A synthetic process of vitamin K1

Abstract

The present invention provides a synthesis process of vitamin K1, and the specific steps include: stirring 2-methyl menaphoquinone, plant-based bromide, a catalyst, and a co-catalyst in an organic solvent, reacting with the aid of ultrasonic treatment and microwave radiation, and after the reaction is completed, eluting and concentrating to obtain vitamin K1. The present invention synthesizes vitamin K1 by optimizing the catalyst system and utilizing ultrasound-microwave coupling auxiliary technology, which is efficient and environmentally friendly, simple to operate, mild conditions, low production cost, high production efficiency, few side reactions, low difficulty in subsequent product separation and purification, and high yield and purity of the obtained vitamin K1. It is verified by the examples that the yield of vitamin K1 obtained by the synthesis process of the present invention is as high as 98%, and the purity is as high as 99.5%. A new approach or idea is provided for the synthesis process of vitamin K1.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a synthesis process of vitamin K1. Background Art

[0002] Vitamin K1 is a polycyclic aromatic ketone with a skeleton based on 2-methyl-1,4-naphthoquinone and a phytane substituent at the third position. Vitamin K1 is a fat-soluble vitamin that is stable to air and moisture, but will be decomposed in sunlight. It is widely present in natural green plants and belongs to vitamin drugs. It is a necessary substance for the liver to synthesize factors II, VII, IX, and X. Vitamin K1 is related to many clinical diseases, such as hemorrhagic diseases, bone metabolism, cardiovascular diseases, diabetes, arthritis, stones, cancer, etc. Therefore, it is of great significance to develop a simple and efficient method for synthesizing vitamin K1.

[0003] Existing methods for synthesizing vitamin K1 include Friedel-Crafts alkylation synthesis, one-pot synthesis, side chain extension, and cyclopentadiene synthesis. The above methods for synthesizing vitamin K1 have their own characteristics. The steps of the menadione-cyclopentadiene method are relatively simple, and the product yield is high, but the separation and purification of the subsequent product is difficult, and it is not suitable for large-scale industrial production; the one-pot method has good stereoselectivity, but the reaction conditions are harsh, the reagents are difficult to obtain, and the yield is not high, which is not conducive to industrial production; the biggest disadvantage of the direct FC reaction is low efficiency and many by-products, but the experimental conditions are simple, the difficulty of separating and purifying the subsequent products is small, and the value of industrial production is large. Among them, the cyclopentadiene synthesis method is currently the most widely used method for synthesizing vitamin K1 in industry. The method is simple to operate, but the difficulty of separating and purifying the subsequent products is relatively large, which is a problem that needs to be solved urgently. Therefore, the present invention optimizes the synthesis of vitamin K1. Summary of the invention

[0004] In view of this, the present invention proposes a synthesis process of vitamin K1.

[0005] The technical solution of the present invention is achieved in this way:

[0006] A synthesis process of vitamin K1 comprises the following steps: adding 2-methylnaphthoquinone, plant-based bromide, a catalyst and a co-catalyst into an organic solvent, reacting with the aid of ultrasonic treatment and microwave radiation, and after the reaction is completed, eluting and concentrating to obtain vitamin K1.

[0007] Furthermore, the preparation of the catalyst includes: adding nano-palladium into tetrahydrofuran, adding bis(diphenylphosphine) methane, ultrasonically stirring, and centrifugally washing to obtain the catalyst.

[0008] Furthermore, the solid-liquid ratio of the nano-palladium to tetrahydrofuran is 1:8-12 g / mL; the molar ratio of the bis(diphenylphosphine) to the nano-palladium is 1-3:1; and the ultrasonic stirring time is 40-60 min.

[0009] Furthermore, the co-catalyst is triphenylphosphine or ethylphosphine.

[0010] Furthermore, the plant-based bromine is obtained by reacting plant alcohol and phosphorus tribromide in a molar ratio of 1:1-3.

[0011] Furthermore, the molar ratio of the 2-methyl menaphoquinone to the plant-based bromide, the catalyst, and the co-catalyst is 1:1-2:0.05-0.08:0.1-0.3.

[0012] Furthermore, the organic solvent is at least one of ethanol, acetone, dichloromethane and tetrahydrofuran; and the liquid-solid ratio of the organic solvent to 2-methylnaphthoquinone is 10-20:1 mL / g.

[0013] Furthermore, the power of the ultrasonic treatment is 100-200W, the time is 40-60min, and the temperature is 30-40°C.

[0014] Furthermore, the microwave radiation is carried out at 60-70° C. and 300-400 W for 5-10 min.

