Synthesis method of lipoic acid

Abstract

The invention relates to a method for synthesizing lipoic acid, which comprises the following steps of: reacting adipic acid monoester serving as an initial raw material with an acylating chlorination reagent to obtain adipic acid ester monoacyl chloride; the preparation method comprises the following steps: reacting acetaldehyde with an amine compound to obtain N-vinylpyrrolidine, carrying out condensation reaction on adipate monoacyl chloride and N-vinylpyrrolidine to obtain 6, 8-dioxocaprylic acid ethyl ester, reducing to obtain 6, 8-dihydroxy caprylic acid ethyl ester, reacting 6, 8-dihydroxy caprylic acid ethyl ester with thiourea in the presence of hydroiodic acid, hydrolyzing and acidifying to obtain dihydrolipoic acid, and oxidizing to obtain lipoic acid. The process has the advantages of easily available raw materials, few synthesis steps, high yield and good product quality, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing thioctic acid. Background Technology

[0002] 1-Lipoic acid (1,2-dithiopentane-3-pentanoic acid), also known as α-lipoic acid, is a disulfide compound and is generally considered a B vitamin. As an important coenzyme in the body, lipoic acid is a crucial cofactor for pyruvate dehydrogenase, ketoglutarate dehydrogenase, and aminocaproic acid dehydrogenase, and is an indispensable component of the tricarboxylic acid cycle. Studies have found that in vitro supplementation with lipoic acid can inhibit lipid oxidation in nerve tissue, prevent protein glycosylation, inhibit aldose reductase, and prevent the conversion of glucose or galactose into sorbitol, making it a potential treatment for diabetic neuropathy or neurological complications. Furthermore, lipoic acid possesses powerful antioxidant properties, eliminating free radicals that accelerate aging, and exhibits various effects including anti-oxidation, anti-aging, immune enhancement, cardiovascular disease prevention, and relief of diabetes symptoms. Its antioxidant efficacy is mainly manifested in three aspects: 1. Direct scavenging of free radicals: After entering cells, lipoic acid can directly scavenge free radicals such as hydroxyl radicals and singlet oxygen; 2. Inhibition of metal-induced oxidation: Lipoic acid has the effect of chelating metal ions, thereby reducing the peroxidation reaction of lipids and other macromolecules caused by metal ions; 3. Promotion of the restoration of other antioxidant components: Lipoic acid can restore the ability of endogenous antioxidants such as vitamin E and glutathione in the body, thereby enhancing the body's overall antioxidant capacity. After being reduced to dihydrolipoic acid in the body, lipoic acid can chelate heavy metal cations and detoxify heavy metal poisoning. Given its powerful health benefits, lipoic acid is listed as a dietary supplement in the United States, Canada, and other regions. The USP includes lipoic acid tablets and capsules, and lipoic acid injections are also available for clinical use.

[0003] .

[0004] Lipoic acid has a chiral center, where the R-(+) isomer is a natural product with physiological activity, while the S-(-) isomer has virtually no physiological activity, but no toxic side effects have been found. Currently, the racemic form is more commonly used clinically; the lipoic acid listed in the USP is the racemic form. The purpose of this invention is to provide a method for synthesizing racemic lipoic acid.

[0005] In existing literature, thioctic acid has the following synthetic routes.

[0006] Route 1 (US 2792406; J. Am. Chem. Soc, 1954, 76, 1828~1832; J. Am. Chem. Soc, 1955, 77, 416~419): Adipic acid monoethyl ester chloride 2 reacts with ethylene in the presence of aluminum trichloride via a Friedel-Craft reaction to yield ethyl 8-chloro-5-oxooctanoate 3. After heating to eliminate hydrogen chloride, it undergoes addition reaction with thioacetic acid and reduction with sodium borohydride to yield ethyl 6-hydroxy-8-mercaptooctanoate 6. This is then hydrolyzed with sodium hydroxide, reacted with thiourea in hydroiodic acid, and finally oxidized to yield racemic lipoic acid 1. Several other methods exist for this route, but the overall disadvantages are the numerous steps, the large amount of aluminum trichloride used (which is difficult to process), the high price of thioacetic acid, and the low yield, making it unsuitable for industrial production.

