Kojic acid derivative containing guaiazulene structure and preparation method and application thereof

A technology of guaiazulene and kojic acid derivatives, which can be applied to medical preparations containing active ingredients, applications, and skin care preparations, etc., and can solve poor skin absorption, poor stability of kojic acid, and restrictions on kojic acid. problems such as the practical application of acid products, and achieve the effect of strong development and application prospects and strong inhibition

Active Publication Date: 2019-03-01
BOHAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003]Kojic acid has poor stability to heat and light, easy to change color after long-term storage, poor skin absorption and other factors limit the practical application of kojic acid products

Method used

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  • Kojic acid derivative containing guaiazulene structure and preparation method and application thereof
  • Kojic acid derivative containing guaiazulene structure and preparation method and application thereof
  • Kojic acid derivative containing guaiazulene structure and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 2-(3,8-Dimethyl-6-isopropylazulene-1-yl)phenylmethyl-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (A 1 )Synthesis

[0032] Ammonium acetate (15mg, 0.2mmol) was added to water (30mL) of guaiazulene (200mg, 1.0mmol) and 3-phenylkojic acid methanol (300mg, 1.2mmol), heated to reflux for 7 hours (using silica gel Chromatographic plate (TLC) to monitor the reaction). After the reaction was completed, the reaction mixture was cooled, filtered, washed with water, and dried to obtain a crude product. Ethanol recrystallization, yield 78%.

[0033] The structural analysis is as follows:

[0034]

[0035] 1 H NMR (400MHz, CDCl 3 )δ: 1.46(d, J=6.6Hz, 6H), 2.62(s, 3H), 3.05(s, 3H), 3.20~3.25(m, 1H), 4.20(s, 2H), 5.68(s, 1H ),6.36(s,1H),7.10-7.19(m,5H),7.28-7.30(m2H),7.78(s,1H),8.26(s,1H).

[0036] IR(KBr)ν:3412(OH),1641(C=O)cm -1 .

[0037] MS(ESI)m / z:429[M+H] + .

[0038] Elemental analysis (C 28 h 28 o 4 ): measured value (theoretical value), C 78.56 (78.48), H 6.67 (...

Embodiment 2

[0040] 2-(3,8-Dimethyl-6-isopropylazulene-1-yl)(4-methylphenyl)methyl-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (A 2 )Synthesis

[0041] Ammonium acetate (23mg, 0.3mmol) was added to guaiazulene (200mg, 1.0mmol) and 3-(4-methylphenyl)methylkojic acid methanol (312mg, 1.0mmol) in water (30mL) , heated to reflux for 7 hours (reaction monitored by silica gel chromatography (TLC)). After the reaction was completed, the reaction mixture was cooled, filtered, washed with water, and dried to obtain a crude product. Ethanol recrystallization, yield 80%.

[0042] The structural analysis is as follows:

[0043]

[0044] 1 H NMR (400MHz, CDCl 3)δ: 1.32(d, J=6.6Hz, 6H), 2.41(s, 3H), 2.60(s, 3H), 3.05(s, 3H), 3.21~3.27(m, 1H), 4.20(s, 2H ),5.68(s,1H),6.36(s,1H),7.19(d,J=8.0Hz,2H),7.23-7.27(m 2H),7.32(d,J=8.0Hz,2H),7.79( s,1H),8.34(s,1H).

[0045] IR(KBr)ν:3419(OH),1637(C=O)cm -1 .

[0046] MS(ESI)m / z:443[M+H] + .

[0047] Elemental analysis (C 29 h 30 o 4 ): measured valu...

Embodiment 3

[0049] 2-(3,8-Dimethyl-6-isopropylazulene-1-yl)(3-methoxyphenyl)methyl-3-hydroxy-6-hydroxymethyl-4H-pyran-4 Ketone (A 3 )Synthesis

[0050] Ammonium acetate (15mg, 0.2mmol) was added to guaiazulene (200mg, 1.0mmol) and 3-(3-methoxyphenyl)methylkojic acid methanol (360mg, 1.3mmol) in water (35mL) , heated to reflux for 8 hours (monitoring the reaction with silica gel chromatography (TLC)). After the reaction was completed, the reaction mixture was cooled, filtered, washed with water, and dried to obtain a crude product. Ethanol recrystallization, yield 81%.

[0051] The structural analysis is as follows:

[0052]

[0053] 1 H NMR (400MHz, CDCl 3 )δ: 1.31(d, J=6.6Hz, 6H), 2.64(s, 3H), 3.07(s, 3H), 3.21~3.25(m, 1H), 3.82(s, 3H), 4.23(s, 2H ),5.65(s,1H),6.33(s,1H),7.13(s,1H),7.18-7.20(m,3H),7.25-7.27(m 2H),7.85(s,1H),8.42(s ,1H).

[0054] IR(KBr)ν:3427(OH),1635(C=O)cm -1 .

[0055] MS(ESI)m / z:459[M+H] + .

[0056] Elemental analysis (C 29 h 30 o 5 ): measured va...

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Abstract

The invention belongs to the field of kojic acid medicinal chemistry and particularly relates to a kojic acid derivative containing a guaiazulene structure and synthesis and application thereof. A structural formula of the kojic acid derivative is shown in the description, wherein R is one of H, an alkyl group, an alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, carboxylic acid and carboxylic ester. A preparation process of the kojic acid derivative includes the steps that (1) under the catalysis of ammonium acetate, water is adopted as a reaction medium, and guaiazulene and 3-aryl kojic acid methanol undergo an alkylation reaction; (2) after the reaction is completed, direct filtration is conducted to obtain a crude product; (3) recrystallization purification is conducted. The preparation process has the advantages that raw materials are easy to obtain, the operation is simple, and the selectivity is high; through structural modification of kojic acid compound molecules, the preparation process can become an important approach of obtaining biologically active compounds.

Description

technical field [0001] The invention belongs to the field of kojic acid medicinal chemistry, and specifically relates to a kojic acid derivative containing a guaiazulene structure, its synthesis and its application. Background technique [0002] Kojic acid (5-hydroxy-2-(hydroxymethyl)-4-hydrogen-pyran-4-one, structure as follows) is an important building block of a large number of natural products and analogues. Low price, wide range of sources, antibacterial, free radical scavenging, antioxidant, tyrosinase inhibitory properties, is a class of substances with multiple biological activities ((a) P.A.Wender, F.E.McDonald.J.Am. Chem.Soc.1990, 112,4956; (b) P.A.Wender, J.L.Mascarenas.J.Org.Chem.1991, 56,6267; (c) J.Y.Wang, Q.Zhang, H.Zhang, Org.Biomol.Chem .2012, 10, 2950). Because it effectively inhibits the synthesis of tyrosinase, it can inhibit the formation of skin melanin, and it is used in whitening cosmetics; it can be used as a food additive for preservation, antisep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/40A61K8/49A61K31/351A61P17/00A61P17/18A61Q19/02A23L3/3544
CPCA61P17/00A61P17/18A61Q19/02A23L3/3544A61K8/498A61K31/351C07D309/40
Inventor 王道林郭思彤张璐邢锦娟
Owner BOHAI UNIV
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