KR100235339B1 - Process for the production of hydroxypiperidincarboxylic acid phenoxyphenyl ester - Google Patents

Abstract

The present invention relates to a method for producing 4-hydroxy-1-piperidinecarboxylic acid 4-phenoxyphenyl ester, wherein 4-phenoxyphenylchloroformmate and 4-hydroxypiperidine are used in a base and an aqueous solution. It is characterized by reacting. This makes it possible to prepare intermediates of triscarbamic acid esters in an industrial method of high purity and high yield and low cost by using environmentally friendly aqueous solutions and bases instead of organic solvents and organic bases that cause environmental pollution.

Description

Method for preparing hydroxypiperidinecarboxylic acid phenoxyphenyl ester

The present invention relates to a method for preparing hydroxypiperidinecarboxylic acid phenoxyphenyl ester, and more particularly, to hydroxypiperidinecarboxylic acid phenoxyphenyl which is an intermediate of triscarbamic acid ester known as cholesterol absorption inhibitor. It relates to a method for producing an ester.

Today, high serum cholesterol (hypercholesterol) is recognized as a dangerous component of cardiovascular disease, one of the major diseases, and coronary vascular disease, the relationship with diseases such as atherosclerosis, familial hypercholesterolemia, and hyperlipidemia Is a well known state.

As enzymes that inhibit the absorption of cholesterol, acyl coenzyme A: cholesterol acyl transferase (hereinafter referred to as "ACAT") and cholesterol esterase (hereinafter referred to as "CEH") are known to be related.

Cholesterol (food cholesterol) taken from food is absorbed by the small intestine mucosa as free cholesterol. Free cholesterol is then esterified by ACAT and collected in chylomicrons, known as particles that collect and transport food cholesterol into the bloodstream and are transported into the bloodstream. ACAT suggests that cholesterol may play an important role in intestinal absorption, according to various studies. DeVries et al, J. Med. Chem. 29, 1131 (1986).

In addition, the removal of CEH from pancreatic fluid in rats has been shown to reduce the absorption of cholesterol in the blood by 80%. Hoisie, J. Biol. Chem. 262, 260-264 (1987). As such, CEH, along with ACAT, is known to be involved in the re-esterification and absorption of exogenous cholesterol.

Tris carbamic acid esters and their intermediates, which are inhibitors of cholesterol absorption, are disclosed in European Patent Publication No. 428, 385 A1, US Patent No. 5,169, 844, and European Patent Publication No. 635, 501 A1. The hydroxypiperidinecarboxylic acid phenoxyphenyl ester of the following structural formula (II), which is an intermediate of triscarbamic acid ester on the phase, is represented by the following general formula (1), and 4-phenoxyphenylchloroform of the following structural formula (I) It is described that the acid is prepared by reacting hydroxypiperidine with an organic base such as pyridine and an organic solvent such as methylene chloride.

However, the method of preparing the compound of formula (II) using the organic solvent and organic base generates impurities and requires a purification process for recrystallization, causing the yield and purity of the desired product to be reduced, and the reaction time is long. The organic solvents and organic bases used in the reaction are industrially uneconomical, and the reactions cause problems of environmental pollution, and have been a problem in the treatment of by-product wastes such as products.

Therefore, the present invention solves the problem of environmental pollution by using environmentally friendly aqueous solution and base instead of organic solvent and organic base, and produces a compound of formula (II) capable of industrial production with high purity and high yield. It is an object to provide a manufacturing method.

1 is an analysis graph of chromatography of a product prepared in an aqueous solution,

2 is an analysis graph of chromatography of a product prepared in a co-solvent,

Figure 3 is an analysis graph of the chromatography of the product prepared according to the conventional manufacturing method,

Figure 4 is an analysis graph of the chromatography of the product prepared by the conventional manufacturing method.

The above object is, according to the present invention, a hydroxypy, characterized in that a phenoxyphenylchloroformmate of the following structural formula (I) is reacted with hydroxypiperidine under a base and an aqueous solution to prepare a compound of the following structural formula (II) It is achieved by the process for preparing ferridinecarboxylic acid phenoxyphenyl ester.

