JP5689191B1 - Process for producing 4-ethylidene-3,4-dihydro-2H-pyrrole - Google Patents

Abstract

A novel method for producing 4-ethylidene-3,4-dihydro-2H-pyrrole is provided. The present invention relates to a process for producing 4-ethylidene-3,4-dihydro-2H-pyrrole, wherein a first intermediate is obtained by condensing γ-butyrolactone and an oxalic acid diester in the presence of a base. A first step of obtaining a second intermediate by treating the first intermediate with a base and then reacting with acetaldehyde to obtain a second intermediate, and reducing the ester portion of the second intermediate to obtain a third intermediate A third step of obtaining, a fourth step of converting the hydroxy group of the third intermediate to a better leaving group and then converting to azide with an azidating agent to obtain a fourth intermediate, and the fourth intermediate A fifth step of reacting with triorganophosphine to obtain 4-ethylidene-3,4-dihydro-2H-pyrrole. [Selection figure] None

Description

  The present invention relates to a method for producing 4-ethylidene-3,4-dihydro-2H-pyrrole.

  It is known that Murasakikiman (Corydalis incisa) belonging to the plant of the genus Papaverales Fumariaceae Corydalis has actions such as insecticide and detoxification (for example, Non-Patent Document 1). Further, it is known that turkeman (also known as turkeyman) (Corydalis ochotensis) has actions such as antipyretic, analgesic and diuretic (for example, Non-Patent Documents 2 and 3).

  The present inventor previously obtained an essential oil from Turkeman or Murasakikiman by a hydro-dispersion method and then purified by gas chromatography to obtain (E)-and (Z) -4-ethylidene-3,4-dihydro- 2H-pyrrole was isolated, and it was reported that this compound has activities such as acetylcholinesterase inhibitory action, insecticidal action, and pest repellent action (Patent Document 1).

  Since (E)-and (Z) -4-ethylidene-3,4-dihydro-2H-pyrrole have the above-mentioned activities, they can be used for acetylcholinesterase inhibitors, insecticides, pest repellents and the like. As expected, in order to use the compound for these applications, it is necessary that the compound can be efficiently produced by a method other than isolating the compound from a natural product.

JP 2012-070883 A

Chuyaku Daiji Dictionary Shogakkan First Edition Volume 2 p1017-1018 Arch. Pharm. Res. 23, 459-460, (2000) Lee, T. B., Illustrated Flora of Korea. Hanygmoonsa, Seoul, p. 385 (1989)

  The main object of the present invention is to provide a novel process for producing 4-ethylidene-3,4-dihydro-2H-pyrrole. The present invention also aims to provide a new use of 4-ethylidene-3,4-dihydro-2H-pyrrole.

  As a result of extensive research, the present inventors have used γ-butyrolactone as a raw material, and produced 4-ethylidene-3,4-dihydro-2H-pyrrole from this γ-butyrolactone through five steps. As a result, the present invention has been completed.

  The present invention relates to the following method for producing 4-ethylidene-3,4-dihydro-2H-pyrrole, and the like.

  Item 1. Formula (1):

(In the formula, wavy lines indicate E-form and / or Z-form geometric isomers.)
A process for producing 4-ethylidene-3,4-dihydro-2H-pyrrole represented by:
Formula (2):

And oxalic acid diester represented by R ¹ OOC-COOR ¹ (wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms) in the presence of a base. Let equation (3):

(Wherein R ¹ is the same as described above.)
A first step of obtaining a first intermediate represented by:
The first intermediate is treated with a base and then reacted with acetaldehyde to give the formula (4):

A second step of obtaining a second intermediate represented by:
By reducing the ester moiety of the second intermediate, the formula (5):

A third step of obtaining a third intermediate represented by:
After converting the hydroxy group of the third intermediate to a better leaving group, it is converted to an azide with an azidating agent to obtain a compound represented by formula (6):

A fourth step of obtaining a fourth intermediate represented by formula (5), and a fifth step of reacting the fourth intermediate with triorganophosphine to obtain 4-ethylidene-3,4-dihydro-2H-pyrrole,
Including methods.

