Preparation method of dotenorad

Abstract

The invention provides a preparation method of dotenorad. The preparation method comprises the following steps: (1) carrying out cyclization reaction on SM1 and paraformaldehyde under the action of an activating agent and a solubilizer to obtain Int1; (2) carrying out substitution reaction on the Int1 and SM2 to obtain Int2; (3) carrying out oxidation reaction on the Int2 and an oxidizing agent in the presence of a catalyst to obtain Int3; and 4, carrying out a demethylation reaction on the Int3 and lithium chloride to obtain dotenorad. The purity and the yield of the dotenorad prepared by the method are greatly improved, the cost is reduced, and the method is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular, relates to a method for preparing polytinorel. Background Art

[0002] Dotinurad, chemically known as (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxidebenzo[d]thiazol-3(2H)-yl)methanone, is a urate reabsorption inhibitor that can target and inhibit the activity of the urate reabsorption transporter (URAT1). The drug was jointly developed by Fujiyama Pharmaceutical and Mochida Pharmaceutical of Japan for the treatment of some hyperuricemia and gout. It was launched on the PMDA on January 23, 2020. It can selectively inhibit URAT1, which reabsorbs uric acid in the kidney, thereby controlling uric acid reabsorption and reducing uric acid levels in the blood.

[0003] A variety of preparation methods of polytinol are disclosed in the prior art. Patent CN201080042866.9 reports the synthesis route and preparation method of polytinol, as shown in Route 1. This method uses 2-aminobenzenethiol and formalin to condense benzothiazole, which is then reacted with benzoyl chloride to obtain a benzothiazole benzamide intermediate, and then oxidized and deprotected to obtain polytinol. However, the benzothiazole prepared by this route has more impurities and lower purity. It is not refined and directly reacts in one pot for the next step, which has a greater impact on the quality of subsequent products. At the same time, this method uses meta-chloroperbenzoic acid for oxidation reaction, which is easy to produce nitrogen oxides and is not easy to remove, affecting the quality of the product. The preparation of the intermediate in this patent is mostly done by directly feeding the next step without purification operations such as crystallization. The combined yield of step acd in Example 1 is 56.84% (based on 2-aminobenzenethiol), the yield of step e is 77.83%, and the total yield is only 44.24%. In this method, although the intermediate is directly fed into the reaction, the yield is still not ideal and the impurities cannot be effectively removed, and the final product has many impurities and low purity.

[0004]

[0005]

[0006] Patent CN202010692765.1 reports an acylation reaction with 2-aminobenzenethiol and 3,5-dichloro-4-hydroxybenzoyl chloride, followed by cyclization with diiodomethane, and finally oxidation to polytinore under the action of an oxidant, as shown in Route 2. However, in this route, both the exposed amino group and the thiol are prone to react during the acylation reaction, resulting in large impurities and relatively poor quality. During the cyclization reaction, the exposed hydroxyl group is also prone to side reactions to generate the corresponding cyclic ethers. The use of diiodomethane is very likely to produce methylated impurities, and diiodomethane is highly toxic and easily decomposes in the air. Combustion produces toxic iodide fumes, which is not suitable for industrial scale-up. Metachloroperbenzoic acid is used in the oxidation reaction, which is prone to produce nitrogen oxides and is difficult to remove, affecting product quality.

[0007]

[0008] Patent CN202010693795.4 reports a condensation reaction between 3,5-dichloro-4-hydroxybenzoic acid and 2-aminobenzenethiol, followed by cyclization, and finally oxidation to obtain dotinore, as shown in Route 3: This route uses a conventional condensing agent during the condensation reaction, making 3,5-dichloro-4-hydroxybenzoic acid more prone to self-condensation, which is not conducive to the reaction. During the cyclization reaction, the exposed hydroxyl groups are also prone to side reactions to generate corresponding cyclic ethers. Meta-chloroperbenzoic acid is used during the oxidation reaction, which is prone to produce nitrogen oxides and is difficult to remove, affecting product quality.

[0009]

[0010]

[0011] In summary, the preparation method of polytinol in the prior art has certain defects in the selection and ratio of reagents, reaction conditions, operation methods, etc., and the side reaction control effect is not good, and the yield and purity of the obtained product are low. In view of the defects of the prior art, the present invention has developed a preparation method of polytinol with simple process operation, few side reactions, low impurity content, good quality, high yield and low cost, and suitable for industrial large-scale production through experiments. Summary of the invention

[0012] The purpose of the present invention is to provide a method for preparing polytinol which is economical, efficient, has few side reactions and can be industrially mass-produced. The present invention greatly improves the purity and yield of polytinol by finely controlling the preparation process, thereby improving production efficiency and reducing costs, and is suitable for industrial mass production.

