KR101388770B1 - Manufacturing method of urocanic acid using novel intermediate compound - Google Patents

Abstract

본 발명에 따른 중간체 화합물의 제조방법은 우로카닌산 제조시 염기 하에서 2-아미노-3-(1H-이미다졸-5-일)프로판산을 요오드메탄과 반응시키는 종래의 제조방법과 달리 1-아릴알킬-4(5)-브로모 이미다졸을 금속 촉매 하에서 반응시키므로 생성물의 정제와 반응 종결이 용이하다. 또한, 본 발명에 따른 중간체 화합물인 (E)-알킬 3-(1-아릴알킬-1H-이미다졸-4(5)-일)아크릴레이트로부터 널리 알려진 탈보호화 반응을 통해 (E)-알킬 3-(1H-이미다졸-4-일)아크릴레이트을 얻을 수 있고, 이후 일반적인 가수분해 반응을 통해 우로카닌산[(E)-3-(1H-이미다졸-4-일)아크릴산]을 수득할 수 있다. 따라서, 본 발명에 따른 중간체 화합물은 우로카닌산를 비롯한 다양한 산업 분야에서 유용하게 사용되는 화합물을 제조하는데 이용될 수 있다.The present invention relates to an intermediate compound useful for the production of urocanic acid and a process for producing the intermediate compound. The present invention provides an intermediate compound represented by the following formula (4) and a process for producing the same.
[Chemical Formula 4]

The process for the preparation of the intermediate compound according to the present invention is characterized in that unlike the conventional preparation method of reacting 2-amino-3- (1H-imidazol-5-yl) propanoic acid with iodomethane under a base in the production of uronic acid, Alkyl-4 (5) -bromoimidazole is reacted in the presence of a metal catalyst, so that purification and termination of the reaction are easy. Further, the deprotection reaction known from the intermediate compound according to the present invention as (E) -alkyl 3- (1-arylalkyl-1H-imidazol-4 (5) - (1H-imidazol-4-yl) acrylate can be obtained, and then a general hydrolysis reaction can be carried out to obtain a urocanin acid [(E) -3- have. Therefore, the intermediate compound according to the present invention can be used for preparing a compound useful in various industrial fields including urocanic acid.

Description

Manufacturing method of urocanic acid using novel intermediate compound

The present invention relates to novel intermediate compounds and methods for their preparation, and more particularly, to intermediate compounds useful for the preparation of urokanoic acid and methods for their preparation.

(E) -3 (1H-imidazol-4-yl) acrylic acid [(E) -3 (1H-imidazol-4-yl) acrylic acid].

[Chemical Formula 1]

Urocannic acid is one of the NMF (natural moisturizing factor) components in the stratum corneum and is known to contribute to defense of DNA damage induced by UVB as a natural ultraviolet absorber. have. Korean Patent Registration No. 10-0533247 also discloses a chitosan derivative modified with urocanic acid and a novel gene carrier capable of raising gene expression rate by inducing rapid release from endosomes as a use thereof and a genetic disease therapeutic agent containing the chitosan derivative as an active ingredient .

The conventional technique for producing the above urocanic acid is as follows.

[Reaction Scheme 1]

2-amino-3- (1H-imidazol-5-yl) propanoic acid] is reacted with 2-amino- And reacted with iodomethane to produce urocanic acid [ Chemistry of Natural Compounds , 2007 , 43, 143-148]. However, in the above production method, there is a problem in that there is a problem in safety because of using an excessive amount of acid in the reaction termination process, and there is a problem in that it is environmentally harmful. In addition, it is disadvantageous in that purification is not easy due to the solubility problem of the final product.

The present invention has been made to solve the conventional problems, and one object of the present invention is to provide novel intermediate compounds useful for the production of urocanic acid.

It is a further object of the present invention to provide a process for preparing novel intermediate compounds useful for the production of urocanic acid.

In order to solve one object of the present invention, the present invention provides an intermediate compound represented by the following formula (4).

[Chemical Formula 4]

In Formula 4, R ₁ represents an alkyl group having 1 to 10 carbon atoms, at least one hydrogen atom of which is substituted with aryl having 6 to 14 carbon atoms, a benzyl group substituted with a halogen group, or a benzyl group substituted with an alkoxy group having 1 to 3 carbon atoms. And R ₂ is alkyl having 1 to 10 carbon atoms.

According to another aspect of the present invention, there is provided a process for preparing an intermediate compound represented by the following formula (4), comprising the step of reacting a compound represented by the formula (2) .