  Item 2. An antioxidant comprising 4-ethylidene-3,4-dihydro-2H-pyrrole (1) or a salt thereof as an active ingredient.

  Item 3. An anti-inflammatory agent comprising 4-ethylidene-3,4-dihydro-2H-pyrrole (1) or a salt thereof as an active ingredient.

  According to the production method of the present invention, 4-ethylidene-3,4-dihydro-2H-pyrrole can be synthesized from γ-butyrolactone. Thus, if the manufacturing method of this invention is used, 4-ethylidene-3,4-dihydro-2H-pyrrole can be manufactured by methods other than isolating from the conventional natural product. Moreover, since 4-ethylidene-3,4-dihydro-2H-pyrrole has a high antioxidant action and an anti-inflammatory action, it can be used as an antioxidant or an anti-inflammatory agent.

2 is a scheme for explaining the production method of Example 1.

  The present invention relates to formula (1):

(In the formula, wavy lines indicate E-form and / or Z-form geometric isomers.)
4-ethylidene-3,4-dihydro-2H-pyrrole represented by the formula (2):

It is the method of manufacturing from (gamma) -butyrolactone represented by these. The 4-ethylidene-3,4-dihydro-2H-pyrrole can be produced from the raw material γ-butyrolactone (2) by the following five steps. Details of the manufacturing method will be described below.

  The first step is the formula (2):

And oxalic acid diester represented by R ¹ OOC-COOR ¹ (wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms) in the presence of a base. Let equation (3):

(Wherein R ¹ is the same as described above.)
Is a step of obtaining a first intermediate represented by:

The alkyl group having 1 to 6 carbon atoms represented by R ^1, include a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl, n-pentyl, n-hexyl and the like.

  As the oxalic acid diester, dimethyl oxalate or diethyl oxalate is preferably used.

  The oxalic acid diester is added in an amount of usually about 1 to 2 times mol, preferably about 1 to 1.5 times mol for γ-butyrolactone (2).

  Bases used include alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride; alkalis such as sodium carbonate and potassium carbonate A metal carbonate etc. are mentioned. Of these, alkali metal alkoxides are preferred, and sodium ethoxide is particularly preferred. The base is usually used in an amount of about 1 to 3 moles, preferably about 1 to 2 moles relative to γ-butyrolactone (2).

  The reaction is carried out in a conventional solvent that does not adversely influence the reaction, for example, alcohols such as methanol, ethanol and propanol. Of these solvents, methanol and ethanol are preferable.

  The reaction temperature is usually about 0 to 50 ° C, preferably about 15 to 40 ° C.

  The reaction time is usually about 0.5 to 10 hours, preferably about 1 to 8 hours.

After the reaction is completed, the reaction mixture is acidified with an acid to obtain the first intermediate (3) in which the R ¹ OOC—CO— group is introduced at the α-position of γ-butyrolactone (2). As the acid, a dilute acid such as dilute hydrochloric acid, dilute acetic acid, dilute sulfuric acid, dilute nitric acid and the like can be used.

  The obtained product can be used as it is in the reaction solution or as a crude product in the next step, but can be isolated from the reaction mixture according to a conventional method, and can be used in usual methods such as chromatography, recrystallization and distillation. It can also be easily purified by separation means.

  In the second step, the first intermediate (3) obtained in the first step is treated with a base and then reacted with acetaldehyde to obtain the formula (4):

Is a step of obtaining a second intermediate represented by

  Bases used include alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkalis such as sodium carbonate and potassium carbonate A metal carbonate etc. are mentioned. Among these, hydrides of alkali metals or alkaline earth metals are preferable, and sodium hydride is particularly preferable. The base is usually used in an amount of about 1 to 3 moles, preferably about 1 to 2 moles compared to the first intermediate (3).

  Acetaldehyde is usually added in an amount of about 2 to 20 times mol, preferably about 5 to 15 times mol for the first intermediate (3).

