Green synthesis method of retinaldehyde

Abstract

The invention belongs to the field of organic synthesis, and relates to a green synthesis method of retinaldehyde, in particular to a heteropolyacid catalyzed safe and green synthesis method of retinaldehyde. The preparation method comprises the following steps: heating, stirring and processing retinol serving as a raw material in an organic solvent under the action of heteropoly acid (HPA), and cooling and directly filtering after the reaction is finished, thereby obtaining the retinol. And the heteropoly acid is CsCu2PMo11VO40, CsCu3PMo11VO40 or CsCu4PMo11VO40, and the molecular formula of the heteropoly acid is CsCu2PMo11VO40 or CsCu3PMo11VO40. The preparation method provided by the invention has the advantages of low cost of used materials, mild reaction conditions, less generation of three wastes in the production process, short process flow and capability of effectively reducing the production cost, and the prepared retinaldehyde has relatively high yield.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a green synthesis method of retinal, in particular to a safe and green synthesis method of retinal catalyzed by heteropolyacid. Background Art

[0002] Retinoic acid plays a wide range of roles in skin diseases, but its clinical application is limited to a certain extent due to local irritation. Retinal is an intermediate metabolite of natural retinoic acid, has similar biological activity to retinoic acid, and is significantly better tolerated by the skin than retinoic acid. Retinoic acid can be used topically to treat photoaged skin, and wrinkles, color, capillary dilation, and pigmentation spots are significantly improved. Retinoic acid can be used topically to treat several indicators of the natural skin aging process, such as epidermal thickness, skin elasticity, dermal thickness, and skin hardness, and is well tolerated.

[0003] Natural retinoic acid plays an important role in epidermal differentiation, dermal reconstruction and skin inflammation. As an important intermediate metabolite of natural retinoic acid, retinal has similar biological activity to retinoic acid and is well tolerated by the skin. Therefore, it will be more widely used in skin diseases and has broad market prospects.

[0004] Heteropolyacid (HPA) is an oxygen-containing polyacid composed of heteroatoms and polyatoms coordinated and bridged by oxygen atoms in a certain structure. It is a bifunctional green catalyst with both acidity and alkalinity and redox properties. It is environmentally friendly and is a promising green catalyst. It can be used for aromatic alkylation and dealkylation reactions, esterification reactions, dehydration / combination reactions, redox reactions, as well as ring opening, condensation, addition and etherification reactions. Due to its unique acidity, "quasi-liquid phase" behavior, and multifunctionality (acid, oxidation, photoelectrocatalysis), heteropolyacids have received extensive attention from researchers in the field of catalysis research.

[0005] There are many problems with the synthesis process of retinal in the prior art:

[0006] Route 1:

[0007]

[0008] This route has a low yield of only 48%, and involves the use of potassium permanganate, which generates a large amount of solid waste during the production process and causes significant environmental pollution. Potassium permanganate is also a hazardous chemical that is easy to make drugs and explosions, increasing production risks.

[0009] Route 2:

[0010]

[0011] This route uses a metallic chromium catalyst, which causes severe environmental pollution, makes wastewater treatment difficult, and increases production costs.

[0012] The above route not only has a low yield, but also may produce a large amount of solid waste, wastewater, etc., which not only pollutes the environment but also increases production costs. Therefore, it is of great significance to develop a synthetic route for retinal that is simple to operate, safe, environmentally friendly and has an ideal yield. Summary of the invention

[0013] In order to overcome the defects of the prior art, the present invention provides a method for synthesizing retinal by heteropolyacid-catalyzed oxidation, which is green and safe, and has high yield and purity.

[0014] The present invention is achieved through the following technical solutions:

[0015] Retinol is used as a raw material, and in an organic solvent, under the action of heteropoly acid (HPA), it is processed by heating and stirring, and after the reaction is completed, the temperature is lowered and directly filtered to obtain the product.

[0016]

[0017] In the above reaction, the organic solvent is: 1,2-dichloroethane, n-heptane, chlorobenzene or chloroform.

[0018] The heteropoly acid is CsCu 2 PMo 11 VO 40 , CsCu 3 PMo 11 VO 40 or CsCu 4 PMo 11 VO 40 .

[0019] The molar ratio of retinol, solvent and heteropoly acid is: 1:4-6:0.005-0.02, preferably: 1:4-6:0.005-0.01.

[0020] The heating temperature is 40 to 90°C, preferably 40 to 70°C, more preferably 40 to 50°C.

[0021] The reaction time is 2 to 8 hours, preferably 2 to 5 hours.