(2)

(3)

[Chemical Formula 4]

Formula 2, R ₁ in the formula (3) and formula (4) is of a carbon number of 1 to 10 hydrogen atoms at least one of the alkyl having 6 to an aryl substituted with a 14 aryl group, a substituted benzyl group, halogen, or C 1 -C 3 alkoxy Substituted benzyl, R ₂ is alkyl having 1 to 10 carbon atoms, and X is a halogen atom.

The process for the preparation of the intermediate compound according to the present invention is characterized in that unlike the conventional preparation method of reacting 2-amino-3- (1H-imidazol-5-yl) propanoic acid with iodomethane under a base in the production of uronic acid, Alkyl-4 (5) -bromoimidazole is reacted in the presence of a metal catalyst, so that purification and termination of the reaction are easy. Further, the deprotection reaction known from the intermediate compound according to the present invention as (E) -alkyl 3- (1-arylalkyl-1H-imidazol-4 (5) - (1H-imidazol-4-yl) acrylate can be obtained, and then a general hydrolysis reaction can be carried out to obtain a urocanin acid [(E) -3- have. Therefore, the intermediate compound according to the present invention can be used for preparing a compound useful in various industrial fields including urocanic acid.

Hereinafter, the present invention will be described in detail.

One aspect of the invention relates to intermediate compounds useful for the production of < RTI ID = 0.0 >

Intermediate compound

The intermediate compound according to the present invention is a compound represented by the following formula (4).

[Chemical Formula 4]

In Formula 4, R ₁ represents an alkyl group having 1 to 10 carbon atoms, at least one hydrogen atom of which is substituted with aryl having 6 to 14 carbon atoms, a benzyl group substituted with a halogen group, or a benzyl group substituted with an alkoxy group having 1 to 3 carbon atoms. And R ₂ is alkyl having 1 to 10 carbon atoms. In this case, R ₁ serves as a protecting group and is preferably selected from the group consisting of benzyl, diphenylmethyl, trimethyl methyl, methoxybenzyl, dimethoxybenzyl, Fluorobenzyl, chlorobenzyl, or dichlorobenzyl. When considering commercial availability and suitability of the protective function, benzyl or trimethyl methyl may be used. Is more preferable. R ₂ is a functional group corresponding to the alkyl of the alkyl acrylate used for preparing the intermediate compound represented by the general formula (4), and is preferably any one selected from methyl, ethyl and propyl, More preferably, it is methyl or ethyl when considering the ease.

The intermediate compounds according to the present invention can be used to prepare a variety of novel compounds and are preferably used as intermediates for the preparation of the urocanic acid. The method for producing the urocanic acid from the intermediate compound according to the present invention will be described in more detail in "Method for producing urotannic acid from the intermediate compound", which uses a known deprotection and hydrolysis reaction.

Another aspect of the present invention relates to a process for preparing an intermediate compound useful for the production of < RTI ID = 0.0 >

Method for preparing intermediate compounds

The process for preparing an intermediate compound represented by the following formula (4) according to the present invention comprises reacting a compound of the following formula (2) with a compound of the following formula (3) in the presence of a base and a metal catalyst.

(2)

(3)

[Chemical Formula 4]

Formula 2, R ₁ in the formula (3) and formula (4) is of a carbon number of 1 to 10 hydrogen atoms at least one of the alkyl having 6 to an aryl substituted with a 14 aryl group, a substituted benzyl group, halogen, or C 1 -C 3 alkoxy Substituted benzyl, R ₂ is alkyl having 1 to 10 carbon atoms, and X is a halogen atom. In this case, R ₁ serves as a protecting group and is preferably selected from the group consisting of benzyl, diphenylmethyl, trimethyl methyl, methoxybenzyl, dimethoxybenzyl, Fluorobenzyl, chlorobenzyl, or dichlorobenzyl. When considering commercial availability and suitability of the protective function, benzyl or trimethyl methyl may be used. Is more preferable. R ₂ is a functional group corresponding to the alkyl of the alkyl acrylate used for preparing the intermediate compound represented by the general formula (4), and is preferably any one selected from methyl, ethyl and propyl, More preferably, it is methyl or ethyl when considering the ease. Also, X is preferably chlorine or bromine when considering commercial availability and reactivity.