  The reaction is carried out using a conventional solvent that does not adversely influence the reaction, for example, alcohols such as methanol, ethanol and propanol; ethers such as diethyl ether and tetrahydrofuran (THF); dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and the like. It is carried out in an aprotic polar solvent or the like or a mixture thereof. Of these solvents, methanol and ethanol are preferable.

  The reaction temperature is usually about 0 to 50 ° C, preferably about 15 to 40 ° C. It is also possible to carry out the reaction at room temperature.

  The reaction time is usually about 3 to 24 hours, preferably about 8 to 20 hours.

  The obtained product can be used as it is in the reaction solution or as a crude product in the next step, but can be isolated from the reaction mixture according to a conventional method, and can be used in usual methods such as chromatography, recrystallization and distillation. It can also be easily purified by separation means.

  The third step is to reduce the ester moiety of the second intermediate (4) obtained in the second step, thereby reducing the formula (5):

Is a step of obtaining a third intermediate represented by

  Any reducing agent can be used without limitation as long as the ester moiety can be reduced to an aldehyde and isolated in the form of an aldehyde. For example, DIBAL-H (diisobutylaluminum hydride), MDBBA (metal diisobutyl-t-butoxyaluminum hydride, M (metal) is Li, Na, or K) can be used. Of these, diisobutylaluminum hydride is preferred. When DIBAL-H is used as the reducing agent, it is used in exactly 1 mole relative to the second intermediate (4), and the reaction is carried out at about -78 ° C. The reaction time is usually about 0.5 to 48 hours, preferably about 1 to 8 hours.

  The reduction reaction is carried out using a conventional solvent that does not adversely influence the reaction, for example, ethers such as diethyl ether and tetrahydrofuran (THF); aprotic polar solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF); acetone, 2 -Ketones such as butanone, aromatic hydrocarbons such as toluene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, or a mixture thereof. Of these solvents, dichloromethane and the like are preferable.

  The obtained product can be used as it is in the reaction solution or as a crude product in the next step, but can be isolated from the reaction mixture according to a conventional method, and can be used in usual methods such as chromatography, recrystallization and distillation. It can also be easily purified by separation means.

  In the fourth step, the hydroxy group of the third intermediate obtained in the third step is converted into a better leaving group, and then converted into an azide with an azidating agent to obtain the formula (6):

Is a step of obtaining a fourth intermediate represented by

  The fourth step is a step of converting a hydroxy group into an azide, and can be performed in two steps: i) conversion of the hydroxy group into a better leaving group, and ii) substitution reaction with an azidating agent.

  First, the hydroxy group is converted to a better leaving group for nucleophilic substitution reactions. As used herein, “better leaving group” means a leaving group than a hydroxy group. Better leaving groups include mesylate (-OMs, Ms is methanesulfonyl), tosylate (-OTs, Ts is toluenesulfonyl), nosylate (-ONs, Ns is p-nitrobenzenesulfonyl), brosylate (-OBs, Bs is p-bromobenzenesulfonyl), triflate (-OTf, Tf is trifluoromethanesulfonyl), nonaflate (nonafluorobutanesulfonate), tresylate (2,2,2, -trifluoroethane) Sulfonate) and the like.

  The conversion of the hydroxy group to the leaving group is performed by contacting the third intermediate with an acid halide or anhydride containing the above-mentioned better leaving group and a base in the presence of a solvent.

  As the solvent, a conventional solvent which is compatible with the third intermediate and does not adversely influence the reaction, for example, dichloromethane, toluene, pyridine and the like or a mixture thereof can be used.

  Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, (bi) sodium carbonate, (bi) potassium carbonate, and organic bases such as trimethylamine, triethylamine, diisopropylethylamine, and pyridine.

  The acid halide or anhydride containing a better leaving group is usually used in an amount of about 1.1 to 4 times mol, preferably about 1.2 to 3 times mol for the third intermediate.

  The reaction temperature is 0 ° C. or lower, usually about −78 to 0 ° C., preferably about −20 to 0 ° C. Further, the reaction may be performed in an inert atmosphere such as nitrogen or argon.

