Preparation method of prohexadione calcium

Abstract

The invention provides a preparation method of prohexadione calcium, and belongs to the technical field of organic synthesis. According to the method, 3, 5-dihydroxybenzoic acid is taken as a raw material, prohexadione calcium is synthesized through four steps of reactions including catalytic hydrogenation reaction, acylation reaction, rearrangement reaction and calcification reaction, and in the acylation reaction, impurities are reduced by controlling the dosage and adding mode of propionyl chloride; the reaction time and temperature are controlled, and the product yield is improved. In the rearrangement reaction, the yield is increased by limiting the pH value, and meanwhile, the industrial production cost can be remarkably reduced by adopting a compound transposition catalyst triethylamine / DMAP; by researching the stability of the compound 3, the reaction conditions of transposition isomerization are determined, and the reaction yield is ensured. Through the reaction and conditions, the yield of the prohexadione calcium in the whole process reaches 65.6%.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of prohexadione calcium. Background Art

[0002] Prohexadione calcium (Prohexadione calcium, Pro-ca), with the chemical name of calcium 3,5-dioxo-4-propionylcyclohexanecarboxylate, is a new type of plant growth regulator, often used as a lodging resistance agent for rice and a shoot control agent for fruit trees. It can effectively promote plant development and lateral bud growth, regulate the flowering period, improve the fruit setting rate of plants, and effectively control the excessive growth of plants, thereby achieving the effects of increasing yield and quality. Due to its advantages such as low toxicity, low environmental pollution, and small dosage, it gradually replaces triazole growth retardants and has good application prospects.

[0003] There are mainly three existing methods for synthesizing prohexadione calcium according to different raw materials: The first method is: using maleic anhydride as the raw material, through ring-opening reaction, Michael addition, Claisen condensation, hydrolysis decarboxylation, acylation, rearrangement, and hydrolysis to form salt, a total of 7 steps of reaction to obtain prohexadione calcium [Zhuang Wenming, Li Suhua, Yu Nanshu. Research progress on the synthesis process of prohexadione calcium [J]. Guangzhou Chemical Industry, 2017, 45(17): 1-2, 9]. The operation is relatively cumbersome and the total yield is relatively low, which is not suitable for industrial production. The second method is: using diethyl maleate as the starting material, through Michael addition, Claisen condensation, acylation reaction, rearrangement, and hydrolysis to form salt, a total of 5 steps of reaction to obtain prohexadione calcium [Zheng Xianfu, Zhao Dongsheng, Sun Bingjian, etc. Synthesis process of prohexadione calcium [J]. Acta Agriculturae Jiangxi, 2011, 23(1): 129-131.]. The reaction conditions for the Michael addition reaction are high temperature and high pressure and a relatively long reaction time. The reaction conditions are harsh and the risk increases. The third method is: using 3,5-dihydroxybenzoic acid as the raw material, through hydrogenation, acylation, rearrangement, and hydrolysis to form salt, a total of 4 steps of reaction to obtain prohexadione calcium [Zhuang Wenming, Li Suhua, Yu Nanshu. Research progress on the synthesis process of prohexadione calcium [J]. Guangzhou Chemical Industry, 2017, 45(17): 1-2, 9]. Although the synthesis route is shortened, the yield is relatively low. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of prohexadione calcium, with a simple and concise synthesis method, high yield, and capable of industrial large-scale production of prohexadione calcium.

[0005] In order to achieve the above invention purpose, the present invention provides the following technical solutions:

[0006] The present invention provides a preparation method of prohexadione calcium, comprising the following steps:

[0007] Mix 3,5-dihydroxybenzoic acid, a base, palladium-carbon catalyst and water, and carry out a hydrogenation reaction to obtain Compound 2;

[0008] Mix the Compound 2, an acid-binding agent, propionyl chloride and a first organic solvent, and carry out an acylation reaction to obtain Compound 3; the molar ratio of the Compound 2 to the acid-binding agent is 1:1.0 to 1:1.5; the molar ratio of the Compound 2 to propionyl chloride is 1:0.9 to 1:1.5; the temperature of the acylation reaction is 25 to 55 °C, and the time is 1 to 6 h;

[0009] Mix the Compound 3, 4-dimethylaminopyridine, triethylamine and a second organic solvent, and carry out a rearrangement reaction to obtain Compound 4; the molar ratio of the Compound 3, 4-dimethylaminopyridine to triethylamine is 1:3.0:0.5 to 1:1.0:1.8; the concentration of the Compound 3 in the second organic solvent is 0.181 to 0.235 mol / L; the pH value of the rearrangement reaction is 7.50 to 8.50, the temperature is 5 to 20 °C, and the time is 1 to 4 h;

[0010] Mix the Compound 4, calcium hydroxide and an alcohol solution, and carry out a calcification reaction to obtain calcium cyclanilate;

[0011] The Compound 2 is The Compound 3 is

[0012] The Compound 4 is

[0013] Preferably, the base includes sodium carbonate, NaOH, potassium carbonate, KOH or sodium bicarbonate; the molar ratio of the 3,5-dihydroxybenzoic acid to the base is 1:1 to 1:3; the mass ratio of the 3,5-dihydroxybenzoic acid to the palladium-carbon catalyst is 1:0.08 to 0.13.

