrrolizidine hydrochloride compound of Formula 3, a hydrate thereof or a solvate thereof produced by step a) or step a'), It is a crystallization step to produce a pyrrolizidine compound.

Step b) is carried out at a temperature of 0°C to 10°C. The reason for controlling the temperature as above is as follows: After adjusting the pH through the hydroxide compound, the reaction solution becomes acidic in the process of adding purified water. In this acidic state, the pyrrolizidine hydrochloride of [Formula 3] A problem arises in which the compound is decomposed. In addition, Patent Document 1 and Non-Patent Document 1 maintain the temperature at a high temperature of 100° C. in the process of performing the reaction using sodium hydride (NaH), resulting in side reactions and yield reduction problems. there is

In order to solve this problem, the present invention maintains the temperature of step b) at 0°C to 10°C. To maintain this temperature, it is preferable to use a refrigerant system.

The crystallization solvent added in step b) is ethyl acetate (Ethyl acetate, EA), acetonitrile (ACN), acetone (Acetone), isopropyl acetate (Isopropyl acetate), n-pentane (n-Pentane) and n -It is at least one selected from the group consisting of heptane, and it is preferable to use acetone or n-heptane in terms of the production yield of the pyrrolizidine compound of [Formula 4], and especially acetone in terms of environment-friendliness It is more preferable to use

On the other hand, step b) may further include removing the crystallization solvent by performing filtration from the crystallization mother liquor (Mother liquir) generated during the reaction with the crystallization solvent. The present invention can provide the advantage that even pyrrolizidine hydrochloride 1/2 hydrate, which will be described later, can be prepared only by a single (1-step) process by taking the crystallization method as described above. This corresponds to a point that cannot be achieved in a method using column chromatography for separation.

In particular, the method for preparing a pyrrolizidine compound according to an aspect of the present invention is a compound in which a methyl group is located at the 2 and 6 positions of the phenyl group of the pyrrolizidine compound of the [Formula 4], N-(2, 6-Dimethylphenyl)-8-pyrrolizidinyl acetamide (N-(2,6-dimethylphenyl)-8-pyrrolizidinyl Acetamide) preparation method.

[Formula 5]

.

.

The compound of [Formula 5] corresponds to pilsicainide, a kind of antiarrhythmic drug described in the background art, and an object of an aspect of the present invention is to reduce the manufacturing cost, in particular, to solve the manufacturing environment problem It is to provide a method for producing the pilsicainide with a high production yield while solving the problem

In order to achieve the above object of the present invention, another aspect of the present invention provides a method for preparing pyrrolizidine hydrochloride 1/2 hydrate comprising the following steps.

In addition to the one aspect of the present invention described above, another aspect of the present invention provides a method for preparing pyrrolizidine hydrochloride 1/2 hydrate (Hemihydrate) of the following [Formula 6]. Specifically, further comprising a crystallization step of crystallizing the pyrrolizidine compound of [Formula 4] produced by step b) as a salt of 1/2 hydrate, to prepare a compound suitable for injection or capsule application provide a way

[Formula 6]

However, in the above formula, R ¹ to R ³ are each independently a hydrogen atom, a halogen atom, a C ₁ to C ₆ straight-chain or branched alkyl group, a C ₁ to C ₆ straight-chain or branched alkoxy group, or an amino group.

At this time, step a') in the process of producing the pyrrolizidine hydrochloride 1/2 hydrate of [Formula 6] is the same as described in the method for preparing the pyrrolizidine compound of the [Formula 4], It may proceed after completing all steps a), or may proceed simultaneously while step a) is in progress. When proceeding simultaneously, phosphoryl chloride (POCl ₃ ), pyridine and aniline intermediates are simultaneously added to the hydrochloride compound of [Formula 1] to proceed with the reaction. In the present invention, step a) and step a') can be carried out at the same time as described above, so that not only the cost but also the reaction time can be shortened.