  The reaction time is usually about 1 minute to 3 hours, preferably about 5 minutes to 2 hours.

  The obtained product can be used as it is in the reaction solution or as a crude product for the next reaction. However, it can be isolated from the reaction mixture according to a conventional method, and can be used in usual methods such as chromatography, recrystallization, distillation, etc. It can also be easily purified by separation means.

  The resulting compound having a better leaving group is then converted to an azide with an azidating agent.

As an azidating agent,
M ¹ (CH ₂ ) _x-1 N ₃
(In the formula, M ¹ represents an alkali metal such as sodium or potassium. X represents 1 or 2.) An alkali metal salt of an organic azide compound represented by the following formula can be used. As the azidating agent, sodium azide is preferred. The azidating agent is usually used in an amount of about 3 to 10 times mol, preferably about 4 to 6 times mol, for a compound having a better leaving group.

  The azidation reaction is a conventional solvent that does not adversely influence the reaction, for example, ethers such as diethyl ether and tetrahydrofuran (THF); aprotic polar solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF); acetone, It is carried out in ketones such as 2-butanone or a mixture thereof. Among these solvents, DMF is preferable.

  The reaction temperature is usually about 50 to 100 ° C., preferably about 60 to 90 ° C.

  The reaction time is usually about 0.5 to 10 hours, preferably about 2 to 8 hours.

  The obtained product can be used as it is in the reaction solution or as a crude product in the next step, but can be isolated from the reaction mixture according to a conventional method, and can be used in usual methods such as chromatography, recrystallization and distillation. It can also be easily purified by separation means.

  The fifth step is a step of obtaining 4-ethylidene-3,4-dihydro-2H-pyrrole (1) by reacting the fourth intermediate obtained in the fourth step with triorganophosphine.

  In this reaction, the triorganophosphine reacts with the azide moiety of the fourth intermediate to produce an azaline ylide, and this azaline ylide reacts with the aldehyde moiety of the fourth intermediate to produce an imine, 4-ethylidene-3,4- Dihydro-2H-pyrrole (1) is formed.

Triorganophosphine is
R ² R ³ R ⁴ P
(Wherein R ² , R ³ and R ⁴ are each a linear or branched alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group or an aralkyl group, or a hydroxy thereof. A group or an alkoxy group-substituted product, each of which may be the same group or different groups.)
It is a compound represented by these.

R ² , R ³ and R ⁴ are methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and the like alkyl groups; cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl A cycloalkyl group such as phenyl, tolyl and xylyl; an aralkyl group such as benzyl and phenethyl; a group obtained by substituting the alkyl group, aryl group or aralkyl group with a hydroxyl group or an alkoxy group. R ² , R ³ and R ⁴ may or may not be the same group.

  Examples of the triorganophosphine include triphenylphosphine, tributylphosphine, diphenylbutylphosphine, dibutylphenylphosphine, and the like, and triphenylphosphine is preferable.

  Triorganophosphine is usually used in an amount of about 1.1 to 2 times mol, preferably about 1.1 to 1.5 times mol of the fourth intermediate.

  The reaction is carried out using a conventional solvent that does not adversely influence the reaction, for example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane; aprotic polarity such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), etc. Solvent: It is carried out in hydrocarbons such as benzene, toluene, hexane, or a mixture thereof. Of these solvents, THF is preferred.

  The reaction temperature is usually about 0 to 150 ° C, preferably about 25 to 60 ° C.

  The reaction time is usually about 3 to 10 hours, preferably about 4 to 8 hours.

  The obtained product can be isolated from the reaction mixture according to a conventional method, and can easily be represented by the following formula (1-E) by an ordinary separation means such as chromatography, recrystallization, distillation and the like. ((E) -4-ethylidene-3,4-dihydro-2H-pyrrole) and a Z-form represented by the following formula (1-Z) ((Z) -4-ethylidene-3,4-dihydro-2H -Pyrrole).

  Thus, 4-ethylidene-3,4-dihydro-2H-pyrrole (1) can be produced from γ-butyrolactone (2) in 5 steps.

