KR100675619B1 - Novel preparation method for preparing piperlonguminine compound having skin whitening activity - Google Patents

Abstract

A method for preparing a piperlonguminine compound is provided to be able to simply mass-produce the piperlonguminine compound having strong whitening activity as an alpha-melanocyte stimulating hormone inhibitor. The method comprises the steps of: (a) after treating an ethyl-4-diethylphosphono-2-butenoate with NaH, performing a modified Wittig condensation on it with a piperonal represented by the formula(2) to obtain an ethyl piperate represented by the formula(4); (b) hydrolyzing the ethyl piperate(4) with a strong base such as KOH so as to obtain a piperinic acid represented by the formula(5); and (c) reacting the piperinic acid(5) with an isobutyl amine in the presence of a boronic acid to obtain a piperlonguminine compound represented by the formula(1a).

Description

 Novel preparation method for preparing piperlonguminine compound having skin whitening activity

The present invention relates to a novel production method capable of producing a large amount of piperlonguminine compound having a whitening activity.

The piperlongumin (piperlonguminine; N-isobutyl-5- (1,3-benzodioxol-5-yl) -2,4-pentadienamide, 1a) as a vegetable alkaloid as well as Piper longum Linn In addition, segregation has been reported in other Piper species and in other genus [A. Chatterjee et al; Tet . Letters , p 1797 (1966); OP Gupta, et al, Phytochemistry 11 , 2646 (1972); A. Patra et al, Phytochemistry 13 , p2889 (1974); VS Parmar et al, Phytochemistry 46 , p597 (1997); JR Stohr, et al, J. Ethnopharm . 75 , p133 (2001)], the plant is named "Pipali" and is known to be effective in treating asthma and bronchitis on Ayurveda therapy, a folk remedy in India (KR Kirtikar and BD Basu, Indian). Medicinal Plants Vol III, Basu, Allahabad, India: p2128 (1933)).

On the other hand the inventors are represented by the formula A patent application has been filed by the present inventors to confirm that piperlonguminine inhibits α-MSH, which induces the synthesis of tyrosinase related to whitening activity (Korean Patent Application No. 10-2004-85631). number)

Anti-allergic activity of piperidine and N-isobutyl- (E, E) -2,4-decadienamide isolated from the essential extracts (SA Dahanukar, et al, Ind . Drugs 19 , p271 (1982)) and anticancer Activity (JW Loder et al, Aust . J. Chem . 22 , p1351 (1969)) has been reported.

As a method for preparing a piperlonguminine compound, a method for producing piperic acid from piperine, a readily available natural substance, has been known (A. Chatterjee and CP Dutta, Tetrahedron , 23 , p1769). (1967); RA Olsen and GO Spessard , J. Agrc . Food Chem . 29 , 942 (1982)).

However, the method for producing piperlonguminin described in the literature is not only a very small amount (0.025 to 6%) in the pepper (pepper) plant of the starting material, but also because the price of pepper raw material is expensive, industrial mass production Therefore, there has been a problem that there is a limit to the application, therefore, there has been a demand for research and development on production methods that are simple and mass-produced by chemically synthesizing the piperlonguminine derivatives.

None of the literature published so far discloses any teaching on the synthetic method for simple and efficient mass production of piperlonguminine compounds.

Therefore, the present inventors have developed a novel manufacturing method capable of producing a simple and large-scale production of a piperungguminin compound having a strong whitening activity as an α-melanosite stimulating hormone inhibitor, thus completing the present invention.

An object of the present invention is to provide a novel production method capable of producing a simple and large amount of a piperlonguminine compound having a strong whitening activity as an α-melanosite stimulating hormone inhibitor.

In order to achieve the above object, the present invention base treatment of ethyl (E) -4-diethylphosphono-2-butenoate (3) with sodium hydride (NaH) or the like and then pipernal (2) A first step of producing ethyl piperate (4) by improved Wittig condensation reaction of Worth-Honner; A second step of hydrolyzing ethyl piperate (4) under a strong base such as KOH to obtain piperic acid (5); Provided is a process for obtaining the piperlonguminine compound (1a) of the present invention by reacting piperinic acid (5) in the second step with isobutylamine in the presence of boronic acid.