In addition, the contents of steps a) to b) described in the method for preparing the pyrrolizidine compound of [Formula 4] are the same as for the method for preparing the pyrrolizidine hydrochloride 1/2 hydrate of [Formula 6] is applied to

The crystallization step of crystallizing into a salt of the 1/2 hydrate is, c) a first reaction step performed under an acid catalyst in a first solvent, and d) a second solvent is added after removing the first solvent It includes two reaction steps. However, the first solvent and the second solvent are each independently methanol (Methanol, MeOH), ethanol (Ethanol), isopropanol (Isopropanol, IPA), ethyl acetate (Ethyl acetate, EA), tetrahydrofuran (Tetrahydrofuran, THF) , acetonitrile (Acetonitrile, ACN), n-heptane (n-Heptane), acetone (Acetone) and dioxane (Dioxane) is at least one solvent selected from the group consisting of.

In particular, in order to achieve the above object of the present invention, methanol (MeOH) or isopropanol (IPA) is used as the first solvent, and as the second solvent, isopropanol (IPA), n-heptane, ethyl acetate (EA), Using at least one selected from the group consisting of acetone, acetonitrile (ACN), and tetrahydrofuran (THF) is advantageous in terms of work-up, which is a series of processes for completing the reaction. In addition, it is preferable to use isopropanol (IPA) for both the first solvent and the second solvent for reasons such as ease of filtration of the final product in terms of scale-up for industrial production.

The acid catalyst usable in step d) may include at least one selected from the group consisting of sulfuric acid, nitric acid, hydrochloric acid, p-toluene sulfonic acid, phosphoric acid, and the like, preferably hydrochloric acid (HCl) dissolved therein. Methanol (MeOH) solution or concentrated hydrochloric acid (c-HCl) is used, and more preferably, concentrated hydrochloric acid (c-HCl) is used in the range of 0.1 to 1 equivalent based on the pyrrolizidine compound of [Formula 4]. .

In another aspect of the present invention, the method for preparing pyrrolizidine hydrochloride 1/2 hydrate is a compound in which methyl groups are located at the 2 and 6 positions of the phenyl groups of the pyrrolizidine hydrochloride 1/2 hydrate of [Formula 6], the following [Formula 6] 7] of N-(2,6-dimethylphenyl)-8-pyrrolizidinyl acetamide hydrochloride 1/2 hydrate (2,6-dimethylphenyl)-8-pyrrolizidinyl Acetamide Hydrochloride Hemihydrate).

The compound of [Formula 7] is a pilcicanide ^{hydrochloride marketed under the trade name Sunrythm ®} , and is a kind of antiarrhythmic drug marketed as injections and capsules.

[Formula 7]

.

.

According to the present invention, _{including the reaction using phosphoryl chloride (POCl 3} ) and pyridine, and further aniline intermediate, while lowering the manufacturing cost of the pyrrolizidine compound and pyrrolizidine hydrochloride 1/2 hydrate, the manufacturing cost is reduced at the same time It provides the effect of increasing the yield.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are only examples to help the overall understanding of the present invention, and the content of the present invention is not limited to the following examples.

<Example 1> Preparation of pyrrolizidine compound (Preparation Examples 1 to 4, Comparative Preparation Examples 1 to 3)

1. Preparation Example 1

In a 50 mL flask, _{5 mL of chloroform (CHCl 3} ) was injected, tetrahydro-1H-pyrrolizidine-7a(5H)-acetic acid hydrochloride (CMOH) 247mg (1.2mmole), pyridine 380mg (4.8mmole, 4eq) and 2 ,6-dimethylaniline (2,6-DMA) 181mg (1.5mmole, 1.25eq) was injected. While maintaining the temperature at 0-10 °C, phosphoryl chloride _{(POCl 3} ) 202 mg (1.32 mmole, 1.1eq _{) was dissolved in 1 mL of chloroform (CHCl 3} ) and added dropwise, followed by stirring at room temperature for 1 hour. The progress of the reaction was confirmed by thin layer chromatography (TLC).

