An efficient and environmentally friendly method for synthesizing vitamin K1

Abstract

The present invention relates to a synthetic method of vitamin K1, a chemical raw drug. Using 2-methyl-1,4-naphthalenediol diacetate as the starting material, the 4-acetyl group is hydrolyzed under the hydrolysis of an alkaline solution to obtain 2-methyl-4-hydroxy-1-naphthol acetate. 2-Methyl-4-hydroxy-1-naphthol acetate and phytol or isophytol are used to catalyze the Friedel-Crafts alkylation on the benzene naphthoquinone ring by replacing strong Lewis acids with solid acid catalysts. Then, through hydrolysis and by using oxygen in the air, the hydrolysis and oxidation reactions are completed in one step during the hydrolysis process, achieving the shortening of reaction steps, obtaining high-purity crude vitamin K1 with high efficiency, greenness, and high yield. After rapid column chromatography, the quality requirements of vitamin K1 in the European Pharmacopoeia can be met. This method is simple to operate, environmentally friendly, suitable for industrial production, and has a high yield. It has great technological advantages compared with traditional processes. This method can further be used as a process substitution method for raw drugs with similar structures in the vitamin system, and its potential applications are also relatively extensive.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing vitamin K1, and in particular to a method for efficiently and environmentally friendly synthesizing vitamin K1. Background Art

[0002] Vitamin K, also known as coagulation vitamin, is a general term for a large class of 2-methyl-1,4-naphthoquinone and its derivatives. Vitamin K was first discovered by the Danish chemist Dam. When studying the principle of cholesterol metabolism, Dam accidentally discovered a substance related to blood coagulation and confirmed it as a fat-soluble vitamin. Therefore, this substance with anti-bleeding effect was named vitamin K. People extracted vitamin K from green plants and used it to treat hypoprothrombinemia and various bleeding disorders, and achieved good results. Vitamin K includes vitamin K1, K2, K3, K4, K5, etc. Vitamin K1, also known as phylloquinone, is a yellow viscous oil and widely exists in green plants and animal livers. The defects of the existing methods are relatively obvious: 1. The reaction route is long and the yield is low; 2. Using boron trifluoride etherate as a catalyst will produce a large amount of wastewater, which is not conducive to the environment; 3. The reaction uses ether as a reaction solvent. Due to its flammable and explosive characteristics, industrialized large-scale production cannot be realized. Therefore, it is imperative to find a method that is environmentally friendly, has low toxicity and is easy to industrialize. Summary of the Invention

[0003] To solve the above defects in the prior art, the present invention discloses a method for efficiently and environmentally friendly synthesizing vitamin K1, which is realized by adopting the following technical solutions.

[0004] A method for efficiently and environmentally friendly synthesizing vitamin K1 specifically includes the following steps: Step 1, using 2-methyl-1,4-naphthalenediol diacetate as a starting material, using an alcohol as a solvent, and under the action of a base, directionally hydrolyzing the 4-position acetyl group to obtain 2-methyl-4-hydroxy-1-naphthol acetate; Step 2, 2-methyl-4-hydroxy-1-naphthol acetate and phytol or isophytol use toluene as a solvent, and under the catalysis of a solid acid, undergo a Friedel-Crafts alkylation reaction to generate 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthol acetate; Step 3, 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthol acetate uses ethanol and water as a mixed solvent, undergoes a hydrolysis reaction under alkaline conditions, and is simultaneously oxidized by oxygen in the air into crude vitamin K1 in the air; Step 4, the crude vitamin K1 is refined and purified by flash column chromatography to obtain the finished vitamin K1.

[0005] As a further improvement of the present technology, in step 1, an alcohol is used as the reaction solvent, and the alcohols include methanol, ethanol, isopropanol, and methanol, ethanol, and isopropanol with different water contents; the bases used for hydrolysis are sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and ammonia water solution, and also include alcohol solutions of sodium methoxide and sodium ethoxide. By controlling the dosage of the alkali solution and the reaction time, the 4-position hydrolyzed product, 2-methyl-4-hydroxy-1-naphthol acetate, can be obtained directionally.

[0006] As a further improvement of the present technology, in step 2, 2-methyl-4-hydroxy-1-naphthol acetate can undergo Friedel-Crafts alkylation reaction with either phytol or isophytol; toluene is used as the reaction solvent, and other solvents with the same or similar boiling points as toluene can also be used, such as, but not limited to: benzene, xylene, 1,4-dioxane, N,N-dimethylformamide, acetic acid, tert-butyl acetate, and pyridine; a solid acid is used as the alkylation catalyst and heated to react to obtain the alkylation product, where the solid acid mainly refers to heteropolyacids, which include phosphotungstic acid and phosphotungstate, silicotungstic acid and silicotungstate salts, phosphomolybdic acid and phosphomolybdate, and silicomolybdic acid and silicomolybdate salts.

