CN101220075A - Preparation method of 7-dehydrocholesterol - Google Patents

Abstract

The invention discloses a preparation method of 7-dehydrocholesterol, comprising the following steps: a) protecting the hydroxyl group at the 3-position of cholesterol; b) oxidizing the carbon at the 7-position of the product obtained in step a) into a carbonyl group; c ) carrying out hydrazone reaction with the product obtained in step b) and a derivative of hydrazine, the structure of the derivative of hydrazine is hydrazine after at most one hydrogen is replaced; d) reacting the product obtained in step c) with a specific hydrogen Sodium oxide reacts with a strong alkaline reagent with strong alkalinity; e) reacting the product obtained in step d) with water or acid. In the preparation method, there is no participation of halogen elements such as bromine element, less side reactions, high yield, and the prepared product is safe and non-toxic.

Description

Preparation method of 7-dehydrocholesterol

technical field

The invention relates to the field of organic synthesis, in particular to a preparation method of 7-dehydrocholesterol. The method can prepare 7-dehydrocholesterol using cholesterol as a raw material under bromine-free conditions.

Background technique

Vitamin D (vitamin D) is a class of substances with anti-rickets activity, also known as D vitamins, belonging to fat-soluble vitamins. Vitamin D ₃ is a type of vitamin D, also known as cholecalciferol, with a molecular formula of C ₂₇ H ₄₃ OH and a relative molecular mass of 384.65. It is a colorless needle-like crystal or white crystalline powder, odorless, easily deteriorated when exposed to light or air; insoluble in water, easily soluble in ethanol, acetone, chloroform or ether, slightly soluble in vegetable oil; melting point is 84 ℃ ~ 88°C, the structure is as follows:

Vitamin D is an essential fat-soluble vitamin for the growth, reproduction, maintenance of life and health of humans, livestock and poultry. Its main functions are manifested in the following aspects:

1. As a pharmaceutical preparation, it can regulate calcium and phosphorus metabolism, promote intestinal calcium and phosphorus absorption and bone calcification, and maintain the balance of blood calcium and blood phosphorus. It is mainly used clinically to treat rickets, rickets, osteoporosis, hypothyroidism and other diseases. In addition, vitamin D ₃ and some of its metabolites can inhibit proliferation and reduce the differentiation of leukemia cells. It is also reported that vitamin D ₃ has a certain auxiliary effect on the treatment of malignant tumors.

2. As food and beverage additives and enhancers. Vitamin D ₃ can be added to milk, dairy products, biscuits, candies and various beverages to supplement or fortify vitamins and prevent vitamin D deficiency.

3. As a feed additive for livestock and poultry. Adding vitamin D ₃ to feed additives for livestock and poultry can increase the yield of meat, eggs, and milk and improve the nutritional value of meat, eggs, and milk.

Fourth, as a cosmetic additive. Adding vitamins as active ingredients to nutritional or therapeutic cosmetics can improve skin quality and delay skin aging.

Vitamin D ₃ is obtained by converting its precursor 7-dehydrocholesterol through ultraviolet light irradiation. The reaction formula is as follows:

The synthesis of 7-dehydrocholesterol has always been the bottleneck restricting the production of vitamin _D3 . The method of synthesizing 7-dehydrocholesterol currently used in production is basically to add a bromine to the 7-position of cholesterol and then remove a molecule of hydrogen bromide through an elimination reaction to obtain the precursor 7-dehydrocholesterol of vitamin _D3 . Dehydrocholesterol, the reaction formula is as follows:

This method was proposed by Ziegler (Ziegler) in 1942, after which scientists have spent a lot of painstaking efforts in the research of this method and finally realized the industrialization of this method. This method seems simple, but there are still the following disadvantages: 1. In the process of bromination, the alpha position of the side chain double bond of the esterified cholesterol will also be brominated; mainly because the bromination reaction is a free radical reaction, so the position of the double bond may be transferred; 2. In the process of dehydrobromination, it is not easy to generate the desired conjugated diene structure; 3. There will be other disadvantages when using this method to prepare 7-dehydrocholesterol The required by-products are formed, which requires many steps to remove brominated by-products and other corresponding by-products; 4. Bromine is harmful to the environment and is not easy to remove; 5. Bromine has an impact on the later photoreaction.