After the reaction was completed, 10 mL of purified water was injected, and 7.2 mL (6 mmole, 5eq) of a 1N aqueous sodium hydroxide (NaOH) solution was added dropwise to adjust the pH of the mixture to 12-13 and separated. After washing twice with 30 mL of purified water _{, drying over sodium sulfate (Na 2} SO ₄ ), filtration, and concentration under reduced pressure, 5 mL of n-heptane was injected, followed by stirring for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide (yield: 227 mg, yield: 69.4%).

2. Preparation Example 2

The same method as in Preparation Example 1 was performed except that pyridine was injected at a dose of 190 mg (2.4 mmole, 2eq) (yield: 244 mg, yield: 74.6%).

3. Preparation 3

In a 50 mL flask, _{10 mL of dichloromethane (DCM) was injected instead of chloroform (CHCl 3} ), and 615 mg (3 mmole) of tetrahydro-1H-pyrrolizidine-7a (5H)-acetic acid hydrochloride (CMOH), 570 mg (7.2 mmole) of pyridine , 2.4eq) and 2,6-dimethylaniline (2,6-DMA) 460mg (3.75mmole, 1.25eq) were injected, and phosphoryl chloride ( _{POCl 3} ) 506mg (3.3 mmole, 1.1eq) was dissolved in 1 mL of dichloromethane (DCM) and added dropwise, followed by stirring at room temperature for 1 hour. The progress of the reaction was confirmed by thin layer chromatography (TLC).

After the reaction is complete, 10 mL of purified water at 20-25 ℃ is injected, and while maintaining the temperature at 10-20 ℃ using a refrigerant from the outside of the flask, 7.2 mL (6 mmole, 5eq) of 1N sodium hydroxide (NaOH) aqueous solution The mixture was gradually added dropwise to adjust the pH of the mixture to 12-13, followed by separation. After washing twice with 30 mL of purified water _{, drying over sodium sulfate (Na 2} SO ₄ ), filtration, and concentration under reduced pressure, 10 mL of n-heptane was injected, followed by stirring for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide (yield: 690 mg, yield: 84.5%).

4. Preparation 4

Into a 50 mL flask, _{10 mL of dichloromethane (DCM) was injected instead of chloroform (CHCl 3} ), and 20.6 g (0.1 mole) of tetrahydro-1H-pyrrolizidine-7a (5H)-acetic acid hydrochloride (CMOH), 19 g of pyridine ( 0.24mole, 2.4eq), 15.2g (0.125mole, 1.25eq) of 2,6-dimethylaniline (2,6-DMA) was injected, and phosphoryl chloride (POCl ₃ ) while maintaining the temperature at 0 ~ 10 ℃ 16.9 g (0.11 mole, 1.1 eq) was dissolved in 10 mL of dichloromethane (DCM) and added dropwise, followed by stirring while maintaining the temperature at 10° C. or less for 1 hour. The progress of the reaction was confirmed by thin layer chromatography (TLC).

After the reaction is complete, 100 mL of purified water at 20-25 ° C is injected, and 120 mL of 5N sodium hydroxide (NaOH) aqueous solution (0.6 mmole, 5 eq) while maintaining the temperature at 10-20 ° C using a refrigerant from the outside of the flask was slowly added dropwise to adjust the pH of the mixture to 12-13 and separated. After washing twice with 30 mL of purified water _{, drying over sodium sulfate (Na 2} SO ₄ ), filtration, and concentration under reduced pressure, 200 mL of purified water and 30 mL of acetone were injected instead of n-heptane, and 15 hours It was stirred for a while to form crystals. This was filtered and dried using an oven at 40° C. to prepare N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide (yield: 237 g, yield: 87.0%).

