CN114031490A

CN114031490A - Method for synthesizing VK2 by one-step method

Info

Publication number: CN114031490A
Application number: CN202111425133.XA
Authority: CN
Inventors: 王俊; 袁毅; 姚欣; 黄树青
Original assignee: Anhui Xianhe Medical Research Co ltd
Current assignee: Anhui Xianhe Medical Research Co ltd
Priority date: 2021-11-26
Filing date: 2021-11-26
Publication date: 2022-02-11

Abstract

The invention discloses a method for synthesizing VK2 by a one-step method, which comprises the following steps: dissolving menadione in tetrahydrofuran, adding cuprous iodide, cooling to-65-90 ℃ under the protection of nitrogen, dropwise adding LDA (lithium diisopropylamide), reacting for 0.5-2 hours at a controlled temperature, dropwise adding geranylgeranium bromide, and naturally reacting for 0.5-2 hours. The invention directly takes menadione as raw material to synthesize VK2 in one step, greatly simplifies the reaction steps, shortens the reaction time, and has low price of used reagent, thereby greatly reducing the production cost.

Description

Method for synthesizing VK2 by one-step method

Technical Field

The invention relates to a one-step method for synthesizing vitamin K2(VK 2).

Background

Vitamin K is a class of compounds with quinone structures, including 5 classes of compounds with different structures, i.e. vitamin K1, K2, K3, K4, K5. The research shows that the vitamin K2 has the function of osteogenesis, promotes calcium metabolism, and simultaneously can inhibit bone absorption caused by osteoclast, thereby increasing bone density and preventing and treating osteoporosis. Vitamin K2chemical book is a series of compounds, which are pale yellow crystals, mainly synthesized by intestinal bacteria, and 14 kinds in total according to the difference in the length of the isoprene side chain on C3, and mainly used for treating osteoporosis is vitamin K2(20), i.e., menatetrenone. Menatetrenone is oily substance and has the characteristics of easy decomposition under visible light, and the like, so the menatetrenone is suitable for being prepared into soft capsule formulations.

Currently, the chemical synthetic route commonly used for vitamin K2 (meso form) is as follows:

the technical problems of the synthesis route are as follows:

(1) the synthesis of compound 1 to compound 3 takes a long time, and the purification of compound 3 is troublesome, and it is not easy to obtain compound 3 with a high purity, which often contains compound 1.

(2) The compound 5 has low yield and low purity, and a large amount of the compound 3 in the compound 5 is incompletely reacted, so that the purity of the synthesized VK2 is low.

(3) The depolymerization of cyclopentadiene in the process is dangerous, flammable and explosive, and can generate a large amount of solid waste and volatile gas.

Disclosure of Invention

In order to solve the technical problems in the synthesis of VK2, the invention provides a one-step synthesis method of VK 2.

The synthesis method of VK2 comprises the following process route:

the method is characterized in that menadione and geranylgeranium bromide react in the presence of LDA (lithium diisopropylamide) and cuprous iodide under the anaerobic condition to obtain VK 2. Namely, menadione is coupled with geranylgeranium bromide to generate VK2 under the action of LDA and cuprous iodide. The reaction needs very low temperature, by-products are generated in the reaction process and can be removed by silica gel column purification, and the dosage of the cuprous iodide is higher than the commonly required catalytic amount although the cuprous iodide is used as a catalyst, otherwise, the reaction is difficult to carry out under the catalytic amount. In the invention, the dosage of the cuprous iodide is preferably 2 to 5 times of the molar weight of the menadione. In general chemical reaction, the mass consumption of the catalyst is about 5-30% of the mass of the reaction materials.

The invention provides a method for synthesizing VK2 by a one-step method, which specifically comprises the following steps: dissolving menadione in a solvent, adding cuprous iodide, cooling to-65 to-90 ℃ under an anaerobic condition, dropwise adding LDA (lithium diisopropylamide), controlling the temperature to-65 to-90 ℃ for reaction for 0.5 to 2 hours, dropwise adding geranylgeranium bromide, and controlling the temperature to-65 to-90 ℃ for reaction for 0.5 to 2 hours after dropwise adding. In the method, the temperature can be reduced to-70 to-80 ℃ under the anaerobic condition. The oxygen-free condition refers to the protection of nitrogen, helium, argon and other gases, and nitrogen is generally used; in the method, the whole reaction process is carried out under the anaerobic condition; the solvent of the invention can be selected from common solvents such as tetrahydrofuran, diethyl ether and the like. The mol ratio of menadione to cuprous iodide to LDA to geranylgeranium bromide is 1: 2-5: 1.8-3: 1.2 to 1.5, preferably 1: 2: 2: 1.4-1.5.