[0007] As a further improvement of the present technology, in step 3, an alcohol-water mixed solvent is used as the reaction solvent, where the alcohol is methanol, ethanol, isopropanol, and ethers such as petroleum ether. Under alkaline conditions, hydrolysis and oxidation are carried out to obtain the crude vitamin K1. The bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and ammonia water solution, and also include alcohol solutions of sodium methoxide and sodium ethoxide. The reaction conditions of this reaction are mild, and hydrolysis and oxidation reactions occur almost simultaneously. After the reaction ends, high-purity crude vitamin K1 is obtained through extraction.

[0008] According to the method for efficiently and environmentally friendly synthesizing vitamin K1 described in claim 1, it is characterized in that in step 4, the high-purity vitamin K1 obtained only contains two major types of impurities with very low polarity and very high polarity. By adjusting the proportion of the developing agent, the low-polarity impurities can flow out with the front of the developing agent, and the high-polarity impurities remain on the chromatography column. Therefore, vitamin K1 can be purified by the fast chromatography column method, and the developing agent is petroleum ether and ethyl acetate or single solvent petroleum ether.

[0009] The present invention is realized through the following technical solutions:

[0010] Synthesis of 2-methyl-4-hydroxy-1-naphthol acetate: Using 2-methyl-1,4-naphthalenediol diacetate as the starting material, add 38.5 - 66.4 g of 2-methyl-1,4-naphthalenediol diacetate into the reaction flask, add 180 - 500 mL of methanol or ethanol, stir to dissolve, add 28.9 - 57.2 g of the alkali solution at room temperature, heat to 50 - 80 °C, and keep the hydrolysis reaction at a constant temperature for 1.0 - 8.0 hours.

[0011] After the reaction, the reaction solvent was concentrated and recovered. After concentration, the temperature was lowered for crystallization to obtain high-purity 2-methyl-4-hydroxy-1-naphthyl acetate with a molar yield of 90-100%. Synthesis of 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthyl acetate: 18.5-42.3 g of 2-methyl-4-hydroxy-1-naphthyl acetate was added to 190-400 ml of toluene solution, and 9.0-20.0 g of solid heteropolyacid was added. The mixture was heated to 50-110 °C and reacted for 1.0-4.0 hours. Phytol or isophytol, 9.5-26.2 g, was added dropwise to the solution, and the reaction was carried out at 50-110 °C for 1.0-4.0 hours.

[0012] After the reaction, the solid heteropolyacid was filtered. The filtrate was concentrated to recover toluene until dry. 50-500 ml of petroleum ether was used to recover 2-methyl-4-hydroxy-1-naphthyl acetate. The ether solution containing 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthyl acetate was directly used in the next hydrolysis without treatment. Synthesis of crude vitamin K1: The above reaction solution was added to 50-500 ml of alcohol solution, and liquid alkali was added dropwise at room temperature for hydrolysis.

[0013] After hydrolysis, the mixture was allowed to stand for stratification, and the organic layer was retained. After the organic layer was extracted with 50-500 ml of water to remove impurities, the organic layer was concentrated to obtain crude vitamin K1. Purification of vitamin K1: 20 g of the crude vitamin K1 was purified by flash column chromatography using 200-1400 silica gel or neutral alumina. The eluent was petroleum ether or a mixture of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 10:1-100:1). The eluent containing the product was concentrated to obtain purified vitamin K1.

[0014] Advantages of the present invention:

[0015] Our company uses a cheap and environmentally friendly heteropolyacid for Friedel-Crafts alkylation reaction to solve this problem, and directly obtains the product vitamin K1 through one-step hydrolysis and oxidation. The advantages of the improved synthesis process are as follows: 1. The process has obvious advantages in terms of environmental protection, can replace ether, can omit heavy metal oxidants, all reaction solvents can be recovered, and some can be recycled, without generating waste water and polluting the environment. 2. The number of reaction steps is reduced, resulting in a greatly improved yield. The actual yield is between 80-90%, and 2-methyl-4-hydroxy-1-naphthyl acetate can be basically recovered at 100%. 3. The proportion of isomers is between 3.9-19.6%, less than 21%. 4. The vitamin content synthesized through the improvement meets the standards, and the content of the crude product of this process can reach more than 97% after column chromatography purification. Specific embodiments

[0016] Example 1: Synthesis of 2-methyl-4-hydroxy-1-naphthyl acetate:

[0017] Add 58 g of 2-methyl-1,4-naphthalenediol diacetate into a reaction flask, add 300 mL of methanol, stir to dissolve, add 29 g of ammonia water solution at room temperature, heat to 65 - 70 °C, keep the temperature for hydrolysis reaction for 1.0 hour. After the reaction, concentrate the reaction solution under reduced pressure until no methanol drips out, cool down to 0 - 10 °C, stir for crystallization for 2 - 3 hours, then filter and dry to obtain 48.5 g of light yellow 2-methyl-4-hydroxy-1-naphthol acetate.