5. Comparative Preparation Example 1

Tetrahydro-1H-pyrrolizidine-7a(5H)-acetic acid hydrochloride (CMOH) 205mg (1mmole) was added to a 100 mL flask, and _{10 mL of chloroform (CHCl 3} ) and 205mg (2mmole) of triethylamine were added. injected. While maintaining the temperature at 25 ~ 30 ℃ thionyl chloride (SOCl ₂ ) 178mg (1.5mmole) was added dropwise. After stirring for 30 minutes, 121.7 mg (1 mmole) of 2,6-dimethylaniline (2,6-DMA) was added dropwise and refluxed for 2 hours. The progress of the reaction was confirmed by thin layer chromatography (TLC).

After the reaction was completed, 10 mL of purified water was injected, and a 1N aqueous sodium hydroxide (NaOH) solution was added dropwise to adjust the pH of the mixture to 12-13, followed by separation. After washing twice with 20 mL of purified water _{, drying over sodium sulfate (Na 2} SO ₄ ), filtration, concentration under reduced pressure, and column chromatography separation with N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide was prepared (yield: 150 mg, yield: 55.1%).

6. Comparative Preparation Example 2

In a 100 mL flask, 615 mg (3 mmole) of tetrahydro-1H-pyrrolizidine-7a(5H)-acetic acid hydrochloride (CMOH) was added, and _{30 mL of chloroform (CHCl 3} ) was injected. While maintaining the temperature at 25 ~ 30 ℃ oxalyl chloride ((COCl) ₂ ) 1900mg (15mmole) was added dropwise. After refluxing for 2 hours, the mixture was concentrated under reduced pressure _{to remove residual oxalyl chloride ((COCl) 2} ), chloroform (CHCl ₃ ) 30 mL was injected, and 2,6-dimethylaniline (2,6-DMA) 548 mg (4.5 mmole) ) was added dropwise and refluxed for 2 hours. The progress of the reaction was confirmed by thin layer chromatography (TLC).

After the reaction was completed, 30 mL of purified water was injected, and a 1N aqueous sodium hydroxide (NaOH) solution was added dropwise to adjust the pH to 12-13, followed by separation. After washing twice with 30 mL of purified water _{, drying over sodium sulfate (Na 2} SO ₄ ), filtration, concentration under reduced pressure, and column chromatography separation with N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide was prepared (yield: 628 mg, yield: 76.9%).

7. Comparative Preparation Example 3

In a 100 mL flask, tetrahydro-1H-pyrrolizidine-7a(5H)-acetic acid hydrochloride (CMOH) 615mg (3mmole) was added, chloroform (CHCl ₃ ) 30 mL and triethylamine 610mg (6mmole) were added injected. While maintaining the temperature at 25 ~ 30 ℃ phosphoryl chloride _{(POCl 3} ) 690mg (4.5mmole) was added dropwise. After stirring for 30 minutes, 548 mg (4.5 mmole) of 2,6-dimethylaniline (2,6-DMA) was refluxed for 2 hours. The reaction progress was confirmed by thin layer chromatography (TLC).

After the reaction was completed, 30 mL of purified water was injected, and a 1N aqueous sodium hydroxide (NaOH) solution was added dropwise to adjust the pH to 12-13, followed by separation. After washing twice with 30 mL of purified water _{, drying over sodium sulfate (Na 2} SO ₄ ), filtration, concentration under reduced pressure, and column chromatography separation with N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide was prepared (yield: 460 mg, yield: 56.3%).

<Example 2> Preparation of pyrrolizidine hydrochloride 1/2 hydrate (Preparation Examples 5 to 10)

1. Preparation 5

Methanol (MeOH) 10 mL was injected into a 50 mL flask, 272 mg (1.0 mmole) of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide, 0.5N hydrochloric acid (HCl) was dissolved in methanol After injecting 3 mL (1.5 mmole) of (MeOH) solution, the mixture was stirred at room temperature for 1 hour.

After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol (MeOH), 3 mL of isopropanol (IPA) and 3 mL of n-heptane were injected, and stirred for 15 hours to form crystals. After filtration, it was dried using an oven at 40° C. to prepare 1/2 hydrate of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride (yield: 298 mg, yield: 93.7%) ).