In addition, the present invention comprises the first step of reacting the aldehyde (7) with triphenylpiperonyl phosphonium halide (8) to produce ethyl piperate (4); A second step of hydrolyzing ethyl piperate (4) under a strong base such as KOH to obtain piperic acid (5); The pipelinic acid (5) of the second step is reacted by adding isobutylamine and boronic acid to provide a production method for obtaining the piperlonguminine compound (1a) of the present invention.

Still another object of the present invention is to base the ethyl (E) -4-diethylphosphono-2-butenoate (3) with sodium hydride (NaH) or the like and then react with aldehyde (2) to ethyl piperate. (4) a first step of manufacturing; A second step of hydrolyzing the ethyl piperate (4) in the first step under a strong base such as KOH to obtain piperic acid (5); Provided is a process for obtaining the piperlonguminine compound (1a) of the present invention by reacting piperinic acid (5) in the second step with isobutylamine in the presence of boronic acid.

  An object of the present invention is to provide a method for preparing a piperlonguminine compound having a strong whitening activity as the α-melanosite stimulating hormone inhibitor, although it can be chemically synthesized by the method shown in the following schemes, these It is not limited only to an example.

The following schemes represent the preparation steps of the compounds of the present invention in stages of preparation. The compounds of the present invention may be prepared with minor changes, such as changing the reagents, solvents, and reaction sequences used in the synthesis of Schemes 1 and 2. Compounds of the present invention were synthesized according to procedures not included in the scope of Schemes 1 and 2, and detailed synthesis procedures for these compounds are described in their respective examples.

First, the reaction first step of the present invention is described by the scheme described in the following scheme,

First, the ethyl (E) -4-diethylphosphono-2-butenoate compound of the formula (3) in the first step is combined with commercially available ethyl (E) -4-bromo-2-butenoate. Almost the same molar amount of triethyl phosphate is heated and reacted at 100 to 150 ° C, preferably at 120 to 130 ° C, for about 1 to 24 hours, preferably about 2 to 4 hours, and the excess of triethylphosphite It can be obtained in a yield of about 90% or more through the Arbuzov reaction to react through a reaction process to remove under reduced pressure;

Ethyl (E) -4-diethylphosphono-2-butenoate (3) obtained in this step was treated with sodium hydride (NaH) or the like in an inert solvent such as DMF, followed by piperonal (2) and 0. Ethyl piperate (4) can be prepared by using the Wadsworth-Horner modified Wittig condensation reaction which is reacted at from -60 [deg.] C., preferably from 30 to 35 [deg.] C.

As another alternative reaction process for preparing ethyl piperate (4) as described above, the reaction process of Scheme 2 can also be carried out:

For example, aldehyde (7) (F. Bohlmann, et. Al. Ber . 89 , p1276 (1956)) triphenylpiperonyl phosphonium halide (8), such as triphenylpiperonyl phosphonium bromide The ethyl piperate (4) can also be produced through the reaction step of reacting. Treating triphenylpiperonyl phosphonium halide (8) with NaH or the like followed by addition of aldehyde (7) at 100-150 ° C, preferably 120-130 ° C for about 1-24 hours, preferably about 2 By heating with stirring for 4 hours to about 90% or more ethyl piperate (4) can be obtained.

As a subsequent process, pipelinic acid (5) can be obtained through the reaction of Scheme 3 below:

To the ethyl piperate (4) obtained in the first step, a strong base such as methanolic KOH, NaOH, or the like is added, and it is preferably about 4 to 8 hours at 100 to 150 ° C, preferably 110 to 120 ° C, for about 1 to 24 hours. Pipeline acid (5) can be obtained through a hydrolysis reaction which is heated for a while with stirring.

