A preparation method for synthesizing the derivative retinol from retinoic acid

Abstract

The present invention provides a preparation method for synthesizing its derivative retinol from retinoic acid, which is characterized in that: using retinoic acid as a raw material, reacting with N-coordinated silicic acid to generate a silicic acid complex intermediate, and then reducing it with a manganese preparation and a silane derivative to generate retinol; wherein, the whole reaction process is carried out at a temperature not higher than 60°C. The present invention provides a method that can achieve synthesis through a low-temperature reaction, thereby avoiding the deterioration of retinol.

Description

Technical Field

[0001] The present invention relates to the field of cosmetics, and specifically, to a preparation method for synthesizing a derivative retinol from retinoic acid. Background Art

[0002] Anti-aging has always been a hot topic for skincare product manufacturers. So far, it is generally believed in the market that the mechanisms of aging are mainly caused by free radical damage, photoaging, glycation, genetic genes, etc. Among the skincare ingredients for skin anti-aging, except for fruit acids that physically change the skin structure, vitamin A (retinoids) recognized by multiple academic studies is the most effective.

[0003] Retinoids are organic small molecule oily compounds in the vitamin A family, including derivatives of retinol such as VA alcohol (retinol), VA aldehyde (retinal), retinyl acetate, and retinyl palmitate, as well as new retinoids such as hydroxypinacolone retinoate (HPR). Simply put, ultimately these retinoids exert their effects by being metabolized by enzymes in the body to form retinoic acid. In the body, after retinoic acid and retinoic acid receptors (RAR, RXR) bind to form various dimers, the activation and expression of RNA are enabled, thereby regulating cell division and differentiation, achieving effects such as stimulating the proliferation of keratinocytes, promoting the metabolic exfoliation of keratinocytes in the epidermal layer, reducing the degradation of collagen in the dermal layer, and stimulating fibroblasts to produce more collagen and hyaluronic acid. However, the preparation process of retinol is not ideal.

[0004] For the preparation of retinol, traditional methods use strong reducing agents to reduce carboxylic acid esters, such as lithium aluminum hydride, etc. This reaction generates a large amount of gas and heat, and the yield is not high, which causes serious troubles for the large-scale production of retinol. At best, the product quality cannot be guaranteed, and at worst, production accidents may occur. In 2021, Emanuele Antico et al. reported a method of using a manganese catalyst and phenylsilane as a reducing agent to reduce carboxylic acids to the corresponding alcohols (JACS Au 2021, 1, 742 - 749). However, this method still has disadvantages such as requiring a relatively high temperature and the high price of the silane reagent used.

[0005] In summary, there are still many technical shortcomings in the large-scale production of retinol at the present stage, and further research and development are needed. Summary of the Invention

[0006] The present invention aims to overcome the above defects, focusing on the problem that retinoid compounds are unstable to temperature, and proposes a solution with a low reaction temperature, capable of being based on relatively inexpensive raw materials, and capable of obtaining retinol in one-pot by in-situ generating an intermediate and performing subsequent reactions on the intermediate.

[0007] The present invention provides a preparation method for synthesizing its derivative retinol from retinoic acid: using retinoic acid as a raw material, reacting with N-coordinated silicic acid to form a silicic acid complex intermediate, and then reducing it with a manganese preparation and a silane derivative to produce retinol;

[0008] Among them, the entire reaction process is carried out at a temperature not higher than 60 °C.

[0009] The above-mentioned N-coordinated silicic acid is selected from the compounds shown in the following structures:

[0010] , where n is a natural number and Ar is an aryl group.

[0011] The above-mentioned manganese preparation is selected from manganese pentacarbonyl bromide.

[0012] In the above-mentioned preparation method for synthesizing its derivative retinol from retinoic acid, there is also such a feature: that is, the reaction of retinoic acid with N-coordinated silicic acid is carried out under the condition of not higher than 10 °C.

[0013] In the above-mentioned preparation method for synthesizing its derivative retinol from retinoic acid, there is also such a feature: that is,

[0014] The above-mentioned silicic acid complex intermediate is a compound shown in the following structure:

[0015] , where n is a natural number and Ar is an aryl group.

[0016] In the above-mentioned preparation method for synthesizing its derivative retinol from retinoic acid, there is also such a feature: that is, the reduction reaction is carried out under the condition of not lower than 20 °C.

[0017] In the above-mentioned preparation method for synthesizing its derivative retinol from retinoic acid, there is also such a feature: that is, the silane derivative is selected from alkylsilane or arylsilane. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 , the 1H spectrum of retinol provided in Example 1 of the present invention.

[0019] Figure 2 , the 13C spectrum of retinol provided in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0020] The present invention can be implemented with various changes and can have various embodiments. Therefore, specific embodiments are illustrated in the drawings and described herein. However, this is not to limit the present invention to a specific embodiment, but should be understood to include all changes, equivalents, and alternatives that fall within the spirit and technical scope of the present invention.