[Formula 1]

In addition, the aqueous solution used in the production method of the present invention is preferably a cosolvent in which water and an organic solvent coexist.

The organic solvent in the co-solvent is any one selected from the group consisting of methylene chloride, ethylene dichloride, chloroform, benzene, toluene, xylene, acetonitrile, tetrahydrofuran, monochlorobenzene, dichlorobenzene and a mixed solvent thereof Preferred, methylene chloride is more preferred.

In addition, the base is preferably any one selected from the group consisting of NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ , KHCO ₃ , K ₂ CO ₃ , Ca (OH) ₂ , Mg (OH) ₂ and mixtures thereof. NaOH is more preferable.

On the other hand, the reaction is preferably carried out in a temperature range of 0 to 50 ℃.

Generally, when the compound of formula (I) and hydroxypiperidine are reacted in a base, two compounds of hydroxypiperidine, that is, an amine group and a hydroxy group, may be used to give the desired compound of formula (II). In addition to the production, impurities of the following structural formula (III) or (IV) are generated, which in turn lowers the yield and purity of the product, so that the compound of the structural formula (II) can be used as a pharmaceutical raw material such as recrystallization of the product. The method requires additional purification.

In addition, in the case of using water as a solvent, the compound of formula (I) reacts with water and is unstable, so water cannot be used alone, and more than one organic solvent causing environmental pollution problem is used, although low yield and low purity are desired. The compound of formula II was prepared.

However, the present inventors have been searching for various methods for obtaining high yield and high purity products using environmentally friendly solvents and bases that can be used instead of organic solvents and organic bases in order to reduce environmental pollution. When reacting in the presence of cosolvent of organic solvent, it is possible to increase the purity and yield considerably more than reacting in organic solvent and organic base, and can be used directly in the next process without the need for further purification of the obtained product. Unexpectedly revealed that the present invention has been completed.

In the preparation process of the present invention, the phenoxyphenol is reacted with phosgene under a basic solution to obtain 4-phenoxyphenylchloroformate of formula (I), and then the compound of formula (I) It is summarized by the preparation process of reacting with hydroxypiperidine in the presence of a base and an aqueous solution or a co-solvent of water / organic solvent to obtain hydroxypiperidinecarboxylic acid phenoxyphenyl ester of the following formula (II).

(1) Preliminary Manufacturing Process

Aprotic solvent, base

Phenoxyphenol + Phosgene ------------------- → Structural Formula (Ⅰ)

The phenoxyphenol used herein is a compound in the market (manufactured by Aldrich), but may be prepared and used by standard methods well known to those skilled in the art.

The phosgene used is a toxic gas that is strictly controlled by the applicant's company and uses a common phosgene.

As the aprotic solvent, benzene, toluene, xylene, methylene chloride, acetonitrile, monochlorobenzene, dichlorobenzene or tetrahydrofuran is used, and the base is N, N-diethylaniline or the like.

(2) Manufacturing Process of Structural Formula (II)

Inorganic base, aqueous solution

Compound of formula (I) + hydroxypiperidine ------------------ → Structural formula (II)

The aqueous solution is pure water or a co-solvent of water and an organic solvent is used, and the organic solvent used in the co-solvent is methylene chloride, ethylene dichloride, chloroform, benzene, toluene, xylene, acetonitrile, tetrahydrofuran, monochloro Benzene, dichlorobenzene, and mixed solvents thereof.

In addition, the base is selected from NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ , KHCO ₃ , K ₂ CO ₃ , Ca (OH) ₂ , Mg (OH) _2, and mixtures thereof. 4-hydroxypiperidine used in the preparation of the compound of formula (I) uses a compound which is commercially available from Aldrich.

Hereinafter, the present invention will be described in detail with reference to Examples.

As a presynthesis step of the compound of the formula (II), the compound of the formula (I) is prepared by performing the phosgenation process of the phenoxyphenol in the preliminary example. Subsequently, the process of synthesizing the compound of formula (II) was performed three times each using the compound of formula (I) in the aqueous layer and the process in the organic layer for comparison, and the results were analyzed by these average values.