As a final reaction process, the piperlonguminine compound (1a) of the present invention can be obtained through the following Scheme 4 reaction process:

1 to 2 times isobutylamine of pipelinic acid (5) molar concentration in pipelinic acid (5) obtained in Scheme 3 in an organic solvent such as toluene, and then about 1/10 to 1/5 times A precipitate obtained after adding boronic acid to reflux for about 1 to 24 hours, preferably about 8 to 16 hours under a Dean-Stark trap, and then adding a hexane solvent to the reaction to induce precipitation. By purifying the piperlonguminine compound (1a) of the present invention can be obtained in high yield (about 91%).

The core step of the manufacturing method for preparing the piperlonguminine compound (1a) is the first step is an improved Wittig reaction of the wardworth-Honer capable of selectively synthesizing the alkaloid compound piperlonguminine compound of the present invention ( Wadsworth-Horner modified Wittig reaction), and the method of the present invention is industrial because of the high cost of pepper itself and its very small amount of piperin (0.025-6%) in the pepper plant. In order to solve the problems of the prior art, which have been limited to application in mass production, a relatively inexpensive commercially available piperonal (2) is used as a starting material, and the expensive piperine is replaced with ethyl (E As a new manufacturing process, reacting with 4-diethyl phosphono-2-butenoate or reacting aldehyde (7) with triphenylpiperonyl phosphonium halide (8). It is a new manufacturing method that solves the problem.

The production method of the present invention provides a synthetic method that provides a simple and mass-produced synthetic method by chemically synthesizing the piperlonguminine compound, which shows a strong whitening activity and has proven its efficacy as a whitening agent. to provide.

      The piperlonguminine compound (1a) of the present invention obtained by the above production method inhibits α-MSH which induces the synthesis of tyrosinase related to the whitening activity, and thus shows a strong whitening activity. It can be used for such purposes as health functional food and cosmetic composition.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Reference Example  1. Device used

1-1. Analyzer

      The instrument used to confirm the structure of the product obtained in this experiment is as follows.

Melting point (mp) was used with a Fischer-Jones melting point apparatus and was not calibrated. Nuclear magnetic resonance spectra ( ¹ H NMR) ¹³ C NMR were 250 MHz or 400 MHz (Bruker NMR spectrometer). The nuclear magnetic resonance spectra ( ¹³ C NMR) were 100 MHz (Bruker NMR spectrometer), and TMS (tetramethylsilane) was used as an internal standard, and CDCl ₃ and DMSO-d ₆ were used as a solvent. Coupling constants ( J ) are expressed in Hz. IR was measured using a Perkin-Elmer 1330 spectrophotometer.

1-2. TLC and Tube chromatography

Thin layer chromatography (TLC) was used as silica gel (Merck F254) manufactured by E. Merck, and silica (Merck EM9385, 230-400 mesh) was used for column chromatography. In addition, using a UV lamp (wavelength 254 nm) or soaked in anisealdehyde (Anisaldehyde), potassium permanganate (KMnO ₄ ) coloring reagent to identify the material separated on TLC, the plate was confirmed by heating.

Reference Example  2. Ethyl (E) -4- Diethylphosphono -2- Butenoate  (3) intermediate production

Ethyl (E) -4-bromo-2-butenoate (18.0 g, 0.10 mmol) was added to triethyl phosphite (18.2 g, 0.104 mmol). Was slowly added dropwise thereto. The resulting reaction was heated at 120-130 ° C. for 2 hours. Excess triethyl phosphite was removed under reduced pressure and the resulting residue was distilled under reduced pressure to prepare 20.2 g of a colorless liquid ethyl (E) -4-diethylphosphono-2-butenoate (3) intermediate having the following physical properties. (Yield 90%).

      Boiling point (bp): 109-112 ° C. (0.01 mmHg, bath temp. 160 ° C.);

IR (thin film): 1725 (C = O), 1658, 1250, 1025 (P = O), 968 cm ⁻¹ .

