KR102717162B1 - Synthesis method of pelubiprofen intermediate and pelubiprofen - Google Patents

Abstract

Disclosed are an intermediate of felubiprofen, a non-steroidal anti-inflammatory drug (hereinafter referred to as NSAID) having a COX-2 inhibitory mechanism, and a method for synthesizing felubiprofen. The present invention includes a step of obtaining a quaternary amine intermediate represented by the following chemical formula 2 through a substitution reaction between 2-(4-(bromomethyl)phenyl)propionic acid represented by the following chemical formula 1 and hexamethylenetetramine in the presence of a polar solvent, and then hydrolyzing the quaternary amine intermediate in the presence of an acid catalyst to obtain 2-(4-(formyl)phenyl)propionic acid represented by the following chemical formula 3, which is a felubiprofen intermediate, and a step of reacting the 2-(4-(formyl)phenyl)propionic acid with 1-morpholinocyclohexene in the presence of an acid catalyst to obtain felubiprofen represented by the following chemical formula 4.
[Chemical Formula 1]

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

Description

{Synthesis method of pelubiprofen intermediate and pelubiprofen}

The present invention relates to an intermediate of felubiprofen and a method for synthesizing felubiprofen, and more particularly, to a novel method for economically and industrially producing 2-(4-(formyl)phenyl)propanoic acid, a key precursor for the synthesis of felubiprofen, a type of non-steroidal anti-inflammatory drug (hereinafter referred to as NSAID) having a COX-2 inhibitory mechanism, and an industrial synthesis method of felubiprofen using the precursor.

Pelubiprofen is a type of non-steroidal anti-inflammatory drug (NSAID) with a COX-2 inhibitory mechanism, which inhibits the biosynthesis of prostaglandins and exhibits antipyretic, anti-inflammatory, and analgesic effects.

[Chemical Formula 4]

Pelubiprofen is more effective than conventional propionic acid NSAIDs such as Loxoprofen, Ketoprofen, Ibuprofen, and Naproxen, and has fewer gastrointestinal disorders, which are the main side effects of conventional NSAIDs, so it shows excellent therapeutic effects when applied to symptoms of osteoarthritis, rheumatoid arthritis, lumbago, and acute upper respiratory tract inflammation.

Referring to patent documents US 4,254,274, US 4,365,076, and US 4,365,076 of SANKYO, the original developer of Pelubiprofen, the synthesis of Pelubiprofen is generally disclosed as producing Pelubiprofen represented by the following chemical formula 4 through an aldol condensation reaction between an aldehyde intermediate and cyclohexanone or its equivalent, Stork-enamine, as shown in the following reaction scheme a.

[Reaction formula a]

2-(4-(formyl)phenyl)propanoic acid, generally represented by the following chemical formula 3, is a key precursor.

[Chemical Formula 3]

2-(4-(formyl)phenyl)propanoic acid represented by the above chemical formula 3 is generally synthesized through an oxidation reaction of an alcohol precursor, as shown in the following reaction scheme b, and a combination of an aqueous sodium hypochlorite solution and various additives such as activated carbon or TEMPO is used as an oxidizing agent (Korean Patent Nos. 10-1393009, 10-1393010 and Japanese Patent No. Hei 04-36353).

[Reaction formula b]

As an additive used in the above reaction formula b, Korean Patent No. 10-1393009 specifically discloses activated carbon, Korean Patent No. 10-1393010 discloses TEMPO, and Japanese Patent Laid-Open No. Hei 04-36353 discloses that no additive is used.

The above synthetic method has the advantage of proceeding under relatively mild reaction conditions, but it produces a large amount of flexible substances, which is disadvantageous in yield and purity, and since 2-(4-(hydroxymethyl)phenyl)propanoic acid, an alcohol intermediate of felubiprofen, is not commercially available, there is a disadvantage in that it must be prepared through a separate synthetic process for industrial production of tens to hundreds of kg.

