Method for synthesizing VE nicotinate

Abstract

The invention discloses a method for synthesizing VE nicotinate, which comprises the following steps: by taking VE and nicotinic acid as initial raw materials and EDCI as a condensing agent, dissolving the nicotinic acid in an aprotic organic solvent, cooling a reaction system to 0 DEG C, slowly adding EDCI (or DCC or CDI) into a reaction solution, sufficiently and uniformly mixing the reaction solution, dissolving VE in dichloromethane, and reacting at the temperature of 0 DEG C to obtain the VE nicotinate. Slowly and dropwise adding into the reaction liquid, heating the reaction liquid to room temperature after the addition is finished, and continuously stirring for more than 20 hours; the reaction has the advantages of high yield, low production cost and obvious price advantage.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical industry, and specifically relates to a method for preparing VE nicotinate. Background Art

[0002] Vitamin E nicotinate is a derivative obtained by condensation of vitamin E (VE) and nicotinic acid. Its chemical name is (+ / -)-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-6-benzodihydropyranol nicotinate; it has the functions of both vitamin E and nicotinic acid. It participates in the lipid metabolism, oxidation process and anaerobic decomposition process of the human body. In medical terms, it can treat peripheral nerve spasms, arteriosclerosis and other diseases. VE nicotinate can also act on the blood vessel wall, and has the effects of vasodilation and inhibition of cholesterol synthesis. Therefore, VE nicotinate can be used to treat a series of cardiovascular and cerebrovascular diseases such as arteriosclerosis, stroke, lipid metabolism disorders, hypertension, hyperlipidemia, coronary artery insufficiency and blood circulation disorders. VE nicotinate is also widely used in the field of cosmetics. Due to its antioxidant effect, it can protect the stability of cell membranes by interrupting the chain reaction of free radicals, prevent the formation of lipofuscin on the membrane, improve skin color, increase glossiness, and delay skin aging. The structural formulas of niacin, VE, VE nicotinate, DMAP, EDCI, DCC, and DIPEA are as follows:

[0003] The synthesis of VE nicotinic acid ester is mainly obtained by esterification reaction between the phenolic hydroxyl group of vitamin E and the ester of nicotinic acid. At present, the synthesis of VE nicotinic acid ester is reported in the following ways: 1: Preparation by condensation reaction using acid and alcohol as starting materials VE nicotinate was synthesized using 2-chloropyridinium iodate and Et3N as catalysts with a yield of 95% (see Japanese patent JP53116380).

[0004] The disadvantage of this synthesis method is that its raw materials are relatively expensive, which is price-unfriendly for corporate production.

[0005] Using nicotinic acid and tocopherol as raw materials, DCC as a condensing agent, and reacting in DMF at 100°C, the yield is 97% (refer to Japanese patent JP51006967); this synthesis method has the following disadvantages: 1) Using DCC as a condensing agent, it is difficult to remove its by-products after the reaction. 2) The reaction needs to be carried out at 100°C, which has high requirements for equipment, and high-temperature reactions are dangerous.

[0006] The post-processing of the above reaction is relatively complicated and not environmentally friendly enough, so it does not have much advantage in large-scale industrial production.

[0007] Using nicotinic acid and tocopherol as raw materials, VE nicotinic acid ester is synthesized using ion exchange resin AmberliteIR-120 (H+ type), and the yield is 70% (refer to Japanese patent JP50030877). The ion exchange resin required for this synthesis route is in high demand during synthesis, and industrialization is difficult to achieve. At the same time, the reaction has only a medium yield, and the production cost of the enterprise is relatively high.

[0008] 2. Reacting with Nicotinic Acid Halide and Tocopherol as Raw Materials Nicotinic acid and some acyl chlorides can exchange acyl chlorides or acyl bromides to generate nicotinyl halides, which are more active than nicotinic acid and can react well with tocopherol to generate VE nicotinate. Nicotinyl chloride hydrochloride is dissolved in tocopherol in benzene and reacted at room temperature for 5 hours to obtain VE nicotinate, with a yield of 86.9% (Japanese patent JP47000062).