[0014] Preferably, the pressure of the hydrogenation reaction is 0.5 to 2.5 MPa, the temperature is 50 to 90 °C, and the time is 1 to 5 h.

[0015] Preferably, the acid-binding agent includes sodium carbonate, NaOH, potassium carbonate, KOH, pyridine, DMAP or triethylamine.

[0016] Preferably, the first organic solvent includes dichloroethane, dichloromethane or toluene.

[0017] Preferably, the addition method of the propionyl chloride is: after diluting the propionyl chloride with a part of the first organic solvent, dropwise add the obtained dilution to the mixture of the Compound 2, the acid-binding agent and the remaining first organic solvent; the dropping rate ≤ 0.3 mol / h; the volume ratio of the part of the first organic solvent to the propionyl chloride in the dilution is 1:2 to 4.

[0018] Preferably, the second organic solvent includes toluene, benzene, dichloromethane, chloroform or tetrahydrofuran.

[0019] Preferably, the mass ratio of the compound 4 to calcium hydroxide is 5:1.78 - 1.85; the alcohol solution is an ethanol aqueous solution; the volume ratio of ethanol to water in the ethanol aqueous solution is preferably 1 - 1.25:1.

[0020] Preferably, the temperature of the calcification reaction is 25 °C.

[0021] The present invention provides a method for preparing calcium cyclanilide. Using 3,5-dihydroxybenzoic acid as a raw material, calcium cyclanilide is synthesized through four steps of catalytic hydrogenation reaction, acylation reaction, rearrangement reaction and calcification reaction. In the acylation reaction: (1) By controlling the dosage and addition method of propionyl chloride, the generation of impurities is reduced; (2) By controlling the reaction time and reaction temperature, the generation of impurities is reduced, and the yield of compound 3 reaches 81.68%. The present invention defines the specific conditions of the acylation reaction, solves the problem that the yield of the acylation reaction is relatively low at 75% when synthesizing calcium cyclanilide with 3,5-dihydroxybenzoic acid as a raw material, and makes the yield of the acylation reaction reach 81.68%. In the rearrangement reaction: (1) The present invention first uses the pH value of the transposition isomerization reaction solution during the rearrangement process to limit the reaction process, and through the specific reaction conditions of the rearrangement reaction, solves the problem that the yield of compound 3 is reduced due to the unstable enol structure; (2) The present invention uses the compound transposition catalyst triethylamine / DMAP. Compared with the commonly used single transposition catalysts DMAP and acetone cyanohydrin, it can significantly reduce the industrial production cost, and at the same time avoid the operation threat and wastewater pollution caused by the use of highly toxic chemicals (acetone cyanohydrin); (3) Through the study of the stability of compound 3, the present invention determines the reaction conditions of transposition isomerization, ensuring that the yield of the rearrangement reaction reaches 86.58%. Through the above reactions and conditions, the overall yield of preparing calcium cyclanilide in the present invention reaches 65.6%. Description of the Drawings

[0022] Figure 1 1H NMR spectrum of compound 2 in Example 1; 1 1H NMR spectrum;

[0023] Figure 2 LC-MS spectrum of compound 2 in Example 1;

[0024] Figure 3 DSC chart of compound 2 in Example 1;

[0025] Figure 4 1H NMR spectrum of compound 3 in Example 1; 1 1H NMR spectrum;

[0026] Figure 5 1H NMR spectrum of compound 3 in Example 1; 1313C NMR spectrum;

[0027] Figure 6 is the HRMS spectrum of Compound 3 in Example 1;

[0028] Figure 7 is the DSC spectrum of Compound 3 in Example 1;

[0029] Figure 8 is of Impurity 1 1 1H NMR spectrum;

[0030] Figure 9 is of Impurity 1 13 13C NMR spectrum;

[0031] Figure 10 is the LC-MS spectrum of Impurity 1;

[0032] Figure 11 is the LC-MS spectrum of Impurity 2;

[0033] Figure 12 is of Compound 4 in Example 1 1 1H NMR spectrum;

[0034] Figure 13 is the LC-MS spectrum of Compound 4 in Example 1;

[0035] Figure 14 is the DSC spectrum of Compound 4 in Example 1;

[0036] Figure 15 is the IR spectrum of calcium cyclanilide in Example 1;

[0037] Figure 16 of Impurity 3 1 1H NMR;

[0038] Figure 17 is of Impurity 3 13 13C NMR spectrum;

[0039] Figure 18 is the LC-MS spectrum of Impurity 3;

[0040] Figure 19 is the DSC spectrum of Impurity 3;

[0041] Figure 20 is of Impurity 4 1 1H NMR spectrum;

[0042] Figure 21 is of Impurity 4 13 13C NMR spectrum;

[0043] Figure 22 is the LC-MS spectrum of Impurity 4;

[0044] Figure 23 It is the DSC chart of impurity 4. Specific implementation manners

[0045] In the present invention, unless otherwise specified, the raw materials or reagents required for preparation are all commercially available products well-known to those skilled in the art.