In the method, preferably, the geranylgeranium bromide is dripped after LDA is dripped and the temperature is controlled to be-70 to-80 ℃ for reaction for 1 to 2 hours, and the temperature is controlled to be-70 to-80 ℃ for reaction for 1 to 2 hours after dripping.

The geranylgeranium bromide in the invention has poor stability, needs to be stored at low temperature, and can be best prepared currently, and the preparation method thereof has various methods, and can be prepared by referring to some known documents or can be customized by professional manufacturers. The invention relates to a method for synthesizing geranylgeranium bromide based on phosphorus tribromide, which is characterized in that 200g of geranylgeranium alcohol, 48g of pyridine and 1L of methyl tert-butyl ether are added into a flask, the temperature is reduced to-5 ℃ under the protection of nitrogen, 260g of phosphorus tribromide is dripped, the temperature is raised to room temperature for reaction for 2 hours, the filtration is carried out, an organic phase is washed once by 5% sodium carbonate and washed once by water, anhydrous sodium sulfate is dried and filtered, and a mother solution is dried by evaporation at 20 ℃ to obtain geranylgeranium bromide liquid.¹HNMR(CDC13),δ:1.56(,S 9H)；1.66(S,6H)；1.9-2.08(m,12H)；4.09(d,2H)；5.07(t,3H)；5.40(t,1H))。

In the method of the present invention, a post-treatment step is further included at the end of the final reaction. The post-treatment comprises the steps of heating the final reaction solution to room temperature, pouring the reaction solution into saturated ammonium chloride aqueous solution for washing, extracting by ethyl acetate, backwashing and drying by saturated salt water, then spin-drying, separating and purifying by a silica gel column, and using ethyl acetate and petroleum ether as eluent, wherein the ratio of ethyl acetate to petroleum ether is 1:10, and the ratio of v/v is 1.

The invention directly takes menadione as raw material to synthesize VK2 in one step, greatly simplifies the reaction steps, reaction links and doping treatment of intermediate products, and the purity of the obtained product reaches up to 99.6 percent, greatly shortens the reaction time, and has low price of used reagent, thereby greatly reducing the production cost.

Drawings

FIG. 1 shows the results of HPLC detection of a sample of the reaction solution;

FIG. 2 shows the results of liquid phase detection of the purified product;

FIG. 3 shows the results of nuclear magnetic assays performed on the purified product;

structural formula (xvi):

molecular weight: 444.65

The molecular formula is as follows: c₃₁H₄₀O₂

Detailed Description

The following examples are further illustrative of the present invention as to the technical content of the present invention, but the essence of the present invention is not limited to the following examples, and one of ordinary skill in the art can and should understand that any simple changes or substitutions based on the essence of the present invention should fall within the protection scope of the present invention.

Example 1

Adding 1g (5.8mmol) of menadione into 20ml of tetrahydrofuran, then adding 2.2g of cuprous iodide (11.6mmol), cooling to-78 ℃ under the protection of nitrogen, then dropwise adding 5.8ml (11.6mmol) of LDA, controlling the temperature to-78 ℃ for reaction for 1 hour, then dropwise adding 3g (8.5mmol) of geranylgeranium bromide, then naturally reacting at-78 ℃ for 1 hour, and detecting by HPLC. A sample was taken and subjected to liquid phase detection, and as shown in FIG. 1, the peak content of VK2 was about 34.2%. Heating the final reaction solution to room temperature, pouring the reaction solution into saturated ammonium chloride aqueous solution for washing, extracting by ethyl acetate, backwashing and drying by saturated saline solution, then spin-drying, separating and purifying by a silica gel column, wherein an eluent is ethyl acetate, petroleum ether is 1:10, v/v, and removing the solvent to obtain about 300mg of a product, the total yield is 12%, and the purity of liquid phase detection is about 99.6%, as shown in figure 2. The results of nuclear magnetic resonance are shown in FIG. 3, HNMR 8.09-8.06(m,2H),7.70-7.67(m,2H), 5.08-5.02(m,4H),3.37(d, J ═ 6.9Hz,2H),2.19(s,3H),2.07-1.92(m,12H),1.79(bs,3H),1.67(s,3H),1.59(s,3H),1.56(s, 6H).

