Preparation method of hydroxyl pinacolone retinoate

Abstract

The invention provides a preparation method of hydroxyl pinacolone retinoate. The preparation method comprises the following steps: preparing corresponding pinacolone by using chloropinacolone through hydrolysis reaction under a strong alkaline condition, and then carrying out condensation reaction on the pinacolone and tretinoin under the conditions of a condensing agent and a catalyst to obtain the hydroxyl pinacolone retinoate. The method is easy to operate, high in reaction yield and suitable for industrial application, and the product obtained through the reaction is free of chloro-pinacolone impurities and can meet the requirement of cosmetics for the quality of the chloro-pinacolone. The invention further provides a novel crystal form of the hydroxyl pinacolone retinoate, and the crystal form is good in stability.

Description

technical field

[0001] The application belongs to the technical field of chemical synthesis, and in particular relates to the preparation of a hydroxypinatone retinoate. Background technique

[0002] Retinoid compounds, including retinol (A alcohol), retinyl palmitate (A ester), and vitamin A acid are currently the most powerful anti-aging ingredients. But in fact, among the three, only tretinoin has a direct biological effect on the skin. However, retinoic acid is used as a prescription drug in most regions, and it is easy to cause adverse skin reactions: such as peeling, redness, and photosensitivity. This also limits the use of tretinoin.

[0003] There are corresponding enzymes in the human body that can convert retinol (A alcohol) and retinyl palmitate (A ester) into vitamin A acid through several steps. This can greatly reduce the side effects of vitamin A acid.

[0004] Hydroxypinacolone retinoate (HPR) is a derivative of retinol, which can directly bind to cell r...

Examples

Embodiment 1

[0037] Embodiment 1, the preparation method of hydroxy pinacolone retinoate

[0038] (1) Hydrolysis reaction: Add tetrahydrofuran (600ml) to chloropinacolone (134.6g, 1mol), then add 2M aqueous sodium hydroxide solution (48g, 1.2mol), heat to 40-60°C for 5-8h, The end point was monitored by GC. After the reaction was completed, spin dry THF, add ethyl acetate (800ml) for extraction, dry the organic phase, and concentrate the organic phase to obtain 110.35 g of hydroxy pinacolone with a yield of 95%.

[0039] (2) Condensation reaction: add tretinoin (300.44g, 1mol) into tetrahydrofuran (2000ml), cool to -5~5°C, add DCC (247.60g, 1.2mol) and catalyst DMAP (1.22g, 0.01mol), After stirring for about 0.5 hours, the temperature was raised to 10°C, and hydroxy pinacolone (116.16 g, 1 mol) was added dropwise. After stirring for about 8 hours, the reaction was complete as monitored by TLC. The DCU was removed by filtration, the organic phase was spin-dried, passed through a column or c...

Embodiment 2

[0041] Embodiment 2, the preparation method of hydroxy pinacolone retinoate

[0042] (1) Hydrolysis reaction: Add tetrahydrofuran (600ml) to chloropinacolone (134.6g, 1mol), then add 2M potassium hydroxide aqueous solution (174.2g, 1.5mol), heat to 40-60°C for 5-8h , GC monitors the end point, after the reaction finishes, spin dry tetrahydrofuran, add ethyl acetate (800ml) to extract, the organic phase is dried, and the organic phase is concentrated to obtain hydroxy pinacolone 112.67g, yield 97%.

[0043](2) Condensation reaction: Add tretinoin (300.44g, 1mol) into tetrahydrofuran (1500ml), cool to -5~5°C, add DCC (309.50g, 1.5mol) and catalyst DMAP (3.66g, 0.03mol), After stirring for about 0.8 hours, the temperature was raised to 10-15° C., and hydroxy pinacolone (174.24 g, 1.5 mol) was added dropwise. After stirring for about 7.5 hours, the reaction was monitored by TLC. The DCU was removed by filtration, the organic phase was spin-dried, and the Column or crystallization...

technical field

[0001] The application belongs to the technical field of chemical synthesis, and in particular relates to the preparation of a hydroxypinatone retinoate. Background technique

[0002] Retinoid compounds, including retinol (A alcohol), retinyl palmitate (A ester), and vitamin A acid are currently the most powerful anti-aging ingredients. But in fact, among the three, only tretinoin has a direct biological effect on the skin. However, retinoic acid is used as a prescription drug in most regions, and it is easy to cause adverse skin reactions: such as peeling, redness, and photosensitivity. This also limits the use of tretinoin.

[0003] There are corresponding enzymes in the human body that can convert retinol (A alcohol) and retinyl palmitate (A ester) into vitamin A acid through several steps. This can greatly reduce the side effects of vitamin A acid.

[0004] Hydroxypinacolone retinoate (HPR) is a derivative of retinol, which can directly bind to cell r...

Examples

Embodiment 1

[0037] Embodiment 1, the preparation method of hydroxy pinacolone retinoate

[0038] (1) Hydrolysis reaction: Add tetrahydrofuran (600ml) to chloropinacolone (134.6g, 1mol), then add 2M aqueous sodium hydroxide solution (48g, 1.2mol), heat to 40-60°C for 5-8h, The end point was monitored by GC. After the reaction was completed, spin dry THF, add ethyl acetate (800ml) for extraction, dry the organic phase, and concentrate the organic phase to obtain 110.35 g of hydroxy pinacolone with a yield of 95%.

[0039] (2) Condensation reaction: add tretinoin (300.44g, 1mol) into tetrahydrofuran (2000ml), cool to -5~5°C, add DCC (247.60g, 1.2mol) and catalyst DMAP (1.22g, 0.01mol), After stirring for about 0.5 hours, the temperature was raised to 10°C, and hydroxy pinacolone (116.16 g, 1 mol) was added dropwise. After stirring for about 8 hours, the reaction was complete as monitored by TLC. The DCU was removed by filtration, the organic phase was spin-dried, passed through a column or c...

Embodiment 2

[0041] Embodiment 2, the preparation method of hydroxy pinacolone retinoate

[0042] (1) Hydrolysis reaction: Add tetrahydrofuran (600ml) to chloropinacolone (134.6g, 1mol), then add 2M potassium hydroxide aqueous solution (174.2g, 1.5mol), heat to 40-60°C for 5-8h , GC monitors the end point, after the reaction finishes, spin dry tetrahydrofuran, add ethyl acetate (800ml) to extract, the organic phase is dried, and the organic phase is concentrated to obtain hydroxy pinacolone 112.67g, yield 97%.

[0043](2) Condensation reaction: Add tretinoin (300.44g, 1mol) into tetrahydrofuran (1500ml), cool to -5~5°C, add DCC (309.50g, 1.5mol) and catalyst DMAP (3.66g, 0.03mol), After stirring for about 0.8 hours, the temperature was raised to 10-15° C., and hydroxy pinacolone (174.24 g, 1.5 mol) was added dropwise. After stirring for about 7.5 hours, the reaction was monitored by TLC. The DCU was removed by filtration, the organic phase was spin-dried, and the Column or crystallization...

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