Korean Patent No. 10-1475136 discloses a method for synthesizing 2-(4-(formyl)phenyl)propanoic acid under oxidation conditions using TEMPO and an aqueous hydrogen peroxide solution, similar to the reaction conditions of Korean Patent No. 10-1393010, by using 2-(4-(formyl)phenyl)propanoic acid as shown in the following reaction scheme c.

[Reaction formula c]

The above synthetic method has the advantage of using 2-(4-(bromomethyl)phenyl)propanoic acid, which is a common precursor with Loxoprofen, a propionic acid NSAID similar to Felubiprofen, as a starting material and is commercially available in large quantities at low cost. However, it also has the disadvantage of forming a large amount of flexible substances in the process of carrying out the oxidation reaction using an aqueous hydrogen peroxide solution, which is disadvantageous for the yield and purity, and requiring the use of a large amount of TEMPO, which is relatively expensive. Therefore, in order to economically produce Felubiprofen, it is necessary to find a precursor of Felubiprofen that is suitable for mass purchase and production from both an economical and industrial perspective, and to develop a manufacturing method for it.

The purpose of the present invention is to economically synthesize felubiprofen intermediates and felubiprofen by developing a new manufacturing method that overcomes the disadvantages of conventional manufacturing methods.

Another object of the present invention is to provide a felubiprofen intermediate and a method for synthesizing felubiprofen having suitable purity and yield, using 2-(4-(bromomethyl)phenyl)propanoic acid, which can be purchased commercially at low cost, as a starting material and a versatile and safe process that excludes the use of an oxidizing agent such as hypochlorite or hydrogen peroxide.

In order to achieve the above object, the present invention provides a method for synthesizing felubiprofen, including the steps of: obtaining a quaternary amine intermediate represented by the following chemical formula 2 through a substitution reaction between 2-(4-(bromomethyl)phenyl)propionic acid represented by the following chemical formula 1 and hexamethylenetetramine in the presence of a polar solvent, and then hydrolyzing the quaternary amine intermediate in the presence of an acid catalyst to obtain 2-(4-(formyl)phenyl)propionic acid represented by the following chemical formula 3, which is a felubiprofen intermediate; and reacting the 2-(4-(formyl)phenyl)propionic acid with 1-morpholinocyclohexene in the presence of an acid catalyst to obtain felubiprofen represented by the following chemical formula 4.

[Chemical Formula 1]

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]

The felubiprofen intermediate and the method for synthesizing felubiprofen according to the present invention use starting materials that can be purchased commercially at low cost, and exclude the use of an oxidizing agent such as hypochlorite or hydrogen peroxide, making it possible to manufacture the felubiprofen intermediate and felubiprofen more industrially safe and economically.

Hereinafter, the present invention will be described in detail.

The felubiprofen intermediate and the method for synthesizing felubiprofen according to the present invention first disclose a method for synthesizing 2-(4-(formyl)phenyl)propanoic acid, which is a felubiprofen intermediate.

Specifically, referring to the following reaction scheme 1, as a starting material, 2-(4-(bromomethyl)phenyl)propanoic acid represented by the following chemical formula 1 is reacted with hexamethylenetetramine (Hexamethylenetetramine) in the presence of a polar solvent. ) and a substitution reaction to obtain a quaternary amine intermediate represented by the following chemical formula 2, which is then hydrolyzed in the presence of an acid catalyst to obtain 2-(4-(formyl)phenyl)propanoic acid represented by the following chemical formula 3. The reaction for synthesizing 2-(4-(formyl)phenyl)propanoic acid, which is the felubipropene intermediate, represented by a Sommlet reaction, is characterized in that it continuously proceeds in one reactor without separate separation, purification, and drying processes.