  4-ethylidene-3,4-dihydro-2H-pyrrole (1) has activities such as a high antioxidant action and an anti-inflammatory action.

  Regarding the antioxidant activity, 4-ethylidene-3,4-dihydro-2H-pyrrole (1) has a higher activity than Trolox, which is a general antioxidant (see Test Example 1).

  Regarding anti-inflammatory activity, 4-ethylidene-3,4-dihydro-2H-pyrrole (1) has higher COX-2 inhibitory activity than aspirin, which is a positive control (see Test Example 2).

  Since 4-ethylidene-3,4-dihydro-2H-pyrrole (1) has the above activity, it can be used as a pharmaceutical composition (antioxidant, etc.) and a cosmetic.

  When 4-ethylidene-3,4-dihydro-2H-pyrrole (1) is used as a pharmaceutical antioxidant, for example, analgesia, anti-AIDS, alcohol poisoning improvement, anti-allergy, anti-anginal, anti-arrhythmia, anti-artery Sclerosis, anti-asthma, antibacterial, anti-diabetic, detoxification, anti-inflammatory, anti-hyperlipidemia, DNA mutation suppression, anti-parkinson's disease, anti-psoriasis, anti-rheumatic, anti-ulcer, ability protection, cell growth suppression, skin disease improvement, Effective in liver function activation, antihypertensive, immunosuppression, renal function activation, neuronal protection, nootropic, ophthalmic disease improvement, radiation protection, vascular activation, antiviral, wound medicine, weak constitution improvement, etc. .

  Antioxidants are tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, old emulsions, suppositories, injections, ointments, ophthalmic ointments, by conventional methods. It can be formulated into agents such as eye drops, nasal drops, ear drops, poultices, lotions and the like.

  Excipients, binders, lubricants, colorants, flavoring agents, etc. that are usually used for formulation, and stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, if necessary Antioxidants and the like can be used, and in general, ingredients and blending amounts used as raw materials for pharmaceutical preparations are appropriately selected to prepare a preparation by a conventional method.

  When the preparation is administered, its form is not particularly limited, and any method that is usually used may be used, and oral administration or parenteral administration may be used. The dosage according to the present invention can be appropriately selected from pharmaceutically effective doses according to the degree of symptoms, age, sex, body weight, dosage form, type of salt, specific type of disease, and the like.

  The proportion of the active ingredient contained in the antioxidant of the present invention is not particularly limited as long as the antioxidant exhibits antioxidant ability. Also, only (E) -4-ethylidene-3,4-dihydro-2H-pyrrole, only (Z) -4-ethylidene-3,4-dihydro-2H-pyrrole, from a mixture of E and Z isomers. It may be. Moreover, these salts may be sufficient. There is no limitation in particular as an acid which can form the salt of 4-ethylidene-3,4-dihydro-2H-pyrrole (1), An inorganic acid and an organic acid are mentioned. Specific examples of the inorganic acid include hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid and the like. Specific examples of organic acids include lower (for example, C 1-11) fatty acids such as formic acid, acetic acid and propionic acid; polybasic acids such as fumaric acid, maleic acid, succinic acid and adipic acid; glycolic acid, lactic acid and tartaric acid Hydroxycarboxylic acids such as malic acid; aromatic carboxylic acids such as benzoic acid and anisic acid; lower (for example, C 1-11) fatty acid sulfonic acids such as methanesulfonic acid and ethanesulfonic acid; benzenesulfonic acid, p- Aromatic sulfonic acids such as toluenesulfonic acid can be used.

  When 4-ethylidene-3,4-dihydro-2H-pyrrole (1) is used as a pharmaceutical product (antioxidant), the E isomer and / or the Z isomer is usually 0.01 to 100 wt. % (Preferably about 0.1 to 5% by weight).