2. Preparation 6

1.5 mL of methanol (MeOH) was injected into a 50 mL flask, 500 mg (1.84 mmole) of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide, 0.168 mL of concentrated hydrochloric acid (c-HCl) (1.92) mmole) was injected, and the mixture was stirred at room temperature for 1 hour.

After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol (MeOH), 3 mL of ethyl acetate (EA) was injected, and the mixture was stirred for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride 1/2 hydrate (yield: 537 mg, yield: 91.8%) .

3. Preparation 7

100 mL of methanol (MeOH) was injected into a 50 mL flask, 500 mg (1.84 mmole) of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide, 0.168 mL (1.92) of concentrated hydrochloric acid (c-HCl) mmole) and stirred at room temperature for 1 hour.

After the reaction was completed, it was concentrated under reduced pressure to remove methanol (MeOH), acetone (3 mL) was injected, and the mixture was stirred for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare 1/2 hydrate of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride (yield: 541 mg, yield: 92.6%) .

4. Preparation 8

1.5 mL of methanol (MeOH) was injected into a 50 mL flask, 500 mg (1.84 mmole) of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide, 0.168 mL of concentrated hydrochloric acid (c-HCl) (1.92) mmole) and stirred at room temperature for 1 hour.

After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol (MeOH), 3 mL of acetonitrile (ACN) was injected, and the mixture was stirred for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare 1/2 hydrate of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride (yield: 542 mg, yield: 92.6%) .

5. Preparation 9

1.5 mL of methanol (MeOH) was injected into a 50 mL flask, 500 mg (1.84 mmole) of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide, 0.168 mL of concentrated hydrochloric acid (c-HCl) (1.92) mmole) and stirred at room temperature for 1 hour.

After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol (MeOH), 3 mL of tetrahydrofuran (THF) was injected, and the mixture was stirred for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare 1/2 hydrate of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride (yield: 552 mg, yield: 94.4%) .

6. Preparation 10

1.5 mL of methanol (MeOH) was injected into a 50 mL flask, 500 mg (1.84 mmole) of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide, 0.168 mL of concentrated hydrochloric acid (c-HCl) (1.92) mmole) and stirred at room temperature for 1 hour.

After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol (MeOH), 3 mL of isopropanol (IPA) was injected, and the mixture was stirred for 15 hours to form crystals. This was filtered and dried using an oven at 40° C. to prepare 1/2 hydrate of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride (yield: 550 mg, yield: 94.0%) .

<Example 3> Preparation of pyrrolizidine hydrochloride 1/2 hydrate through a single (1-step) process (Preparation Example 11)

1. Preparation 11

100 mL of dichloromethane (DCM) was injected into a 500 mL flask, tetrahydro-1H-pyrrolizidine-7a (5H)-acetic acid hydrochloride (CMOH) 20.6 g (0.1 mole), pyridine 19 g (0.24 mole, 2.4 eq) And 2,6-dimethylaniline (2,6-DMA) 460mg (3.75mmole, 1.25eq) was injected, while maintaining the temperature at 0 ~ 10 ℃ phosphoryl chloride _{(POCl 3} ) 16.9g (0.11mol, 1.1) eq) was dissolved in 10 mL of dichloromethane (DCM) and added dropwise, followed by stirring while maintaining the temperature at 10° C. or less for 1 hour. The progress of the reaction was confirmed by thin layer chromatography (TLC).

After the reaction is complete, 100 mL of purified water at 20-25 ° C is injected, and 120 mL of 5N sodium hydroxide (NaOH) aqueous solution (0.6 mmole, 5 eq) while maintaining the temperature at 10-20 ° C using a refrigerant from the outside of the flask was slowly added dropwise to adjust the pH of the mixture to 12-13 and separated. After washing twice with 30 mL of purified water _{, it was dried over sodium sulfate (Na 2} SO ₄ ), filtered, and concentrated under reduced pressure.