[0021] This embodiment provides a method for preparing a retinol and retinoic silicate complex intermediate. Using retinoic acid as a raw material under the condition of no higher than 10 °C, it reacts with N-coordinated silicic acid (the molar ratio of retinoic acid to N-coordinated silicic acid is 1:1 - 1.5) to generate a VA silicate complex intermediate. Subsequently, this VA silicate complex intermediate is reduced by a manganese preparation (the molar ratio of retinoic acid to the manganese preparation is 10 - 30:1) at a temperature of no higher than 60 °C to generate retinol.

[0022] The above-mentioned N-coordinated silicic acid is selected from the compounds shown in the following structures:

[0023] , n is a natural number, and Ar is an aryl group.

[0024] Preferably selected from the compounds shown in the following structures:

[0025]

[0026] The synthesis method is based on the article "THE ONE-POT CONVERSION OF CARBOXYLIC ACIDS TO ALDEHYDES VIA ACTIVATED SILYL CARBOXYLATES. R.J.P. Corriu, G.F. Lanneau, M. Perrot, Tetrahedron Letters, Vol.28, No.34, pp 3941 - 3944, 1987" and is for on-site synthesis and direct use.

[0027] In the process of preparing AV alcohol, during the process of reducing the silicate complex intermediate to retinol by a manganese preparation, a silane derivative also needs to be added (the molar ratio of retinoic acid to the silane derivative is 1:1.5 - 5). The silane derivative is selected from alkylsilanes or arylsilanes. Among them, the alkylsilane can be a mono-substituted, di-substituted or tri-substituted alkyl group with no more than 10 carbon atoms, and can be any one of a straight-chain, branched-chain or cyclic alkyl group, such as: methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, cyclopentyl, hexyl, etc. The arylsilane can be a mono-substituted, di-substituted or tri-substituted phenyl group, an alkyl-substituted phenyl group, an anthryl group, an alkyl-substituted anthryl group, a naphthyl group, an alkyl-substituted naphthyl group, etc.

[0028] The reaction solvent can be selected from nitriles, aromatics, ether solvents, and halogenated alkane solvents.

[0029] The specific reaction equation of the above-mentioned retinol is as follows:

[0030]

[0031] In this equation, the N - coordinated silicic acid is exemplified by Si - H species A. When the N - coordinated silicic acid changes, the equation can be adjusted synchronously.

[0032] Example 1: (Best)

[0033] A magnetic stir bar, 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si - H species A, and 30 mL of toluene were added to a 100 mL round - bottom flask. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol, referring to 5% of the molar amount of retinoic acid, the same below) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane were added. The mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added. After liquid - liquid separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was carried out to obtain 217.4 mg of retinol, with a yield of 76% and a purity of 98.2%.

[0034] 1 H NMR (400 MHz, cdcl3) δ 6.60 (dd, J = 15.2, 11.2 Hz, 1H), 6.28 (d, J = 15.1 Hz, 1H), 6.16 (d, J = 16.3 Hz, 1H), 6.13 – 6.05 (m, 2H), 5.68 (t, J =7.1 Hz, 1H), 4.30 (d, J = 7.0 Hz, 2H), 1.97 (d, J = 22.8 Hz, 5H), 1.70 (s,3H), 1.60 (dt, J = 9.5, 6.2 Hz, 3H), 1.49 – 1.42 (m, 2H), 1.27 (d, J = 9.5Hz, 1H), 1.01 (d, J = 1.5 Hz, 6H).

[0035] 1313C NMR (101 MHz, CDCl3) δ 137.80, 137.65, 136.62, 136.38, 136.01, 130.21, 130.13, 129.20, 126.66, 125.04, 59.30, 39.60, 34.22, 33.04, 28.94, 21.72, 19.26, 12.70, 12.60。

[0036] Example 2: (Changing the manganese source)

[0037] A magnetic stir bar was added to a 100 mL round-bottom flask, followed by 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of toluene. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 10.7 mg (5% mol) of manganese bromide and 232.6 mg (2 eq.) of triethylsilane were added. The reaction mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. HPLC analysis showed no detection of the product retinol.

[0038] Example 3: (Changing the manganese source)

[0039] A magnetic stir bar was added to a 100 mL round-bottom flask, followed by 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of toluene. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 17.9 mg (5% mol) of manganese(II) bromide bis(tetrahydrofuran) and 232.6 mg (2 eq.) of triethylsilane were added. The reaction mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. HPLC analysis showed no detection of the product retinol.

[0040] Example 4: (Changing the silane)

[0041] A magnetic stir bar was added to a 100 mL round-bottom flask, followed by 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of toluene. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 368 mg (2 eq.) of diphenylsilane were added. The reaction mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added. After phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 214.4 mg of retinol, with a yield of 75% and a purity of 97.1%.

[0042] Example 5: (Changing the silane)

[0043] A magnetic stir bar was added to a 100 mL round-bottom flask, followed by 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of toluene. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 521 mg (2 eq.) of triphenylsilane were added. The reaction mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added, and after phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 200.2 mg of retinol with a yield of 70% and a purity of 97.4%.

[0044] Example 6: (Heating up)

[0045] A magnetic stir bar was added to a 100 mL round-bottom flask, followed by 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of toluene. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane were added. The reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added, and after phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 128 mg of retinol with a yield of 45% and a purity of 97.1%.

