CN112341421A - Method for synthesizing tretinoin E ester by solvent-free method - Google Patents
Method for synthesizing tretinoin E ester by solvent-free method Download PDFInfo
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- CN112341421A CN112341421A CN202011492128.6A CN202011492128A CN112341421A CN 112341421 A CN112341421 A CN 112341421A CN 202011492128 A CN202011492128 A CN 202011492128A CN 112341421 A CN112341421 A CN 112341421A
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- tretinoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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Abstract
The invention discloses a solvent-free method for synthesizing tretinoin E ester, belonging to the technical field of organic synthesis. The method comprises the following steps: mixing tretinoin, vitamin E, a dehydrating agent and a catalyst according to a molar ratio of 1:1.0-1.2:1.0-1.2:0.05-0.2, grinding and reacting for 1-3 hours at room temperature, and purifying by a silica gel chromatographic column after the reaction is finished to obtain tretinoin ester. The invention has the following advantages: (1) no reaction solvent is needed, the environmental protection is better, and the cost is lower. (2) After the reaction is finished, concentration is not needed, and energy consumption is saved. (3) The product after reaction is oily matter and can be directly loaded on a column, and the purification is convenient. (4) The conversion rate of tretinoin is 100 percent, the yield is more than 75 percent, and the method is higher than that of a solvent method.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing tretinoin E ester by a solvent-free method.
Background
Tretinoin is effective in preventing wrinkles, treating acne and repairing skin, but is generally not used in cosmetics due to its irritancy. Vitamin E is the most commonly used antioxidant, can effectively capture free radicals, and is widely applied to cosmetics. Tretinoin vitamin E ester is the esterification product of vitamin A acid and vitamin E. Tretinoin vitamin E ester has effects of preventing skin aging and repairing wrinkle, and has no irritation of tretinoin and antioxidant effect of tretinoin. U Hoppe et al found that tretinoin vitamin E ester can prevent acne, remove speckle, and repair skin damage caused by light, and has no common side effects of tretinoin. TAMURA HIROAKI reports that tretinoin ester can improve rough skin and prevent skin aging without causing skin irritation when used in cosmetics.
Although there are many reports on the use of tretinoin E ester, the synthesis of tretinoin E ester is not reported, and Toyoda et al, using tretinoin and tretinoin as raw materials, trifluoroacetic anhydride as a catalyst, isopropyl ether as a solvent to synthesize tretinoin E ester, and then washing off excess acid with ammonia water to obtain a purified target product. However, this method requires the use of a large amount of volatile organic solvents (such as methylene chloride, isopropyl ether, etc.), is unsafe and environmentally unfriendly, and requires the cooperation of a large-volume reaction tank.
In addition, although the prior art discloses a solvent-free method for preparing tretinoin E ester (ionic liquid catalyzed synthesis of tretinoin E ester, Shandong chemical industry, Yuliei, Xuchao, Zhang Ying, Jingzheng), ionic liquid pyrrolidone sulfate is adopted as a solvent and a catalyst. But the yield is only about 10 percent at most, and the yield is very low, thus being not suitable for industrial production.
Disclosure of Invention
The invention provides a solvent-free method for synthesizing tretinoin E ester, which does not need a reaction solvent, has better environmental protection property and lower cost; meanwhile, after the reaction is finished, concentration is not needed, and energy consumption is saved; in addition, the product after reaction is oily matter and can be directly loaded on a column, and the purification is convenient. The scheme is as follows:
the embodiment of the invention provides a solvent-free method for synthesizing tretinoin E ester, which comprises the following steps: mixing tretinoin, vitamin E, dehydrating agent and catalyst in a molar ratio of 1:1.0-1.2:1.0-1.2:0.05-0.2, grinding at room temperature (such as 15-30 deg.C) for 1-3 hr, and purifying with silica gel chromatographic column to obtain tretinoin ester.
The dehydrating agent in the present invention is selected from N, N ' -Dicyclohexylcarbodiimide (DCC), N ' -Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), and the like, and N, N ' -dicyclohexylcarbodiimide is preferable.
The catalyst in the present invention is selected from 4-Dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (4PPY), 1-hydroxybenzotriazole (HOBt), etc., and preferably 4-dimethylaminopyridine.
Wherein, the rotation speed of the grinding reaction is 300-.
Wherein, in the purification of the silica gel chromatographic column, diethyl ether and petroleum ether are used as mobile phases according to the volume ratio of 1: 0.8-1.5.
Preferably, in the purification of the silica gel chromatographic column, diethyl ether and petroleum ether are used as mobile phases according to the volume ratio of 1:1.
Preferably, tretinoin, vitamin E, dehydrating agent and catalyst are mixed in a molar ratio of 1:1.01:1.01:0.1 for grinding reaction.
Preferably, the method provided by the invention comprises the following steps: mixing tretinoin, vitamin E, N, N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine in a molar ratio of 1:1.01:1.01:0.1, carrying out a grinding reaction at room temperature for 1-3 hours at a rotation speed of 300-500 r/min, and after the reaction is finished, using diethyl ether and petroleum ether in a volume ratio of 1:1 as a mobile phase, and purifying by a silica gel chromatographic column to obtain tretinoin E ester.
The invention has the following advantages:
(1) no reaction solvent is needed, the environmental protection is better, and the cost is lower.
(2) After the reaction is finished, concentration is not needed, and energy consumption is saved.
(3) The product after reaction is oily matter and can be directly loaded on a column, and the purification is convenient.