[0013] The present invention provides a method for preparing polytinorel, characterized in that the chemical reaction equation of the preparation method is as follows:

[0014]

[0015] The preparation method comprises the following steps:

[0016] Step 1): SM1 and paraformaldehyde undergo a cyclization reaction in the presence of an activator and a solubilizer to obtain Int1;

[0017] Step 2): Int1 and SM2 undergo substitution reaction to obtain Int2;

[0018] Step 3): Int2 is subjected to an oxidation reaction with an oxidant in the presence of a catalyst to obtain Int3;

[0019] Step 4): Int3 is subjected to a demethylation reaction with lithium chloride to obtain polytinorethoxylate.

[0020] In the preparation method of the present invention, in the step 1), the ring-closure reaction is carried out by mixing paraformaldehyde in a solvent with an activator and a solubilizer, and then dropping a solution of SM1 therein; further, in the step 1), the ring-closure reaction is carried out by mixing paraformaldehyde in a solvent with an activator and a solubilizer, and then dropping a solution of SM1 therein; after the reaction is completed, water is added to the reaction solution, and the reaction solution is concentrated under reduced pressure until there is substantially no droplet, and then extracted with dichloromethane, and the organic phase is washed with a sodium chloride solution and concentrated to dryness. The solvent is a C1-C3 lower monohydric alcohol, preferably methanol and ethanol, and more preferably methanol.

[0021] In the preparation method of the present invention, in step 2), the substitution reaction method is to dissolve Int1 in dichloromethane, add triethylamine, and add SM2 solution dropwise at a controlled temperature. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, ethanol is added for crystallization, and filtered and dried to obtain Int2.

[0022] In the preparation method of the present invention, in step 3), the oxidation reaction method is to dissolve Int2 in a solvent, add a catalyst, add an oxidant under temperature control, add a sodium sulfite solution to the reaction solution after the reaction is completed, concentrate under reduced pressure, filter the residue, slurry the filter cake with ethanol, filter and dry to obtain Int3. The solvent is selected from methanol and ethanol, preferably methanol.

[0023] In the preparation method of the present invention, in step 4), the method of the demethylation reaction is to dissolve Int3 in N,N-dimethylformamide, add lithium chloride, and react at a high temperature. After the reaction is completed, the reaction solution is cooled and added dropwise to a hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake is dried to obtain polytinore.

[0024] The activator described in step 1) of the above-mentioned preparation method refers to a reagent that can promote the decomposition or reaction of paraformaldehyde, which can increase the reaction rate or change the reaction conditions. For example, ethylenediamine phosphate, propylenediamine phosphate, dimethylbenzene, sodium fluorosilicate, ammonium sulfate, ammonium chloride, ferrous sulfate, ammonium hydroxide, etc. can all be used as activators. The technicians of the present invention have found through a large number of experiments that the reaction effects of the above-mentioned activators for step 1) of the present invention are quite different, and some activators cannot make the reaction stable and fast. In addition, although the activator can be used alone to make the reaction proceed, its reaction rate and degree are not ideal. The present invention selects a suitable activator to make the reaction proceed, and then adds an appropriate amount of solubilizing agent to dissolve the reaction reagent and maintain a certain solubility while making the reaction mainly react in a homogeneous phase. In this case, the reaction rate is further improved and the reaction is stably carried out, and the final reaction is more thorough, avoiding too many side reactions, and improving the conversion yield and product quality of the product. Commonly used organic solvents can be used as solubilizers for certain reactions, but in different reaction types, due to the complexity of chemical reactions, when different activators are used in combination with different solubilizers, there are sometimes huge differences in yield and product content. Some combinations of activators and solubilizers do not even work, making the reaction impossible. The present invention provides a preparation method that uses an effective and preferred combination of an activator and a solubilizer to improve the reaction efficiency.

[0025] In the present invention, in step 1) of the preparation method, the activator is selected from one or more of ammonium sulfate, ammonium chloride, calcium chloride, and calcium oxide; and the solubilizer is selected from one or more of water and dimethyl sulfoxide.