Then, 100 mL of acetone (Acetone) and 10.5 mL (0.12 mmole, 1.2eq) of concentrated hydrochloric acid (c-HCl) were injected, crystals were formed, and the mixture was stirred at room temperature for 1 hour. This was filtered and dried using an oven at 40° C. to prepare 1/2 hydrate of N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride (yield: 27.7 g, yield: 87.1%) ).

Although the present invention has been described with reference to the above-mentioned preferred embodiments, various modifications and variations are possible without departing from the spirit and scope of the invention. Accordingly, it is intended that the appended claims cover such modifications and variations as fall within the scope of the present invention.

Claims (19)

_{a) performing a reaction with phosphoryl chloride (POCl 3} ) and pyridine with respect to the hydrochloride compound of the following [Formula 1], a hydrate or a solvate thereof to produce an intermediate of the following [Formula 2]; and
a') using the intermediate of [Formula 2] and the aniline intermediate of the following [Formula 2] produced by step a) to produce a pyrrolizidine hydrochloride compound of the following [Formula 3], a hydrate or a solvate thereof
Including, wherein the molar ratio of the hydrochloride compound and pyridine of [Formula 1] is 1:1 to 5, the method for preparing a pyrrolizidine compound of the following [Formula 4]:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

However, in the above formula, R ¹ to R ³ are each independently a hydrogen atom, a halogen atom, a C ₁ to C ₆ linear or branched alkyl group, a C ₁ to C ₆ linear or branched alkoxy group, or an amino group. a) A pyrrolizidine hydrochloride compound of the following [Formula 3] by performing a reaction with _{phosphoryl chloride (POCl 3} ), pyridine and an aniline intermediate with respect to the hydrochloride compound of the following [Formula 1], a hydrate or a solvate thereof, producing a hydrate thereof or a solvate thereof;
Including, wherein the molar ratio of the hydrochloride compound and pyridine of [Formula 1] is 1:1 to 5, the method for preparing a pyrrolizidine compound of the following [Formula 4]:
[Formula 1]

[Formula 3]

[Formula 4]

However, in the above formula, R ¹ to R ³ are each independently a hydrogen atom, a halogen atom, a C ₁ to C ₆ straight-chain or branched alkyl group, a C ₁ to C ₆ straight-chain or branched alkoxy group, or an amino group. 3. The method of claim 1 or 2,
b) adding a crystallization solvent to the pyrrolizidine hydrochloride compound of [Formula 3], a hydrate thereof or a solvate thereof produced by step a) or step a')
Further comprising, a pyrrolizidine compound preparation method. 3. The method of claim 1 or 2,
wherein step a) is carried out in one or more organic solvents selected from the group consisting of dichloromethane, chloroform, chlorobenzene, dichlorobenzene, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethane, and tetrachloroethylene, A method for preparing a pyrrolizidine compound. 4. The method of claim 3,
wherein step a) is carried out in one or more organic solvents selected from the group consisting of dichloromethane, chloroform, chlorobenzene, dichlorobenzene, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethane, and tetrachloroethylene, A method for preparing a pyrrolizidine compound. 4. The method of claim 3,
The step b) is carried out at a temperature of 0 ℃ to 10 ℃, pyrrolizidine compound preparation method. 4. The method of claim 3,
The crystallization solvent added in step b) is at least one selected from the group consisting of ethyl acetate, acetonitrile, acetone, isopropyl acetate, n-pentane and n-heptane, a method for preparing a pyrrolizidine compound. 3. The method of claim 1 or 2,
The produced pyrrolizidine compound of [Formula 4] is N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide of the following [Formula 5], a method for preparing a pyrrolizidine compound:
[Formula 5]