[0046] The present invention provides a preparation method of calcium cyclanilide, comprising the following steps:

[0047] Mix 3,5-dihydroxybenzoic acid, an alkali, palladium-carbon catalyst and water, and carry out a hydrogenation reaction to obtain compound 2;

[0048] Mix the compound 2, an acid-binding agent, propionyl chloride and a first organic solvent, and carry out an acylation reaction to obtain compound 3; the molar ratio of the compound 2 to the acid-binding agent is 1:1.0 to 1:1.5; the molar ratio of the compound 2 to propionyl chloride is 1:0.9 to 1:1.5; the temperature of the acylation reaction is 25 to 55 °C, and the time is 1 to 6 h;

[0049] Mix the compound 3, 4-dimethylaminopyridine, triethylamine and a second organic solvent, and carry out a rearrangement reaction to obtain compound 4; the molar ratio of the compound 3, 4-dimethylaminopyridine to triethylamine is 1:3.0:0.5 to 1:1.0:1.8; the concentration of the compound 3 in the second organic solvent is 0.181 to 0.235 mol / L; the pH value of the rearrangement reaction is 7.50 to 8.50, the temperature is 5 to 20 °C, and the time is 1 to 4 h;

[0050] Mix the compound 4, calcium hydroxide and an alcohol solution, and carry out a calcification reaction to obtain calcium cyclanilide;

[0051] The compound 2 is The compound 3 is

[0052] The compound 4 is

[0053] The reaction formula for preparing calcium cyclanilide in the present invention is:

[0054]

[0055] In the present invention, 3,5-dihydroxybenzoic acid, an alkali, palladium-carbon catalyst and water are mixed, and a hydrogenation reaction is carried out to obtain compound 2.

[0056] In the present invention, the alkali preferably includes sodium carbonate, NaOH, potassium carbonate, KOH or sodium bicarbonate; the palladium-carbon catalyst is preferably 10% Pd / C.

[0057] In the present invention, the molar ratio of the 3,5-dihydroxybenzoic acid to the base is preferably 1:1 to 1:3, more preferably 1:2 to 2.4, and further preferably 1:2.17; the mass ratio of the 3,5-dihydroxybenzoic acid to the palladium-carbon catalyst is preferably 1:0.08 to 0.13, more preferably 1:0.115.

[0058] In the present invention, the pressure of the hydrogenation reaction is preferably 0.5 to 2.5 MPa, more preferably 2.0 MPa, the temperature is preferably 50 to 90 °C, more preferably 50 °C, and the time is preferably 1 to 5 h, more preferably 2 h.

[0059] In the present invention, preferably, 3,5-dihydroxybenzoic acid, a base, a palladium-carbon catalyst and water are added to an autoclave. After sealing, according to the operation specifications of the autoclave, the gas in the autoclave is replaced with nitrogen three times in sequence first, and then the gas in the autoclave is replaced with hydrogen three times. Hydrogen is introduced until the pressure of the reaction kettle is the pressure of the hydrogenation reaction, and the reaction is carried out at the set temperature. Sampling and monitoring are carried out through the sampling port of the autoclave, and TLC monitoring is carried out until the end of the reaction. After the reaction solution is taken out, the catalyst is filtered off, and the pH is adjusted to 1 to 2 with concentrated hydrochloric acid, stirred at 0 °C, white solid is precipitated, filtered by suction, the filtrate is added with an aqueous NaCl solution and then stirred at 0 °C continuously. The two filter cakes are combined and dried to obtain Compound 2, and the yield is 99 to 100%.

[0060] In the present invention, Compound 2, an acid-binding agent, propionyl chloride and a first organic solvent are mixed to carry out an acylation reaction to obtain Compound 3.

[0061] In the present invention, the acid-binding agent preferably includes sodium carbonate, NaOH, potassium carbonate, KOH, pyridine, DMAP or triethylamine, and more preferably triethylamine.

[0062] In the present invention, the first organic solvent preferably includes dichloroethane, dichloromethane or toluene, and more preferably dichloroethane. There is no special limitation on the total amount of the first organic solvent in the present invention, and it can be adjusted according to actual needs.

[0063] In the present invention, the addition method of the propionyl chloride is preferably as follows: after diluting the propionyl chloride with a part of the first organic solvent, the obtained dilution is added dropwise to the mixture of Compound 2, the acid-binding agent and the remaining first organic solvent; the dropping rate is preferably ≤0.3 mol / h, and more preferably 0.2 mol / h; the volume ratio of the part of the first organic solvent to the propionyl chloride in the dilution is preferably 1:2 to 4, and more preferably 1:3. The part of the first organic solvent and the remaining first organic solvent in the present invention constitute the total amount of the first organic solvent.

[0064] In the present invention, the molar ratio of the compound 2 to the acid-binding agent is 1:1.0 to 1:1.5, more preferably 1:1.2 to 1.3; the molar ratio of the compound 2 to propionyl chloride is 1:0.9 to 1:1.5, more preferably 1:0.92 to 1.2.

[0065] In the present invention, the temperature of the acylation reaction is 25 to 55 °C, more preferably 40 °C; the time is 1 to 6 h, more preferably 2 to 3 h.