[0015] Furthermore, the elution is performed using ethyl acetate and ethanol in a volume ratio of 3-5:2 as the eluent.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] 1. The present invention optimizes the catalyst system and utilizes ultrasound-microwave coupling-assisted technology to synthesize vitamin K1, which has simple operation, mild conditions, low production cost, high production efficiency, few side reactions, no pollution, and low difficulty in subsequent product separation and purification. The yield and purity of the obtained vitamin K1 are high. The yield of vitamin K1 obtained by the synthesis process of Example 1 of the present invention reaches 98%, and the purity is 99.5%.

[0018] 2. The bis(diphenylphosphine) methane of the present invention is a bidentate phosphine ligand, which can improve the reaction activity and selectivity of the palladium catalyst, compound the co-catalyst, reduce the generation of reaction by-products, improve the reaction efficiency of synthesizing vitamin K1, and is highly efficient and reusable. The ligand-modified palladium catalyst is more stable, can reduce the amount of palladium catalyst used, and is more environmentally friendly. DETAILED DESCRIPTION

[0019] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0020] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0021] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0022] The impurity most likely to be produced by the existing cyclopentadiene synthesis method for synthesizing vitamin K1 is the vitamin K1 cis isomer impurity (impurity 3).

[0023] Example 1

[0024] A synthesis process of vitamin K1 comprises the following steps:

[0025] (1) 100 mg of nano-palladium was added to 1 mL of tetrahydrofuran, and 730 mg of bis(diphenylphosphine) was added, and the mixture was ultrasonically stirred for 50 min, centrifuged, the supernatant was removed, and the product was washed to obtain a catalyst;

[0026] (2) adding 300 mg of plant alcohol to 5 mL of isopropyl ether, adding 546.98 mg of phosphorus tribromide, reacting at -8°C-5°C for 35 min, quenching the unreacted phosphorus tribromide, and removing the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0027] (3) 200 mg of 2-methylnaphthoquinone, 626.19 mg of plant-based bromide, 41.0 mg of catalyst, and 14.4 mg of ethyl phosphine were added to 3 mL of acetone in sequence, and ultrasonic treatment was first performed at a power of 150 W and a temperature of 35° C. for 50 min, and then microwave radiation reaction was continued at a power of 350 W and a temperature of 65° C. for 8 min. After the reaction, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 4:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 98%, the purity was 99.5%, and the cis-isomer impurity of vitamin K1 (impurity 3) was not detected.

[0028] Example 2

[0029] A synthesis process of vitamin K1 comprises the following steps:

[0030] (1) 100 mg of nano-palladium was added to 0.8 mL of tetrahydrofuran, and 365 mg of diphenylphosphine was added, and the mixture was ultrasonically stirred for 40 min, centrifuged, the supernatant was removed, and the product was washed to obtain a catalyst;

[0031] (2) adding 300 mg of plant alcohol to 5 mL of isopropyl ether, adding 273.49 mg of phosphorus tribromide, reacting at -8°C to 5°C for 30 min, quenching the unreacted phosphorus tribromide, and removing the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0032] (3) 200 mg of 2-methylnaphthoquinone, 417.29 mg of plant-based bromide, 29.3 mg of catalyst, and 7.2 mg of ethyl phosphine were added to 2 mL of acetone in sequence, and ultrasonic treatment was first performed at a power of 100 W and a temperature of 30° C. for 40 min, and then microwave radiation reaction was continued at a power of 300 W and a temperature of 60° C. for 5 min. After the reaction, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 3:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 97.8%, the purity was 99.3%, and the cis-isomer impurity of vitamin K1 (impurity 3) was not detected.

[0033] Example 3

[0034] A synthesis process of vitamin K1 comprises the following steps:

[0035] (1) 100 mg of nano-palladium was added to 1.2 mL of tetrahydrofuran, and 1095 mg of bis(diphenylphosphine) was added. The mixture was ultrasonically stirred for 60 min, centrifuged, the supernatant was removed, and the product was washed to obtain a catalyst;

[0036] (2) adding 300 mg of plant alcohol to 5 mL of isopropyl ether, adding 820.47 mg of phosphorus tribromide, reacting at -8°C-5°C for 40 min, quenching the unreacted phosphorus tribromide, and removing the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0037] (3) 200 mg of 2-methylnaphthoquinone, 835.39 mg of plant-based bromide, 46.9 mg of catalyst, and 21.6 mg of ethyl phosphine were added to 4 mL of acetone in sequence, and firstly ultrasonically treated at a power of 200 W and a temperature of 40° C. for 60 min, and then microwave irradiated at a power of 400 W and a temperature of 70° C. for 10 min. After the reaction, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 5:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 97.9%, the purity was 99.4%, and the cis-isomer impurity of vitamin K1 (impurity 3) was not detected.