[Reaction Formula 1]

The polar solvent used in the substitution process during the above sommlet reaction is an organic solvent, and specifically, the organic solvent is toluene, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide (DMSO), etc., and preferably acetonitrile, dimethylformamide or dimethylsulfoxide (DMSO). The amount of the polar solvent used is 1 to 10 times, and preferably 1 to 5 times.

The amount of hexamethylenetetramine used in the above substitution reaction is 1 to 10 equivalents, preferably 1 to 3 equivalents. If the amount of hexamethylenetetramine used is too small, there is a problem that the yield decreases due to unreacted products, and if it is too large, there is no economic benefit.

The amount of water used for the above hydrolysis is 1 to 5 times, preferably 1 to 5 times.

It is preferable that the crystallization solvent of 2-(4-(formyl)phenyl)propanoic acid represented by the above chemical formula 3 is water.

The intermediate 2-(4-(formyl)phenyl)propanoic acid represented by the chemical formula 3, which is manufactured and separated through the reaction represented by the above reaction formula 1, is 1-Morpholinocyclohexen, as represented by the following reaction formula 2. ) and synthesizes felubiprofen represented by the following chemical formula 4 through stork enamine alkylation in the presence of an organic solvent and an acid catalyst.

Specifically, the enamine of 1-Morpholinocyclohexen is added to the aldehyde portion of 2-(4-(formyl)phenyl)propanoic acid, forming an iminium ion as an intermediate. When an acid catalyst (H+) is added to the formed iminium ion to promote dehydration-condensation and hydrolysis reactions, the enamine is hydrolyzed again into a ketone, and a carbon-carbon double bond is formed through a reaction in which water is removed, thereby synthesizing felubiprofen represented by the following chemical formula 4.

[Reaction Formula 2]

The organic solvent used in the above-mentioned Stoke-enamine condensation reaction is toluene, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide dimethylsulfoxide, etc., and is preferably acetonitrile, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran. The amount of the organic solvent used is 1 to 20 times, and preferably 5 to 15 times.

The acid catalyst used in the above condensation reaction is sulfuric acid, methanesulfonic acid, tosylic acid, acetic acid, formic acid, phosphoric acid, etc., and is preferably acetic acid or phosphoric acid. In addition, the amount of the acid catalyst used is 1 to 10 equivalents, and preferably 1 to 3 equivalents. If the amount of the acid catalyst used is too little, there is a problem that the yield decreases due to unreacted substances, and if it is too much, there is a problem that the yield and purity decrease due to the generation of flexible substances.

It is preferable that the crystallization solvent of felubiprofen represented by the above chemical formula 4 is n-heptane.

The present invention provides a felubiprofen intermediate and a method for synthesizing felubiprofen, which consists of two steps, and comprises using 2-(4-(formyl)phenyl)propanoic acid, which is available in large quantities commercially at a relatively low cost, as a starting material, and producing 2-(4-(formyl)phenyl)propanoic acid, which is a key precursor and an intermediate of felubiprofen, through a sommlet reaction with hexamethylenetetramine. The present invention also provides a method for synthesizing felubiprofen in a safe process by excluding the use of an oxidizing agent such as hypochlorite or hydrogen peroxide.

The present invention is described in more detail through the following examples, but the present invention is not limited to the following examples.

[Example 1] Preparation of intermediate 2-(4-( formyl )phenyl)propanoic acid

Add 80 L of DMSO, 120 L of purified water, and 20 L of acetic acid to the reactor and stir. Add 40 kg of 2-(4-(formyl)phenyl)propanoic acid to the prepared mixed solvent and dissolve completely. Add 46.1 kg of hexamethylenetetramine in small portions while maintaining the temperature below 30°C. After raising the temperature of the reactant to 70 to 80°C, stir for 15 hours to complete the reaction. Add 400 L of purified water to dilute the reactant and use concentrated hydrochloric acid to adjust the pH of the reaction solution to 3 or lower. Add 160 L of MC to the reaction solution, stir for 20 minutes, let stand to separate the layers, and add 160 L of MC to the aqueous layer, stir for 20 minutes, let stand to separate the layers. After combining the extracted organic layers, add 200 L of brine, stir for 20 minutes, allow to settle, separate the layers, and concentrate the organic layer under reduced pressure at 40°C or lower.