[0066] In the present invention, preferably, compound 2, an acid-binding agent and a part of the first organic solvent are added to a reaction vessel, stirred evenly, cooled to below 10 °C, propionyl chloride is diluted with the remaining first organic solvent, and the obtained dilution is added dropwise to the mixture. After the addition is completed, the temperature is naturally raised to room temperature, and the reaction is heated. The reaction is monitored by HPLC until no raw materials remain. After filtration and rotary evaporation of the filtrate, the crude product of compound 3 is obtained.

[0067] In the present invention, when preparing compound 3 by acylation reaction, the crude product of compound 3 is separated by preparative chromatography (chromatographic column: Hedera 0DS-2 30 mm × 250 mm; column temperature: 27 °C; detection wavelength: 236 nm; injection volume: 5.00 mL; mobile phase: methanol: water = 8:2; flow rate: 40 mL / min) to separate out impurity 1 and impurity 2. The presence of impurities will affect the yield of compound 3. When the mass percentage contents of impurity 1 and impurity 2 in the crude product of compound 3 are respectively controlled at 5.0 ± 0.4% and 4.0 ± 0.2%, a higher yield can be achieved. If the reaction time is too long or the reaction temperature is too high, the generated compound 3 will undergo double bond shift and lose the propionyl group, converting into compound 2. At the same time, it will also lead to an increase in impurity 2, that is, the molecules of the generated compound 3 and compound 2 undergo esterification condensation. The amount of propionyl chloride directly affects the generation of impurity 1, and impurity 1 will promote the reaction of impurity 2 (as shown in the following reaction formula). When propionyl chloride is added dropwise too fast, the local concentration of propionyl chloride in the reaction system becomes high, resulting in an increase in impurity 1. Therefore, the addition method and amount of propionyl chloride can effectively avoid the generation of impurity 1, thereby indirectly reducing the generation of impurity 2.

[0068]

[0069] Impurity 1: 5-oxo-3-(propionyl)cyclohex-3-en-1-carboxylic anhydride

[0070]

[0071] 11H NMR (400 MHz, CDCl3) δ 5.96 (s, 1H), 4.19 (dd, J = 15, 10 Hz, 2H), 3.15 - 3.13 (m, 1H), 2.91 - 2.84 (m, 1H), 2.79 - 2.58 (m, 3H), 2.52 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 10 Hz, 3H), 1.21 (t, J = 10 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 196.03, 171.41, 170.40, 167.09, 162.76, 109.60, 63.12, 52.19, 51.92, 36.40, 31.53, 14.24, 7.79. MS: [M + C3H5O - 2H] + = 156.80. Calcd. for C 13 H 16 O6. (See Figures 8 - 10 )

[0072] Impurity 2: 5 - oxo - 3 - (5 - oxo - 3 - (propionyl)cyclohex - 3 - en - 1 - carboxyl)cyclohex - 3 - en - 1 - carboxylic acid

[0073] MS: [M + H] + = 350.95. (See Figure 11 )

[0074]

[0075] In the present invention, the compound 3, 4 - dimethylaminopyridine, triethylamine and a second organic solvent are mixed and subjected to a rearrangement reaction to obtain compound 4.

[0076] In the present invention, the molar ratio of the compound 3, 4 - dimethylaminopyridine to triethylamine is 1:3.0:0.5 - 1:1.0:1.8, more preferably 1:1.5:1.4; the concentration of the compound 3 in the second organic solvent is 0.181 - 0.235 mol / L, more preferably 0.188 - 0.214 mol / L.

[0077] In the present invention, the second organic solvent preferably includes toluene, benzene, dichloromethane, chloroform or tetrahydrofuran.

[0078] In the present invention, the pH value of the rearrangement reaction is 7.50 - 8.50, more preferably 8.03 - 8.44, further preferably 8.07 - 8.33; the temperature of the rearrangement reaction is 5 - 20 °C, more preferably 10 °C; the time is 1 - 4 h, more preferably 1 - 2 h.

[0079] In the present invention, preferably, compound 3 and a second organic solvent are stirred and dissolved, then 4-dimethylaminopyridine (DMAP) and triethylamine are added, and a rearrangement reaction is carried out at the required reaction temperature, monitored by HPLC until the reaction end point; after the reaction is completed, water is added to the reaction solution and stirred, the liquid is separated, extracted with ethyl acetate, the aqueous phase is adjusted to pH = 3 - 4 with hydrochloric acid, extracted with dichloromethane, dried, and concentrated to obtain the crude product of compound 4, and then recrystallized with isopropanol to obtain the yellowish-brown compound 4.

[0080] In the present invention, compound 4, calcium hydroxide and an alcohol solution are mixed to carry out a calcification reaction to obtain calcium cyclanilide.

[0081] In the present invention, the mass ratio of compound 4 to calcium hydroxide is preferably 5:1.78 - 1.85; the alcohol solution is preferably an ethanol aqueous solution; the volume ratio of ethanol to water in the ethanol aqueous solution is preferably 1 - 1.25:1. The present invention has no special limitation on the dosage ratio of the alcohol solution to compound 4, as long as the reaction proceeds smoothly.

[0082] In the present invention, the temperature of the calcification reaction is preferably 25 °C.