[0007] Route 2 (J. Am. Chem. Soc, 1957, 79(13), 3503~3505; Chinese Journal of Medicinal Chemistry, 1999, 9(4), 304-305): Cyclohexanone 7 reacts with pyrrolidine to produce N Cyclohexenyltetrahydropyrrole 8 reacts with ethyl bromoacetate to generate ethyl 2-cyclohexanone 9. After carbonyl protection of 9, it is reduced with lithium aluminum hydride, esterified with acetic anhydride, and hydrolyzed with p-toluenesulfonic acid to give 2-(2-acetoxy)ethyl-cyclohexanone 12. 12 is oxidized by Baeyer-Villiger oxidation to give lactone 13. 13 reacts with thiourea under hydroiodic acid catalysis, undergoes alkaline hydrolysis, and is acidified to give dihydrolipoic acid 14, which is then oxidized to give lipoic acid 1. There are other methods along this route, but the overall disadvantages are numerous steps, low yield, high cost, and harsh reaction conditions, making it unsuitable for industrial production.

[0008] Based on this, this application was developed. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a new method for synthesizing lipoic acid. Lipoic acid prepared using this method has advantages such as mild reaction conditions, inexpensive and readily available raw materials, high yield, and high product purity.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: A method for synthesizing lipoic acid, comprising the following steps: Step 1: Condensation reaction: Adipate monoester reacts with an acyl chloride reagent in the presence of solvent one to give adipate monoacyl chloride; acetaldehyde reacts with an amine compound under reflux in the presence of a catalyst and solvent two to generate... N -Vinylpyrrolidone, adipate monoacyl chloride and N- Ethyl 6,8-dioxooctanoate is given by condensation reaction of ethylene pyrrolidine in the presence of an acid-binding agent and solvent. Step 2: Reduction reaction: Ethyl 6,8-dioxooctanoate is reduced in solvent four with a reducing agent to give ethyl 6,8-dihydroxyoctanoate; Step 3: Thiohydration hydrolysis reaction: Ethyl 6,8-dihydroxyoctanoate reacts with thiourea in the presence of a phase transfer catalyst, hydroiodic acid and solvent V. The product is hydrolyzed and then acidified to obtain dihydrothiooctanoic acid. Step 4: Oxidation and cyclization reaction: Dihydrolipoic acid under alkaline conditions (pH above 10, preferably 10-12), Fe... 3+ It is oxidized to lipoic acid by passing air through a catalyst and disodium ethylenediaminetetraacetate.

[0011] Specifically, in step 1), the starting material, adipic acid monoester, can be monomethyl adipic acid or monoethyl adipic acid, preferably monoethyl adipic acid; the acyl chloride reagent can be thionyl chloride, phosphorus trichloride, or phosphorus pentachloride, preferably thionyl chloride, and the amount of acyl chloride reagent is 1.3 to 2.0 times the molar amount of adipic acid monoester, preferably 1.5 times; the first solvent is dichloromethane or trichloromethane, preferably dichloromethane, and the amount of the first solvent is 3.5 to 6 times the amount of adipic acid monoester, preferably 4.5 times (g / g); the acyl chloride temperature is 20 to 45°C, preferably reflux temperature (about 40°C), and the reaction time is 1 to 3 hours. More preferably, after the raw material is added dropwise, the reaction is first stirred at 0 to 5°C for 0.5 to 1.5 hours, and then the temperature is raised to about 40°C for reflux reaction. This initial low-temperature stirring reaction is to prevent the reaction from becoming too vigorous when the temperature is raised.

[0012] Furthermore, in step 1), the amine compound used in the acetaldehyde enamidation reaction can be a secondary amine such as pyrrolidine, piperidine, or tetrahydropyran, preferably pyrrolidine, and the amount of the amine compound used is 1.1 to 1.4 times the molar amount of acetaldehyde, preferably 1.15 times; the catalyst is p-toluenesulfonic acid, and the amount of the catalyst used is 0.09 to 0.11 times the molar amount of acetaldehyde, preferably 0.1 times; the solvent used is toluene, and the amount used is 4 to 8 times (ml / g) of acetaldehyde, preferably 5.7 times; the reflux reaction temperature is about 110±10℃.