[0046] Example 7: (Cooling down)

[0047] A magnetic stir bar was added to a 100 mL round-bottom flask, followed by 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of toluene. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane were added. The reaction mixture was stirred at 20 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added, and after phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 28 mg of retinol with a yield of 10% and a purity of 58.7%.

[0048] Example 8: (Solvent change)

[0049] A magnetic stir bar, 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of tetrahydrofuran were added to a 100 mL round-bottom flask. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane were added. The mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added. After phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 188 mg of retinol with a yield of 66% and a purity of 96.4%.

[0050] Example 9: (Solvent change)

[0051] A magnetic stir bar, 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of cyclohexane were added to a 100 mL round-bottom flask. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane were added. The mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added. After phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 199.8 mg of retinol with a yield of 70% and a purity of 96.7%.

[0052] Example 10: (Solvent change)

[0053] A magnetic stir bar, 300 mg (1 mmol) of retinoic acid, 323.4 mg (1.1 mmol) of Si-H species A, and 30 mL of 2-methyltetrahydrofuran were added to a 100 mL round-bottom flask. The mixture was stirred at 0 °C under nitrogen protection for 30 minutes. Then, 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane were added. The mixture was stirred at 40 °C under a nitrogen atmosphere for 12 hours. 50 mL of 0.5 M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. Then, 50 mL of ethyl acetate was added. After phase separation, the upper ethyl acetate phase was obtained. After rotary evaporation at low temperature, column chromatography was performed to obtain 174 mg of retinol with a yield of 61% and a purity of 95.3%.

[0054] Example 11: (Without adding Si-H species)

[0055] Maintain at 0 °C. Add a magnetic stir bar into a 100 mL round-bottom flask, 300 mg (1 mmol) of retinoic acid, 30 mL of toluene. Stir evenly under nitrogen protection, then add 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane. Stir at 40 °C under a nitrogen atmosphere for 12 hours. HPLC detection found no product retinol. Heat up to 60 °C and stir under a nitrogen atmosphere for 5 hours. HPLC detection found no obvious product retinol, but unknown by-products appeared. Heat up to 90 °C and stir under a nitrogen atmosphere for 1 hour. A large amount of unknown by-products were produced and the experiment was stopped.

[0056] Example 12: (Replace with Si-H species B)

[0057] Add a magnetic stir bar into a 100 mL round-bottom flask, 300 mg (1 mmol) of retinoic acid, 304.7 mg (1.1 mmol) of Si-H species B, and 30 mL of toluene. Stir at 0 °C under nitrogen protection for 30 minutes. Then add 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane. Stir at 40 °C under a nitrogen atmosphere for 12 hours. Add 50 mL of 0.5 M dilute hydrochloric acid and stir at room temperature for 10 minutes. Then add 50 mL of ethyl acetate. After stratification, the upper ethyl acetate phase is obtained. After rotary evaporation at low temperature, column chromatography separation is carried out to obtain 188.5 mg of retinol, with a yield of 66% and a purity of 95.6%.

[0058] Example 13: (Replace with Si-H species C)

[0059] Add a magnetic stir bar into a 100 mL round-bottom flask, 300 mg (1 mmol) of retinoic acid, 289.2 mg (1.1 mmol) of Si-H species C, and 30 mL of toluene. Stir at 0 °C under nitrogen protection for 30 minutes. Then add 13.8 mg (5% mol) of manganese pentacarbonyl bromide and 232.6 mg (2 eq.) of triethylsilane. Stir at 40 °C under a nitrogen atmosphere for 12 hours. Add 50 mL of 0.5 M dilute hydrochloric acid and stir at room temperature for 10 minutes. Then add 50 mL of ethyl acetate. After stratification, the upper ethyl acetate phase is obtained. After rotary evaporation at low temperature, column chromatography separation is carried out to obtain 148.9 mg of retinol, with a yield of 52% and a purity of 94.9%.

[0060] Although the above has been described centering around embodiments, this is merely illustrative and does not limit the present invention. Those of ordinary skill in the art will understand that various modifications and applications not illustrated above can be made without departing from the essential characteristics of this embodiment. For example, each component specifically shown in the embodiment can be implemented with modifications. Moreover, various differences related to such modifications and applications should be construed as being included within the scope of the present invention defined in the appended claims.

Claims

1. A preparation method for synthesizing a derivative retinol from retinoic acid, characterized in that: Using retinoic acid as a raw material, reacting with N-coordinated silicic acid to form a silicic acid complex intermediate, and then reducing it with a manganese preparation and a silane derivative to produce retinol; Among them, the whole reaction process is carried out at a temperature not higher than 60 °C, and the reduction reaction is carried out at a temperature not lower than 20 °C; The manganese preparation is selected from manganese pentacarbonyl bromide; The N-coordinated silicic acid is selected from the compounds shown in the following structures: ； The silane derivative is selected from triethylsilane, diphenylsilane, and triphenylsilane.

2. The preparation method of synthesizing its derivative retinol based on retinoic acid according to claim 1, characterized in that: The reaction of retinoic acid with N-coordinated silicic acid is carried out at a temperature not higher than 10 °C.

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