[0083] In the present invention, preferably, an aqueous alcohol solution is added to compound 4 and stirred at room temperature, then calcium hydroxide powder is added, and the reaction continues at room temperature. The reaction end point is when there is no ultraviolet spot monitored by TLC. After the reaction is completed, filtration is carried out to obtain a yellowish-brown filter cake, which is dried to obtain the calcium cyclanilide solid.

[0084] The specific embodiments of the present invention will be described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the protection scope of the present invention. The experimental methods described in the embodiments of the present invention are all conventional methods unless otherwise specified.

[0085] The following experimental methods and detection methods are all conventional methods unless otherwise specified; the following reagents and raw materials are all commercially available unless otherwise specified.

[0086] In the present invention, the conversion of compound 3 has the best reaction effect under appropriate alkaline conditions. The pH of compound 3 in anhydrous toluene at different concentrations is measured, and the pH adjustment pre-experiment steps are as follows:

[0087] Take a 50 mL reaction flask, add 1.00 g (0.0047 mol) of compound 3, 10 mL of anhydrous toluene, and 2.59 g (0.0212 mol) of 4-dimethylaminopyridine. First, measure the pH value of 10 mL of the solvent with a pH meter, then add 5 mL of the solvent to the reaction flask and measure the pH value with an acid-base meter, increasing sequentially by 5 mL of the solvent each time. The experimental results are shown in Table 1.

[0088] Table 1 pH Adjustment Preliminary Experiment

[0089]

[0090] Based on the experimental data in Table 1, when the pH is around 8, experiments were carried out with the concentration of compound 3 in anhydrous toluene being 0.470 - 0.134 mol / L.

[0091] According to the above - mentioned preliminary experiment procedure, 0.5 g (0.0024 mol) of compound 3 was dissolved in different volumes of anhydrous toluene, 2.59 g (0.0212 mol) of DMAP (only using DMAP) was added, the reaction temperature was 80 °C, the reaction time was 1 h, and the obtained crude product was separated by column chromatography (eluent: petroleum ether: ethyl acetate = 9:1) to obtain impurity 3, impurity 4 and compound 4. The influence of the reaction pH on the reaction yield was studied, and the experimental results are shown in Table 2.

[0092] Table 2 Influence of Reaction Solution pH on Reaction Yield

[0093]

[0094] a Impurity 3: 3 - (Propionyl)benzoic acid, Impurity 4: m - Hydroxybenzoic acid

[0095] b Calculated after determining the content of each substance in the reaction solution by HPLC external standard method

[0096] The experimental data in Table 2 show that when the pH is in the range of 8.03 - 8.33, the reactions for generating the two impurities can be better inhibited and the yield is optimal.

[0097] It was found through experiments that compound 3 will undergo further enolization and ester elimination reactions (or elimination of water after ester hydrolysis) during the reaction due to condition influence to generate the aromatized compound impurity 3 and water, and impurity 3 will further hydrolyze under basic conditions to generate impurity 4.

[0098] Impurity 3:

[0099]

[0100] 1 H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 7.7, 1.3 Hz, 1H), 7.87 (s, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.43 - 7.35 (m, 1H), 2.66 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). 1313C NMR (126 MHz, CDCl3) δ 172.76, 171.25, 150.85, 130.86, 129.58, 127.56, 127.27, 123.47, 27.75, 9.04. MS: [M-H] - = 193.05. M.p. 86.86 °C. (See Figures 16 - 19 )

[0101] Impurity 4:

[0102]

[0103] 1 1H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.35 (m, 2H), 7.29 (t, J = 7.9 Hz, 1H), 7.05 - 6.98 (m, 1H). 13 13C NMR (126 MHz, DMSO-d6) δ 167.82, 157.89, 132.53, 130.07, 120.48, 120.34, 116.31. MS: [M-H] - = 137.02. M.p. 208.80 °C. (See Figures 20 - 23 )

[0104] Furthermore, triethylamine is used to replace part of DMAP in the rearrangement reaction to reduce the cost.

[0105] The specific operating conditions are as follows: 0.5 g (0.0024 mol) of compound 3 is mixed with 12.0 mL of anhydrous toluene, and DMAP and triethylamine are added according to the molar ratio of compound 3:DMAP:triethylamine in Table 3. The reaction temperature is 80 °C and the reaction time is 1 h. The experimental results are shown in Table 3.

[0106] Table 3 Experimental data on the dosage conditions of DMAP-TEA

[0107]

[0108]

[0109] a Molar ratio of compound 3:DMAP:triethylamine

[0110] b Calculated after determining the content of each substance in the reaction solution by HPLC external standard method

[0111] As can be seen from Table 3, the composite transposition isomerization catalyst can well promote the completion of the reaction. Excessive dosage of triethylamine will increase the yield of impurity 3, thereby promoting the yield of compound 2 and reducing the formation of compound 4.

[0112] Since compound 3 has an enol structure, its molecular stability is poor and it is easily affected by acids, bases, reaction temperature and time, resulting in conversion to compound 2 and failure of the transposition reaction. Therefore, the stability of compound 3 has a great impact on the reaction.