[0038] Comparative Example 1

[0039] The difference from Example 1 is that palladium chloride is used as the catalyst, and the rest is the same as Example 1.

[0040] A synthesis process of vitamin K1 comprises the following steps:

[0041] (1) Add 300 mg of plant alcohol to 5 mL of isopropyl ether, add 546.98 mg of phosphorus tribromide, react at -8°C-5°C for 35 min, quench the unreacted phosphorus tribromide, and remove the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0042] (2) 200 mg of 2-methylnaphthoquinone, 626.19 mg of plant-based bromide, 14.4 mg of palladium chloride, and 14.4 mg of ethyl phosphine were added to 3 mL of acetone in sequence, and firstly ultrasonically treated at a power of 150 W and a temperature of 35° C. for 50 min, and then microwave irradiated at a power of 350 W and a temperature of 65° C. for 8 min. After the reaction, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 4:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 90%, the purity was 92.4%, and the content of the cis-isomer impurity of vitamin K1 (impurity 3) was 0.07%.

[0043] Comparative Example 2

[0044] The difference from Example 1 is that the promoter is missing and the amount of the catalyst is increased to 55.4 mg. The rest is the same as Example 1.

[0045] A synthesis process of vitamin K1 comprises the following steps:

[0046] (1) 100 mg of nano-palladium was added to 1 mL of tetrahydrofuran, and 730 mg of diphenylphosphine was added, and the mixture was ultrasonically stirred for 50 min, centrifuged, the supernatant was removed, and the product was washed to obtain a catalyst;

[0047] (2) adding 300 mg of plant alcohol to 5 mL of isopropyl ether, adding 546.98 mg of phosphorus tribromide, reacting at -8°C-5°C for 35 min, quenching the unreacted phosphorus tribromide, and removing the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0048] (3) 200 mg of 2-methylnaphthoquinone, 626.19 mg of plant-based bromide and 55.4 mg of catalyst were added to 3 mL of acetone in sequence, and ultrasonic treatment was first performed at a power of 150 W and a temperature of 35° C. for 50 min, and then microwave radiation reaction was continued at a power of 350 W and a temperature of 65° C. for 8 min. After the reaction, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 4:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 88%, the purity was 93.7%, and the content of the cis-isomer impurity of vitamin K1 (impurity 3) was 0.08%.

[0049] Comparative Example 3

[0050] The difference from Example 1 is that bis(diphenylphosphinothioate) is missing, and the rest is the same as Example 1.

[0051] A synthesis process of vitamin K1 comprises the following steps:

[0052] (1) Add 300 mg of plant alcohol to 5 mL of isopropyl ether, add 546.98 mg of phosphorus tribromide, react at -8°C-5°C for 35 min, quench the unreacted phosphorus tribromide, and remove the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0053] (2) 200 mg of 2-methylnaphthoquinone, 626.19 mg of plant-based bromide, 41.0 mg of nano-palladium catalyst, and 14.4 mg of ethyl phosphine were added to 3 mL of acetone in sequence, and ultrasonic treatment was first performed at a power of 150 W and a temperature of 35° C. for 50 min, and then microwave radiation reaction was continued at a power of 350 W and a temperature of 65° C. for 8 min. After the reaction, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 4:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 85.7%, the purity was 93.5%, and the content of the cis-isomer impurity of vitamin K1 (impurity 3) was 0.14%.

[0054] Comparative Example 4

[0055] The difference from Example 1 is that only ultrasonic treatment is performed, and the rest is the same as Example 1.

[0056] A synthesis process of vitamin K1 comprises the following steps:

[0057] (1) 100 mg of nano-palladium was added to 1 mL of tetrahydrofuran, and 730 mg of diphenylphosphine was added, and the mixture was ultrasonically stirred for 50 min, centrifuged, the supernatant was removed, and the product was washed to obtain a catalyst;

[0058] (2) adding 300 mg of plant alcohol to 5 mL of isopropyl ether, adding 546.98 mg of phosphorus tribromide, reacting at -8°C-5°C for 35 min, quenching the unreacted phosphorus tribromide, and removing the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0059] (3) 200 mg of 2-methylnaphthoquinone, 626.19 mg of plant-based bromide, 41.0 mg of catalyst, and 14.4 mg of ethyl phosphine were added to 3 mL of acetone in sequence, and ultrasonic treatment was performed at a power of 150 W and a temperature of 35° C. for 50 min. After the reaction was completed, crude vitamin K1 was obtained. The crude vitamin K1 was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 4:2 as eluents, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain finished vitamin K1. The yield of vitamin K1 was 89.9%, the purity was 90.7%, and the content of the cis-isomer impurity of vitamin K1 (impurity 3) was 0.11%.