Preparative Example (Synthesis of 4-phenoxyphenylchloroformate)

After dissolving 600 ml of methylene chloride and 91.42 g of 4-phenoxyphenol in a 1000 ml four-necked round bottom flask, the solution was cooled to -5 to 5 ° C. 52 ml of phosgene is carefully added to the flask and stirred. Subsequently, a solution of 80.20 g of N, N-diethylaniline and 100 ml of methylene chloride was added dropwise to the flask while maintaining the temperature of the flask at -5 to 5 DEG C for 1-2 hours through a dropping funnel.

After dropping, the temperature is raised to room temperature (15-25 ° C.) and stirred for about 3-4 hours. Subsequently, after confirming completion of the reaction by TLC, excess phosgene is removed under a nitrogen stream, and then washed twice with 1N HCl.

Then, the organic layer was washed twice with cold water (0-10 ° C.), and then a solution of methylene chloride of 4-phenoxyphenylchloroformate (compound of formula (I)) was obtained. In the aqueous solution reaction and the organic solvent reaction, the solvent was evaporated and dried after dehydration to obtain 4-phenoxyphenylchloroformate as a solid powder (yield 95%; melting point 42.0 -43.2 ° C).

Example 1 Synthesis of Compound of Structural Formula (II) under Aqueous Solution

4.07 g of 4-hydroxypiperidine and 200 ml of water are added to 300 ml of a three-necked round bottom flask, followed by stirring to dissolve 1.73 g of sodium hydroxide, followed by stirring for 30 minutes. After raising the temperature of the reaction solution to 40 ° C., 5.0 g of 4-phenoxyphenylchloroformate as a solid powder synthesized in the preliminary example was slowly added for about 30 minutes. After the addition was completed, the reaction was continued for about 16-18 hours while maintaining the temperature of 40 ℃, cooled to room temperature, the pH of the reaction solution was adjusted to 1-2 with 1N hydrochloric acid solution and filtered.

The filter cake obtained is then washed twice with water and once with normal hexane. The product obtained is dried in a vacuum dryer, then weighed and analyzed (melting point: 130.6-132.3 ° C., yield: 90.8%, purity: 99.1%). The results are shown in Table 1 below.

Elemental analysis results: C ₁₈ H ₁₉ NO ₄ Calculated: C: 69.0%, H: 6.11%, N: 4.47%

Measured value: C: 69.3%, H: 6.29%, N: 4.48%

In addition, high performance liquid chromatography (HPLC) was performed to confirm the purity of the obtained product. The analytical conditions used here were columns: CAPCELLPAK (manufactured by Shiseido Co., Ltd.), 5μm, 150 x 4.6mm, the detector was UV-VIS, the wavelength was 230 nm, and the mobil phase used as a developer was methanol / water = 4 / 1 and the flow rate was 1 ml / min. The obtained result is shown in FIG.

Example 2

Except for using 2.65 g of calcium hydroxide instead of sodium hydroxide used in Example 1, the remainder was the same experiment as in Example 1 with the same ingredients and amounts are shown in Table 1 below (melting point: 131.7 -132.6 ° C., yield: 90.2%, purity: 99.2%).

Example 3 Synthesis of Compound of Structural Formula (II) in Co-solvent

4.07 g of 4-hydroxypiperidine and 100 ml of water are added to 300 ml of a three-neck round bottom flask, followed by stirring to dissolve. 1.73 g of sodium hydroxide was added to the obtained solution, dissolved, 100 ml of methylene chloride was added thereto, and the reaction solution was cooled to 5-10 ° C. with sufficient stirring. Then, 5.0 g of 4-phenoxy synthesized in the preliminary example was added. 50 ml of methylene chloride solution in which phenylchloroformate is dissolved is added dropwise for about 1 hour while maintaining the reaction temperature of 5-10 ° C. through a dropping funnel. After dropping, the reaction solution was heated to room temperature and reacted for about 2 hours. After adjusting the pH to 1-2 with 1N hydrochloric acid solution, the organic layer and the water layer were separated, and the organic layer was washed twice with water. The organic layer was removed again with magnesium sulfate, and the solvent was evaporated using a rotary evaporator to obtain a product. The resulting product is dried by vacuum drying to weigh and analyze (melting point: 130.3-131.6 ° C., yield: 98.1%, purity: 99.8%). The results are shown in Table 1 below, and the HPLC results are shown in FIG. 2.