[0009] The above reaction uses benzene as a solvent, which is very unfriendly to the environment. Moreover, benzene has a high carcinogenicity and will cause great harm to the reaction operators during the production process.

[0010] Natural a-tocopherol and nicotinoyl chloride hydrochloride are reacted in a mixed solvent of V (toluene): V (pyridine) = 1:1 at room temperature overnight, and then recrystallized in an acetone-n-hexane system to obtain vitamin E nicotinate (US Patent US6423847). This process uses pyridine as a solvent, which is highly polluting to the environment and is not conducive to industrialization.

[0011] When using nicotinyl halide as raw material, the acyl chloride usually needs to be prepared by nicotinic acid and reagents such as phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, etc., and its cost is often higher than nicotinic acid. In addition, this type of reaction often requires an anhydrous environment and has high requirements for equipment. It is very easy to corrode the equipment, and large-scale industrial production often has high costs.

[0012] Nicotinyl chloride is prepared on-site using nicotinic acid and triphosgene, and then reacted with VE in the presence of triethylamine. The temperature should be controlled at -5 – 10 °C. This reaction can prepare VE nicotinate in one pot with a yield of about 95%.

[0013] The above method has high temperature requirements. If the temperature is low, the reaction is incomplete and the yield is low. When the reaction temperature is high, the side reactions increase significantly. The stability is not high in industrial synthesis (refer to Chinese invention patent CN102816153A).

[0014] 3. Using nicotinate ethyl ester as raw material The process of synthesizing vitamin E nicotinate by the ester exchange method can produce VE nicotinate with a yield of 77% by reacting VE acetate with nicotinate ethyl ester in xylene at 170°C (refer to Japanese patent JP53059672).

[0015] The temperature required for the above reaction is relatively high, and industrial production is relatively dangerous, and enterprises have relatively high risks in production. In addition, the yield of the reaction is only moderate, and the production cost of enterprises is relatively high.

[0016] In view of the skin whitening and anti-aging effects of VE nicotinic acid esters, as well as their clinical uses in treating peripheral nerve spasms, arteriosclerosis and other diseases, many research teams have explored the synthesis of VE nicotinic acid esters and developed a series of synthesis processes. Due to the good medical and whitening uses of VE nicotinic acid esters, the development of new mild, cheap and easy-to-operate synthesis processes has good market prospects. In addition, we have invented a new method for synthesizing VE nicotinic acid esters. Summary of the invention

[0018] To achieve the above object, the present invention discloses a method for synthesizing VE nicotinate, which is characterized by following the steps: A method for synthesizing VE nicotinate, characterized in that it is carried out according to the following steps: (1) Under the protection of inert gas, nicotinic acid is dissolved in an aprotic organic solvent, and the reaction system is cooled to 0°C; (2) Slowly adding the condensing agent to the reaction solution in step (1) in batches and mixing them thoroughly. The temperature of the reaction solution is kept at 15-30° C. during the addition. The molar ratio of nicotinic acid to the condensing agent is 1:1-1.5. The condensing agent is EDCI, DCC or CDI.

[0019] (3) adding a catalytic amount of DMAP to the reaction solution, maintaining the temperature of the reaction solution at 15-30°C during the addition; the molar ratio of DMAP:VE is 1:10-15; (4) Slowly adding the acid-binding agent DIPEA or Et3N to the reaction solution of step 3; after the addition is completed, the reaction system is carried out at room temperature for 8-20 hours; the molar ratio of the acid-binding agent to nicotinic acid is 2:1 - 1.5; (5) Dissolve VE in an aprotic organic solvent and slowly add it dropwise to the reaction solution (step 4). After the addition is completed, warm the reaction solution to room temperature and continue stirring for 20-30 hours. The reaction concentration of VE in the reaction solution is 1.0-1.5 M. (6) After the reaction is completed, a volume of dichloromethane, ethyl acetate, ether or saturated sodium bicarbonate solution equivalent to the organic solvent is added to the reaction system. After sufficient extraction, the organic phase is concentrated and the crude product is repeatedly recrystallized to obtain the target compound VE nicotinate; The molar ratio of niacin:VE in the entire reaction solution is 1.5:1 - 2:1.