The compound represented by the general formula (2) is generally named 1-arylalkyl-4 (5) -haloimidazole and is commercially available or can be prepared by various methods . For example, by reacting 4 (5) -halo-1H-imidazole (specific example, 4 (5) -bromo-1H-imidazole) with an arylalkyl halide (specific example is benzyl chloride, triphenylmethyl chloride) Benzyl imidazole, 1-triphenylmethyl imidazole] and N-halosuccinimide [specific examples include N-bromosuccinimide (NBS), N-chlorosuccinimide Succinimide (NCS), N-fluorosuccinimide (NFS), or N-iodosuccinimide (NIS)].

The compound represented by the above formula (3) is generally named alkyl acrylate and may be commercially available or may be prepared by various methods.

The method for preparing the intermediate compound represented by Chemical Formula 4 according to the present invention is carried out in the presence of a base and a metal catalyst. The base used is not particularly limited and includes, for example, sodium bicarbonate, sodium carbonate, Potassium, potassium carbonate, triethylamine, tributylamine, or tribenzylamine. Of these, potassium carbonate or triethylamine can be preferably used. The type of the metal catalyst is not particularly limited as long as it functions to substitute the halogen group (X) of the compound represented by the formula (2) with a compound represented by the formula (3), such as a platinum catalyst, a vanadium catalyst and a palladium catalyst. In consideration of selectivity and reactivity, palladium catalyst is preferable.

Hereinafter, the method for preparing the intermediate compound represented by Formula 4 according to the present invention will be described in detail with reference to Reaction Scheme 2 below. In the following Reaction Scheme 2, 1-arylalkyl-4 (5) -bromoimidazole is used as a compound represented by Formula 2 and a palladium catalyst is used as a metal catalyst.

[Reaction Scheme 2]

The reaction of Reaction Scheme 2 is carried out in an organic solvent. The type of the organic solvent is not limited as long as it is a known inert organic solvent, and examples thereof include acetonitrile, tetrahydrofuran, toluene, N, It may be selected from one or more of amide, hexane, cyclohexane, diethyl ether, diisopropyl ether, acetone, isobutyl methyl ketone, ethyl methyl ketone and the like. Toluene, N, N-dimethylformamide, and the like can be used. First, 1-arylalkyl-4 (5) -bromoimidazole and a palladium catalyst are dissolved in an organic solvent as a compound represented by the general formula (2), and then the alkyl acrylate and the base compound represented by the general formula (3) And reacted for a predetermined time to prepare an (E) -alkyl 3- (1-arylalkyl-imidazol-4 (5) -yl) acrylate represented by the formula (4). At this time, the alkyl acrylate is preferably used in an amount of about 2 to 2.5 molar equivalents based on 1 molar equivalent of 1-arylalkyl-4 (5) -bromoimidazole. In addition, the type of the palladium catalyst is not limited as long as it contains palladium as an active ingredient, and dichlorobis (triphenylphosphine) palladium or tetrakis (triphenylphosphine) palladium is preferable considering commercial availability, Palladium. The amount of the palladium catalyst to be used is preferably about 0.1 to 0.25 molar equivalent based on 1 molar equivalent of 1-arylalkyl-4 (5) -bromoimidazole. The reaction temperature is about 60 to 120 ° C, preferably 80 to 110 ° C, more preferably 90 to 100 ° C, and the reaction time is 2 to 36 hours, preferably 10 to 30 hours, more preferably 20 ~ 28 hours.

The intermediate compound according to the present invention is not greatly limited in its use, but is preferably used for the preparation of urotanic acid. Hereinafter, a method for preparing urotanic acid using the intermediate compound according to the present invention will be described.

From the intermediate compound Urotanic acid  How to make

The intermediate compound represented by the following formula (4) according to the present invention is converted into a compound represented by the following formula (5) via a deprotection reaction, and then converted to urocanin acid through a hydrolysis reaction.

[Chemical Formula 4]

[Chemical Formula 5]

In Formula 4 and Formula 5 R ₁ it is substituted with alkoxycarbonyl having 1 an aryl alkyl, substituted by halogen, at least one of to 10 alkyl, a substituted with hydrogen atoms aryl having 6 to 14, benzyl, or 1 to 3 carbon atoms Benzyl, and R < ₂ > is alkyl having 1 to 10 carbon atoms.

The method for preparing the urocanic acid from the intermediate compound according to the present invention can be represented more specifically by the following Reaction Schemes 3 and 4.