Elemental analysis results: C ₁₈ H ₁₉ NO ₄ Calculated: C: 69.0%, H: 6.11%, N: 4.47%

Measured value: C: 69.4%, H: 6.29%, N: 4.49%

Example 4

Except for the use of ethylene chloride instead of methylene chloride as a solvent used in Example 3, the remainder was the same experiment as in Example 3 with the same components and amounts are shown in Table 1 below (melting point: 130.3-131.8 ° C., yield: 99.0%, purity: 99.9%).

Example 5

4.07 g of 4-hydroxypiperidine and 100 ml of water are added to 300 ml of a three-neck round bottom flask, followed by stirring to dissolve. 1.73 g of sodium hydroxide was added to the obtained solution, dissolved, 100 ml of toluene was added thereto, and the reaction solution was heated to 40 ° C. with sufficient stirring. Then, 5.0 g of 4-phenoxyphenylchloroformate synthesized in the preliminary example was added. The dissolved 70 ml of toluene solution was added dropwise for about 1 hour while maintaining the reaction temperature of 40 ℃ through the dropping funnel. After dropping, the reaction solution was maintained for about 2 hours while maintaining the temperature of the reaction solution, cooled to room temperature, the pH was adjusted to 1-2 with 1N hydrochloric acid solution, the organic layer and the water layer were separated, and the organic layer was washed twice with water. Wash. The organic layer was removed again with magnesium sulfate, and the solvent was evaporated using a rotary evaporator to obtain a product. The resulting product is dried by vacuum drying to weigh and analyze (melting point: 130.8-132.3 ° C., yield: 96.6%, purity: 99.8%). The results are shown in Table 1 below.

Table 1: Synthesis results of the compound of formula II on the aqueous layer Example Solvent Use base Response time (HR) Reaction temperature (℃) Yield (%) Purity of the product (HPLC, area%) One water NaOH 18 40 90.8 99.1 2 water KOH 18 40 90.2 99.2 3 Water / MC NaOH 3 5-20 98.1 99.8 4 Water / EDC NaOH 3 5-20 99.0 99.9 5 Water / toluene NaOH 3 40 96.3 99.8 * MC: methylene chloride ** EDC: ethylene dichloride

The compound of formula (II) prepared by the preparation method of the present invention from the HPLC and yields of Examples 1 to 5 was 90% or more in pure water only, and the HPLC purity was 99% or more. It could be synthesized in high yield and high purity without purification. In addition, when used as a co-solvent of an aqueous solution and an organic solvent, the yield is 96% or more, the HPLC purity is 99% or more, the yield was higher than when using an aqueous solution solvent.

Comparative Example 6 (method of Example 1 of known US Pat. No. 5,169,844)

2.03 g of 4-hydroxypiperidine and 100 ml of benzene were added to a 500 ml three-necked round bottom flask, followed by stirring to dissolve. 3.18 g of pyridine is added to the obtained solution, 15 ml each of methylene chloride and tetrahydrofuran are added thereto, followed by stirring sufficiently, and the temperature of the reactant is cooled to 5 ° C.

50 g of benzene and dioxane solution in which 5.0 g of 4-phenoxyphenylchloroformate dissolved in the preliminary example was dissolved using a dropping funnel prepared in advance was slowly added dropwise for 50 minutes while maintaining the temperature of the reaction solution at 5-10 ° C. After stirring for 3 hours while maintaining the temperature, the reaction mixture was heated to room temperature for about 15 hours. After the sample was collected, the reaction was not completed by TLC. The reaction was terminated by further reacting for 40 hours. After completion of the reaction, benzene was added and the organic layer was separated by washing with 1N hydrochloric acid solution. Then, the organic layer was washed with water, the organic layer was dehydrated with magnesium sulfate, and evaporated under reduced pressure to obtain 3.21 g of a solid product. HPLC analysis results are shown in FIG. 3 (yield: 50.9%, purity: 71.1%).