Add 40 L of acetonitrile and 40 L of n-heptane to the concentrated residue to dissolve everything, then add 400 L of purified water. Maintain the temperature at 0 to 10°C and stir for an additional hour to crystallize, then filter and wash the filtrate with 80 L of purified water. The filtered wet body was dried under reduced pressure at 50°C or lower to obtain the target compound, 2-(4-(formyl)phenyl)propanoic acid, as a white solid in the form of 18 kg, with a yield of 60%.

[Example 2] Synthesis of Pelubiprofen

Add 180 L of acetonitrile, 19.7 kg of 85% phosphoric acid, and 18 kg of 2-(4-(formyl)phenyl)propanoic acid to the reactor. Maintain the temperature below 30°C, add 25.2 kg of 1-Morpholinocyclohexen, and stir for 15 additional hours while maintaining the same temperature. Increase the temperature of the reactant to 50 to 60°C, stir for 2 more hours to complete the reaction, and concentrate under reduced pressure below 50°C. Add 144 L of MC and 180 L of purified water to the concentrated residue, stir, allow to stand, and separate the layers. Add 180 L of purified water to the separated organic layer, stir, allow to stand, separate the layers, wash, add 1.8 K of anhydrous magnesium sulfate, stir for 30 minutes, and dry. After filtering the dried organic layer, wash with 18 L of MC and concentrate the filtrate under reduced pressure at 40°C or lower. Add 54 L of acetone to the concentrated residue until completely dissolved, then add 125 L of n-heptane. Cool the mixture to 20 to 25°C and stir for 2 more hours to crystallize. Filter the resulting solid, wash with 36 L of n-heptane, and dry under vacuum at 40 to 50°C to obtain 22.1 kg of the target compound, felubiprofen, in a yield of 85%.

Claims (6)

A step of obtaining a quaternary amine intermediate represented by the following chemical formula 2 through a substitution reaction of 2-(4-(bromomethyl)phenyl)propionic acid represented by the following chemical formula 1 with hexamethylenetetramine in the presence of a polar solvent, and then hydrolyzing the quaternary amine intermediate in the presence of an acid catalyst, crystallizing it with water, and filtering it to obtain 2-(4-(formyl)phenyl)propionic acid represented by the following chemical formula 3 in a solid form, which is a felubipropene intermediate; and
A method for synthesizing felubiprofen, comprising the step of reacting the above 2-(4-(formyl)phenyl)propionic acid with 1-morpholinocyclohexene in the presence of an organic solvent and an acid catalyst to obtain felubiprofen represented by the following chemical formula 4.
[Chemical Formula 1]

[Chemical formula 2]

[Chemical Formula 3]

[Chemical Formula 4]
A method for synthesizing felubiprofen, wherein in the step of obtaining the felubiprofen intermediate in claim 1, the polar solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide (DMSO), and mixtures thereof. A method for synthesizing felubiprofen, wherein in the step of obtaining the felubiprofen intermediate in the first paragraph, the amount of hexamethylenetetramine used is 1 to 10 equivalents. A method for synthesizing felubiprofen, wherein in the step of obtaining felubiprofen in claim 1, the organic solvent is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide dimethyl sulfoxide, and mixtures thereof. A method for synthesizing felubiprofen, wherein in the step of obtaining felubiprofen in the first paragraph, the acid catalyst is selected from the group consisting of sulfuric acid, methanesulfonic acid, tosylic acid, acetic acid, formic acid, and phosphoric acid. A method for synthesizing felubiprofen, wherein the amount of the acid catalyst used in claim 5 is 1 to 10 equivalents.