¹ H NMR (250 MHz, CDCl ₃ ): 6.85 (dtd, J _trans = 15.6, ² J = 7.8, ³ J _PH = 7.5 Hz, H3), 5.94 (ddt, J _trans = 15.6, ³ J = 1.3, ⁴ J _PH = 6.3 Hz, H2), 4.18 (q, J = 7.2 Hz, 4H), 4.09 (q, J = 7.1 Hz, 2H), 2.72 (ddd, ¹ J _PH = 22.9, J = 8.0, 1.4 Hz, 2H), 1.30 (t, J = 7.0 Hz, 6H), 1.26 (t, J = 7.5 Hz, 3H).

Example  One. Ethyl piperate  (4) manufacturing

1-1. Wardworth - Horner  Improved Whitig Condensation reaction  Manufacturing Method With (1)

About 0.05 mol (55% in mineral oil 2.3 g) of sodium hydride (NaH) washed with hexane in 70 mL of dry DMF was left under nitrogen gas. While stirring the slurry at 0 ° C. with a magnetic stirrer, ethyl (E) -4-diethylphosphono-2-butenoate (11.2 g, 0.05 mol) dissolved in dry DMF (10 mL) was maintained at 30-35 ° C. And slowly added with cooling if necessary. The resulting mixture was stirred for 4 hours. 0.05 mol piperonal (molecular weight 150.13, 7.5 g, Aldrich, Catalog # P4,910-4) dissolved in dry DMF (10 mL) was slowly added dropwise to the reaction mixture over 20 minutes. The mixture was kept at room temperature for 16 hours, diluted with water and extracted four times with 50 mL of ether. The obtained organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ). The solvent was removed under reduced pressure to obtain a crude product, which was eluted with methylene chloride and subjected to silica gel column chromatography. Ethyl piperate of light yellow platelet crystals having the following physical properties by recrystallization from an initially obtained fraction (Rf = 0.7, from CH ₂ Cl ₂ ) with a recrystallization solvent (ether: hexane = 1: 1). 10.90 g (94%) was obtained.

1-2. Wardworth - Horner  Improved Whitig Condensation reaction  Manufacturing method that used (2)

About 0.05 mol (55% in mineral oil 2.3 g) of sodium hydride (NaH) washed with hexane in 70 mL of dry DMF was left under nitrogen gas. The slurry was stirred with a magnetic stirrer at 0 ° C. and triphenylpiperonyl phosphonium bromide (8) (4.77 g, 0.01 mol) dissolved in dry DMF (10 mL) was kept at 30-35 ° C. and slowly cooled if necessary. Added dropwise. The resulting mixture was stirred for 4 hours. To this reaction mixture was slowly added dropwise aldehyde (7) (1.28 g, 0.01 mol) dissolved in dry DMF (10 mL) over 20 minutes. The mixture was kept at room temperature for 16 h and diluted four times with 50 mL of ether after dilution with water. The obtained organic layer was dried over magnesium sulfate (MgSO 4). The solvent was removed under reduced pressure to obtain a crude product, which was eluted with methylene chloride and subjected to silica gel column chromatography. The initially obtained fraction (Rf = 0.7, from CH ₂ Cl ₂ ) was recrystallized with a recrystallization solvent (ether: hexane = 1: 1), and ethyl piperate of light yellow platelet crystals having the following physical properties. ) 2.10 g (85%) were obtained.

       Melting point (mp): 76-77 ° C;

¹ H NMR (250 MHz, CDCl ₃ ): 7.39 (dd, 1H, J = 15.3, 10.3 Hz, H3), 6.97 (d, 1H, J = 1.5 Hz, H2 '), 6.89 (dd, 1H, J = 8.0, 1.5 Hz, H6 '), 6.77 (dd, 1H, J = 15.0, 10.0 Hz, H4), 6.76 (d, 1H, J = 8.0 Hz, H5'), 6.70 (d, 1H, J = 10.3 Hz , H5), 5.97 (s, 2H, OCH ₂ O), 5.92 (d, 1H, J = 15.3 Hz, H2), 4.20 (q, 2H, J = 7.1 Hz), 1.29 (t, 3H, J = 7.1 Hz);

¹³ C NMR (CDCl ₃ , 62.5 MHz) 167.17, 148.49, 148.24, 144.70, 140.07, 130.54, 124.51, 122.91, 120.41, 108.51, 105.82, 101.36, 60.27, 14.31.