At present, there are only a few countries in the world that can produce vitamin D3, mainly concentrated in several companies, such as: Ross (Rose), BASF (BASF) and Aventis Animal Nutrition (AAN) and other companies. The annual output of vitamin D ₃ is between 50t and 60t, but the demand exceeds 100t. Therefore, vitamin D ₃ is deficient in many countries and regions, especially most African countries are even more deficient in vitamin D ₃ . The key to the production of vitamin _D3 lies in the production of its precursor 7-dehydrocholesterol. The production of 7-dehydrocholesterol and the quality of the product can largely determine the vitamin _D3 status.

In summary, it is necessary to increase the yield and product quality of vitamin D ₃ or its precursor 7-dehydrocholesterol to meet market demand.

Contents of the invention

Aiming at the deficiency of the existing production technology, the present invention proposes a preparation method of 7-dehydrocholesterol. In the preparation method, there is no participation of halogen elements such as bromine element, less side reactions, high yield, and the prepared product is safe and non-toxic.

In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:

1, the preparation method of 7-dehydrocholesterol, comprises the following steps:

a) protecting the hydroxyl group on the 3-position of cholesterol;

b) oxidizing the carbon on the 7-position of the product obtained in step a) into a carbonyl group;

c) subjecting the product obtained in step b) to a hydrazone-forming reaction with a derivative of hydrazine, the structure of which is hydrazine after at most one hydrogen has been replaced;

d) reacting the product obtained in step c) with a strong alkaline reagent stronger than sodium hydroxide;

e) reacting the product obtained in step d) with water or acid.

7-dehydrocholesterol has the following structural formula:

The positions of the 1-7 position are marked in the structural formula, and in the present invention, the 1-7 position is unchanged during the reaction and will not be changed due to the change of the functional group. For example, if hydrogen is added to a carbon at the 7-position, then that carbon is still the 7-position carbon.

Each step is described below:

Step a): protecting the hydroxyl group on the 3-position of cholesterol

Cholesterol is also known as cholesterol.

Hydroxyl protection is a commonly used method in chemical synthesis. There are many methods for hydroxyl protection. For details, please refer to the second chapter of the book "Protective Groups in Organic Synthesis" (East China University of Science and Technology Press, first edition in 2004). It is preferable to use a protection method in which the hydroxyl group at the 3-position of cholesterol is formed into an ester group after reaction.

The method for generating ester bonds can be the reaction of cholesterol with carboxylic acid, carboxylic acid anhydride or acid chloride.

The carboxylic acid can be a saturated carboxylic acid or an unsaturated carboxylic acid, preferably a saturated carboxylic acid; the carboxylic acid can be a monocarboxylic acid or a dibasic or more dibasic carboxylic acid, preferably a monobasic carboxylic acid. Among the monocarboxylic acids, C2 _or higher monocarboxylic acids can be selected, preferably acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, dodecanoic acid, myristic acid, benzoic acid, more preferably acetic acid.

The carboxylic acid anhydride can be a monoanhydride or a mixed anhydride; it can be an aliphatic carboxylic anhydride or an aromatic carboxylic anhydride. Specific acid anhydrides can be selected from: acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, benzoic anhydride, succinic anhydride, phthalic anhydride, etc., preferably acetic anhydride.

The acid chloride may be acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, etc.; preferably acetyl chloride.

The method of using carboxylic acid or carboxylic acid anhydride to protect the hydroxyl group can adopt the following two methods:

(1) Using acetic anhydride as both a solvent and a reactant, the specific method can be: feed cholesterol and acetic anhydride according to a molar ratio of 1:10 to 1:30, and then react at a temperature of 100°C to 160°C for 2 hours (hour) ~ 4h. The acid anhydride functional group reacts with the hydroxyl group of cholesterol to form an ester bond structure, which can prevent oxidation or other forms of damage in the subsequent reaction process. The reaction temperature is preferably 115°C to 155°C, more preferably 135°C to 145°C.