[0022] The invention uses retinol as a raw material, adopts heteropoly acid for catalytic oxidation, and obtains retinal by one-step reaction. The material cost used in the preparation method of the invention is low, the reaction conditions are mild, less three wastes are generated in the production process, the process flow is short, the production cost can be effectively reduced, and the prepared retinal has a high yield. DETAILED DESCRIPTION

[0023] The following examples are only some specific embodiments of the present invention, and the present invention is not limited to the following embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by ordinary technicians in this field should be considered as the protection scope of the present invention.

[0024] Process screening process:

[0025] Process 1: 100 g of 1,2-dichloroethane, 50 g of retinol, CsCu 4 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 48.01 g of a light yellow solid with a yield of 96.7% and a purity of 98.4%.

[0026] Different process parameters were changed to investigate the effects of different experimental conditions on the yield and purity of retinal aldehyde.

[0027] 1. Retinal prepared from different heteropoly acids

[0028] According to the above process 1, different types of catalysts were selected, and other conditions remained unchanged to prepare retinal. The results are as follows:

[0029] Heteropoly Acid Yield purity <![CDATA[CsCu 2 PMo 11 VO 40 ]]> 94.8％ 98.4％ <![CDATA[CsCu 3 PMo 11 VO 40 ]]> 95.3％ 98.3％ <![CDATA[CsCu 4 PMo 11 VO 40 ]]> 96.7％ 98.4％ <![CDATA[MnO 2 ]]> 75.8％ 95.6％ <![CDATA[Cu 2 The]]> 72.5％ 92.4％ <![CDATA[C 5 H 6 N·ClCrO 3 ]]> 77.6％ 93.8％ <![CDATA[Ag 2 The]]> 76.7％ 94.6％

[0030] The results showed that CsCu 2 PMo 11 VO 40 , CsCu 3 PMo 11 VO 40 , CsCu 4 PMo 11 VO 40 When used as heteropoly acid, the purity of the target compound can reach more than 98%, and the yield can reach more than 90%. 2 , Cu 2 O.C 5 H 6 N·ClCrO 3 、Ag 2 The target compound prepared by using the Keggin-type heteropolyacid catalysis reaction can obtain high-purity and high-yield retinal under the parameter conditions of the present invention.

[0031] 2. Preparation of retinal at different reaction temperatures:

[0032] According to the reaction of process 1, different reaction temperatures were selected, and other conditions remained unchanged to prepare retinal. The results are as follows:

[0033] temperature Yield purity 45±5℃ 96.7％ 98.4％ 65±5℃ 92.5％ 98.3％ 85±5℃ 87.5％ 98.2％

[0034] The results show that under the condition of 40-90°C, the yield of the prepared o-nitrobenzaldehyde is above 85% and the purity is above 98.0%. When the reaction temperature is 40-50°C, the yield of o-nitrobenzaldehyde is above 95%. It can be seen that the purity of retinal does not change much with increasing temperature, but the yield decreases with increasing temperature. Therefore, the preferred reaction temperature of the present invention is 40-50°C.

[0035] 3. Effect of solvent type on the yield and purity of target product retinal:

[0036] According to the reaction of process 1, different organic solvents were selected, and other conditions remained unchanged to prepare retinal. The results are as follows:

[0037] Solvent type Yield purity 1,2-Dichloroethane 96.7％ 98.4％ n-Heptane 94.9％ 98.3％ chlorobenzene 94.2％ 98.4％ Chloroform 95.8％ 98.5％

[0038] The results show that the purity of the retinal prepared in the above four different solvents is above 98%, and the yield is above 90%. It can be seen that the above solvents have no significant effect on the yield and purity of retinol.

[0039] 4. Retinol, 1,2-dichloroethane and CsCu 4 PMo 11 VO 40 Effect of the molar ratio of on the yield and purity of the target product retinal aldehyde:

[0040] According to the reaction of process 1, retinol, 1,2-dichloroethane and CsCu 4 PMo 11 VO 40 Select different ratios and keep other conditions unchanged to prepare retinal. The results are as follows:

[0041] <![CDATA[Retinol: Solvent: Heteropolyacid CsCu 4 PMo 11 VO 40 > Yield purity 1:4:0.005 94.7％ 98.1％ 1:5:0.005 94.9％ 98.3％ 1:6:0.005 96.2％ 98.4％ 1:6:0.01 95.8％ 98.5％ 1:6:0.02 92.6％ 98.2％

[0042] The results showed that the molar ratio of retinol, solvent and heteropoly acid was 1:4-6:0.005-0.02, the purity of the prepared retinal reached more than 98%, and the yield was more than 90%. It can be seen that changing the retinol, 1,2-dichloroethane and CsCu 4 PMo 11 VO 40 The molar ratio of has little effect on the purity of retinal, but the yield decreases with the increase of the amount of catalyst. Therefore, the optimal molar ratio of the reaction is preferably 1:4-6:0.005-0.01.