[0113] Stability experiment of compound 3: Simulating the reaction solution conditions, a reaction solution with pH = 8.15 (anhydrous toluene-triethylamine solution) was prepared. A 50 mL three-necked flask was taken, 100 mg of compound 3 and 20 mL of toluene-triethylamine solution were added, and compound 3 was tested at 10 °C, 20 °C, 40 °C, 60 °C, and 80 °C respectively using a stability test chamber. The concentrations of compound 3 and compound 2 at different times were tracked and monitored by high performance liquid chromatography. The experimental results are shown in Table 4.

[0114] Table 4 Stability experiment of compound 3 and compound 2

[0115]

[0116]

[0117] According to the stability data, in the temperature range of 10 °C to 40 °C, the concentrations of compound 3 and compound 2 did not change significantly for a long time; in the temperature range of 80 °C, the concentration of compound 2 changed little within 0 - 4 h, and with the extension of time, the concentration of compound 2 gradually increased. Based on the analysis of the above data results, when the reaction temperature does not exceed 60 °C, compound 3 does not change significantly for a long time, and when the temperature is higher than 60 °C, the concentration of compound 3 begins to decrease slowly after 4 h with the extension of time.

[0118] Based on the stability experiment, the temperature and time of the rearrangement reaction were determined:

[0119] The specific operating conditions were as follows: 0.5 g (0.0024 mol) of compound 3 was mixed with anhydrous toluene, the concentration of compound 3 in anhydrous toluene was 0.196 mol / L, 0.439 g (0.0036 mol) of DMAP and 0.339 g (0.00336 mol) of triethylamine were added, pH = 8.07, and the experimental results are shown in Table 5.

[0120] Table 5 Influence of reaction time and temperature on reaction yield

[0121]

[0122] According to the data in Table 5, after the reaction at 10 °C was extended to 2 h, compound 3 could be completely converted.

[0123] Example 1

[0124] Add 2 g (0.0128 mol) of 3,5-dihydroxybenzoic acid, 1.13 g (0.0278 mol) of sodium hydroxide, 0.23 g of 10% Pd / C and 20 mL of water into an autoclave. After sealing, according to the operating specifications of the autoclave, first displace the gas in the autoclave three times with nitrogen, and then displace the gas in the autoclave three times with hydrogen. Introduce hydrogen until the pressure in the reaction kettle reaches 2.0 MPa, and react at 50 °C for 2 h. Sampling and monitoring are carried out through the sampling port of the autoclave, and TLC monitoring is carried out until there is no remaining raw material. After taking out the reaction solution, filter out the catalyst, adjust the pH to 2 with concentrated hydrochloric acid, stir at 0 °C, precipitate white solid, carry out suction filtration, add 20 mL of NaCl aqueous solution to the filtrate and continue to stir at 0 °C. Combine the two filter cakes, dry them, and obtain Compound 2 with a yield of 100%. 1 HNMR (500 MHz, DMSO-d6) δ: 12.50 (s, 1H), 11.22 (s, 1H), 5.21 (s, 1H), 3.04 - 2.99 (m, 1H), 2.48 (s, 4H). MS: [M + H] + = 156.95. M.p. 166.70 °C. (See Figures 1 - 3 )

[0125] Add 2.00 g (0.0128 mol) of Compound 2, 1.68 g (0.0166 mol) of the acid-binding agent triethylamine and 30 mL of the solvent dichloroethane into a three-necked flask. After stirring evenly, cool down to below 10 °C, dilute propionyl chloride with dichloroethane (volume ratio 1:3), and drop the obtained dilution (1.41 g of propionyl chloride, 0.0153 mol) into the mixture at a dropping rate of 0.2 mol / h. After the dropping is completed, naturally warm up to room temperature, and then heat up to 40 °C and react for 2 h. HPLC monitoring is carried out until there is no remaining raw material. After filtration, the filtrate is rotary evaporated, and the obtained solid product is directly used for the next step of the reaction. The total yield of this step is 81.68%, among which the yield of Compound 3 is 56.89% and the yield of Compound 4 is 24.79%). 1 HNMR (500 MHz, CDCl3) δ 6.04 (s, 1H), 3.26 - 3.21 (m, 1H), 2.95 - 2.89 (m, 1H), 2.87 - 2.73 (m, 2H), 2.67 (dd, J = 16.8, 10.4 Hz, 1H), 2.55 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). 13 CNMR (126 MHz, CDCl3) δ 196.86, 177.70, 170.87, 167.49, 117.25, 38.32, 38.27, 30.41, 27.91, 8.75. HRMS (ESI) m / z calcd. for C 10 H 12O5[M-H] - : 211.0608, found 212.0685. M.p. 82.76 °C. (See Figures 4 - 7 )

[0126] To a 150 mL three-necked flask, 2.00 g (0.0094 mol) of the above solid product and 50 mL of toluene were added and stirred until dissolved. Then, 1.71 g (0.014 mol) of 4-dimethylaminopyridine and 1.33 g (0.013 mol) of triethylamine were added. The reaction was carried out at pH = 8.07 and 10 °C for 2 h. The reaction was monitored by HPLC until the end point. After the reaction was completed, water was added to the reaction solution and stirred. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The aqueous phase was adjusted to pH = 3 with hydrochloric acid and then extracted with dichloromethane. After drying and concentration, the crude product of compound 4 was obtained. After recrystallization with isopropanol, a yellowish-brown compound 4 was obtained. The yield was 86.58%. 1 1H NMR (500 MHz, CDCl3) δ 3.19–3.13 (m, 1H), 3.10 (q, J = 7.2 Hz, 2H), 3.02–2.92 (m, 2H), 2.86–2.82 (m, 1H), 2.75 (dd, J = 16.8, 9.8 Hz, 1H), 1.16 (t, J = 7.2 Hz, 3H). MS: [M-H] - = 211.22. M.p. 121.40 °C. (See Figures 12 - 14 )