  When used as a cosmetic, in addition to 4-ethylidene-3,4-dihydro-2H-pyrrole (1), if necessary, powder, pigment, fats and oils, moisturizer, surfactant, antioxidant, thickening Ingredients used in normal cosmetics such as agents, detergents, excipients, emulsifiers, plasticizers, antiseptics, antifungal agents, pH adjusters, ultraviolet absorbers, amino acids, fragrances, etc. do not impair the effects of the present invention It can mix | blend suitably in the range.

  The dosage form of the cosmetic is arbitrary, and may be a dosage form such as a solution system, a solubilization system, an emulsification system, a powder split acid system, a water-oil two-layer system, and a water-oil-powder three-layer system. The pH is preferably adjusted to about 4 to 8 from the viewpoint of safety to the skin.

  Examples of cosmetics include all cosmetics applied to the skin, face skin, lips, etc., and examples of cosmetic applications include lotions, emulsions, creams, serums, packs, foundations, lipsticks, lip balms, It can be used for eye shadow, body lotion, body cream, cleansing foam, face wash, hand soap, body soap and the like.

  The content of the active ingredient in the cosmetic varies depending on the purpose of use of the cosmetic, dosage form, composition, set expiration date, set storage state, coexisting ingredients, etc., but is usually about 0.001 to 5% by weight. The amount is preferably about 0.05 to 1% by weight.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples etc.

Example 1
The operation of synthesizing 4-ethylidene-3,4-dihydro-2H-pyrrole (1) from γ-butyrolactone (2) is shown in FIG. In FIG. 1, the R ¹ group of the first intermediate (3) is ethyl (Et). In the following steps, the vacuum concentration was performed using a rotary evaporator.

(1) First Step Diethyl oxalate (17.0 g, 0.116 mol) was added at 0 ° C. to a solution of sodium ethoxide (8.46 g, 0.124 mol) dissolved in ethanol (40 ml). Γ-butyrolactone (2) (10.0 g, 0.116 mol) was added dropwise thereto over 15 minutes, and the reaction mixture was stirred at 0 ° C. for 1 hour. The solution was warmed to room temperature and stirred for an additional 5 hours. The reaction mixture was partitioned between diethyl ether and water. The aqueous layer was acidified with dilute hydrochloric acid and extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain lactone (3) (21.4 g, yield 99%).

¹ H NMR (400MHz, CDCl ₃ ) δ = 4.49 (3H, t, J = 8.0 Hz), 4.37 (2H, q, J = 7.2Hz), 3.29 (2H, t, J = 8.0Hz), 1.39 (3H , t, J = 7.2Hz)
¹³ C NMR (100MHz, CDCl ₃ ) δ = 176.5, 161.9, 151.9, 105.5, 67.8, 62.3, 26.0, 14.1.
IR (film) ν = 1773, 1739, 1702, 1647, 1238, 1191, 1018 cm ^-1 .

(2) Second Step Lactone (3) (21.4 g, 0.115 mol) was dissolved in ethanol (200 ml), and an aqueous sodium hydroxide solution (4.60 g, 0.115 mol) was added. Acetaldehyde (64.6 ml, 1.15 mol) was added to the mixture and stirred at room temperature for 16 hours. The solution was then diluted with water (600 ml) and sodium bicarbonate (77 g) was added. After stirring for 1 hour, the reaction solution was extracted with dichloromethane (200 ml × 3). The extract was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain lactone (4) (11.26 g, yield 88%).

¹ H NMR (400MHz, CDCl ₃ ) δ = 5.63 (1H, q, J = 6.8Hz), 3.68 (2H, t, J = 6.0Hz), 2.41 (2H, t, J = 6.0Hz), 1.65 (2H , d, J = 6.8Hz)
¹³ C NMR (CDCl ₃ ) δ = 194.5, 136.9, 125.3, 61.3, 32.0, 13.2
IR (film) ν = 1757, 1681, 1218, 1169, 1131, 1033, 1010, 990 cm ^-1 .