[0043] Embodiment 1:

[0044] 100 g of 1,2-dichloroethane, 50 g of retinol, CsCu 2 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 47.06 g of a light yellow solid with a yield of 94.8% and a purity of 98.4%.

[0045] Embodiment 2:

[0046] 100 g of 1,2-dichloroethane, 50 g of retinol, CsCu 3 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 47.3 g of a light yellow solid with a yield of 95.3% and a purity of 98.3%.

[0047] Embodiment 3:

[0048] 100 g of 1,2-dichloroethane, 50 g of retinol, CsCu 4 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 48.01 g of a light yellow solid with a yield of 96.7% and a purity of 98.4%.

[0049] Example 4

[0050] 100 g of 1,2-dichloroethane, 50 g of retinol, CsCu 4 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 65±5°C for 5 h, cooled to room temperature and filtered to obtain 45.9 g of a light yellow solid with a yield of 92.5% and a purity of 98.3%.

[0051] Example 5

[0052] 100 g of n-heptane, 50 g of retinol, CsCu 4 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 47.12 g of a light yellow solid with a yield of 94.9% and a purity of 98.3%.

[0053] Example 6

[0054] Chlorobenzene 100g, retinol 50g, CsCu 4 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 25±5°C for 5 h, cooled to room temperature and filtered to obtain 46.77 g of a light yellow solid with a yield of 94.2% and a purity of 98.4%.

[0055] Example 7

[0056] Chloroform 100g, retinol 50g, CsCu 4 PMo 11 VO 40 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 25±5°C for 5 h, cooled to room temperature and filtered to obtain 47.56 g of a light yellow solid with a yield of 95.8% and a purity of 98.5%.

[0057] Example 8

[0058] 100 g of 1,2-dichloroethane, 50 g of retinol, MnO 2 (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 37.89 g of a light yellow solid with a yield of 75.8% and a purity of 95.6%.

[0059] Example 9

[0060] 150g of 1,2-dichloroethane, 50g of retinol, CsCu 4 PMo 11 VO 40 (0.01 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 65±5°C for 5 h, cooled to room temperature and filtered to obtain 45.87 g of a light yellow solid with a yield of 92.4% and a purity of 98.3%.

[0061] Example 10

[0062] 150g of 1,2-dichloroethane, 50g of retinol, (NH 4 ) 4 [N(CH 3 ) 4 ] 2 MnMoO 32 9H 2 O (0.005 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, and the reaction was stirred at about 65±5°C for 5 h. After cooling to room temperature and filtering, 41.3% of a light yellow solid was obtained with a yield of 83.2% and a purity of 88.3%.

[0063] Embodiment 11

[0064] 1,2-dichloroethane 600g, retinol 50g, CsCu 4 PMo 11 VO 40 (0.03 mol) was added into a three-necked flask equipped with a thermometer and a stirrer, stirred at about 45±5°C for 5 h, cooled to room temperature and filtered to obtain 45.37 g of a light yellow solid with a yield of 91.4% and a purity of 98.2%.

Claims

1. A green synthesis method of retinal, characterized in that: Retinol is used as a raw material, and in an organic solvent, under the action of a heteropoly acid, the reaction is stirred and heated, and after the reaction is completed, the temperature is lowered and directly filtered to obtain retinal.

2. The green synthesis method of retinal according to claim 1, characterized in that: The organic solvent is one or more of 1,2-dichloroethane, n-heptane, chlorobenzene or chloroform.

3. The green synthesis method of retinal according to claim 1 or 2, characterized in that: The heteropoly acid is CsCu2PMo 11 VO 40 、CsCu3PMo 11 VO 40 or CsCu4PMo 11 VO 40 .

4. The green synthesis method of retinal according to any one of claims 1 to 3, characterized in that: The heating temperature is 40-90°C.

5. The green synthesis method of retinal according to any one of claims 1 to 3, characterized in that: The heating temperature is 40-70°C.

6. The green synthesis method of retinal according to any one of claims 1 to 3, characterized in that: The reaction time is 2 to 8 hours.

7. The green synthesis method of retinal according to any one of claims 1 to 3, characterized in that: The reaction time is 2 to 5 hours.

8. The green synthesis method of retinal according to any one of claims 1 to 7, characterized in that: The molar ratio of o-nitrotoluene, organic solvent and heteropoly acid is 1:4-6:0.005-0.

02.

9. The green synthesis method of retinal according to any one of claims 1 to 7, characterized in that: Retinol was used as raw material, in 1,2-dichloroethane, in CsCu2PMo 11 VO 40 、CsCu3PMo 11 VO 40 or CsCu4PMo 11 VO 40 Under the action of , stirring and heating at 40-50°C, react for 2-5 hours, cool down and filter directly after reaction to obtain retinal.

10. Use of the method for synthesizing retinal according to any one of claims 1 to 9 in the preparation of retinal.

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