(2) Utilize acetic acid or acetic anhydride as the reactant, the specific method can be: feed cholesterol and acetic anhydride according to the molar ratio of 1:1.2 to 1:2.0, then react at a reaction temperature of 60°C to 90°C, and the reaction time It can be 2h to 8h, and the reaction is carried out in a non-protonated solvent. The non-protonated solvent is benzene. Aprotic solvents, also known as aprotic solvents, aprotic solvents, aprotic solvents, deionized solvents or deionized solvents, have extremely weak proton self-transfer reactions or no self-transfer tendency. According to the non-protonated solvent solvent, this type can be divided into non-polar non-protonated solvent and polar non-protonated solvent. For example, benzene, ether, carbon tetrachloride, etc. are non-polar solvents, and dimethyl sulfoxide, N,N-dimethylformamide, acetone, etc. are polar solvents. Because polar solvent molecules have polarity, they will affect the solute molecules and produce solvation effects. In this step, a non-polar non-protonated solvent is preferably used, more preferably benzene as the solvent.

Step b): oxidizing the carbon on the 7-position of the product obtained in step a) into a carbonyl group

The carbon at the 7-position is oxidized to a carbonyl.

The carbon on the 7-position of the product obtained in step a) can be oxidized into a carbonyl group by an oxidizing agent, and the oxidizing agent is selected from: chromium trioxide, chromium trioxide/peroxy tert-butyl alcohol composite oxidant, tert-butyl hydroperoxide / chromium hexacarbonyl composite oxidant, ammonium chloride/chromium trioxide composite oxidant, tert-butyl hydroperoxide/CuI ₂ composite oxidant, chromium trioxide/3,5-lutidine composite oxidant. Chromium trioxide is preferably used for reaction at a temperature of 55°C to 65°C, or peroxy tert-butanol is preferably used for reaction at a temperature of 25°C to 45°C.

Step c) subjecting: the product obtained in step b) to a hydrazone-forming reaction with a derivative of hydrazine, the structure of the derivative of hydrazine is hydrazine after at most one hydrogen is replaced

The derivative of hydrazine has the following structure:

The derivative of hydrazine of above-mentioned structure can form hydrazone reaction with the product that step b) makes, and reaction formula is:

As in the above reaction formula, for the present invention, R ₂ and R ₃ are determined, and the nitrogen atom with two hydrogens connected to the hydrazine derivative is finally connected with the carbonyl carbon double bond. The hydrazine derivative is preferably p-toluenesulfonyl hydrazide.

The reaction of step c) is preferably carried out in a polar solvent. The polar solvent can be: methanol, ethanol, propanol, n-butanol, acetone, ether, isopropyl ether, chloroform, bromoethane, etc., preferably methanol or ethanol.

Step d): reacting the product obtained in step c) with a strong alkaline reagent that is stronger than sodium hydroxide

The invention does not wish to be bound by a theory as to the reactions that occur in this step.

The strongly basic reagent described in step d) can be: sodium hydride, lithium hydride, methyllithium, sodium hydride is preferably used, and the reaction speed is more appropriate when sodium hydride is used. When sodium hydride is selected, the reaction temperature is 80°C to 150°C, preferably 140°C to 150°C.

The reaction in this step is preferably carried out in an aprotic solvent, which may be N,N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, pyridine and its derivatives, acetonitrile.

Step e): reacting the product obtained in step d) with water or acid.

The invention does not wish to be bound by a theory as to the reactions that occur in this step.

The acid described in this step can be hydrochloric acid, preferably dilute hydrochloric acid, more preferably 1%-2% hydrochloric acid.

Detailed ways

Below in conjunction with embodiment, further set forth the present invention:

The amount of the reaction product in each step of the embodiment does not affect the use of other steps. If the amount of the reaction product cannot meet the needs of other steps, it can be prepared multiple times to meet the required amount of other steps.

Example 1

a) Take 5g (grams) of cholesterol and add it to 36.8ml (milliliters) of acetic anhydride, add two zeolites and reflux at 140°C±5°C for 3h to generate cholest-5ene-3-acetate. The acetic anhydride is analytically pure and has a density of 540g/500ml.

The purity of the cholest-5-ene-3-acetate formed by the reaction was determined by the internal standard method, and the yield was 87%.

b) Dissolve 5 g of cholest-5-ene-3-acetate and 4 equivalents of anhydrous sodium acetate in 40 ml of glacial acetic acid, shake well at 25°C, and then heat to 59°C±1°C in a water bath. Take 2 equivalents of CrO ₃ (chromium trioxide) and add them to the reaction solution in stages, first less and then more, first slow and then fast, and the addition is completed within 30 minutes (minutes). Stir at 59°C±1°C for 4.5h, cool to 25°C, then cool with water at 4°C for 12h, crystals will precipitate, use a glass sand core funnel to filter, and then wash the crystals with deionized water until colorless, Dry in vacuum oven at 50°C for 8h.