Example  2. Preparation of Piperinic Acid (5)

The mixture of ethyl piperate (2.46 g, 0.01 mol) and 10% methanolic KOH (100 mL) obtained in Example 1 was heated to reflux at 110 ° C. for 6 hours. The pale yellow precipitate obtained was recovered and redissolved in distilled water (60 mL). The resulting aqueous solution was acidified with 6N hydrochloric acid to give a flocculent yellow precipitate which was recrystallized from methanol to give 2.10 g (96%) of piperic acid of light yellow acicular crystals having the following physical properties in quantitative yield. .

       Melting point (mp): 217-218 ° C. (literature; 217-218 ° C.)

¹ H NMR (250 MHz, DMSO-d ₆ ) d 7.28 (ddd, J = 15.0, 4.8, 1.2 Hz, 1H, H3), 7.22 (s, H2 '), 7.01-6.89 (m, 4H), 6.03 ( s, 2H, -OCH ₂ 0-, 5.91 (d, J = 15.0 Hz, H2);

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) d 167.98, 148.40, 148.27, 144.99, 140.14, 130.80, 125.13, 123.46, 121.40, 108.83, 105.99, 101.68.

Example  3. Pepperonguminine  Preparation of (1a)

Isobutylamine (3.00 g, 0.4 mol) was added dropwise while stirring the solution obtained by dissolving pipelinic acid (6.54 g, 0.3 mol) and boric acid (Boric acid; 0.02 g) obtained in Example 2 in 70 mL of toluene. It was. The resulting mixture was refluxed for 16 hours and about 0.6 mL of distilled water was recovered in a Dean-Stark trap. The mixture was cooled to room temperature and 500 mL hexane was added to cause an immediate precipitate. Further stirring was maintained for 30 minutes and the precipitate was recrystallized with 10% aqueous methanol to obtain 7.45 g (91%) of piperlonguminine of light yellow fine acicular crystals having the following physical properties.

       Melting point (mp): 166-168 ° C. (literature; 166-168 ° C.)

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 0.84 (d, 6H, J = 6.6 Hz), 1.69 (heptet, 1H), 2.95 (t, 2H, J = 6.0 Hz), 6.03 (s, 2H, -OCH ₂ 0-,), 6.10 (d, 1H, J = 15.0 Hz, H 2), 6.79-6.99 (m, 4H), 7.12 (dd, 1H, J = 15.0, 9.5 Hz, H 3). 8.03 (t, J = 6.7 Hz, NH);

¹³ C NMR (62.5 MHz, DMSO-d ₆ ) δ 165.36, 148.13, 147.88, 139.37, 1137.94, 131.09, 125.48, 124.89, 122.85, 108.65, 105.81, 101.46, 46.39, 28.37, 20.41;

        High resolution mass (MS): 273.33.

The novel production method for preparing the piperlongumin compound useful as a whitening agent of the present invention is a manufacturing method to enable mass production of the target material in high yield and low cost by improving disadvantages such as high cost and small amount production, which are problems in the prior art.

Claims (4)

The following piperonal (2) was treated with NaH in ethyl (E) -4-diethylphosphono-2-butenoate (3) to carry out an improved Wittig condensation reaction of the Wadworth-Honner to ethyl piperate. A first step of manufacturing (4); A second step of hydrolyzing ethyl piperate (4) under methanolic KOH to give piperic acid (5); A method for producing a piperlonguminine compound (1a) by reacting piperinic acid (5) in the second step with isobutylamine in the presence of boronic acid:

delete A first step of reacting the following aldehyde (7) with triphenylpiperonyl phosphonium halide (8) to produce ethyl piperate (4); A second step of hydrolyzing ethyl piperate (4) under methanolic KOH to give piperic acid (5); A method for producing a piperlonguminine compound (1a) by reacting piperinic acid (5) in the second step with isobutylamine in the presence of boronic acid:

delete