[0026] Although suitable solubilizers can increase the reaction rate, in the present invention, the technicians found in the experiment that the addition of solubilizers is not the more the better, and it is difficult to achieve the effect if too little solubilizer is added; after the addition of a certain amount of solubilizer, with the further addition of solubilizer, the reaction effect will not be linearly improved, but with the further addition of solubilizer, the reaction rate is no longer mentioned or even begins to decrease, and the by-products also increase, which may be related to the concentration of the reactants and the reaction rate. The technicians of the present invention also found that the amount of paraformaldehyde used in step 1) and the temperature and time of the reaction also have a great influence on the reaction. Increasing the amount, increasing the temperature and the reaction time will cause certain side reactions in the reaction; on the contrary, reducing the amount, lowering the temperature and reducing the reaction time will reduce the reaction efficiency, and incomplete reactions will also produce side reactions. Therefore, the reaction temperature and reaction time also play a key role in the quality of the reaction product in step 1) of the method of the present invention. The technicians of the present invention further optimized the reactant ratio and its economically suitable reaction temperature and reaction time through a large number of experiments on the basis of screening activators and solubilizers.

[0027] In one embodiment of the present invention, in step 1) of the preparation method, the suitable molar ratio of SM1: paraformaldehyde: activator: solubilizer is 1: (1.0-1.2): (0.01-0.05): (0.1-1.0); the reaction temperature is 20-60° C.; and the reaction time is 2-10 h.

[0028] In one embodiment of the present invention, in step 2) of the above-mentioned preparation method, the molar ratio of Int1:SM2 is (1.0-1.5):1; and the reaction temperature is 10-40°C.

[0029] In step 3) of the preparation method of the present invention, an oxidant is required to oxidize the intermediate Int2. Selecting a suitable oxidant and determining its dosage are very important steps for controlling side reactions. At the same time, the reaction temperature plays an important balancing role in the main reaction to generate the target product and the side reaction to generate a series of impurities. Low temperature slows down the reaction, causes incomplete reaction or fails to proceed smoothly, resulting in prolonged reaction time, and the long contact time between the chemical substances in the reaction system and the oxidant, thereby causing a corresponding increase in side reactions; high temperature accelerates the reaction, but is also likely to aggravate the occurrence of side reactions.

[0030] The technician of the present invention has selected the preferred oxidant and catalyst combination mode to realize oxidation reaction through series test.It will be appreciated by those skilled in the art that for the same reaction type, the effect of different reaction reagents, catalysts and reaction conditions on different reaction substrates is often unpredictable.For example, in chemical reactions, the change of the substituent on the reaction substrate may have a significant impact on the reaction, and even if the same reaction reagents, catalysts and reaction conditions are used, different reaction substrates may be affected in terms of reaction rate, reaction selectivity, reaction mechanism, product distribution, catalyst activity, solvent effect, thermodynamics and kinetic stability.Therefore, in organic synthesis, the technician often needs to consider various factors to design and verify the optimal reaction conditions that can obtain the desired product through experiments.

[0031] The method for preparing Int3 from Int2 in the present invention provides a preferred implementation scheme of an oxidation reaction with high efficiency and few side reactions. The directional oxidation is carried out by combining a preferred oxidant and a catalyst, which greatly reduces the generation of nitrogen oxide impurities generated by the oxidant, and at the same time can reduce the amount of oxidant used, thereby improving the conversion rate and quality.

[0032] In one embodiment of the present invention, in step 3) of the preparation method, the oxidant is one or more of tert-butyl perbenzoate, cumene hydroperoxide, and methyl ethyl ketone peroxide; the catalyst is one or more of sodium tungstate, ammonium tungstate, sodium molybdate, and ammonium molybdate.

[0033] In some embodiments, in step 3) of the preparation method described above, the molar ratio of Int2: oxidant: catalyst is 1: (1.2-2.5): (0.05-0.5).

[0034] In some embodiments, in step 3) of the above-mentioned preparation method, the reaction temperature is 20 to 80° C.; and the reaction time is 0.5 to 5 h.

[0035] In some embodiments, in step 4) of the above-mentioned preparation method, the reaction temperature is 90-120° C.; and the reaction time is 6-12 hours.

[0036] In some embodiments, in step 4) of the preparation method described above, the molar ratio of Int3: lithium chloride is 1:(4-7).

[0037] In some embodiments, in step 4) of the preparation method described above, the post-treatment method is that after the reaction is completed, the reaction solution is added dropwise to a hydrochloric acid solution at a temperature of 0 to 10° C. for crystallization, and the solid is separated from the reaction solution to obtain polytinorel.