[0013] Furthermore, in step 1), the adipate monoacyl chloride and N The molar ratio of ethylenepyrrolidine to adipic acid monoester is 1:1.1~1.5, preferably 1:1.2; the acid-binding agent can be triethylamine or sodium carbonate, preferably triethylamine, and the molar ratio of the acid-binding agent to adipic acid monoester is 1:1.1~1.5, preferably 1:1.2; the solvent is toluene, and the amount of toluene is 3.0~5.0 times (ml / g) of adipic acid monoester, preferably 3.5 times; the condensation reaction temperature is 70~100℃, preferably 80~90℃, and the reaction time is 2~4 hours.

[0014] Specifically, in step 2), the reducing agent can be potassium borohydride or sodium borohydride, preferably potassium borohydride. The molar ratio of the reducing agent to ethyl 6,8-dioxooctanoate is 0.55~0.7:1, preferably 0.60:1. The solvent is an 85~95% (v / v) ethanol aqueous solution, and the amount of solvent is 2.5~4.0 times (ml / g) of ethyl 6,8-dioxooctanoate, preferably 3.0 times. The reaction temperature is reflux temperature, and the reaction time is 2.5~4 hours, preferably 3 hours.

[0015] Specifically, in step 3), ethyl 6,8-dihydroxyoctanoate undergoes a substitution reaction with thiourea in the presence of a phase transfer catalyst and catalyzed by hydroiodic acid, followed by hydrolysis with a strong base to generate 6,8-dimercaptooctanoic acid, which is then acidified to obtain dihydrolipoic acid. The phase transfer catalyst can be tetrabutylammonium chloride or tetramethylammonium chloride, preferably tetrabutylammonium chloride. The molar ratio of the phase transfer catalyst to ethyl 6,8-dihydroxyoctanoate is 0.01~0.05:1, preferably 0.02:1; the molar ratio of hydroiodic acid to ethyl 6,8-dihydroxyoctanoate is 0.05~0.15:1, preferably 0.10:1; the molar ratio of thiourea to ethyl 6,8-dihydroxyoctanoate is 2.2~3.0:1, preferably 2.5:1; the solvent is a mixed solvent composed of toluene and water, with the amount of toluene being 1.8~2.5 times (ml / g) of ethyl 6,8-dihydroxyoctanoate, preferably 2.0 times, and the amount of water being 1.2~1.5 times (ml / g) of ethyl 6,8-dihydroxyoctanoate, preferably 1.5 times; the reaction temperature is 30~60℃, preferably 40~50℃, and the reaction time is 3~5 hours, preferably 4 hours.

[0016] Furthermore, in step 3), the hydrolysis (saponification) reaction is carried out under a strong alkali, which can be sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The molar ratio of the strong alkali to ethyl 6,8-dihydroxyoctanoate is 2.5~4.0:1, preferably 3.0:1. The reaction temperature is 60~100℃, preferably 70~80℃, and the reaction time is 2.5~4 hours, preferably 3 hours.

[0017] Furthermore, in step 3), the pH is adjusted to 2-3 during acidification.

[0018] Specifically, in step 4), dihydrolipoic acid is reacted under alkaline conditions in Fe... 3+ The iron used is oxidized to lipoic acid by air under catalysis, and is either ferric chloride or ferric sulfate, preferably ferric chloride. 3+ The molar ratio of ethyl 6,8-dihydroxyoctanoate to ethyl 6,8-dihydroxyoctanoate is 0.01 to 0.02:1, preferably 0.015:1.

[0019] Furthermore, in step 4), the role of disodium ethylenediaminetetraacetate is to react with Fe.3+ Formation of complexes to prevent Fe 3+ Precipitation occurs under alkaline conditions. The molar ratio of disodium ethylenediaminetetraacetate to ethyl 6,8-dihydroxyoctanoate is 0.01~0.04:1, preferably 0.02:1; the reaction temperature is 15~25℃, and the reaction time is 3~5 hours, preferably 4 hours.