. _{a) performing a reaction with phosphoryl chloride (POCl 3} ) and pyridine with respect to the hydrochloride compound of the following [Formula 1], a hydrate or a solvate thereof to produce an intermediate of the following [Formula 2]; and
a') using the intermediate of [Formula 2] and the aniline intermediate of the following [Formula 2] produced by step a) to produce a pyrrolizidine hydrochloride compound of the following [Formula 3], a hydrate or a solvate thereof
Including, wherein the molar ratio of the hydrochloride compound of [Formula 1] and pyridine is 1:1 to 5, the method for preparing pyrrolizidine hydrochloride 1/2 hydrate of the following [Formula 6]:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 6]

However, in the above formula, R ¹ to R ³ are each independently a hydrogen atom, a halogen atom, a C ₁ to C ₆ straight-chain or branched alkyl group, a C ₁ to C ₆ straight-chain or branched alkoxy group, or an amino group. a) A pyrrolizidine hydrochloride compound of the following [Formula 3] by performing a reaction with _{phosphoryl chloride (POCl 3} ), pyridine and an aniline intermediate with respect to the hydrochloride compound of the following [Formula 1], a hydrate or a solvate thereof, producing a hydrate thereof or a solvate thereof;
Including, wherein the molar ratio of the hydrochloride compound of [Formula 1] and pyridine is 1:1 to 5, the method for preparing pyrrolizidine hydrochloride 1/2 hydrate of the following [Formula 6]:
[Formula 1]

[Formula 3]

[Formula 6]

However, in the above formula, R ¹ to R ³ are each independently a hydrogen atom, a halogen atom, a C ₁ to C ₆ straight-chain or branched alkyl group, a C ₁ to C ₆ straight-chain or branched alkoxy group, or an amino group. 11. The method of claim 9 or 10,
b) adding a crystallization solvent to the pyrrolizidine hydrochloride compound of [Formula 3], a hydrate thereof or a solvate thereof produced by step a) or step a')
Further comprising, pyrrolizidine hydrochloride 1/2 hydrate production method. 11. The method of claim 9 or 10,
wherein step a) is carried out in one or more organic solvents selected from the group consisting of dichloromethane, chloroform, chlorobenzene, dichlorobenzene, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethane, and tetrachloroethylene, Method for preparing pyrrolizidine hydrochloride 1/2 hydrate. 12. The method of claim 11,
wherein step a) is carried out in one or more organic solvents selected from the group consisting of dichloromethane, chloroform, chlorobenzene, dichlorobenzene, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethane, and tetrachloroethylene, Method for preparing pyrrolizidine hydrochloride 1/2 hydrate. 12. The method of claim 11,
Step b) is carried out at a temperature of 0 °C to 10 °C, pyrrolizidine hydrochloride 1/2 hydrate preparation method. 12. The method of claim 11,
The crystallization solvent added in step b) is at least one selected from the group consisting of ethyl acetate, acetonitrile, acetone, isopropyl acetate, n-pentane and n-heptane, pyrrolizidine hydrochloride 1/2 hydrate. 12. The method of claim 11,
c) a first reaction step carried out under an acid catalyst in a first solvent; and
d) a second reaction step performed by adding a second solvent after removing the first solvent
A method for preparing pyrrolizidine hydrochloride 1/2 hydrate further comprising:
However, the first solvent and the second solvent are each independently at least one solvent selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, n-heptane, acetone and dioxane. 11. The method of claim 9 or 10,
The generated pyrrolizidine hydrochloride 1/2 hydrate of [Formula 6] is N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride 1/2 hydrate of the following [Formula 7], P Method for preparing Rolizidine Hydrochloride 1/2 hydrate:
[Formula 7]

. 12. The method of claim 11,
The generated pyrrolizidine hydrochloride 1/2 hydrate of [Formula 6] is N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride 1/2 hydrate of the following [Formula 7], P Method for preparing Rolizidine Hydrochloride 1/2 hydrate:
[Formula 7]

. 17. The method of claim 16,
The generated pyrrolizidine hydrochloride 1/2 hydrate of [Formula 6] is N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride 1/2 hydrate of the following [Formula 7], P Method for preparing Rolizidine Hydrochloride 1/2 hydrate:
[Formula 7]

.