(3) Third Step To a solution of lactone (4) (6.57 g, 59 mmol) dissolved in dichloromethane (270 ml), DIBAL-H (58.7 ml, 59 mmol, containing 1M hexane) was added at −78 ° C. Dropped and stirred for 40 minutes. Dichloromethane (270 ml) was added thereto, the temperature was raised to −40 ° C., and water (2.3 ml), 15% aqueous sodium hydroxide solution (2.3 ml) and water (3.4 ml) were added in this order. After the liquid temperature reached room temperature, the mixture was stirred for 1 hour. To this mixture was added sodium sulfate (65 g) and stirred vigorously for an additional 2 hours. The mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain alcohol (5) (4.72 g, yield 70%).

¹ H NMR (400MHz, CDCl ₃ ): δ = 9.42 (1H, s), 6.75 (1H, q, J = 7.2Hz), 3.67 (2H, t, J = 6.4Hz), 2.57 (2H, t, J = 6.4 Hz), 2.05 (3H, d, J = 7.2 Hz)
¹³ C NMR (100MHz, CDCl3): δ = 195.8, 152.3, 141.5, 61.3, 27.4, 15.0.
IR (film) ν = 3430, 1685, 1678, 1644, 1043 cm ^-1 .

(4) Fourth Step Alcohol (5) (1.6 g, 14 mmol) was dissolved in dichloromethane (30 ml), and triethylamine (3.0 ml, 22 mmol) was added at 0 ° C. Mesyl chloride (1.3 ml, 17 mmol) was then added dropwise and the reaction mixture was stirred at 0 ° C. for 30 minutes. This was quenched with water (2.0 ml) and stirred at room temperature for 1.5 hours. The reaction solution was extracted twice with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain mesylate (2.43 g), which was immediately used for the next reaction. The above mesylate was dissolved in dry DMF (10 ml), sodium azide (2.47 g, 38 mmol) was added, and the mixture was stirred at 60 ° C. for 7 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain azidoaldehyde (6) (1.40 g, yield 72%).

¹ H NMR (400MHz, CDCl ₃ ): δ = 9.40 (1H, s), 6.76 (1H, q, J = 6.8Hz), 3.34 (2H, t, J = 6.8Hz), 2.57 (2H, t, J = 6.8Hz), 2.06 (3H, d, J = 6.8Hz)
¹³ C NMR (CDCl ₃ ): δ = 194.5, 152.5, 140.7, 49.8, 23.6, 15.0.
IR (film) ν = 2882, 2824, 2715, 2099, 1685, 1646, 1269, 1054 cm ^-1 .

(5) Fifth Step Azidoaldehyde (6) (945 mg, 6.8 mmol) and molecular sieves 4A (300 mg) were added to a tetrahydrofuran (13 ml) solvent. After stirring for 30 minutes, triphenylphosphine (2.14 g, 8.17 mmol) was added. The mixture was allowed to stir at 50 ° C. for 4 hours. After adding diethyl ether to the reaction mixture and filtering through a glass filter, the filtrate was partitioned between 3% aqueous HCl (7.0 ml) and in diethyl ether (10 ml). The aqueous layer was basified by the addition of solid sodium carbonate. The resulting mixture was extracted with diethyl ether (2 × 20 ml). This was dried over sodium sulfate and concentrated under reduced pressure to obtain 4-ethylidene-3,4-dihydro-2H-pyrrole (1). This was purified by silica gel column chromatography (hexane: acetone = 1: 1) to obtain (E / Z) -1 (488 mg, yield 75%). ^{It was determined by 1} H NMR that the E and Z forms were 6: 1. All physical property values were consistent with 4-ethylidene-3,4-dihydro-2H-pyrrole (1) isolated from natural products. The NMR spectrum data of the obtained compound (1) are shown in Table 1.

Test Example 1 (Antioxidation Test (ORAC))
Oxygen Radical Absorbance Capacity (ORAC) evaluates the suppression of the process of losing fluorescence due to decomposition of fluorescein, which is a fluorescent probe, by peroxy radicals derived from AAPH. The operating method is as follows. A lipophilic sample was preincubated with a 1% β-cyclodextrin solution and a phosphate buffer solution for 1 hour at room temperature, fluorescein was added, and the mixture was incubated at 37 ° C. for 30 minutes. After incubation, AAPH which is also a reaction initiator was added thereto, and the fluorescence wavelength was measured every minute for 90 minutes. The inhibition value was calculated and evaluated by expressing the obtained inhibition value in terms of Trolox equivalent, which is a general antioxidant, under the following formula. The results are shown in Table 2.