[0038] Furthermore, in step 4) described in the above preparation method, a method for further purifying polytinol may be optionally included. The method for further purification is to pulp or recrystallize the polytinol solid in a solvent, and the preferred purification method is pulping. When the purity of the separated product is poor or the impurity content is slightly high, a method for further purifying the solid can be selected, and the pulping or recrystallization operation can be selected according to the purity of the product. The pulping method can be to stir the solid obtained by crystallization separation in 5-10 times (V / m, volume / mass) C1-C3 monohydric alcohol at room temperature or slightly elevated temperature for a certain period of time, and separate and dry the solid after pulping. The recrystallization method can be to add the polytinol solid obtained by crystallization separation to C1-C3 monohydric alcohol and heat it, and optionally dissolve all or most of the solid, and after the solution is cooled and crystallized, separate and dry the solid. The C1-C3 monohydric alcohol described above is methanol, ethanol, propanol, preferably ethanol. The amount of the C1-C3 monohydric alcohol is such that the recrystallized product is completely dissolved or mostly dissolved, and the amount is preferably 5-20 times (V / m, volume / mass), more preferably 5-15 times, and most preferably 5-10 times. The above-mentioned mostly dissolved means that more than 50% of the solids are dissolved, preferably more than 60% of the solids are dissolved, more preferably more than 70% of the solids are dissolved, further preferably more than 80% of the solids are dissolved, further preferably more than 90% of the solids are dissolved, and most preferably all of the solids are dissolved. The above-mentioned method of separating the solids is usually filtration or centrifugation, and the above-mentioned drying method can usually be carried out by vacuum drying or room temperature drying, and is carried out at a suitable temperature that does not change the product; the above-mentioned beating or recrystallization method can further remove a small amount of impurities in the product.

[0039] The term "optionally" in the present invention means that it can be selected or not.

[0040] The present invention uses 2-aminobenzenethiol and 3,5-dichloro-4-methoxybenzoyl chloride as starting materials for reaction, and has the following advantages: more complete reaction, less side reaction, and significantly improves the reaction efficiency, yield and product quality of the prior art.

[0041] 1) Under the dual effects of the optimal and quantitative activator and solubilizer, paraformaldehyde achieved unexpected results, its reaction activity was significantly improved, the reaction conversion rate and yield were greatly improved, and the quality of the intermediate was also significantly improved.

[0042] 2) The reaction conditions of each step are mild, the operation is simple, the power cost is greatly reduced, and it is suitable for industrial production;

[0043] 3) The oxidation reaction uses oxidants such as cumene hydroperoxide, which reduces the disadvantages of nitrogen oxides and other by-products that are easily produced by strong oxidants. At the same time, the use of catalysts makes the reaction directional, thereby improving the conversion rate and quality;

[0044] 4) The preparation method of the present invention has reliable process. Through the effective control of the reaction and operation of each step, the quality and yield of the intermediates in each step are systematically improved. The final obtained polytinol product has high purity, good stability and is not easy to degrade. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 : The amount of polytinol in Example 1 1 H-NMR spectrum;

[0046] Figure 2 : MS graph of dotinorex in Example 1; DETAILED DESCRIPTION

[0047] The technical solution of the present invention is now further described in conjunction with specific embodiments. These embodiments are merely exemplary and do not constitute any limitation to the scope of the present invention. For those skilled in the art, it is not necessary and is not possible to list all implementation methods exhaustively. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements fall within the scope of protection of the present invention. The experimental methods for which specific experimental conditions are not indicated in the following examples are generally carried out under conventional conditions or under the conditions recommended by the manufacturer.

[0048] Embodiment 1:

[0049] Add paraformaldehyde (7.20 g) to 90 ml of methanol, then add ammonium sulfate (0.317 g) and water (0.432 g), and stir at 20°C for 1 h. Add SM1 solution (dissolve SM1 (30.0 g) in 90 ml of methanol), control the temperature at 20°C, and stir at 20°C for 10 h. Add 200 ml of water to the reaction solution, concentrate under reduced pressure until there is almost no droplet, and then extract with 3×150 ml of dichloromethane, combine the dichloromethane phases, wash with 150 ml of 10% sodium chloride solution, dry the dichloromethane phase with anhydrous sodium sulfate, and concentrate to obtain a light yellow oil Int1 (28.87 g), with a yield of 87.8%.

[0050] Dissolve Int1 (20.06 g) in 100 ml of dichloromethane, add triethylamine (22.13 g), and add SM2 solution (SM2 (35.0 g) dissolved in 50 ml of dichloromethane) dropwise at a temperature of 0-10°C. After the addition, react at 10°C for 3 h. Concentrate the reaction solution under reduced pressure until there is almost no droplet, add 150 ml of anhydrous ethanol for crystallization, filter, and dry to obtain an off-white solid Int2 (40.42 g) with a yield of 81.3%.

