CN106631950A - Vitamin A compound and paeonol condensed derivatives and preparation method - Google Patents
Vitamin A compound and paeonol condensed derivatives and preparation method Download PDFInfo
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- CN106631950A CN106631950A CN201610843071.7A CN201610843071A CN106631950A CN 106631950 A CN106631950 A CN 106631950A CN 201610843071 A CN201610843071 A CN 201610843071A CN 106631950 A CN106631950 A CN 106631950A
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- paeonol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses vitamin A compound and paeonol condensed derivatives and a preparation method. The vitamin A compound and paeonol condensed derivatives include derivatives in structures I-VII shown as follows; a structure I is ester formed by paeonol and all-trans retinoic acid; a structure II is ester formed by paeonol and 13-cis-retinoic acid; a structure III is ester formed by paeonol and acitretin; a structure IV is ester formed by paeonol and 9-cis-retinoic acid; a structure V is ester formed by paeonol and adapalene; a structure VI is ester formed by paeonol and tazarotene; a structure VII is ester formed by paeonol and bexarotene. By the vitamin A compound and paeonol condensed derivatives and the preparation method, irritation of vitamin A compounds to skin mucosa is relieved; after application to skin, the vitamin A compounds and paeonol are released under the action of hydrolase to dissolve cutin, promote epithelial cell differentiation and the like so as to realize anti-inflammatory and anti-oxidation functions.
Description
Technical field
The present invention relates to physiological activator field, more particularly to a kind of vitamin a compound and Paeonol condensation
Derivative and preparation method.
Background technology
Vitamin A intervenes biosynthesis, embry ogenesis, cell growth and the differentiation of visual purple.Retinol and Vitamin A
Fat acid esters is mutually converted in vivo, and retinol fatty acid ester is main storage form.Retinol is oxidized to retinene, the latter
Continue to be oxidized to retinoic acid.Retinoic acid is considered as the activity form of vitamin A, is combined with nuclear receptor, controlling gene expression.
The natural vitamin A class compound for using at present, predominantly retinol, retinol fatty acid ester, retinene, retinoic acid, regarding Huang
Acid derivative, retinoic acid isomers (alitretinoin, isotretinoin).These compounds belong to first generation retinoid material.The
The representative of two generation vitamin a compound is Acitretin acid and etretinate.Comprising many in third generation vitamin a compound structure
Ring, representative species have Adapalene, bexarotene and tazarotene.
System is used or external preparation for skin vitamin a compound, is widely used in treatment cutaneous diseases.Retinoid
Compound can be used to treat skin aging, effective to natural aging and light aging.Vitamin a compound is used to treat Cuo
The maintaining treatment of sore, especially acne.Vitamin a compound is used to treat hyperkeratosis.Vitamin a compound is used to control
Treat psoriasis.Vitamin a compound is used to treat t cell lymphoma, cutaneum carcinoma and auto-immune disease.
External application vitamin a compound, especially with free hydroxyl (retinol), aldehyde radical (retinene), carboxyl (depending on yellow
Acid, Adapalene, isotretinoin, Acitretin acid, bexarotene) vitamin a compound, common side effect be exactly stimulate with
Cause " retinoid dermatitis ", show as rubescent, peeling, itch, calcination, shouting pain and drying.These symptoms are often being used
First month is obvious, then can slowly disappear.Sometimes stimulate obvious, cause user to abandon retinoid chemical combination
Thing.With form " closing " these groups of " prodrug ", the Skin and mucosa irritation of vitamin a compound can be substantially reduced.Than
Such as retinol fatty acid ester (acetic acid esters, propionic ester, palmitate, stearate) is less than regarding Huang to the excitant of skin
Alcohol.Retinol retinoic acid ester, MDI-101, Viaminate (Viaminate), Suwei A amine (Fenretinide),
The esterification of the retinoic acids such as Tretinoin Tocoferil (TOCORETINATE) or the skin irritation of amide derivatives are again smaller than retinoic acid.
It is to adopt slow release method to reduce irritating another approach.Such as retinol and hydroxypropyl cyclodextrin are formed into adduct,
Substantially reduce the excitant of retinol.Retinoic acid is carried on into microsponge (Tretinoin Gel Microsphere) and forms slow
Release system, also reduces excitant and improves drug effect.
In the disease of skin with vitamin a compound is needed, inflammation and oxidative pressure also exist simultaneously.By antioxygen
The composition of change and vitamin a compound composition compound preparation, such as Viaminate vitamin E cream (《Chemical drug terrestrial reference rises GB the tenth
Volume》Page 254), effect is better than vitamin a compound is used alone.Using practical with anti-while vitamin a compound
The cosmetics of function of releiving are aoxidized, can also alleviate stimulation and drying that vitamin a compound brings.