[0020] The method of this invention uses adipic acid monoester and acetaldehyde as starting materials to synthesize lipoic acid. This process uses readily available raw materials, involves fewer synthesis steps, achieves high yield, and produces high-quality products, making it suitable for industrial production. Compared with existing methods, the synthesis method of this invention has the following advantages and beneficial effects: 1) The method of this invention has a short synthetic route, high yield, and low cost. Existing synthetic routes mostly use adipic acid monoester and ethylene as starting materials, undergoing a Friedel-Craft reaction under aluminum trichloride catalysis to obtain ethyl 8-chloro-5-oxooctanoate. After heating to eliminate hydrogen chloride, it undergoes addition with thioacetic acid and reduction with sodium borohydride to obtain ethyl 6-hydroxy-8-mercaptooctanoate. This is followed by hydrolysis with sodium hydroxide, reaction with thiourea in hydroiodic acid, and finally oxidation to racemic lipoic acid. This route involves many reaction steps, complex operation, low yield, and the high and unstable price of thioacetic acid, which is not conducive to industrialization. This invention uses adipic acid monoester and acetaldehyde as starting materials, undergoing a condensation reaction and reduction to obtain ethyl 6,8-dihydroxyoctanoate. This is then reacted with thiourea in the presence of hydroiodic acid, followed by alkaline hydrolysis and acidification to obtain dihydrolipoic acid, which is finally oxidized to lipoic acid. The reaction of ethyl 6,8-dihydroxyoctanoate with thiourea, alkaline hydrolysis, and acidification are completed using a one-pot cooking method. The method of this invention is relatively simple to operate, uses inexpensive and readily available raw materials with ample market supply, has low cost, few synthesis steps, high yield, and good product quality, which is conducive to industrial production. 2) The existing synthetic route Friedel-Craft reaction uses aluminum trichloride as a catalyst. After the reaction, the reaction solution is easy to form a colloidal state, which is not easy to handle and produces a lot of solid waste. This invention eliminates aluminum trichloride and the reaction is easy to handle. Detailed Implementation

[0021] The technical solution of the present invention will be further described in detail below with reference to implementation examples, but the scope of protection of the present invention is not limited thereto.

[0022] In the embodiments, all raw materials used are common commercially available products that can be directly purchased in the art or can be prepared using conventional methods in the art. Room temperature refers to 25±5℃.

[0023] The synthetic route of the present invention is as follows: ethyl adipic acid (15) reacts with thionyl chloride to obtain ethyl adipic acid acyl chloride (2); acetaldehyde (16) reacts with pyrrolidine (17) to obtain... N- Ethylenepyrrolidine (18), (2) and (18) condense to give ethyl 6,8-dioxooctanoate (19); reduced to give ethyl 6,8-dihydroxyoctanoate (20); (20) reacts with thiourea in the presence of hydroiodic acid, the product is hydrolyzed with an alkali and acidified to give dihydrolipoic acid (14), and oxidized to give lipoic acid (1).

[0024] .

[0025] Example 1 Preparation of ethyl 6,8-dioxooctanoate (19) 780g of dichloromethane and 174.2g (1.0mol, 1.0eq) of monoethyl adipic acid (15) were added to the reaction flask. The gas absorption device was connected, and the mixture was stirred and cooled to 0~5℃. 178.5g (1.5mol, 1.5eq) of thionyl chloride was added dropwise. After the addition was completed, the mixture was stirred at 0~5℃ for 1 hour. Then the temperature was raised to about 40℃ and refluxed for 2 hours. After the reaction was completed, the dichloromethane was distilled off and then concentrated under reduced pressure below 50℃. 300ml of toluene was added to the residue and stirred to obtain a toluene solution of monoethyl adipic acid chloride (2).

[0026] Add 300 ml of toluene, 52.8 g (1.2 mol, 1.2 eq) of acetaldehyde (16), 99.5 g (1.4 mol, 1.4 eq) of pyrrolidine (17), and 22.8 g (0.12 mol, 0.12 eq) of p-toluenesulfonic acid monohydrate to the reaction flask. Install a reflux separator, stir, heat, and reflux to separate water until no water is discharged (about 4 hours). Cool to room temperature to obtain... N - Ethylenepyrrolidine (18) toluene solution.

