Method for preparing hemiacetal from monoether

Abstract

The invention belongs to the field of fine chemicals, and specifically discloses a method for preparing hemiacetal from monoether, comprising the following steps: using monoether as a raw material, and carrying out a high-temperature isomerization reaction under the action of a catalyst; cooling the obtained reaction mixture containing monoether and hemiacetal to 80±10°C, and then adding toluene and sodium hydroxide aqueous solution for alkali washing and extraction, and obtaining an organic phase I through layering; washing the organic phase I with water, and layering at rest to obtain an organic phase II; separating toluene from the organic phase II through atmospheric distillation to obtain a crude hemiacetal; adding a weak base protective agent to the crude hemiacetal for vacuum distillation, thereby obtaining monoether and hemiacetal respectively. The method for preparing hemiacetal from monoether of the invention has the characteristics of simple process, high conversion rate and excellent quality, and not only solves the problem of the outlet of byproducts (monoether), but also can significantly reduce the production cost of hemiacetal, and has good economic and social benefits.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, and specifically relates to a synthesis and purification technology of fine pharmaceutical intermediates, and in particular to a hemiacetal synthesis method. Background Art

[0002] Hemiacetal is a key intermediate in the synthesis of amprolium hydrochloride, accounting for about 30% of the cost of raw materials for the synthesis of amprolium hydrochloride. Therefore, the production cost of hemiacetal directly affects the production cost of amprolium hydrochloride.

[0003] The production process of hemiacetal uses acrylonitrile as raw material and reacts with sodium methoxide to obtain methoxypropionitrile first, and then reacts with carbon monoxide in the environment of methyl formate and sodium methoxide to obtain an intermediate. The intermediate and dimethyl sulfate undergo methylation reaction to obtain the main product hemiacetal. However, in the reaction system and post-treatment process, hemiacetal will isomerize to form monoether under acidic or alkaline conditions, or produce impurities such as acetal due to side reactions. The reaction formula is as follows:

[0004]

[0005] In the above reaction formula: 1 is an intermediate, 2 is hemiacetal (3-methoxy-2-(methoxymethyl)acrylonitrile), 3 is monoether (2-dimethoxymethylacrylonitrile), and 4 is acetal (3,3-dimethoxy-2-(methoxymethyl)propionitrile).

[0006] Since hemiacetal and monoether are isomers, in an acidic system, the monoether will continue to rise during the heating of hemiacetal, that is, the hemiacetal will gradually convert into monoether during the distillation process. When evaporating under alkaline conditions (sufficient triethylamine), the monoether will gradually transfer to the hemiacetal, but when the molar ratio of hemiacetal to monoether is close to 1:1, the mutual conversion stops and reaches an equilibrium state.

[0007] However, both hemiacetal and monoether will react with butyrimidine hydrochloride. The molar ratio of hemiacetal and butyrimidine is 1:1 to synthesize the key intermediate cyclized pyrimidine of amprolium hydrochloride, while the molar ratio of monoether and butyrimidine is 1:2, which results in the waste of butyrimidine hydrochloride and forms more pollutants, consuming a large amount of raw materials to synthesize other impurities. Therefore, the content of monoether in the hemiacetal finished product needs to be strictly controlled to reduce the subsequent production cost and improve the raw material conversion rate.

[0008] In the production process of hemiacetal, in addition to reducing the generation of monoether by controlling the reaction conditions, the monoether is separated from the finished hemiacetal product by distillation (by vacuum distillation). The content of the obtained monoether (as a by-product of the production of hemiacetal) is >90%. Since the monoether has no other use for the time being, it can only be disposed of as hazardous waste, resulting in a serious waste of resources. Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a method for preparing hemiacetal from monoether, which has simple process, high product yield and can reduce cost.