Example 2

Adding 10g (58mmol) menadione into 200ml tetrahydrofuran, then adding 22g cuprous iodide (116mmol), cooling to-78 ℃ under the protection of nitrogen, then dropwise adding 58ml (116mmol) LDA, controlling the temperature to-78 ℃ for reaction for 1 hour, dropwise adding 30g (85mmol) geranylgeranium bromide, then naturally reacting for 1 hour at-78 ℃, heating the final reaction solution to room temperature, pouring the reaction solution into a saturated ammonium chloride aqueous solution for washing, extracting with ethyl acetate, backwashing and drying with saturated saline water, separating and purifying with a silica gel column, wherein an eluent is ethyl acetate and petroleum ether is 1:10, v/v. About 3.1g of product was obtained.

Example 3

Adding 15g (87mmol) menadione into 250ml tetrahydrofuran, then adding 33g cuprous iodide (174mmol), cooling to-78 ℃ under the protection of nitrogen, then dropwise adding 87ml (174mmol) LDA, controlling the temperature to-78 ℃ for reaction for 1 hour, then dropwise adding 45g (127.5mmol) geranylgeranium bromide, then naturally reacting for 1 hour at-78 ℃, heating the final reaction solution to room temperature, then pouring the reaction solution into saturated ammonium chloride aqueous solution for washing, extracting with ethyl acetate, backwashing and drying with saturated saline water, separating and purifying with a silica gel column, wherein the eluent is ethyl acetate and petroleum ether is 1:10, v/v, and obtaining about 4.5g of product.

Example 4

Adding 1g (5.8mmol) of menadione into 20ml of tetrahydrofuran, then adding 220mg of cuprous iodide (1.2mmol), cooling to-78 ℃ under the protection of nitrogen, then dropwise adding 5.8ml (11.6mmol) of LDA, controlling the temperature to-78 ℃ to react for 1 hour, dropwise adding 3g (8.5mmol) of geranylgeranium bromide, then naturally reacting for 1 hour at-78 ℃, and detecting no peak of VK2 by HPLC. This example was tested with the conventional amount of cuprous iodide catalyst and found that the target product VK2 was not present after the reaction.

Example 5

Only 220mg of cuprous iodide was replaced with 100mg of cuprous iodide and the other process conditions were the same as in example 4. No peak of the target product VK2 was detected by HPLC.

Example 6

Only 220mg of cuprous iodide was replaced with 600mg of cuprous iodide and the other process conditions were the same as in example 4. The absorption peak of VK2 was weak by HPLC.

It should be noted that the technical contents described above are only explained and illustrated to enable those skilled in the art to know the technical spirit of the present invention, and therefore, the technical contents are not to limit the scope of the present invention. The scope of the invention is defined by the appended claims. It should be understood by those skilled in the art that any modification, equivalent replacement, and improvement made based on the spirit of the present invention should be considered to be within the spirit and scope of the present invention.

Claims

1. A one-step process for synthesizing VK2, comprising the steps of: dissolving menadione in a solvent, adding cuprous iodide, cooling to-65 to-90 ℃ under an anaerobic condition, dropwise adding LDA, controlling the temperature to-65 to-90 ℃ for reaction for 0.5 to 2 hours, dropwise adding geranylgeranium bromide, and naturally reacting for 0.5 to 2 hours after controlling the temperature to-65 to-90 ℃ after dropwise adding.

2. The method of claim 1, wherein the menadione, cuprous iodide, LDA, geranylgeranium bromide are present in a molar ratio of 1: 2-5: 1.8-3: 1.2 to 1.5.

3. The method of claim 1, wherein the temperature is reduced to-70 to-80 ℃ in the absence of oxygen.

4. The method of claim 1, wherein the oxygen-free condition is under nitrogen, helium or argon protection.

5. The method of claim 1, wherein LDA is added dropwise, geranylgeranium bromide is added dropwise after the temperature is controlled to be-70 to-80 ℃ and the reaction is carried out for 1 to 2 hours after the temperature is controlled to be-70 to-80 ℃.

6. The method of claim 1, wherein the natural reaction further comprises post-treatment.

7. The method of claim 6, wherein the post-treatment comprises heating the final reaction solution to room temperature, washing the reaction solution with saturated aqueous ammonium chloride solution, extracting with ethyl acetate, backwashing with saturated saline solution, drying, separating and purifying with silica gel column, and eluting with ethyl acetate and petroleum ether at a ratio of 1: 10.

8. The method of claim 1, comprising the steps of: dissolving menadione in tetrahydrofuran, adding cuprous iodide, cooling to-75 to-80 ℃ under an oxygen-free condition, dropwise adding LDA, controlling the temperature to be-75 to-80 ℃ for reaction for 1-2 hours, dropwise adding geranylgeranium bromide, and controlling the temperature to be-75 to-80 ℃ for natural reaction for 1-2 hours after dropwise adding.