[0027] exist N - Add 121.4 g (1.2 mol, 1.2 eq) of triethylamine to a toluene solution of ethylenepyrrolidine (18), and add a toluene solution of adipic acid monoethyl ester chloride (2) dropwise under stirring at room temperature (20~30℃). The addition is completed in about 2 hours. After the addition is completed, control the temperature at 80~90℃ and stir for 3 hours. After the reaction is completed, cool to room temperature, add 300 ml of water, stir at 20~30℃ for 1 hour, separate the aqueous layer, wash the organic layer with water (300 ml × 2), and evaporate the toluene under reduced pressure to obtain 172.5 g of ethyl 6,8-dioxooctanoate (19), with a yield of 86%.

[0028] Example 2 Preparation of ethyl 6,8-dihydroxyoctanoate (20) Weigh 172.2 g (0.86 mol) of ethyl 6,8-dioxooctanoate (19) prepared in Example 1 above, add 520 ml of 95% ethanol aqueous solution, start stirring, add 27.9 g (0.52 mol, 0.60 eq) of potassium borohydride in batches at room temperature, stir for 30 minutes after addition, heat to reflux for 3 hours, the reaction is completed, evaporate the ethanol under reduced pressure below 80°C, cool to room temperature, add 200 ml of water, 2 ml of hydrochloric acid and 300 ml of ethyl acetate, stir for 10 minutes, separate the aqueous layer, wash the organic layer once with 200 ml of water, dry with 50 g of anhydrous magnesium sulfate and concentrate under reduced pressure to remove ethyl acetate, and prepare 137.4 g (20) of ethyl 6,8-dihydroxyoctanoate, yield 78%.

[0029] Example 3 Preparation of dihydrolipoic acid (14) Add 200 ml of water, 260 ml of toluene, 130 g (0.64 mol) of ethyl 6,8-dihydroxyoctanoate (20) prepared in Example 2 above, 17.4 g (0.064 mol, 0.1 eq) of 47% hydroiodic acid, 3.2 g (0.013 mol, 0.02 eq) of tetrabutylammonium chloride, and 121.8 g (1.6 mol, 2.5 eq) of thiourea to the reaction flask. Heat to 40-50℃ and stir for 4 hours. After the reaction is complete, cool to room temperature and add 256 g (1.92 mol, 3.0 eq) of 30% sodium hydroxide aqueous solution. Stir and hydrolyze at 70-80℃ for 3 hours. Separate the organic layer. Add 390 ml of methyl tert-butyl ether to the aqueous layer and adjust the pH to 2-3 with concentrated hydrochloric acid (about 180 g is needed). Separate the aqueous layer and wash the organic layer once with 200 ml of water. Evaporate the methyl tert-butyl ether under reduced pressure to obtain crude dihydrolipoic acid (14).

[0030] Example 4 Preparation of lipoic acid (1) Add sodium hydroxide aqueous solution (composed of 260g water and 28g sodium hydroxide), 4.3g disodium ethylenediaminetetraacetate (0.0128mol, 0.02eq), and 1.6g ferric chloride (0.01mol, 0.015eq) to the crude dihydrolipoic acid (14) prepared in Example 3. At this time, the pH of the system is about 11. Air is introduced under stirring at 15~25℃ (about 0.3L / min) and the reaction is carried out for 4 hours. After the reaction is completed, the temperature is cooled to 0~10℃ and the pH is adjusted to 1~2 with hydrochloric acid (about 65g of 37% hydrochloric acid is required). A yellow solid is precipitated, filtered, and dried under reduced pressure to obtain 95.1g of lipoic acid (1), with a yield of 72% and a content of 99.8% (USP-NF-2024, HPLC, external standard method). 1H-NMR (400MHz, CDCl3)δ: 11.51(br, s, 1H), 3.54-3.59(m,1H), 3.15-3.19(m, 1H), 3.09-3.13(m, 1H),2.44-2.47(m, 1H), 2.35-2.38(t, 2H), 1.89-1.93(m, 1H), 1.64-1.70(m, 4H), 1.46-1.52(m, 2H)。