The product was recrystallized once with normal hexane once to obtain 2.87 g (yield: 45.5%, purity: 92.8%), and again recrystallized twice to obtain 1.09 g, and the HPLC analysis showed a purity of 99.1%. , The results are shown in Table 2 and FIG. 4 (melting point: 130.9-132.6 ° C., yield: 17.3%, document yield: 21%, purity: 99.1%).

Table 2: Synthesis Results of Compound of Structural Formula (II) in an Organic Solvent Recrystallization Solvent Use base Response time (HR) Reaction temperature (℃) Yield (%) Purity of the product (HPLC, area%) Unresolved Benzene / Dioxane / THF / MC Pyridine 40 5-20 50.9 71.1 One-time decision Same as above 45.5 92.8 Re-decision twice Same as above 17.3 99.1 Reference Example Same as above 21.0 * MC: methylene chloride, ** THF: tetrahydrofuran *** Reference Example: Results of Example 1 of US Pat. No. 5,169,844

In order to compare the reaction time, purity and yield in the results of the above Examples and Comparative Examples are shown in Table 3 below.

Table 3: Comparison of Aqueous and Organic Reactions Type of solvent Response time (hr) yield(%) Purity of the product (HPLC, area%) Remarks water 18 90.8 99.1 Example 1 Water / organic solvent 3 98.1 99.8 Example 3 Organic solvents (before purification) 40 50.9 71.1 Comparative Example 6 Organic solvent (after purification) 17.3 99.1

Comparing the aqueous layer reaction and the organic solvent reaction based on the results of the above Examples and Comparative Examples,

First, the reaction was not completed even if the reaction under the organic solvent for 18 hours as in Comparative Example 6, the reaction was completed after 40 hours or more. In addition, the reaction was completed even in the aqueous layer reaction in which only water was synthesized in a solvent for 18 hours. Therefore, the shortening of the reaction time on the industrial side will give a considerable economic effect.

Second, in terms of yield, the yield of water reaction and co-solvent reaction of water / organic solvent are much higher than organic solvent reaction, and the yield is much higher than 40%, which will give significant cost saving effect in industrial aspect.

Third, in terms of purity, the water reaction and the co-solvent reaction of water / organic solvents showed more than 99% of the result without the purification process, and the organic solvent reaction showed the purity of 99% only after the purification process.

According to the recent environmental protection trend, the method for preparing the compound of formula (II) of the present invention should be able to reduce environmental pollution, and because the compound obtained here is used as a raw material of cholesterol absorption inhibitor which is a pharmaceutical, high purity is required. From a perspective, all of these requirements can be met.

As described above, the method for preparing the compound of formula (II) according to the present invention is much better in terms of yield and purity than the conventional method using organic bases of organic solvents and amines, and can also shorten the reaction time and environment. The use of a friendly aqueous solution and inorganic base can solve the environmental pollution problem, when produced on an industrial scale can be produced at low cost triscarbamic acid esters used as cholesterol absorption inhibitors.

Claims (5)

Hydroxypiperidinecarboxylic acid phenoxyphenyl ester characterized by reacting phenoxyphenylchloroformate of formula (I) with hydroxypiperidine in a water solution with a base to produce a compound of formula (II) Manufacturing method. [Formula 1]

The method of claim 1, A method for producing a hydroxypiperidinecarboxylic acid phenoxyphenyl ester, wherein the aqueous solution is a cosolvent of water and an organic solvent. The method of claim 2, The organic solvent in the co-solvent is any one selected from the group consisting of methylene chloride, ethylene dichloride, chloroform, benzene, toluene, xylene, acetonitrile, tetrahydrofuran, monochlorobenzene, dichlorobenzene and a mixed solvent thereof A method for producing a hydroxypiperidinecarboxylic acid phenoxyphenyl ester. The method according to any one of claims 1 to 3, The base is any one selected from the group consisting of NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ , KHCO ₃ , K ₂ CO ₃ , Ca (OH) ₂ , Mg (OH) ₂ and mixtures thereof Method for producing hydroxypiperidinecarboxylic acid phenoxyphenyl ester. The method according to any one of claims 1 to 3, Method for producing a hydroxypiperidinecarboxylic acid phenoxyphenyl ester, characterized in that the reaction is carried out at a temperature range of 0 to 50 ℃.

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