[0051] Int2 (30.0 g) was dissolved in 120 ml of methanol, and sodium tungstate (1.30 g) was added, and the mixture was stirred at 20°C for 15 min, and tert-butyl perbenzoate (20.56 g) was added, and the mixture was stirred at 20°C for 5 h. 200 ml of 10% sodium sulfite solution was added to the reaction solution, and the mixture was concentrated under reduced pressure until there was almost no droplets. The residue was filtered, and the filter cake was slurried with 180 ml of ethanol, filtered, and dried to obtain an off-white solid Int3 (27.34 g) with a yield of 83.3%.

[0052] Int3 (20.0 g) was added to 100 ml of N, N-dimethylformamide to dissolve, and then lithium chloride (9.12 g) was added and reacted at 90°C for 12 h. The reaction solution was cooled to 5°C, and added dropwise to 400 ml of 5°C 1 mol / L hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake (purity 99.0%) was added to 160 ml of ethanol for slurrying for 1 h, filtered, and dried to obtain off-white solid polytinore (17.38 g), with a yield of 90.3%. Its H NMR spectrum is: 1 H NMR (600MHz, DMSO-d6): δ5.3492ppm (2H, s), δ7.4354ppm (1H, dd, J=7.44Hz), δ7.7699-7.7438ppm (3H, m), δ7.8995ppm (1H, d, J=7.47Hz), δ8.0331ppm (1H, d, J=8.34Hz), δ11.0183ppm (1H, brs). Its mass spectrum is: molecular ion peak [M-1] - The molecular weight of dotinorel is 355.96 (the exact molecular weight of dotinorel is 356.96).

[0053] Embodiment 2:

[0054] Add paraformaldehyde (7.20 g) to 90 ml of methanol, then add ammonium chloride (0.64 g) and dimethyl sulfoxide (18.73 g), and stir at 20°C for 1 h. Add SM1 solution (dissolve SM1 (30.0 g) in 90 ml of methanol), control the temperature at 60°C, and stir at 60°C for 10 h. Add 200 ml of water to the reaction solution, concentrate under reduced pressure until there is almost no droplet, and then extract with 3×150 ml of dichloromethane, combine the dichloromethane phases, wash with 150 ml of 10% sodium chloride solution, dry the dichloromethane phase with anhydrous sodium sulfate, and concentrate to obtain a light yellow oil Int1 (28.01 g), with a yield of 85.2%.

[0055] Dissolve Int1 (30.07 g) in 100 ml of dichloromethane, add triethylamine (22.13 g), and add SM2 solution (SM2 (35.0 g) dissolved in 50 ml of dichloromethane) dropwise at a temperature of 0-10°C. After the addition, react at 40°C for 3 h. Concentrate the reaction solution under reduced pressure until there is almost no droplet, add 150 ml of anhydrous ethanol for crystallization, filter, and dry to obtain an off-white solid Int2 (41.62 g) with a yield of 83.7%.

[0056] Int2 (30.0 g) was dissolved in 120 ml of methanol, and then ammonium tungstate (9.69 g) was added, and the mixture was stirred at 20°C for 15 min, and then 80% cumene hydroperoxide (41.93 g) was added, and the mixture was stirred at 80°C for 0.5 h. 200 ml of 10% sodium sulfite solution was added to the reaction solution, and the mixture was concentrated under reduced pressure until there was almost no droplets. The residue was filtered, and the filter cake was slurried with 180 ml of ethanol, filtered, and dried to obtain an off-white solid Int3 (27.37 g) with a yield of 83.4%.

[0057] Int3 (20.0 g) was added to 100 ml of N, N-dimethylformamide to dissolve, and then lithium chloride (15.94 g) was added and reacted at 120°C for 6 h. The reaction solution was cooled to 5°C, and added dropwise to 400 ml of 5°C 1 mol / L hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake (purity 99.3%) was added to 160 ml of ethanol and slurried for 1 h, filtered, and dried to obtain off-white solid polytinore (17.65 g) with a yield of 91.7%.

[0058] Embodiment 3:

[0059] Add paraformaldehyde (7.20 g) to 90 ml of methanol, then add calcium chloride (0.79 g) and water (2.16 g), and stir at 20°C for 1 h. Add SM1 solution (dissolve SM1 (30.0 g) in 90 ml of methanol), control the temperature at 40°C, and stir at 40°C for 10 h. Add 200 ml of water to the reaction solution, concentrate under reduced pressure until there is almost no droplet, and then extract with 3×150 ml of dichloromethane, combine the dichloromethane phases, wash with 150 ml of 10% sodium chloride solution, dry the dichloromethane phase with anhydrous sodium sulfate, and concentrate to obtain a light yellow oil Int1 (28.83 g), with a yield of 87.7%.