[0018] Example 2: Synthesis of 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthol acetate:

[0019] Dissolve 18 g of 2-methyl-4-hydroxy-1-naphthol acetate in 150 ml of toluene at 60 - 70 °C, add 5 g of phosphotungstic acid, activate at 60 - 70 °C for 1 hour, add 9 g of phytol, heat to 60 - 70 °C and react for 2 hours, filter the solid phosphotungstic acid, concentrate the filtrate to dryness under reduced pressure at 50 °C, add 60 ml of petroleum ether, stir to dissolve, and then let it stand for crystallization at 0 - 10 °C. Filter, recycle the unreacted 2-methyl-4-hydroxy-1-naphthol acetate from the filter cake, and keep the filtrate directly for the next step.

[0020] Example 3: Synthesis of crude vitamin K1:

[0021] Dissolve 9 g of potassium hydroxide in 30 ml of water to prepare an alkaline solution. Add the reserved filtrate from Example 2 into 120 ml of methanol, cool the reaction solution to 0 °C - 10 °C, then add the alkaline solution into the reaction solution, heat up to 10 °C - 20 °C and react for 4 to 5 hours. After the reaction, extract with 200 ml of water each time for three times, collect the organic layer, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 50 °C to obtain 12.5 g of crude vitamin K1 in yellow oil form.

[0022] Example 4: Purification of crude vitamin K1:

[0023] Purify 12.5 g of the crude vitamin K1 from Example 3 by flash column chromatography with 125 g of silica gel. The eluent is petroleum ether. Dissolve 12.5 g of the crude vitamin K1 in 25 ml of petroleum ether, and then slowly add it to the chromatography column for chromatographic separation. Separate and collect the yellow band in the dark. After collecting the vitamin K1 solution, concentrate it to dryness under reduced pressure at 60 °C, and continue to dry under reduced pressure at 60 - 70 °C for 3 - 4 hours to obtain 11 g of the finished vitamin in light yellow oil form. The molar yield is 80.4% (calculated based on phytol), the cis isomer is 12.8%, and the content is 99.9%.

[0024] Although the present invention is described in conjunction with the above embodiments, the present invention is not limited to the above embodiments, but only limited by the appended claims. Those of ordinary skill in the art can easily modify and change it without departing from the spirit and scope of the present invention.

Claims

1. A method for synthesizing vitamin K1, characterized in that, specifically including the following steps: Step 1, using 2-methyl-1,4-naphthalenediol diacetate as the starting material, using alcohols as the solvent, and under the action of a base, the 4-position acetyl group is directionally hydrolyzed to obtain 2-methyl-4-hydroxy-1-naphthol acetate; Step 2, 2-methyl-4-hydroxy-1-naphthol acetate and phytol or isophytol react with toluene as the solvent under the catalysis of a solid acid to carry out Friedel-Crafts alkylation reaction to generate 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthol acetate; Step 3, 2-methyl-3-20-alkenyl-4-hydroxy-1-naphthol acetate uses ethanol and water as a mixed solvent, undergoes hydrolysis reaction under alkaline conditions, and is simultaneously oxidized by oxygen in the air to obtain crude vitamin K1 in the air; Step 4, the crude vitamin K1 is purified by fast column chromatography to obtain the finished product of vitamin K1.

2. The method according to claim 1, characterized in that, in Step 1, alcohols are used as the reaction solvent, and the alcohols include methanol, ethanol, isopropanol and methanol, ethanol, isopropanol with different water contents; the base used for hydrolysis is sodium bicarbonate, potassium carbonate and ammonia water solution, and by controlling the dosage of the base solution and the reaction time, the 4-position hydrolyzed product 2-methyl-4-hydroxy-1-naphthol acetate can be obtained directionally.

3. The method according to claim 1, characterized in that, in Step 2, 2-methyl-4-hydroxy-1-naphthol acetate can carry out Friedel-Crafts alkylation reaction with either phytol or isophytol; toluene is used as the reaction solvent, or other solvents with the same or similar boiling point as toluene are used, and the other solvents are selected from: benzene, xylene, 1,4-dioxane, N,N-dimethylformamide; a solid acid is used as the alkylation catalyst and heated to react to obtain the alkylation product, wherein the solid acid includes phosphotungstic acid, silicotungstic acid and phosphomolybdic acid.

4. The method according to claim 1, characterized in that, in Step 3, an ethanol-water mixed solvent is used as the reaction solvent, and crude vitamin K1 is obtained by hydrolysis and oxidation under alkaline conditions. The base is selected from one of sodium hydroxide and potassium hydroxide. The hydrolysis and oxidation reactions occur almost simultaneously, and high-purity crude vitamin K1 is obtained after extraction at the end of the reaction.

5. According to the method of claim 1, in Step 4, vitamin K1 is purified by the fast chromatography column method, and the developing agent is petroleum ether and ethyl acetate or a single solvent of petroleum ether.