  As a result, it was confirmed that Compound 1 has an antioxidant capacity about 3.2 times that of Trolox.

Test Example 2 (Anti-inflammatory test (COX inhibition test))
Inhibition of cyclooxygenase (COX) was assessed colorimetrically using a COX (sheep derived) screening assay kit (Cayman Chemical, USA). COX-1 or COX-2 (10 μl), inhibitor (10 μl) (inhibition solution adjusted to a final concentration of 1000, 800, 400, 200 or 100 μM for each substance in EtOH), and heme (10 μl) Mix in wells and add assay buffer (150 μl). The mixture was preincubated at 25 ° C. for 5 minutes. Colorimetric substrate solution (20 ml) was added to the mixture and the reaction was started by adding arachidonic acid (20 μl). The mixture was then kept at 25 ° C. for 15 minutes. Absorbance at 590 nm was measured with a microplate reader (MTP-800Lab, Corona Electric Co., Ltd.), and all tests and control assays were corrected by non-enzymatic hydrolysis using a blank. Each assay was performed at least three times. The COX activity was determined by the following formula.

COX activity (%) = [(A−B) / (C _p −C _n )] × 100
Where A is the absorbance of the sample (inhibitor in COX, EtOH, heme, colorimetric substrate solution, assay buffer, and arachidonic acid) and B is the absorbance of the test blank sample (inhibitor in EtOH, heme, colorimetric) Substrate solution, assay buffer, and arachidonic acid), C _p is the absorbance of the positive control (COX, EtOH, heme, colorimetric substrate solution, assay buffer, and arachidonic acid), and C _n is the absorbance of the negative control (EtOH, heme) , Colorimetric substrate solution, assay buffer, and arachidonic acid).

  Table 3 shows the results obtained by the test method.

As a result, Compound 1 showed 50% inhibition at 2000 μM for COX-1 inhibitory activity and 50% inhibition at 465.7 μM for COX-2 inhibitory activity. Therefore, (COX-1 / COX-2) is a high value of 4.3, and thus showed strong inhibition of COX-2 selection. As a comparative standard substance, aspirin, which is a non-steroidal anti-inflammatory agent, was also examined for IC ₅₀ value (μM), and as a result, Compound 1 showed a COX-1 inhibitory activity causing side effects even when compared with aspirin. This was a very favorable result and the risk of side effects was considered low.

Claims (3)

Formula (1):

(In the formula, wavy lines indicate E-form and / or Z-form geometric isomers.)
A process for producing 4-ethylidene-3,4-dihydro-2H-pyrrole represented by:
Formula (2):

And oxalic acid diester represented by R ¹ OOC-COOR ¹ (wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms) in the presence of a base. Let equation (3):

(Wherein R ¹ is the same as described above.)
A first step of obtaining a first intermediate represented by:
The first intermediate is treated with a base and then reacted with acetaldehyde to give the formula (4):

A second step of obtaining a second intermediate represented by:
By reducing the ester moiety of the second intermediate, the formula (5):

A third step of obtaining a third intermediate represented by:
After converting the hydroxy group of the third intermediate to a better leaving group, it is converted to an azide with an azidating agent to obtain a compound represented by formula (6):

A fourth step of obtaining a fourth intermediate represented by formula (5), and a fifth step of reacting the fourth intermediate with triorganophosphine to obtain 4-ethylidene-3,4-dihydro-2H-pyrrole,
Including methods.   An antioxidant comprising 4-ethylidene-3,4-dihydro-2H-pyrrole (1) or a salt thereof as an active ingredient.   An anti-inflammatory agent comprising 4-ethylidene-3,4-dihydro-2H-pyrrole (1) or a salt thereof as an active ingredient.

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