[0060] Dissolve Int1 (24.06 g) in 100 ml of dichloromethane, add triethylamine (22.13 g), and add SM2 solution (SM2 (35.0 g) dissolved in 50 ml of dichloromethane) dropwise at a temperature of 0-10°C. After the addition, react at 25°C for 3 h. Concentrate the reaction solution under reduced pressure until there is almost no droplet, add 150 ml of anhydrous ethanol for crystallization, filter, and dry to obtain an off-white solid Int2 (42.56 g) with a yield of 85.6%.

[0061] Int2 (30.0 g) was dissolved in 120 ml of methanol, and sodium molybdate (5.45 g) was added, and the mixture was stirred at 20°C for 15 min, and then 50% methyl ethyl ketone peroxide (66.73 g) was added, and the mixture was stirred at 50°C for 3 h. 200 ml of 10% sodium sulfite solution was added to the reaction solution, and the mixture was concentrated under reduced pressure until there was almost no droplets. The residue was filtered, and the filter cake was slurried with 180 ml of ethanol, filtered, and dried to obtain an off-white solid Int3 (26.75 g) with a yield of 81.5%.

[0062] Int3 (20.0 g) was added to 100 ml of N, N-dimethylformamide to dissolve, and then lithium chloride (12.53 g) was added and reacted at 105°C for 9 h. The reaction solution was cooled to 5°C, and added dropwise to 400 ml of 5°C 1 mol / L hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake (purity 99.1%) was added to 160 ml of ethanol and slurried for 1 h, filtered, and dried to obtain off-white solid polytinore (17.50 g), with a yield of 90.9%.

[0063] Embodiment 4:

[0064] Add paraformaldehyde (7.20 g) to 90 ml of methanol, then add calcium oxide (0.40 g) and water (2.16 g), and stir at 20°C for 1 h. Add SM1 solution (dissolve SM1 (30.0 g) in 90 ml of methanol), control the temperature at 40°C, and stir at 40°C for 10 h. Add 200 ml of water to the reaction solution, concentrate under reduced pressure until there is almost no droplet, and then extract with 3×150 ml of dichloromethane, combine the dichloromethane phases, wash with 150 ml of 10% sodium chloride solution, dry the dichloromethane phase with anhydrous sodium sulfate, and concentrate to obtain a light yellow oil Int1 (29.00 g), with a yield of 88.2%.

[0065] Dissolve Int1 (24.06 g) in 100 ml of dichloromethane, add triethylamine (22.13 g), and add SM2 solution (SM2 (35.0 g) dissolved in 50 ml of dichloromethane) dropwise at a temperature of 0-10°C. After the addition, react at 25°C for 3 h. Concentrate the reaction solution under reduced pressure until there is almost no droplet, add 150 ml of anhydrous ethanol for crystallization, filter, and dry to obtain an off-white solid Int2 (42.81 g) with a yield of 86.1%.

[0066] Int2 (30.0 g) was dissolved in 120 ml of methanol, and ammonium molybdate (5.18 g) was added, and the mixture was stirred at 20°C for 15 min, and tert-butyl perbenzoate (30.83 g) was added, and the mixture was stirred at 50°C for 3 h. 200 ml of 10% sodium sulfite solution was added to the reaction solution, and the mixture was concentrated under reduced pressure until there was almost no droplets. The residue was filtered, and the filter cake was slurried with 180 ml of ethanol, filtered, and dried to obtain an off-white solid Int3 (28.39 g) with a yield of 86.5%.

[0067] Int3 (20.0 g) was added to 100 ml of N, N-dimethylformamide to dissolve, and then lithium chloride (12.53 g) was added and reacted at 105°C for 9 h. The reaction solution was cooled to 5°C, and added dropwise to 400 ml of 5°C 1 mol / L hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake (purity 99.5%) was added to 160 ml of ethanol and slurried for 1 h, filtered, and dried to obtain off-white solid polytinore (17.69 g), with a yield of 91.9%.

[0068] Embodiment 5:

[0069] Add paraformaldehyde (7.20 g) to 90 ml of methanol and stir at 20°C for 1 h. Add SM1 solution (dissolve SM1 (30.0 g) in 90 ml of methanol) dropwise, control the temperature at 40°C, and stir at 40°C for 10 h. Add 200 ml of water to the reaction solution, concentrate under reduced pressure until there is almost no droplet, and then extract with 3×150 ml of dichloromethane, combine the dichloromethane phases, wash with 150 ml of 10% sodium chloride solution, dry the dichloromethane phase with anhydrous sodium sulfate, and concentrate to obtain a light yellow oil Int1 (26.04 g) with a yield of 79.2%.