[0010] In order to solve the above technical problems, the present invention provides a method for preparing hemiacetal from monoether, comprising the following steps:

[0011] 1) Using monoether as raw material, in the presence of a catalyst, an isomerization reaction is carried out at a high temperature of 100±5°C (preferably 100±2°C) for 3 to 5 hours (preferably 3.5 to 5 hours) to obtain a reaction mixture containing monoether and hemiacetal;

[0012] The catalyst is concentrated sulfuric acid (mass concentration 98% concentrated sulfuric acid), and the catalyst is 0.8-1.2% (preferably 1%) of the weight of the monoether;

[0013] 2) first cooling the reaction mixture containing monoether and hemiacetal obtained in step 1) to 80±10° C., then adding toluene and sodium hydroxide aqueous solution for alkali washing and extraction, and obtaining organic phase I (located at the upper layer) by layering;

[0014] The mass ratio of toluene to sodium hydroxide aqueous solution is 1:0.9-1.1 (preferably 1:1);

[0015] The mass concentration of the sodium hydroxide aqueous solution is 2.5-3.5% (preferably 3%);

[0016] Toluene: monoether in step 1) = 1:1.6-1.8 weight ratio;

[0017] Note: Perform alkali washing and extraction under stirring (time is 30±5min), then turn off the stirring, let it stand and separate into layers to obtain organic phase I;

[0018] 3) Wash the organic phase I with water (production water), and let it stand for stratification to obtain the organic phase II (located in the upper layer);

[0019] 4) separating toluene from the organic phase II by atmospheric distillation (i.e., separating toluene from the material) to obtain a crude hemiacetal product;

[0020] 5) adding a weak base protective agent to the crude hemiacetal product to carry out vacuum distillation to obtain monoether and hemiacetal respectively;

[0021] The weak alkaline protective agent is triethanolamine, and the triethanolamine is 2.5-3.5% (preferably 3%) of the weight of the crude hemiacetal product.

[0022] As an improvement of the method for preparing hemiacetal from monoether of the present invention: the monoether obtained in step 5) is returned to step 1) for recycling as a raw material.

[0023] As a further improvement of the method for preparing hemiacetal from monoether of the present invention: the mass ratio of water (production water) in step 3) to toluene in step 2) is 1:0.9-1.1 (preferably 1:1).

[0024] As a further improvement of the method for preparing hemiacetal from monoether of the present invention: in step 5), the vacuum distillation is carried out in a distillation tower, the temperature of the distillation tower bottom does not exceed 170° C., the vacuum degree is 5-10 Kpa, the reflux ratio is 3.5-4.5:1 (i.e., the volume ratio of the fraction returned to the distillation tower: the fraction discharged from the distillation tower = 3.5-4.5:1, preferably 4:1), and the fractions are collected in sections according to the tower top temperature:

[0025] The fraction with top temperature of 10-50°C is mainly toluene and low-boiling impurities (low-boiling unknown single impurities);

[0026] The fraction with a top temperature of 50-80° C., whose main component is monoether, is returned to step 1) for recycling;

[0027] The fraction with a top temperature of 80-110° C. is hemiacetal as a product (the hemiacetal content is greater than 96%, and the monoether content is less than 1%. The above % is mass %).

[0028] The present invention has found through a large number of experimental studies that monoether can be isomerized and converted into hemiacetal in a concentrated sulfuric acid system at high temperature. The present invention has investigated the effects of different catalyst and solvent dosages on the reaction to obtain the optimal process conditions.

[0029] The invention provides a method for preparing hemiacetal from monoether. The monoether can be isomerized and converted into hemiacetal in a concentrated sulfuric acid system at high temperature, and then a crude hemiacetal product is obtained by alkali washing, extraction, and desolventization (normal pressure distillation); the crude hemiacetal product is subjected to vacuum distillation under a weak base protective agent to separate the monoether and the hemiacetal. The monoether can be returned to the above step 1) for recycling, and the hemiacetal is used for the production of amprolium hydrochloride.

[0030] The method for preparing hemiacetal from monoether of the present invention has the characteristics of simple process, high conversion rate and excellent quality, etc., which not only solves the problem of outlet of byproduct (monoether), but also can significantly reduce the production cost of hemiacetal, and has good economic and social benefits. The present invention adds a synthetic route that reduces raw material cost and is more concise to the synthesis of hemiacetal, and the obtained hemiacetal can be used for the synthesis of amprolium hydrochloride in a conventional manner. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The specific implementation modes of the present invention are further described in detail below with reference to the accompanying drawings.

[0032] Figure 1 It is a process flow chart of the present invention. DETAILED DESCRIPTION

[0033] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0034] The raw materials of the present invention are:

[0035] 1. Monoether is a by-product of the production of hemiacetal, obtained by vacuum distillation, with a content of >90%.