The content of the invention
The invention mainly solves the technical problem of providing the derivative of a kind of vitamin a compound and Paeonol condensation
And preparation method, excitant of the vitamin a compound to skin and mucosa is solved, preferably treat some skin symptoms.
To solve above-mentioned technical problem, one aspect of the present invention is：A kind of vitamin a compound is provided
The derivative being condensed with Paeonol, including the derivative of following I～VII structures：
Wherein, structure I is the fat that Paeonol is formed with all-trans retinoic acid；
Structure I I is the fat that Paeonol is formed with the cis- Tretinoins of 13-；
Structure III is the fat that Paeonol is formed with Acitretin acid；
Structure I V is the fat that Paeonol is formed with the cis- Tretinoins of 9-；
Structure V is the fat that Paeonol is formed with Adapalene；
Structure VI is the fat that Paeonol is formed with tazarotene；
Structure VII is the fat that Paeonol is formed with bexarotene.
In a preferred embodiment of the present invention, the tazarotene is carboxylic acid type tazarotene.
In a preferred embodiment of the present invention, the route of administration of the derivative is external application.
In a preferred embodiment of the present invention, the route of administration of the derivative is oral or injection.
In a preferred embodiment of the present invention, the derivative be used for treat acne, seborrhea, hyperkeratosis,
Rosacea, psoriasis, light aging, chloasma and freckle.
To solve above-mentioned technical problem, another technical scheme that the present invention is adopted is：A kind of derivative preparation method is provided,
Using one-step synthesis method, comprise the following steps：
Corresponding carboxylic acid and Paeonol are dissolved in solvent, condensation reagent is added, and carry out heating response；
Solids removed by filtration, is left solution concentration；
Enriched product is purified or recrystallization purifying using column chromatography；
Reaction equation is as follows：
In a preferred embodiment of the present invention, the carboxylic acid is all-trans retinoic acid, the cis- Tretinoins of 13-, Acitretin acid, 9-
One kind in cis- Tretinoin, Adapalene, tazarotene and bexarotene, the solvent be tetrahydrofuran, methyltetrahydrofuran,
Acetone, 2- butanone, DMF, methyl tertiary butyl ether(MTBE), normal heptane, hexane, dichloromethane, ethyl acetate, acetic acid
One kind or several mixtures in isopropyl ester, toluene, acetonitrile.
In a preferred embodiment of the present invention, the condensation reagent is dicyclohexylcarbodiimide, is to accelerate reaction,
N, N- dimethyl aminopyridines (DMAP) are added before heating response.
To solve above-mentioned technical problem, the yet another aspect that the present invention is adopted is：A kind of derivative preparation method is provided,
Synthesized using two-step method, comprised the following steps：
Corresponding carboxylic acid is converted into the form of activity, is typically changed into acyl chlorides or mixed acid anhydride, then add pellet
Skin phenol and appropriate alkali, so as to form ester；
Reactant mixture is quenched with water, and adjustment pH value is 6.0～7.0, point liquid；
Organic phase is concentrated, and enriched product is purified or recrystallization purifying using column chromatography；
Reaction equation is as follows：
In a preferred embodiment of the present invention, it is that phosphorus trichloride, POCl3, grass is added dropwise that the carboxylic acid is converted into acyl chlorides
Acyl chlorides or thionyl chloride, it is that trifluoro-acetic anhydride is added dropwise that the carboxylic acid is converted into mixed acid anhydride.
The invention has the beneficial effects as follows：A kind of vitamin a compound that the present invention is pointed out is derivative with Paeonol condensation
Thing and preparation method, using the carboxyl of vitamin a compound and the phenolic hydroxyl group of Paeonol ester is condensed into, and is on the one hand enclosed certainly
By carboxylic acid group and free phenolic hydroxyl group, on the other hand Paeonol is incorporated into molecule, due to enclosing carboxyl and phenolic hydroxyl group,
Therefore the fat-soluble increase of derivative, reduces excitant of the vitamin a compound to skin and mucosa, is more distributed after external application
In sebaceous glands-hair follicle region, after being used in skin, in the presence of hydrolase, these derivatives will discharge retinoid
Compound and Paeonol, the former plays dissolving cutin, promotes the effects such as epithelial cell differentiation, the latter to play the anti-oxidant work(of its anti-inflammatory
Can, preferably treat some skin symptoms.
Specific embodiment
The technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described enforcement
Example is only a part of embodiment of the present invention, rather than the embodiment of whole.Based on the embodiment in the present invention, this area is common
All other embodiment that technical staff is obtained under the premise of creative work is not made, belongs to the model of present invention protection
Enclose.