2.8 g of solid cholest-5-ene-7-carbonyl-3-acetate was obtained, the purity of which was verified to be 87.1%, and the yield was 60%.

c) Dissolve 0.174 g of cholest-5-ene-7-carbonyl-3-acetate and 2 equivalents of p-toluenesulfonyl hydrazide in 40 ml of absolute ethanol, stir at 25° C. and monitor with TLC (thin Monitoring by layer chromatography), the reaction was stopped after 20 h, and 0.251 g of the product 3-cholest-5-ene-7-p-toluenesulfonylhydrazone-3-acetate was obtained after rotary evaporation.

The tested purity was 95%, and the yield was 99%.

d, e) Dissolve 0.1787 g of 3-cholest-5-ene-7-p-toluenesulfonylhydrazone-3-acetate in 25 ml of dimethyl sulfoxide, and add 7 equivalents of NaH (sodium hydride), stirred for 6h. Cool to 25°C, wash with 25ml of 1% dilute hydrochloric acid until weakly acidic, then wash with deionized water until neutral, then add 5ml of deionized water and shake well. Extracted three times with ethyl acetate, using 30ml of ethyl acetate each time. The ethyl acetate layers extracted three times were combined and dried with anhydrous Na ₂ SO ₄ , Na ₂ SO ₄ was filtered off under normal pressure and then rotary evaporated to obtain 0.1843 g of a tan solid with a content of 0.0787 g.

It was detected to be 7-dehydrocholesterol with a purity of 42.72% and a yield of 70%.

The amount of the reactant weighed in each step is the converted net content. For example: get 0.174g of cholest-5-ene-7-carbonyl-3-acetate described in step c), from step b) it can be seen that its purity is 87.1%, so the actually weighed purity is 87.1% % of cholest-5-ene-7-carbonyl-3-acetate was 0.200 g. The reactants weighed in each step in the following examples are also net contents.

Example 2

a) Dissolve 5 g of cholesterol in 40 ml of dried benzene, then add 2 equivalents of acetic anhydride, reflux at 80° C. for 3 h. After the reaction solution was cooled to 25°C, it was washed with 1% dilute hydrochloric acid until weakly acidic, then washed with 5% NaHCO ₃ (sodium bicarbonate) aqueous solution until weakly alkaline, and finally washed with deionized water until neutral. The aqueous phase was extracted three times with an appropriate amount of ether, and the three extracted benzene layers were combined and dried with anhydrous Na ₂ SO ₄ . The dried benzene-ether solution was rotary evaporated to obtain 5.44 g of cholest-5-ene-3-acetate.

The tested purity is 97%, and the yield of cholest-5-ene-3-acetate is greater than 95%.

b) Dissolve 4ml of tert-butanol peroxide with a volume fraction of 70% and 1.71g (4mmol) of cholest-5-ene-3-acetate in 16ml of dichloromethane, and stir at 25°C for 24h, Then the solvent was rotary evaporated to obtain 2.61 g of solid cholest-5-ene-7-carbonyl-3-acetate.

The detected purity was 51%, and the yield of cholest-5-ene-7-carbonyl-3-acetate was 70%.

The following steps are the same as steps c, d, and e) in Example 1.

Example 3

In this embodiment, step b) is different from Embodiment 1, and other steps are the same as those in Embodiment 1. Step b) of the present embodiment is:

Take 2.0 grams of cholesterol acetate and 0.029 equivalent of cuprous iodide, dissolve it in 30 ml of benzene, and finally add 5.6 equivalents of tert-butyl hydroperoxide. Under the protection of nitrogen, the reaction was stirred at 70°C for 26h.

The obtained cholest-5-ene-7-carbonyl-3-acetate solid was checked for purity and the calculated yield was 30%.