[0036] 2. Concentrated sulfuric acid, 98%, industrial grade, commercially available.

[0037] 3. Toluene, technical grade, commercially available.

[0038] 4. Triethanolamine, technical grade, commercially available.

[0039] 5. Liquid caustic soda, 30% sodium hydroxide, industrial grade, commercially available.

[0040] 6. DBU (1,8-diazabicycloundec-7-ene), chemically pure, commercially available.

[0041] 7. p-Toluenesulfonic acid, chemically pure, commercially available.

[0042] 8. Sodium methoxide, technical grade, 30.21%, commercially available.

[0043] 9. Butyrimidine hydrochloride, technical grade, 97.32%, commercially available.

[0044] 10. Liquid caustic soda, 30% sodium hydroxide, industrial grade, commercially available.

[0045] The following experiments were conducted during the invention process:

[0046] The raw material monoether used in all the following experiments 1 to 8 is a by-product of the production of hemiacetal, obtained by vacuum distillation, with a content of 98.6%.

[0047] Experiment 1, monoether + DBU (1,8-diazabicycloundec-7-ene)

[0048] The monoether and DBU were reacted at different temperatures, and the results are shown in Table 1, but they are not the results expected by the present invention.

[0049] Table 1. Experimental data of monoether + DBU under different reaction temperature conditions

[0050]

[0051] As can be seen from Table 1, monoether reacts with DBU. Monoether can react to less than 3% under strong alkalinity, but polymerization reaction mainly occurs, and very little acetal and hemiacetal are generated. The material after the reaction is very viscous, indicating that strong alkalinity DBU is not suitable for preparing hemiacetal from monoether.

[0052] Experiment 2: Monoether + DBU + Methanol

[0053] The present invention analyzes the reason for the failure of Experiment 1 (too strong alkalinity) and intends to optimize the reaction conditions. Therefore, methanol is added to the reaction system and then reflux reaction is performed. The reaction system and reaction conditions are as follows:

[0054] 10.0g monoether + 0.1g DBU + 20mL methanol, after reaction at 80℃, evaporate the methanol and add 6.0g toluene, and reflux at 100℃ for different reaction times (such as 2.5h, 6h, 9h, 24h).

[0055] The reaction results are shown in Table 2 below:

[0056] Table 2. Monoether + 1% DBU + methanol

[0057]

[0058]

[0059] Note: The gas chromatographic peak interval of impurity 1 is 2.1 min.

[0060] From the results of Experiment 2, it can be seen that the monoether generates acetal with a content of about 80% under the catalytic action of DBU in methanol as solvent; therefore, it can be known that the monoether and 1% DBU in methanol or toluene solvent cannot obtain the expected results of the present invention.

[0061] Experiment 3: Monoether + concentrated sulfuric acid + methanol

[0062] The reaction system and reaction conditions are shown in Table 3 below.

[0063] From the experimental results, monoether can be directly converted into hemiacetal under the catalysis of concentrated sulfuric acid in methanol solvent. From reaction numbers 1, 2, 3 and 4, it can be seen that under the same reaction conditions, when the amount of monoether added exceeds 4% concentrated sulfuric acid, the monoether will be converted into acetal, which is not conducive to the main reaction. From reaction number 7, it can be seen that when the amount of monoether added is less than 1% concentrated sulfuric acid, the reaction yield is low; from reaction numbers 5 and 6, it can be seen that the amount of methanol added has little conversion of monoether to hemiacetal. From reaction numbers 8 and 9, it can be seen that when there is no methanol and the reaction is at 120°C, the hemiacetal content is 71.4%, but the material is relatively viscous and a small amount of polymer is produced. Therefore, according to the comparison of reaction numbers 1 to 9, the appropriate reaction conditions should be the reaction of monoether with 2% concentrated sulfuric acid at 100°C without adding methanol solvent.

[0064] Table 3, monoether + methanol + concentrated sulfuric acid

[0065]

[0066]

[0067] Experiment 4: Monoether + p-toluenesulfonic acid

[0068] The reaction system and reaction conditions are shown in Table 4 below.