The present invention provides a series of derivative of vitamin a compound, the derivative by vitamin a compound carboxylic
Base is condensed into ester with the phenolic hydroxyl group of Paeonol, on the one hand encloses free carboxylic acid group and free phenolic hydroxyl group, another aspect handle
Paeonol is incorporated into molecule.Due to enclosing carboxyl and free phenolic hydroxyl group, the excitant of skin and mucosa is reduced, and derived
The fat-soluble increase of thing, is more distributed in sebaceous glands-hair follicle region after external application.After being used in skin, in the effect of hydrolase
Under, these derivatives will discharge vitamin a compound and Paeonol.The former plays dissolving cutin, promotes epithelial cell point
The effect such as change, the latter plays its anti-inflammatory anti-oxidation function, preferably treats some skin symptoms.If oral, the series derivatives
Thing can be hydrolyzed to corresponding vitamin a compound and Paeonol in alimentary canal, or be hydrolyzed into again into after system circulation
For vitamin a compound and Paeonol.
The derivative that a kind of vitamin a compound that the present invention is provided is condensed with Paeonol, including following I～VII knots
The derivative of structure：
Wherein, structure I is the fat that Paeonol is formed with all-trans retinoic acid；
Structure I I is the fat that Paeonol is formed with the cis- Tretinoins of 13-；
Structure III is the fat that Paeonol is formed with Acitretin acid；
Structure I V is the fat that Paeonol is formed with the cis- Tretinoins of 9-；
Structure V is the fat that Paeonol is formed with Adapalene；
Structure VI is the fat that Paeonol is formed with tazarotene；
Structure VII is the fat that Paeonol is formed with bexarotene.
Embodiment 1
One-step method, using one-step synthesis method compound I ((2E, 4E, 6E, 8E) -2-acetyl-5-methoxyphenyl
3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate)。
In 250mL round-bottomed flasks, dry methylene chloride 100mL, Tretinoin 10.0g, Paeonol 5.56g, DCC are added
6.87g and DMAP 0.21g, under the conditions of room temperature under nitrogen lucifuge 24h is stirred；
Solids removed by filtration, concentrates filtrate, and the oil product for obtaining is purified with silica gel column chromatography, and column chromatography leacheate is for oneself
Alkane-ethyl acetate (100:1 to 5:1)；
Corresponding efflux is collected, Rotary Evaporators concentrate drying is used, yellow solid is obtained.LCMS：449.4(M+1).mp:
101-102℃。H NMR(Brucker AV-300,CDCl3,δppm):1.04(s,6H),1.46–1.49(m,2H),1.59–
1.64 (m, 2H), 1.73 (s, 3H), 2.03 (brs, 5H), 2.40 (s, 3H), 2.52 (s, 3H), 3.83 (s, 3H), 6.02 (s,
1H),6.15–6.41(m,4H),6.91(d,1H),7.10(dd,1H),7.44(s,1H),7.81(d,1H)。
The one-step synthesis method method of compound II-VII is similar to the above.
Embodiment 2
Synthesize compound I using two-step method
((2E,4E,6E,8E)-2-acetyl-5-methoxyphenyl3,7-dimethyl-9-(2,6,6-trimeth
ylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoate)。
In 250mL round-bottomed flasks, dry methylene chloride 70mL, Tretinoin 10.0g are added；
Interior temperature being cooled to for 5 DEG C, being slowly added dropwise oxalyl chloride 4.2g, ice-water bath is stirred 2 hours after completion of dropping with frozen water；
Paeonol 5.56g and triethylamine 6.72g are dissolved in 50mL dry methylene chlorides, are slowly added dropwise；
Completion of dropping, removes ice-water bath, is stirred at room temperature 2 hours, and add water 50mL, point liquid；
Organic phase is washed three times, each 50mL；
Organic phase Na2SO4It is dried, concentration, the oil product for obtaining is purified with silica gel column chromatography.Column chromatography leacheate is
Hexane-ethylacetate (100:1 to 5:1).
Corresponding efflux is collected, Rotary Evaporators concentrate drying is used, yellow solid is obtained.
The two-step method synthetic method of compound II-VII is similar with said process.
Embodiment 3
The configuration of vitamin a compound solution.Compound I (10.0g) is dissolved in into isobide acid anhydride dimethyl ether (90.0g)
10% solution can be obtained, the solution need to keep in dark place.
Embodiment 4
Excitant tests the making of emulsion.Liquid paraffin 30g is taken, compound II 0.30g are added, water 70mL, benzene oxygen is added
Ethanol 0.4g, Sensiva SC50 0.1g, pungent glycol 0.4g, Sepigel305 3.2g, mechanical agitation obtains yellow emulsion.
The emulsion foundation for arriving《Cosmetics health specification》(version in 2007) carries out toxicity test, has no skin irritation.
Embodiments of the invention are the foregoing is only, the scope of the claims of the present invention is not thereby limited, it is every using this
Equivalent structure or equivalent flow conversion that bright description is made, or directly or indirectly it is used in other related technology necks
Domain, is included within the scope of the present invention.