[0127] To a 500 mL reaction flask, 5.00 g (0.024 mol) of compound 4 was added, followed by 150 mL of ethanol and 150 mL of water. The mixture was stirred at room temperature, and then 1.78 g of calcium hydroxide powder was added. The reaction was continued at room temperature. The reaction was monitored by TLC, and the end point was reached when there was no ultraviolet spot. After the reaction was completed, the reaction solution was filtered by suction to obtain a yellowish-brown filter cake. After drying, calcium cyclanilide solid was obtained. The yield was 92.8%, the content was 92.0%, and the overall yield was 65.6%.

[0128] Figure 15 This is the infrared spectrum of calcium cyclanilide prepared in Example 1. Among them, IR (cm -1 ): 2359, 1640, 1549, 1378, which proves the successful synthesis of calcium cyclanilide.

[0129] Example 2

[0130] Add 2 g (0.0128 mol) of 3,5-dihydroxybenzoic acid, 1.02 g (0.0256 mol) of sodium hydroxide, 0.23 g of 10% Pd / C and 20 mL of water into an autoclave. After sealing, first displace the gas in the autoclave three times with nitrogen according to the operating specifications of the autoclave, and then displace the gas in the autoclave three times with hydrogen. Introduce hydrogen until the pressure in the reaction kettle reaches 2.0 MPa, and react at 50 °C. Sample and monitor through the sampling port of the autoclave. Monitor by TLC until no raw materials remain. After taking out the reaction solution, filter out the catalyst, adjust to pH = 2 with concentrated hydrochloric acid, stir at 0 °C, precipitate white solid, filter by suction. Add 20 mL of NaCl aqueous solution to the filtrate and continue to stir at 0 °C. Combine the two filter cakes, dry to obtain Compound 2 with a yield of 99%;

[0131] Add 2.00 g (0.0128 mol) of Compound 2, 1.68 g (0.0166 mol) of the acid-binding agent triethylamine and 30 mL of dichloroethane into a three-necked flask. After stirring evenly, cool down to below 10 °C, dilute propionyl chloride with dichloroethane (volume ratio 1:3). Add the obtained diluted solution (1.41 g of propionyl chloride, 0.0153 mol) dropwise to the mixture at a dropping rate of 0.2 mol / h. After the dropping is completed, naturally warm up to room temperature, and then heat up to 40 °C and react for 3 h. Monitor by HPLC until no raw materials remain. Filter, and directly use the obtained solid product after rotary evaporation of the filtrate for the next step of the reaction.

[0132] Add 2.00 g (0.0094 mol) of the above solid product and 50 mL of toluene into a 150 mL three-necked flask, stir to dissolve, then add 1.71 g (0.014 mol) of 4-dimethylaminopyridine and 1.33 g (0.013 mol) of triethylamine, react at pH = 8.07 and 10 °C for 1 h. Monitor by HPLC until the reaction end point. After the reaction is completed, add water to the reaction solution and stir, separate the layers, extract with ethyl acetate, adjust the aqueous phase to pH = 3 with hydrochloric acid, add dichloromethane for extraction, dry, and concentrate to obtain the crude product of Compound 4. After recrystallization with isopropanol, obtain the yellowish-brown Compound 4 with a yield of 76.3%.

[0133] Add 5.00 g (0.024 mol) of Compound 4 into a 500 mL reaction flask, add 150 mL of ethanol and 150 mL of water, stir at room temperature, then add 1.85 g of calcium hydroxide powder, and continue to react at room temperature. Monitor by TLC until there is no ultraviolet spot as the reaction end point. After the reaction is completed, filter the reaction solution by suction to obtain a yellowish-brown filter cake, dry to obtain the calcium cyclanilide solid with a yield of 91.8% and a content of 92.0%.

[0134] Example 3

[0135] Add 2 g (0.0128 mol) of 3,5-dihydroxybenzoic acid, 1.22 g (0.0307 mol) of sodium hydroxide, 0.23 g of 10% Pd / C and 20 mL of water into an autoclave. After sealing, displace the gas in the autoclave with nitrogen three times in accordance with the operating specifications of the autoclave, and then displace the gas in the autoclave with hydrogen three times. Introduce hydrogen until the pressure in the reaction kettle reaches 2.0 MPa, and react at 50 °C. Sample and monitor through the sampling port of the autoclave. Monitor by TLC until there is no remaining raw material. After taking out the reaction solution, filter out the catalyst, adjust the pH to 2 with concentrated hydrochloric acid, stir at 0 °C, precipitate white solid, filter by suction. Add 20 mL of NaCl aqueous solution to the filtrate and continue to stir at 0 °C. Combine the two filter cakes, dry them, and obtain compound 2 with a yield of 99%;

[0136] Add 2.59 g (0.0166 mol) of compound 2, 1.68 g (0.0166 mol) of the acid-binding agent triethylamine and 30 mL of dichloroethane into a three-necked flask. After stirring evenly, cool down to below 10 °C, dilute propionyl chloride with dichloroethane (volume ratio 1:3). Add the obtained diluted solution (1.41 g of propionyl chloride, 0.0153 mol) dropwise to the mixture at a dropping rate of 0.2 mol / h. After the dropping is completed, let it warm up to room temperature naturally, and then heat up to 40 °C and react for 3 h. Monitor by HPLC until there is no remaining raw material. Filter, and directly use the obtained solid product after rotary evaporation of the filtrate for the next step of the reaction.