Claims

1. A method for synthesizing lipoic acid, characterized in that, Includes the following steps: Step 1: Adipic acid monoester reacts with an acyl chloride reagent in the presence of solvent one to give adipic acid monoacyl chloride. Acetaldehyde reacts with an amine compound under reflux in the presence of a catalyst and solvent two to generate... N -Vinylpyrrolidone, adipate monoacyl chloride and N - Ethyl 6,8-dioxooctanoate is given by condensation reaction of ethylene pyrrolidine in the presence of an acid-binding agent and solvent. Step 2: Ethyl 6,8-dioxooctanoate is reduced in solvent four with a reducing agent to obtain ethyl 6,8-dihydroxyoctanoate; Step 3: Ethyl 6,8-dihydroxyoctanoate reacts with thiourea in the presence of a phase transfer catalyst, hydroiodic acid, and solvent V. The product is hydrolyzed and then acidified to obtain dihydrolipoic acid. Step 4: Dihydrolipoic acid under alkaline conditions, Fe 3+ It is oxidized to lipoic acid by passing air through a catalyst and disodium ethylenediaminetetraacetate.

2. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 1), the adipic acid monoester is either monomethyl adipic acid or monoethyl adipic acid; the acyl chloride reagent is thionyl chloride, phosphorus trichloride, or phosphorus pentachloride, and the amount of acyl chloride reagent used is 1.3 to 2.0 times the molar amount of adipic acid monoester; the solvent used is either dichloromethane or chloroform; the acyl chloride temperature is 20 to 45°C, and the reaction time is 1 to 3 hours.

3. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 1), the amine compound is pyrrolidine, piperidine, or tetrahydropyran, etc., and the amount of the amine compound is 1.1 to 1.4 times the molar amount of acetaldehyde; the catalyst is p-toluenesulfonic acid, and the amount of the catalyst is 0.09 to 0.11 times the molar amount of acetaldehyde; the solvent used is toluene.

4. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 1), the adipate monoacyl chloride and N The molar ratio of ethylenepyrrolidine is 1:1.1~1.5; the acid-binding agent is triethylamine or sodium carbonate, and the molar ratio of the acid-binding agent to adipate monoester is 1:1.1~1.5; the solvent is toluene; the condensation reaction temperature is 70~100℃, and the reaction time is 2~4 hours.

5. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 2), the reducing agent is potassium borohydride or sodium borohydride, the molar ratio of the reducing agent to ethyl 6,8-dioxooctanoate is 0.55~0.7:1, the solvent is 85~95% aqueous ethanol solution, the reaction temperature is reflux temperature, and the time is 2.5~4 hours.

6. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 3), the phase transfer catalyst is tetrabutylammonium chloride or tetramethylammonium chloride, and the molar ratio of the phase transfer catalyst to ethyl 6,8-dihydroxyoctanoate is 0.01~0.05:1; the molar ratio of hydroiodic acid to ethyl 6,8-dihydroxyoctanoate is 0.05~0.15:1; the molar ratio of thiourea to ethyl 6,8-dihydroxyoctanoate is 2.2~3.0:1; the solvent is a mixed solvent composed of toluene and water; the reaction temperature is 30~60℃, and the reaction time is 3~5 hours.

7. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 3), the hydrolysis reaction is carried out under a strong base, which can be sodium hydroxide or potassium hydroxide. The molar ratio of the strong base to ethyl 6,8-dihydroxyoctanoate is 2.5~4.0:

1. The reaction temperature is 60~100℃ and the reaction time is 2.5~4 hours.

8. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 3), the pH is adjusted to 2-3 during acidification.

9. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 4), dihydrolipoic acid is reacted under alkaline conditions in Fe... 3+ Catalytic oxidation with air to lipoic acid, using ferric chloride or ferric sulfate as the iron. 3+ The molar ratio with ethyl 6,8-dihydroxyoctanoate is 0.01~0.02:

1.

10. The method for synthesizing lipoic acid as described in claim 1, characterized in that, In step 4), the molar ratio of disodium ethylenediaminetetraacetate to ethyl 6,8-dihydroxyoctanoate is 0.01~0.04:1; the reaction temperature is 15~25℃; and the reaction time is 3~5 hours.

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