Scheme 3

[Reaction Scheme 4]

Scheme 3 shows a process for producing an (E) -alkyl 3- (1H-imidazol-4-yl) acrylate represented by the formula (5) by deprotecting an intermediate compound represented by the formula (4). At this time, the deprotonation reaction can be carried out using a known method as hydrogenolysis ( Tetrahedron Letters 2002 , 43, 399-402]. For example, the deprotection reaction may be carried out by feeding oxygen in the presence of potassium t-butoxide, or may be carried out using a palladium / carbon (Pd / C) catalyst. At this time, a catalyst in which palladium is supported on activated carbon, carbon black or activated carbon aerogels using the palladium / carbon (Pd / C) catalyst can be used, and the deprotection reaction is performed in the presence of atmospheric pressure hydrogen. (4) can be obtained by hydrolyzing (E) -alkyl 3- (1H-imidazol-4-yl) acrylate represented by Chemical Formula 5 to obtain urocanic acid of formula (1) (E) -3 (1H-imidazol-4-yl) acrylic acid]. At this time, the hydrolysis reaction can be carried out using a known method [ Tetrahedron Letters 2007 48, 8230-8233], for example under basic conditions. The base used may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are intended to clearly illustrate the present invention and do not limit the scope of protection of the present invention.

1. 1-Benzyl-4 (5) - Bromo Imidazole  Produce

Production Example 1

14 ml of acetone was added to the reactor, and 306 mg of 4 (5) -bromo-1H-imidazole and 374 mg of calcium carbonate (K ₂ CO ₃ ) were added thereto and stirred for dissolution at room temperature for 30 minutes. Then, 0.31 ml of benzyl chloride was added to the reactor, the reaction temperature was raised to 80 캜, and the mixture was refluxed and stirred for 48 hours. After the reaction was completed, the insoluble solid was filtered and removed to obtain a first filtrate, which was then concentrated under reduced pressure. Subsequently, 80 ml of water was added to the first filtrate under reduced pressure and in the form of oil, and extracted three times with 100 ml of dichloromethane. Then, 20 g of sodium sulfate (Na ₂ SO ₄ ) was added to the dichloromethane organic layer, followed by complete removal of water, followed by filtration to obtain a second filtrate. The second filtrate was concentrated under reduced pressure, and the resulting oil was separated by silica gel column chromatography to obtain the target compound. As a developing solvent, a mixed solvent of 80: 1 by volume ratio of ethyl acetate and hexane was used. The objective compound was concentrated under reduced pressure to give an oil, 1-benzyl-4-bromoimidazole and 1-benzyl-5-bromoimidazole. The total amount of 1-benzyl-4 (5) -bromoimidazole thus obtained was 356 mg, and the yield was 72%. The obtained 1-benzyl-4 (5) -bromoimidazole was analyzed by ¹ H-NMR and the results are as follows.

¹ H-NMR (Acetone-d ₆ , ppm) of ¹ -benzyl-4-bromoimidazole:? 7.7 (s, 2H)

1-benzyl-5-bromo already ^{1 H-NMR (Acetone-d} 6, ppm) imidazole: δ 7.9 (s, 1H) , 7.3 (m, 3H), 7.2 (m, 2H), 7.0 (s, 1H), 5.3 (s, 2H)

Production Example 2

26 ml of N, N-dimethylformamide was added to the reactor, and 4 g of 1-benzylimidazole was added thereto and dissolved. Subsequently, 5 g of N-bromosuccinimide (NBS) was separately prepared in 60 ml of N, N-dimethylformamide in the reactor, which was slowly added to the reactor for about 30 minutes and reacted for one day with stirring. After the reaction was completed, the insoluble solid was filtered and removed to obtain a first filtrate, which was then concentrated under reduced pressure. Then, 100 ml of ethyl acetate was added to the first filtrate under reduced pressure and the oil form, and the ethyl acetate organic layer was washed three times with 80 ml of water. Thereafter, 20 g of sodium sulfate (Na ₂ SO ₄ ) was added to the organic layer of ethyl acetate and stirred. Then, water was completely removed and then filtered to obtain a second filtrate. The second filtrate was concentrated under reduced pressure, and the resulting oil was separated by silica gel column chromatography to obtain the desired compound. As a developing solvent, a mixed solvent of ethyl acetate and hexane in a volume ratio of 1: 3 was used. The objective compound was concentrated under reduced pressure to give an oil, 1-benzyl-4-bromoimidazole and 1-benzyl-5-bromoimidazole. The total amount of 1-benzyl-4 (5) -bromoimidazole thus obtained was 1.8 g, and the yield was 30%.

2. (E) -Ethyl 3- (1-benzyl- Imidazole Yl) Acrylate  Produce

Example 1.