[0137] Add 2.00 g (0.0094 mol) of the above solid product and 50 mL of toluene into a 150 mL three-necked flask, stir to dissolve, then add 1.15 g (0.0094 mol) of 4-dimethylaminopyridine and 1.71 g (0.017 mol) of triethylamine, and react at pH = 8.44 and 10 °C for 2 h. Monitor by HPLC until the reaction end point. After the reaction is completed, add water to the reaction solution and stir. Separate the layers, extract with ethyl acetate. Adjust the aqueous phase to pH = 3 with hydrochloric acid, add dichloromethane for extraction, dry, and concentrate to obtain the crude product of compound 4. After recrystallization with isopropanol, obtain the yellowish-brown compound 4 with a yield of 76.1%.

[0138] Add 5.00 g (0.024 mol) of compound 4 into a 500 mL reaction flask, add 150 mL of ethanol and 120 mL of water, stir, and then stir at room temperature. Add 1.78 g of calcium hydroxide powder and continue to react at room temperature. Monitor by TLC until there is no ultraviolet spot as the reaction end point. After the reaction is completed, filter the reaction solution by suction to obtain a yellowish-brown filter cake, dry it to obtain the calcium cyclamate solid with a yield of 90.9% and a content of 92.0%.

[0139] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of calcium cyclanilide, characterized in that, It includes the following steps: Mix 3,5-dihydroxybenzoic acid, a base, palladium-carbon catalyst and water, and carry out a hydrogenation reaction to obtain Compound 2; Mix the Compound 2, an acid-binding agent, propionyl chloride and a first organic solvent, and carry out an acylation reaction to obtain Compound 3; the molar ratio of the Compound 2 to the acid-binding agent is 1:1.0 - 1:1.5; the molar ratio of the Compound 2 to propionyl chloride is 1:0.9 - 1:1.5; the temperature of the acylation reaction is 25 - 55°C, and the time is 1 - 6 h; Mix the Compound 3, 4-dimethylaminopyridine, triethylamine and a second organic solvent, and carry out a rearrangement reaction to obtain Compound 4; the molar ratio of the Compound 3, 4-dimethylaminopyridine to triethylamine is 1:3.0:0.5 - 1:1.0:1.8; the concentration of the Compound 3 in the second organic solvent is 0.181 - 0.235 mol / L; the pH value of the rearrangement reaction is 7.50 - 8.50, the temperature is 5 - 20°C, and the time is 1 - 4 h; Mix the Compound 4, calcium hydroxide and an alcohol solution, and carry out a calcification reaction to obtain calcium cyclanilate; The compound 2 is The compound 3 is The said compound 4 is 2. The preparation method according to claim 1, wherein, The base includes sodium carbonate, NaOH, potassium carbonate, KOH or sodium bicarbonate; the molar ratio of the 3,5-dihydroxybenzoic acid to the base is 1:1 - 1:3; the mass ratio of the 3,5-dihydroxybenzoic acid to the palladium-carbon catalyst is 1:0.08 - 0.

13.

3. The preparation method according to claim 1 or 2, characterized in that, The pressure of the hydrogenation reaction is 0.5 - 2.5 MPa, the temperature is 50 - 90°C, and the time is 1 - 5 h.

4. The preparation method according to claim 1, characterized in that, The acid-binding agent includes sodium carbonate, NaOH, potassium carbonate, KOH, pyridine, DMAP or triethylamine.

5. The preparation method according to claim 1, wherein The first organic solvent includes dichloroethane, dichloromethane or toluene.

6. The preparation method according to claim 1, characterized in that, The addition method of the propionyl chloride is: dilute the propionyl chloride with a part of the first organic solvent, and then drop the obtained dilution into the mixture of the Compound 2, the acid-binding agent and the remaining first organic solvent; the dropping rate ≤ 0.3 mol / h; the volume ratio of the part of the first organic solvent to the propionyl chloride in the dilution is 1:2 - 4.

7. The preparation method according to claim 1, wherein The second organic solvent includes toluene, benzene, dichloromethane, chloroform or tetrahydrofuran.

8. The preparation method according to claim 1, wherein, The mass ratio of the Compound 4 to calcium hydroxide is 5:1.78 - 1.85; the alcohol solution is an ethanol aqueous solution; the volume ratio of ethanol to water in the ethanol aqueous solution is preferably 1 - 1.25:

1.

9. The preparation method according to claim 1 or 8, characterized in that, The temperature of the calcification reaction is 25°C.

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