Example 4

In this embodiment, step b) is different from Embodiment 2, and other steps are the same as those in Embodiment 2. Step b) of the present embodiment is:

Take 0.2g cholest-5-ene-3-acetate, 0.101g 4A molecular sieve, 1.0g PCC- _Al2O3 and _40ml benzene. Firstly, cholest-5-ene-3-acetate was dissolved in benzene, and then 4A molecular sieve and PCC-Al ₂ O ₃ were quickly poured into it. After stirring at 70°C for 24 h, the reaction was stopped, filtered, and the filter residue was repeatedly washed with ethyl acetate, combined with ethyl acetate and benzene, and finally dried with anhydrous Na ₂ SO ₄ .

The solid of cholest-5-ene-7-carbonyl-3-acetate was obtained, and the calculated yield was 15% after checking the purity.

The PCC is pyridinium chlorochromate, Al ₂ O ₃ is aluminum oxide, 1.0 g of PCC is contained in every 2.5 g of PCC-Al ₂ O ₃ , and the 4A molecular sieve is sodium A molecular sieve.

Example 5

In this embodiment, step b) is different from Embodiment 1, and other steps are the same as those in Embodiment 1. Step b) of the present embodiment is:

Take 0.5g of cholest-5-ene-3-acetate and 0.058g of Bi(NO ₃ ) ₃ ·5H ₂ O and dissolve them in 40ml of acetonitrile, then add 2.264gt-BuOOH, stir and react at 70°C for 22h, then spin evaporate Acetonitrile was evaporated to dryness. Dissolve the product with ethyl acetate, filter under normal pressure, wash the organic phase with 5% _NaHCO3 solution to weak alkalinity, then wash the organic phase with deionized water until neutral, and finally extract the water with ethyl acetate phase twice, and combine the organic phases. After rotary evaporation, 0.531 g of white solid was obtained.

A solid of cholest-5-ene-7-carbonyl-3-acetate was obtained, and the calculated yield was 10% after checking the purity.

The Bi(NO ₃ ) ₃ ·5H ₂ O is bismuth nitrate pentahydrate, and t-BuOOH is tert-butyl hydroperoxide.

Example 6

In this embodiment, steps d, e) are different from Embodiment 1, and other steps are the same as those in Embodiment 1. Steps d and e) of this example differ from Example 1 in that benzene is used as a solvent instead of dimethyl sulfoxide, and the reaction temperature is 80° C.

It was detected that the final reaction product was 7-dehydrocholesterol, and the yield was 15%.

Example 7

In this embodiment, steps d, e) are different from Embodiment 6, and other steps are the same. The difference is that toluene is used as the solvent, and the reaction temperature is 80°C.

It was detected that the final reaction product was 7-dehydrocholesterol, and the yield was 15%.

Example 8

The final product of embodiment 1～7 gained is carried out infrared spectrometer and nuclear magnetic resonance instrument detection, and gained result is:

The assignment of the main infrared characteristic peaks: 3294cm ^-1 OH stretching vibration, 1657cm ^-1 ring double bond stretching vibration, 1066 and 1034cm ^-1 C-OH stretching vibration, 984 and 946cm ^-1 =CH stretching vibration.

The assignment of the main NMR characteristic peaks: 5.559 and 5.378 (d, 2H, 6-CH and 8-CH), 3.628 (m, 1H, 3α-CH).

It can be seen that the final product is 7-dehydrocholesterol.

Description of test method

In the above-mentioned embodiment, the method for detecting the purity of the reaction product mentioned in each step adopts the internal standard method, and the specific test method is: take the standard substance as the internal standard substance to be made into standard solutions of different concentrations, and use the liquid Xiang in the Measure the peak areas of standard solutions with different concentrations at a certain ultraviolet wavelength, and use the peak area normalization method to make a standard curve. Then make a solution with a certain concentration to measure the peak area with liquid Xiang, and then compare it with the standard curve, and calculate the purity of the product to be tested. Take 3-cholest-5-ene-7-p-toluenesulfonylhydrazone-3-acetate as an example: take 3-cholest-5-ene-7-p-toluenesulfonylhydrazone-3-acetic acid Take 0.0387 g of the pure product of the ester, dissolve it in methanol and put it into a 25ml volumetric flask, take 8 10ml volumetric flasks numbered 1-8, and pipette 400, 800, 1200, 1600, 2000, 2400, 2800, 3200 μl (microliter) mother liquor And fixed solution to 10ml each injection 20μl, measured the absorption peak area of the standard solution with different concentrations under the ultraviolet wavelength of 235nm by high performance liquid phase, and then obtained the standard curve by the peak area normalization method.