[0020] The aprotic organic solvent refers to: DCM, DMF, MeCN, CHCl3, DMSO, ether, THF, CCl4, toluene, benzene, acetone, DMI, p-xylene, ethyl acetate, or a mixed solvent of the above solvents.

[0021] The stepwise addition mentioned in the present invention refers to adding in three times, with the time interval between each addition being 30 minutes.

[0022] The present invention is described in more detail as follows: Using nicotinic acid and VE as raw materials, EDCI (EDC) as a condensation agent, DMAP as a catalyst, and DIPEA (TEA) as an acid-binding agent, the reaction yield is high, reaching more than 94%. After repeated recrystallization, the reaction yield can also reach more than 90%. The inventive method has the characteristics of mild conditions, low toxicity, and fewer side reactions. The inventive reaction only requires one step and has a good yield.

[0023] The specific operation process includes: In the first step, nicotinic acid is dissolved in an aprotic solvent, and the temperature of the reaction system is lowered to 0°C.

[0024] For aprotic solvents, we prefer DCM or acetonitrile, which are easier to concentrate and less toxic. The VE concentration in the reaction solution is about 1.0 M.

[0025] In the second step, EDCI (or DCC) was added to the reaction solution in batches, with an interval of 30 min between each addition, and the temperature of the reaction solution was kept below 30°C during the addition.

[0026] In the third step, DMAP was added to the reaction solution in batches, with an interval of 30 min between each addition, and the temperature of the reaction solution was kept below 30°C during the addition.

[0027] In the fourth step, the acid-binding agent DIPEA (or TEA) is slowly added to the above reaction solution. After the addition is completed, the reaction system is carried out at room temperature for 8-20 hours.

[0028] The fifth step is to slowly add VE to the reaction solution in batches, with an interval of 30 min between each addition. During the addition, the temperature of the reaction solution is kept below 30°C.

[0029] After the reaction is completed by TLC detection, the reaction system is cooled to 0 °C, saturated sodium bicarbonate is slowly added to the reaction system, the reaction solution is washed and extracted with DCM, and the organic phase is separated. The organic phase is concentrated under reduced pressure to precipitate a solid. The precipitated solid is recrystallized in anhydrous ethanol to obtain the target. The ethanol mother liquor is concentrated and recrystallized again. This is repeated several times to obtain a relatively pure VE nicotinate with a yield of about 94%.

[0030] The positive effects of the method for synthesizing VE nicotinate disclosed in the present invention are: The synthesis method of the invention has mild reaction conditions, low toxicity, few side reactions, is environmentally friendly, has low cost and high yield. DETAILED DESCRIPTION

[0031] The present invention is described below through specific embodiments. Unless otherwise specified, the technical means used in the present invention are methods known to those skilled in the art. In addition, the embodiments should be understood as illustrative rather than limiting the scope of the present invention, and the essence and scope of the present invention are limited only by the claims. For those skilled in the art, various changes or modifications to the material components and dosages in these embodiments, without departing from the essence and scope of the present invention, also belong to the protection scope of the present invention. The raw materials used in the present invention, such as nicotinic acid and VE (tocopherol), are commercially available. Example

[0032] In the first step, 1.85 g (15.0 mmol) of nicotinic acid was dissolved in 20 mL of DCM, an aprotic solvent, and the temperature of the reaction system was lowered to 0°C.

[0033] In the second step, 2.88 g (15.0 mmol) of EDCI was added to the reaction solution three times, with an interval of 30 min between each addition. The temperature of the reaction solution was kept below 30 °C during the addition.

[0034] In the third step, 122 mg (1.0 mmol) of DMAP was added to the reaction solution, and the temperature of the reaction solution was kept below 30°C during the addition.

[0035] In the fourth step, 2.58 g (20.0 mmol) of the acid-binding agent DIPEA was slowly added to the above reaction solution. After the addition was completed, the reaction system was carried out at room temperature for 10 h.