[0070] Dissolve Int1 (24.06 g) in 100 ml of dichloromethane, add triethylamine (22.13 g), and add SM2 solution (SM2 (35.0 g) dissolved in 50 ml of dichloromethane) dropwise at a temperature of 0-10°C. After the addition, react at 25°C for 3 h. Concentrate the reaction solution under reduced pressure until there is almost no droplet, add 150 ml of anhydrous ethanol for crystallization, filter, and dry to obtain an off-white solid Int2 (41.81 g) with a yield of 84.1%.

[0071] Int2 (30.0 g) was dissolved in 120 ml of methanol, and tert-butyl perbenzoate (30.83 g) was added, and stirred at 50°C for 3 h. 200 ml of 10% sodium sulfite solution was added to the reaction solution, and the mixture was concentrated under reduced pressure until there was almost no droplets. The residue was filtered, and the filter cake was slurried with 180 ml of ethanol, filtered, and dried to obtain an off-white solid Int3 (25.38 g) with a yield of 77.3%.

[0072] Int3 (20.0 g) was added to 100 ml of N, N-dimethylformamide to dissolve, and then lithium chloride (12.53 g) was added and reacted at 105°C for 9 h. The reaction solution was cooled to 5°C, and added dropwise to 400 ml of 5°C 1 mol / L hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake (purity 90.6%) was added to 160 ml of ethanol and slurried for 1 h, filtered, and dried to obtain off-white solid polytinore (17.20 g), with a yield of 89.4%.

[0073] Comparative Example 1 (prepared with reference to CN201080042866.9):

[0074] 37% formalin (5.2 ml) was diluted with water (80 ml), and diisopropyl ether (80 ml) and 2-aminobenzenethiol (7.84 g) were added, and stirred at room temperature for 0.5 h. The organic phase was separated, and the aqueous phase was extracted with diisopropyl ether. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Int1 with a yield of 75.5%.

[0075] Toluene (170 ml), N,N-dimethylformamide (5 drops), and thionyl chloride (6 ml) were added to 3,5-dichloro-4-methoxybenzoic acid (8.81 g), and the mixture was stirred at 60°C for 16 h. The solvent was removed by concentration under reduced pressure, and 3,5-dichloro-4-methoxybenzoyl chloride was obtained by azeotropy with toluene. The above-mentioned Int1 was dissolved in chloroform (50 ml), and triethylamine (17.4 ml) and 3,5-dichloro-4-methoxybenzoyl chloride were added, and the mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure, and water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, 1N sodium hydroxide, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Int2 with a yield of 67.4%.

[0076] Dissolve Int2 in chloroform (230 ml), add 70% m-chloroperbenzoic acid (43.25 g) at 0°C, stir at room temperature for 20 h, and neutralize with 10% sodium thiosulfate. Concentrate under reduced pressure to remove the solvent, add 1N sodium hydroxide, and extract with ethyl acetate. The organic phase is washed with 1N sodium hydroxide and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to remove the solvent to obtain Int3 with a yield of 72.1%.

[0077] Int3 (1.0 g) was dissolved in N, N-dimethylformamide (5 ml), lithium chloride (0.57 g) was added, and the mixture was stirred at 130°C for 2 h. 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was dissolved by heating with ethanol, and then recrystallized, filtered, and dried to obtain dotinorel, with a yield of 86.7%.

[0078] Test Example 1: The products prepared in Examples 1-5 and Comparative Example 1 were tested, and the test results are shown in the following table:

[0079]

[0080] Test Example 2: The stability of the dotinorex obtained in Examples 1-5 and Comparative Example 1 was studied. The test results are shown in the following table (the stability study conditions are 40°C ± 2°C, RH 75% ± 5%):

[0081]

[0082] It can be seen from the results of the test examples that in Examples 1-4 of the present invention, the purity and yield of the products obtained in each step are relatively high, and the purity of the obtained polytinol is also kept stable in the stability study; in addition, in the preparation method of the present invention, when polytinol is synthesized, the purity of the obtained polytinol crude filter cake reaches more than 99%, which basically meets the requirements for pharmaceutical use, and the purity can be further improved after the crude product is purified by simple pulping.

[0083] The outstanding contribution of the present invention is firstly to provide a method for preparing polytinol. Based on the existing synthetic route, the method obtains a preparation method with high product purity and good stability through design and experimental exploration and verification, which is more suitable for large-scale industrial production.