(4) The conversion rate of tretinoin is 100 percent, the yield is more than 75 percent, and the method is higher than that of a solvent method.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
The first embodiment is as follows:
tretinoin 300g (1mol), vitamin E431g (1.01mol), N, N' -Dicyclohexylcarbodiimide (DCC) 208g (1.01mol) and 4-Dimethylaminopyridine (DMAP) 12g (0.1mol) are put into a planetary ball mill, the mixture is ground at the room temperature (15 ℃) for 1 hour at 500 revolutions/min, the reaction product is oily, ether petroleum ether =1:1 is taken as a mobile phase, and the product is purified by a silica gel chromatographic column, the conversion rate of the tretinoin is 100 percent, and the yield is 80 percent.
Example two:
tretinoin 300g (1mol), vitamin E431g (1.01mol), N, N' -Dicyclohexylcarbodiimide (DCC) 208g (1.01mol) and 4-Dimethylaminopyridine (DMAP) 12g (0.1mol) are put into a planetary ball mill, 400 r/min and ground for 1 hour at room temperature (30 ℃), the reaction product is oily, ether: petroleum ether =1:1 is used as a mobile phase, and the product is purified by a silica gel chromatographic column, the conversion rate of the tretinoin is 100 percent, and the yield is 81 percent.
Example three:
tretinoin 300g (1mol), vitamin E431g (1.01mol), N, N' -Dicyclohexylcarbodiimide (DCC) 208g (1.01mol) and 4-Dimethylaminopyridine (DMAP) 12g (0.1mol) are put into a planetary ball mill, 400 r/min and ground for 3 hours at room temperature (20 ℃), the reaction product is oily, ether-petroleum ether =1:1 is used as a mobile phase, and the product is purified by a silica gel chromatographic column, the conversion rate of the tretinoin is 100 percent, and the yield is 78 percent.
Comparative example one:
tretinoin 30g (0.1mol), vitamin E43.1g (0.101mol), N, N' -Dicyclohexylcarbodiimide (DCC) 20.8g (0.101mol), 4-Dimethylaminopyridine (DMAP) 1.2g (0.01mol), dichloromethane 500ml, reacted in a three-necked flask at room temperature (15 ℃) for 1 hour, filtered, the filtrate was washed with water 3 times, and the organic phase was concentrated. The product was purified by silica gel column chromatography with ethyl ether to petroleum ether =1 to 1 as the mobile phase, with a conversion of tretinoin of 95% and a yield of 68%.
Comparative example two:
raw materials, tretinoin 300g (1mol), vitamin E431g (1.01mol), N, N' -Dicyclohexylcarbodiimide (DCC) 208g (1.01mol) and 4-Dimethylaminopyridine (DMAP) 12g (0.1mol) were mixed and left to stand overnight without grinding and without reaction.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A method for synthesizing tretinoin E ester by a solvent-free method, the method comprising: mixing tretinoin, vitamin E, a dehydrating agent and a catalyst according to a molar ratio of 1:1.0-1.2:1.0-1.2:0.05-0.2, grinding and reacting for 1-3 hours at room temperature, and purifying by a silica gel chromatographic column after the reaction is finished to obtain tretinoin ester.
2. The solvent-free method of synthesizing tretinoin E ester according to claim 1, characterized in that the dehydrating agent is selected from N, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
3. The solvent-free process for the synthesis of tretinoin E ester according to claim 1, characterized in that the dehydrating agent is N, N' -dicyclohexylcarbodiimide.
4. The solvent-free process for synthesizing tretinoin E ester according to claim 1, wherein the catalyst is selected from 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or 1-hydroxybenzotriazole.
5. The solvent-free process for synthesizing tretinoin E ester according to claim 1, wherein the catalyst is 4-dimethylaminopyridine.
6. The method for synthesizing tretinoin E ester according to claim 1, wherein the rotation speed of the milling reaction is 300-500 rpm.
7. The solvent-free method for synthesizing tretinoin E ester according to claim 1, wherein diethyl ether and petroleum ether are used as mobile phase in a volume ratio of 1:0.8-1.5 during the purification by silica gel chromatography column.
8. The solvent-free method for synthesizing tretinoin E ester according to claim 1, wherein diethyl ether and petroleum ether are used as mobile phase in a volume ratio of 1:1 during the purification by silica gel chromatography.
9. The solvent-free method for synthesizing tretinoin ester according to claim 1, characterized in that the tretinoin, vitamin E, dehydrating agent and catalyst are mixed in a molar ratio of 1:1.01:1.01:0.1 for grinding reaction.
10. The solvent-free process for synthesizing tretinoin E ester according to claim 1, which comprises: mixing tretinoin, vitamin E, N, N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine in a molar ratio of 1:1.01:1.01:0.1, carrying out a grinding reaction at room temperature for 1-3 hours at a rotation speed of 300-500 r/min, and after the reaction is finished, using diethyl ether and petroleum ether in a volume ratio of 1:1 as a mobile phase, and purifying by a silica gel chromatographic column to obtain tretinoin E ester.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05202020A (en) * | 1992-01-29 | 1993-08-10 | Nisshin Flour Milling Co Ltd | Preparation of highly pure tocopheryl retinoate |
| CN102964605A (en) * | 2012-11-30 | 2013-03-13 | 南京林业大学 | Esterification modification method for wood fiber biomasses |
-
2020
- 2020-12-17 CN CN202011492128.6A patent/CN112341421A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05202020A (en) * | 1992-01-29 | 1993-08-10 | Nisshin Flour Milling Co Ltd | Preparation of highly pure tocopheryl retinoate |
| CN102964605A (en) * | 2012-11-30 | 2013-03-13 | 南京林业大学 | Esterification modification method for wood fiber biomasses |
Non-Patent Citations (2)
| Title |
|---|
| 于金兰等: "香豆素-3-甲酸芳酯的无溶剂快速合成", 《甘肃农业大学学报》 * |
| 曹园等: "芳胺转化为酰芳胺的方法", 《大学化学》 * |
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