[0036] In the fifth step, 4.31 g (10.0 mmol) of VE was slowly added into the reaction solution in three batches, with an interval of 30 min between each addition. The temperature of the reaction solution was kept below 30 °C during the addition.

[0037] After the reaction was completed by TLC detection, the reaction system was cooled to 0 °C, and a saturated sodium bicarbonate solution (100 mL) was slowly added to the reaction system. The reaction solution was washed and extracted with DCM (150 mL × 3) and the organic phase was separated. The organic phase was concentrated under reduced pressure to precipitate a solid. The precipitated solid was repeatedly recrystallized in anhydrous ethanol to obtain 5.04 g of pure VE nicotinate, with a yield of 94%. Example

[0038] In the first step, 1.85 g (15.0 mmol) of nicotinic acid was dissolved in 20 mL of DMF, an aprotic solvent, and the temperature of the reaction system was lowered to 0°C.

[0039] In the second step, 2.88 g (15.0 mmol) of EDCI was added to the reaction solution three times, with an interval of 30 min between each addition. The temperature of the reaction solution was kept below 30 °C during the addition.

[0040] In the third step, 122 mg (1.0 mmol) of DMAP was added to the reaction solution, and the temperature of the reaction solution was kept below 30°C during the addition.

[0041] In the fourth step, 2.02 g (20.0 mmol) of acid-binding agent TEA was slowly added to the above reaction solution. After the addition was completed, the reaction system was carried out at room temperature for 10 h.

[0042] In the fifth step, 4.31 g (10.0 mmol) of VE was slowly added into the reaction solution in three batches, with an interval of 30 min between each addition. The temperature of the reaction solution was kept below 30 °C during the addition.

[0043] After the reaction was completed by TLC detection, the reaction system was cooled to 0 °C, and a saturated sodium bicarbonate solution (100 mL) was slowly added to the reaction system. The reaction solution was washed and extracted with DCM (150 mL × 3) and the organic phase was separated. The organic phase was concentrated under reduced pressure to precipitate a solid. The precipitated solid was repeatedly recrystallized in anhydrous ethanol to obtain 4.49 g of pure VE nicotinate, with a yield of 84%.

Claims

1. A method for synthesizing VE nicotinate, characterized in that Proceed as follows: (1) Under the protection of inert gas, nicotinic acid is dissolved in an aprotic organic solvent and the reaction system is cooled to 0 °C; (2) slowly adding the condensing agent to the reaction solution of step (1) in portions and mixing them thoroughly, and maintaining the temperature of the reaction solution at 15-30° C. during the addition; the molar ratio of nicotinic acid: condensing agent is 1:1-1.5; the condensing agent is EDCI, DCC or CDI; (3) adding a catalytic amount of DMAP to the reaction solution, maintaining the temperature of the reaction solution at 15-30° C. during the addition; the molar ratio of DMAP:VE is 1:10-15; (4) Slowly adding the acid-binding agent DIPEA or Et3N to the reaction solution (step 3); after the addition is completed, the reaction system is carried out at room temperature for 8-20 hours; the molar ratio of the acid-binding agent to nicotinic acid is 2:1-1.5; (5) Dissolve VE in an aprotic organic solvent and slowly add it dropwise to the reaction solution (step 4). After the addition is completed, warm the reaction solution to room temperature and continue stirring for 20-30 hours. The VE reaction concentration in the reaction solution is 1.0-1.5 M. (6) After the reaction is completed, a volume of dichloromethane, ethyl acetate, ether or saturated sodium bicarbonate solution equivalent to the organic solvent is added to the reaction system. After sufficient extraction, the organic phase is concentrated and the crude product is repeatedly recrystallized to obtain the target compound VE nicotinate; The molar ratio of niacin:VE in the entire reaction solution is 1.5:1 - 2:1; The aprotic organic solvent refers to: DCM, DMF, MeCN, CHCl3, DMSO, ether, THF, CCl4, toluene, benzene, acetone, DMI, p-xylene, ethyl acetate, or a mixed solvent of the above solvents.

2. The method for synthesizing VE nicotinate according to claim 1, characterized in that The said adding in batches refers to adding in three batches, with the time interval between each addition being 30 minutes.

Images