The yield of the reaction product can be calculated from the purity of the reaction product.

The reaction formula of the preparation method described in Example 1 of the present invention is as follows. It can be seen from the formula that this method for preparing 7-dehydrocholesterol starts from cholesterol as a raw material, first undergoes hydroxyl protection, and specific carbon Oxidation at the carbonyl position, followed by a hydrazone reaction at the carbonyl position, and finally reacting with a strong alkaline reagent stronger than sodium hydroxide, and then reacting with water or acid to obtain 7-dehydrocholesterol.

The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.

Claims (21)

1.7-the preparation method of dehydrocholesterol may further comprise the steps:

A) with the hydroxyl protection on 3 of the cholesterol;

B) oxidation of coal on 7 of the product that step a) is made becomes carbonyl;

C) product that step b) is made and hydrazine derivative are carried out to hydrazone reaction, and the structure of described hydrazine derivative is that a hydrogen is replaced later hydrazine at the most;

D) product that step c) is made and strong basicity reagent react;

E) product that step d) is made and water or acid-respons.

2. method according to claim 1, wherein, step a) with the hydroxyl protection on 3 of the cholesterol is: cholesterol and carboxylic acid, carboxylic acid anhydride or acyl chloride reaction.

3. method according to claim 2, wherein said carboxylic acid, carboxylic acid anhydride or acyl chlorides are acetate, diacetyl oxide or Acetyl Chloride 98Min..

4. method according to claim 3, wherein, the mol ratio of described cholesterol and diacetyl oxide is 1: 10～1: 30, and the temperature of reaction is 100 ℃～160 ℃, and the reaction times is 2h～4h.

5. method according to claim 4, wherein, temperature of reaction is 115 ℃～155 ℃.

6. method according to claim 5, wherein, temperature of reaction is 125 ℃～145 ℃.

7. method according to claim 3, wherein, the mol ratio of cholesterol and acetate or diacetyl oxide is: 1: 1.2～1: 2.0, temperature of reaction was 60 ℃～90 ℃, was reflected in the non-protonization solvent and carried out.

8. method according to claim 7, wherein said non-protonization solvent is a benzene.

9. method according to claim 1, wherein, oxidation of coal on 7 of the product that step b) makes step a) becomes carbonyl to be: utilize the oxidation of coal on 7 of product that oxygenant makes step a) to become carbonyl, described oxygenant is selected from: chromium trioxide, peroxy tert-butyl alcohol, tertbutyl peroxide/Chromium hexacarbonyl composite oxidant, ammonium chloride/chromium trioxide composite oxidant, tertbutyl peroxide/CuI ₂Composite oxidant, chromium trioxide/3,5-lutidine composite oxidant.

10. method according to claim 9, wherein, described oxygenant is a chromium trioxide, temperature of reaction is 55 ℃～65 ℃.

11. method according to claim 9, wherein, described oxygenant is a peroxy tert-butyl alcohol, and temperature of reaction is 25 ℃～45 ℃.

12. method according to claim 1, wherein, described hydrazine derivative is to the Methyl benzenesulfonyl hydrazine.

13. method according to claim 1, being reflected in the polar solvent of step c) carried out.

14. method according to claim 13, described polar solvent are methyl alcohol or ethanol.

15. method according to claim 1, wherein, the strong basicity reagent described in the step d) is selected from: sodium hydride, lithium hydride, lithium methide.

16. method according to claim 15, wherein, the strong basicity reagent described in the step d) is sodium hydride, and temperature of reaction is 80 ℃～150 ℃.

17. method according to claim 16, wherein, the temperature of the reaction of step d) is 140 ℃～150 ℃.

18. method according to claim 1, wherein, being reflected in the non-protonization solvent of step d) carried out.

19. method according to claim 18, wherein, the non-protonization solvent described in the step d) is N, dinethylformamide, methyl-sulphoxide, benzene, toluene, pyridine and derivative thereof, acetonitrile.

20. method according to claim 1, wherein, the acid described in the step e) is hydrochloric acid.

21. method according to claim 20, wherein said hydrochloric acid are concentration is 1%～2% hydrochloric acid.