[0060] Comparative Example 5

[0061] The difference from Example 1 is that only microwave radiation is used, and the rest is the same as Example 1.

[0062] A synthesis process of vitamin K1 comprises the following steps:

[0063] (1) 100 mg of nano-palladium was added to 1 mL of tetrahydrofuran, and 730 mg of diphenylphosphine was added, and the mixture was ultrasonically stirred for 50 min, centrifuged, the supernatant was removed, and the product was washed to obtain a catalyst;

[0064] (2) adding 300 mg of plant alcohol to 5 mL of isopropyl ether, adding 546.98 mg of phosphorus tribromide, reacting at -8°C-5°C for 35 min, quenching the unreacted phosphorus tribromide, and removing the isopropyl ether by rotary evaporation to obtain plant-based bromide;

[0065] (3) 200 mg of 2-methylnaphthoquinone, 626.19 mg of plant-based bromide, 41.0 mg of catalyst, and 14.4 mg of ethyl phosphine were added to 3 mL of acetone in sequence, and the microwave irradiation reaction was continued at a power of 350 W and a temperature of 65° C. for 8 min. After the reaction, a crude vitamin K1 product was obtained. The crude vitamin K1 product was purified by column chromatography using ethyl acetate and ethanol in a volume ratio of 4:2 as eluent, and the eluent containing vitamin K1 was collected. The eluent was concentrated under reduced pressure to obtain a finished vitamin K1 product. The yield of vitamin K1 was 89.7%, the purity was 90%, and the content of the cis-isomer impurity of vitamin K1 (impurity 3) was 0.10%.

[0066] It can be seen that the present invention optimizes the catalyst system and utilizes ultrasound-microwave coupling assisted technology to synthesize vitamin K1, and the yield of vitamin K1 obtained is as high as 98%, and the purity is as high as 99.5%. Comparative Example 1 uses palladium chloride as a catalyst, Comparative Example 2 lacks a co-catalyst, Comparative Example 3 lacks a ligand, and Comparative Examples 4-5 use a single treatment method, and the yield and purity of the vitamin K1 obtained therefrom are reduced to varying degrees.

[0067] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A synthesis process of vitamin K1, characterized in that: The following steps are involved: 2-methylnaphthoquinone, plant-based bromide, a catalyst and a co-catalyst are added to an organic solvent, and reacted with the aid of ultrasonic treatment and microwave radiation. After the reaction is completed, the reaction is eluted and concentrated to obtain vitamin K1; The molar ratio of the 2-methyl menthoquinone to the plant-based bromide, the catalyst, and the co-catalyst is 1:1-2:0.05-0.08:0.1-0.3; The preparation of the catalyst comprises: adding nano palladium into tetrahydrofuran, adding diphenylphosphine, ultrasonically stirring, centrifugally washing, and obtaining the catalyst; The co-catalyst is triphenylphosphine or ethylphosphine.

2. A process for synthesizing vitamin K1 as claimed in claim 1, characterized in that: The solid-liquid ratio of the nano-palladium to tetrahydrofuran is 1:8-12 g / mL; the molar ratio of the bis(diphenylphosphine) to the nano-palladium is 1-3:1; and the ultrasonic stirring time is 40-60 min.

3. A process for synthesizing vitamin K1 as claimed in claim 1, characterized in that: The plant-based bromide is obtained by reacting plant alcohol and phosphorus tribromide in a molar ratio of 1:1-3.

4. A process for synthesizing vitamin K1 as claimed in claim 1, characterized in that: The organic solvent is at least one of ethanol, acetone, dichloromethane and tetrahydrofuran; the liquid-to-solid ratio of the organic solvent to 2-methylnaphthoquinone is 10-20:1 mL / g.

5. A process for synthesizing vitamin K1 as claimed in claim 1, characterized in that: The power of the ultrasonic treatment is 100-200W, the time is 40-60min, and the temperature is 30-40°C.

6. A process for synthesizing vitamin K1 as claimed in claim 1, characterized in that: The microwave irradiation is carried out at 60-70° C. with 300-400 W microwave irradiation for 5-10 min.

7. A process for synthesizing vitamin K1 as claimed in claim 1, characterized in that: The elution is carried out using ethyl acetate and ethanol in a volume ratio of 3-5:2 as the eluent.