Claims

1. A method for preparing polytinoride, characterized in that: The chemical reaction equation of the preparation method is as follows: The preparation method comprises the following steps: Step 1): SM1 and paraformaldehyde undergo a cyclization reaction in the presence of an activator and a solubilizer to obtain Int1; Step 2): Int1 and SM2 undergo substitution reaction to obtain Int2; Step 3): Int2 is subjected to an oxidation reaction with an oxidant in the presence of a catalyst to obtain Int3; Step 4): Int3 is subjected to a demethylation reaction with lithium chloride to obtain polytinorethoxylate.

2. The preparation method according to claim 1, characterized in that: In the step 1), the cyclization reaction is performed by mixing paraformaldehyde in a solvent with an activator and a solubilizer, and then adding a solution of SM1 thereto; preferably, in the step 1), the cyclization reaction is performed by mixing paraformaldehyde in a solvent with an activator and a solubilizer, and then adding a solution of SM1 thereto; after the reaction is completed, water is added to the reaction solution, and the reaction solution is concentrated under reduced pressure until there is substantially no droplets, and then extracted with dichloromethane, and the organic phase is washed with a sodium chloride solution and concentrated to dryness; the solvent is a C1-C3 lower monohydric alcohol, preferably methanol and ethanol, and more preferably methanol.

3. The preparation method according to claim 1 or 2, characterized in that: In step 1), the activator is selected from one or more of ammonium sulfate, ammonium chloride, calcium chloride, and calcium oxide; and the solubilizer is selected from one or more of water and dimethyl sulfoxide.

4. The preparation method according to any one of claims 1 to 3, characterized in that: In step 1), the molar ratio of SM1: paraformaldehyde: activator: solubilizer is 1: (1.0-1.2): (0.01-0.05): (0.1-1.0); the reaction temperature is 20-60° C.; and the reaction time is 2-10 h.

5. The preparation method according to claim 1, characterized in that: In step 2), the molar ratio of Int1:SM2 is (1.0-1.5):1; and the reaction temperature of the reaction is 10-40°C.

6. The preparation method according to claim 1, characterized in that: In step 3), the oxidant is one or more of tert-butyl perbenzoate, isopropylbenzene hydroperoxide, and methyl ethyl ketone peroxide; the catalyst is one or more of sodium tungstate, ammonium tungstate, sodium molybdate, and ammonium molybdate; the molar ratio of Int2: oxidant: catalyst is 1: (1.2-2.5): (0.05-0.5); the reaction temperature is 20-80°C; and the reaction time is 0.5-5h.

7. The preparation method according to claim 1, characterized in that: In step 4), the molar ratio of Int3: lithium chloride is 1:(4-7); the reaction temperature is 90-120° C.; and the reaction time is 6-12 hours.

8. The preparation method according to claim 1 or 7, characterized in that: In the step 4), after the reaction is completed, the reaction solution is added dropwise to a hydrochloric acid solution at a temperature of 0 to 10° C. for crystallization, and the solid is separated from the reaction solution to obtain polytinol.

9. The preparation method according to claim 1, characterized in that: In the step 1), the method of the cyclization reaction is that paraformaldehyde is first mixed with an activator and a solubilizer in a solvent, and then a solution of SM1 is added dropwise thereto; after the reaction is completed, water is added to the reaction solution, and the reaction solution is concentrated under reduced pressure until there is substantially no droplet, and then extracted with dichloromethane, and the organic phase is washed with a sodium chloride solution and concentrated to dryness; the solvent is a C1-C3 lower monohydric alcohol, preferably methanol and ethanol, and more preferably methanol; In the step 2), the substitution reaction method is to dissolve Int1 in dichloromethane, add triethylamine, and add SM2 solution dropwise at a controlled temperature. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, ethanol is added for crystallization, and filtered and dried to obtain Int2; In the step 3), the oxidation reaction method is to dissolve Int2 in a solvent, add a catalyst, add an oxidant under temperature control, add a sodium sulfite solution to the reaction solution after the reaction is completed, concentrate under reduced pressure, filter the residue, slurry the filter cake with ethanol, filter and dry to obtain Int3; the solvent is selected from methanol and ethanol, preferably methanol; In the step 4), the method of the demethylation reaction is to dissolve Int3 in N,N-dimethylformamide, add lithium chloride, and heat the reaction. After the reaction is completed, the reaction solution is cooled and added dropwise to a hydrochloric acid aqueous solution for crystallization, filtered, and the filter cake is dried to obtain polytinore.

10. The preparation method according to any one of claims 1, 8 and 9, characterized in that: In the step 4), a method for further purifying polytinorethinol may be optionally included; the method for further purification is slurrying or recrystallizing the polytinorethinol solid in a solvent, and the preferred purification method is slurrying; the solvent is selected from methanol, ethanol, propanol, preferably ethanol.

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