To the reactor, 26 ml of N, N-dimethylformamide was added, and 200 mg of 1-benzyl-4-bromoimidazole and 59 mg of dichlorobis (triphenylphosphine) palladium were dissolved therein. Then, 0.22 ml of ethyl acrylate and 0.94 ml of triethylamine (Et ₃ N) were added to the reactor, and the reaction temperature was raised to about 90-100 ° C, and the mixture was stirred under reflux for about 24 hours. After the reaction was completed, the insoluble solid and the palladium metal catalyst were filtered and removed to obtain a first filtrate, which was then concentrated under reduced pressure. Then, 100 ml of ethyl acetate was added to the first filtrate under reduced pressure and the oil form, and the ethyl acetate organic layer was washed three times with 80 ml of water. Thereafter, 20 g of sodium sulfate (Na ₂ SO ₄ ) was added to the organic layer of ethyl acetate and stirred. Then, water was completely removed and then filtered to obtain a second filtrate. The second filtrate was concentrated under reduced pressure, and the resulting brown oil was separated by silica gel column chromatography to obtain the target compound. As a developing solvent, a mixed solvent of ethyl acetate and hexane in a volume ratio of 1: 1 was used. The objective compound was concentrated under reduced pressure to obtain an oil (E) -ethyl 3- (1-benzyl-imidazol-4-yl) acrylate. The total amount of (E) -ethyl 3- (1-benzyl-imidazol-4-yl) acrylate thus obtained was 190 mg, and the yield was 90%.

The resulting (E) -ethyl 3- (1-benzyl-imidazol-4-yl) acrylate was analyzed by ¹ H-NMR and the results were as follows.

^{1 H-NMR (Acetone-d} 6, ppm): δ 7.8 (s, 1H), 7.5 (d, 2H), 7.3 (m, 5H), 6.5 (d, 1H), 5.3 (s, 2H), 4.2 (m, 2 H), 1.3 (m, 3 H)

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. In addition, many modifications may be made to adapt a particular situation and material to the teachings of the invention without departing from the essential scope thereof. Accordingly, the protection scope of the present invention should not be construed as being limited to the particular embodiments disclosed as the best mode contemplated for carrying out the invention but to cover all embodiments falling within the scope of the appended claims.

Claims (10)

Converting the compound represented by Formula 4 to a compound represented by Formula 5 by a deprotection reaction; And
A method for preparing urocanoic acid comprising converting a compound represented by the following Chemical Formula 5 into urocanic acid by a hydrolysis reaction.
[Chemical Formula 4]

[Chemical Formula 5]

In Formulas 4 and 5, R ₁ is arylalkyl substituted with at least one hydrogen atom of alkyl having 1 to 10 carbon atoms, aryl having 6 to 14 carbon atoms, benzyl substituted with halogen group and benzyl substituted with alkoxy group having 1 to 3 carbon atoms. It is either, and R <_2> is C1-C10 alkyl.
According to claim 1, wherein R ₁ is benzyl, diphenylmethyl, triphenylmethyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, chlorobenzyl and dichlorobenzyl, characterized in that the preparation of urokanoic acid Way.
The method of claim 1, wherein R ₂ is one of methyl, ethyl and propyl.
delete According to claim 1, wherein the compound represented by the formula (4)
A process for producing urokanoic acid, which is prepared by reacting a compound of formula 2 with a compound of formula 3 in the presence of a base and a metal catalyst.
(2)

(3)

In Formulas 2 and 3, R ₁ is arylalkyl substituted with at least one hydrogen atom of alkyl having 1 to 10 carbon atoms, aryl having 6 to 14 carbon atoms, benzyl substituted with halogen group and benzyl substituted with alkoxy group having 1 to 3 carbon atoms. Is any one of, R ₂ is alkyl having 1 to 10 carbon atoms, and X is a halogen atom.
6. The process for producing urokanoic acid according to claim 5, wherein the metal catalyst is a palladium catalyst.
The method of claim 6, wherein the palladium catalyst is dichlorobis (triphenylphosphine) palladium or tetrakis (triphenylphosphine) palladium.
6. The process for producing urokanoic acid according to claim 5, wherein the base is triethylamine or potassium carbonate.
9. The method of claim 5, wherein R ₁ is any one of benzyl, diphenylmethyl, triphenylmethyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, chlorobenzyl and dichlorobenzyl. A process for producing urokanoic acid characterized by the above-mentioned.
9. The method of claim 5, wherein R ₂ is any one of methyl, ethyl and propyl. 10.