Claims (10)
1. the derivative that a kind of vitamin a compound is condensed with Paeonol, it is characterised in that including following I～VII structures
Derivative：
Wherein, structure I is the fat that Paeonol is formed with all-trans retinoic acid；
Structure I I is the fat that Paeonol is formed with the cis- Tretinoins of 13-；
Structure III is the fat that Paeonol is formed with Acitretin acid；
Structure I V is the fat that Paeonol is formed with the cis- Tretinoins of 9-；
Structure V is the fat that Paeonol is formed with Adapalene；
Structure VI is the fat that Paeonol is formed with tazarotene；
Structure VII is the fat that Paeonol is formed with bexarotene.
2. the derivative that vitamin a compound according to claim 1 is condensed with Paeonol, it is characterised in that described
Tazarotene is carboxylic acid type tazarotene.
3. the derivative that vitamin a compound according to claim 1 is condensed with Paeonol, it is characterised in that described
The route of administration of derivative is external application.
4. the derivative that vitamin a compound according to claim 1 is condensed with Paeonol, it is characterised in that described
The route of administration of derivative is oral or injection.
5. the derivative that vitamin a compound according to claim 1 is condensed with Paeonol, it is characterised in that described
Derivative is used to treat acne, seborrhea, hyperkeratosis, rosacea, psoriasis, light aging, chloasma and freckle.
6. the preparation side of a kind of arbitrary described vitamin a compound of Claims 1 to 5 and the derivative of Paeonol condensation
Method, it is characterised in that adopt one-step synthesis method, comprises the following steps：
Corresponding carboxylic acid and Paeonol are dissolved in solvent, condensation reagent is added, and carry out heating response；
Solids removed by filtration, is left solution concentration；
Enriched product is purified or recrystallization purifying using column chromatography；
Reaction equation is as follows：
7. derivative preparation method according to claim 6, it is characterised in that the carboxylic acid is all-trans retinoic acid, 13-
One kind in cis- Tretinoin, Acitretin acid, the cis- Tretinoins of 9-, Adapalene, tazarotene and bexarotene, the solvent is four
Hydrogen furans, methyltetrahydrofuran, acetone, 2- butanone, DMF, methyl tertiary butyl ether(MTBE), normal heptane, hexane, two
One kind or several mixtures in chloromethanes, ethyl acetate, isopropyl acetate, toluene, acetonitrile.
8. derivative preparation method according to claim 6, it is characterised in that the condensation reagent is dicyclohexyl carbon two
Imines, is to accelerate reaction, and N, N- dimethyl aminopyridines are added before heating response.
9. the preparation side of a kind of arbitrary described vitamin a compound of Claims 1 to 5 and the derivative of Paeonol condensation
Method, it is characterised in that synthesized using two-step method, comprised the following steps：
Corresponding carboxylic acid is converted into the form of activity, is typically changed into acyl chlorides or mixed acid anhydride, then add Paeonol
With appropriate alkali, so as to form ester；
Reactant mixture is quenched with water, and adjustment pH value is 6.0～7.0, point liquid；
Organic phase is concentrated, and enriched product is purified or recrystallization purifying using column chromatography；
Reaction equation is as follows：
10. derivative preparation method according to claim 9, it is characterised in that it is to be added dropwise that the carboxylic acid is converted into acyl chlorides
Phosphorus trichloride, POCl3, oxalyl chloride or thionyl chloride, it is that trifluoro-acetic anhydride is added dropwise that the carboxylic acid is converted into mixed acid anhydride.
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| CN201610843071.7A CN106631950A (en) | 2016-09-23 | 2016-09-23 | Vitamin A compound and paeonol condensed derivatives and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114436924A (en) * | 2022-02-21 | 2022-05-06 | 青岛三人行化学有限公司 | Synthesis method of hydroxy pinacolone retinoic acid ester |
| CN115925666A (en) * | 2022-11-24 | 2023-04-07 | 上海克琴科技有限公司 | Small molecule compound and application and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114436924A (en) * | 2022-02-21 | 2022-05-06 | 青岛三人行化学有限公司 | Synthesis method of hydroxy pinacolone retinoic acid ester |
| CN114436924B (en) * | 2022-02-21 | 2023-09-29 | 青岛三人行化学有限公司 | Synthesis method of hydroxy pinacolone retinoic acid ester |
| CN115925666A (en) * | 2022-11-24 | 2023-04-07 | 上海克琴科技有限公司 | Small molecule compound and application and preparation method thereof |
| WO2024007726A1 (en) * | 2022-11-24 | 2024-01-11 | 上海克琴科技有限公司 | Small-molecule compound, and use thereof and preparation method therefor |
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Application publication date: 20170510 |
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