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1,3,4-thiadiazole-containing novel kojic acid derivative and application thereof

A technology of kojic acid derivatives and thiadiazoles, which can be used in pharmaceutical combinations, cosmetic preparations, cosmetics, etc., can solve the problems of easy oxidation and instability of kojic acid, and achieve the effects of easy availability of materials and simple synthesis methods.

Active Publication Date: 2019-02-22
HUNAN UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, kojic acid is unstable, sensitive to light and heat, and easily oxidized in the air. In addition, kojic acid is easy to chelate with many metal ions, especially chelating with Fe to produce a yellow complex, which makes the use of kojic acid Formulated skin whitening products often gradually turn yellow-brown during use

Method used

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  • 1,3,4-thiadiazole-containing novel kojic acid derivative and application thereof
  • 1,3,4-thiadiazole-containing novel kojic acid derivative and application thereof
  • 1,3,4-thiadiazole-containing novel kojic acid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] (E)-N-(5-((5-Hydroxy-4-oxo-4H-pyran-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-3 - Synthesis of (p-tolyl)acrylamide (Ia).

[0021] First place the reaction bottle containing kojic acid (21.0 mmol) in an ice bath, then slowly add 40ml of thionyl chloride dropwise into the reaction bottle and stir it magnetically, and track the reaction progress by TLC. After the reaction is over, add petroleum ether to the reaction solution, a large amount of solids are precipitated, filter, dry the solids and recrystallize with ethanol to obtain the intermediate product 2-chloromethyl-5-hydroxy-4H-pyran-4-one 1 .

[0022] Weigh the above intermediate 1 2-chloromethyl-5-hydroxy-4H-pyran-4-one (10mmol) and 2-amino-5-mercapto-1,3,4-thiadiazole (10mmol) and dissolve in 30ml In ethanol, triethylamine (12mmol) was added dropwise, heated to reflux, and the reaction progress was tracked by TCL. After the reaction was completed, it was cooled to room temperature, and a solid was precipitated. Th...

Embodiment 2

[0027] (E)-N-(5-((5-Hydroxy-4-oxo-4H-pyran-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-3 -Synthesis of (4-methoxyphenyl)acrylamide (Ib).

[0028] The preparation method of this example is the same as in Example 1 except that p-methoxyphenylacrylic acid is used instead of p-tolylacrylic acid, and finally a white solid (E)-N-(5-((5-hydroxyl-4-oxo -4H-pyran-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-3-(4-methoxyphenyl)acrylamide, its chemical structural formula is as formula (Ib ), yield: 77.1%.

[0029]

[0030] 1 HNMR (500 MHz, DMSO) δ : 8.59 (s, 1H), 7.81 (s, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.44 (s, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 15.5Hz, 1H),6.47(s, 1H), 4.28(s, 2H), 3.34(s, 3H); 13 CNMR (125 MHz, DMSO) δ IR (KBr) v : 3349, 3110, 1733, 1653,1504, 1418, 1328, 1255, 1201, 1128, 1030 cm -1 ; HRMS (ESI, m / z) calcd for [C 18 h 16 N 3 o 5 S 2 ] + (M+H) + 418.0526, found 418.0527.

Embodiment 3

[0032] (E)-N-(5-((5-Hydroxy-4-oxo-4H-pyran-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-3 -Synthesis of (3-fluorophenyl)acrylamide (Ic).

[0033] The preparation method of this example is the same as in Example 1 except that 3-fluorophenylacrylic acid is used instead of p-tolylacrylic acid, and finally a white solid (E)-N-(5-((5-hydroxyl-4-oxo -4H-pyran-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-3-(3-fluorophenyl)acrylamide, its chemical structure is as formula (Ic) As shown, the yield: 74.8%.

[0034]

[0035] 1 HNMR (500 MHz, DMSO) δ : 8.63 (s, 1H), 7.85 (d, J = 16.0 Hz, 1H), 7.75(d, J = 10.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.50 (q, J = 8.0 Hz, 1H), 7.45 (s, 2H), 7.31 (td, J = 8.5, 2.0 Hz, 1H), 6.96 (d, J = 16.5 Hz, 1H), 6.48(s, 1H), 4.29 (s, 2H); 13 CNMR (125 MHz, DMSO ) δ :171.99, 171.28, 165.09,163.86, 163.58, 161.92, 150.12, 147.68, 146.47, 140.81, 136.68, 136.61,131.48, 131.41, 125.77, 118.34 , 118.17, 118.06, 115.74, 115.42, 115.24,35.94; IR (KBr) v...

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Abstract

The invention discloses a 1,3,4-thiadiazole-containing novel kojic acid derivative and application thereof. The structural formula is shown as a formula (I). The structural formula is as shown in thespecification. In the formula (I), the substituent group R is H, -CH3, -CF3, -CH2CH3, -OCH3, F, Cl, Br, -COCH3, -OH, -COOH, -SO3H, -C6H5 or substituted phenyl. The (E)-N-(5-((5-hydroxy-4-oxo-4H-pyran-2-yl) methylthio)-1,3,4-thiadiazole-2-yl)-3-arylacrylamide compound disclosed by the invention has a certain inhibitory activity on tyrosinase, and can be used for preparing whitening cosmetics and drugs. Moreover, the synthetic method is simple, and the materials are readily available.

Description

technical field [0001] The present invention relates to a novel kojic acid derivative containing 1,3,4-thiadiazole, namely a novel (E)-N-(5-((5-hydroxyl-4-oxo-4H-pyran- 2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-3-arylacrylamide compounds, new tyrosinase inhibitors, as melanin inhibitors or whitening agents It is used in the fields of medicine, food and daily chemical industry. More specifically, the present invention provides (E)-N-(5-((5-hydroxy-4-oxo-4H-pyran-2-yl)methylthio)- as a tyrosinase inhibitor A preparation method of 1,3,4-thiadiazol-2-yl)-3-arylacrylamide compounds and a pharmaceutical composition containing them. Background technique [0002] Tyrosinase (EC 1.14.18.1, Tyrosinase) is a copper-containing metalloenzyme widely distributed in microorganisms, animals, plants and humans. Tyrosinase is mainly involved in two reaction processes: catalyzing the hydroxylation of L-tyrosine into L-dopa and the oxidation of L-dopa to form dopaquinone. After a series of reac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61P17/00A61K8/49A61Q19/02
CPCA61K8/498A61Q19/02A61P17/00C07D417/12
Inventor 谢文林刘仁志梅期红
Owner HUNAN UNIV OF SCI & TECH