[0069] From the experimental results, monoether can be directly converted to hemiacetal under the catalysis of p-toluenesulfonic acid, and the conversion rate is above 45%. From reaction numbers 12 and 17, it can be seen that under the same reaction conditions, the conversion rates of monoether to hemiacetal are similar when 1% and 2% p-toluenesulfonic acid are added. As the p-toluenesulfonic acid content increases, the conversion rate decreases instead. Therefore, 1% p-toluenesulfonic acid is more suitable; from reaction numbers 10 and 11, it can be seen that when 1 times the amount of methanol of monoether is added to the reaction system, the amount of monoether converted to hemiacetal decreases, which is not conducive to the reaction. From reaction numbers 12, 15 and 16, it can be seen that the higher the temperature, the lower the hemiacetal content, and the more impurities there are during the reaction. The reaction temperature of 100°C is the best. Therefore, the optimal reaction condition is the reaction of monoether with 1% p-toluenesulfonic acid at 100°C. Compared with concentrated sulfuric acid, the use of p-toluenesulfonic acid as a catalyst has a high hemiacetal conversion rate and a 1% less catalyst dosage.

[0070] Table 4, monoether + p-toluenesulfonic acid

[0071]

[0072]

[0073] The reaction was carried out according to the optimal reaction conditions set above, and the obtained product was subsequently treated in order to obtain qualified hemiacetal. The inventors conducted 4 groups of amplification experiments (300 g of monoether, 3 g of p-toluenesulfonic acid, and reacted at 100° C. for 3.5 h), and the post-treatment method was specifically as follows:

[0074] 1. (Reaction No. 18) Add 250 ml of 0.5% sodium hydroxide solution, stir for 30 minutes, let the liquid stand and separate, and distill the organic phase under reduced pressure.

[0075] 2. (Reaction No. 19) Add 250 ml of 3% sodium hydroxide solution and 300 g of toluene, stir for 30 min, let the liquid stand, add 3.5 g of triethanolamine to the organic phase, and then distill under reduced pressure.

[0076] 3. (Reaction No. 20) 3.5 g of triethylamine was directly added to the reaction system, followed by vacuum distillation.

[0077] 4. (Reaction No. 21), add 250 ml of 5% sodium hydroxide solution and 300 g of toluene, stir for 30 minutes, let the liquid stand, add 3.5 g of triethylamine to the organic phase, and then distill under reduced pressure.

[0078] The parameters of the reduced pressure distillation are as follows: vacuum degree -0.098MPa, temperature 170°C.

[0079] That is, the post-processing data is shown in Table 5.

[0080] According to reaction number 20, triethylamine is directly added without washing with alkaline solution and the distillation is reduced, and the hemiacetal is converted into monoether during the distillation process; according to reaction number 18, alkaline solution is added for washing without adding triethylamine, and the hemiacetal is converted into monoether during the distillation process; according to reaction number 21, 250ml of 5% sodium hydroxide solution and 300g of toluene are added, stirred for 30min, and the liquid is separated at rest, and 3.5g of triethylamine is added to the organic phase, and then reduced pressure distillation is performed, and the conversion of hemiacetal to monoether during the distillation process becomes less; according to reaction number 19, 250ml of 3% sodium hydroxide solution and 300g of toluene are added, stirred for 30min, and the liquid is separated at rest, and 3.5g of triethanolamine (inhibitor) is added to the organic phase, and then reduced pressure distillation is performed, and the conversion of hemiacetal to monoether during the distillation process becomes less.

[0081] Table 5. Post-treatment data of monoether + p-toluenesulfonic acid

[0082]

[0083]

[0084] As can be seen from the results in Table 5, the hemiacetal content in the reaction product obtained by reacting monoether with p-toluenesulfonic acid is about 50%, but no matter which post-treatment method is adopted, satisfactory results cannot be obtained (the hemiacetal content of the target product is less than 30%), indicating that p-toluenesulfonic acid is not suitable as a catalyst for preparing hemiacetal from monoether.

[0085] Experiment 5: Monoether + concentrated sulfuric acid

[0086] Based on the preliminary results of Experiment 3 (monoether + concentrated sulfuric acid + methanol), concentrated sulfuric acid was directly added to the system without adding solvent methanol during normal pressure stirring and then the temperature was raised. The reaction results at different sulfuric acid addition ratios are shown in Table 6 (three replicates were set).

[0087] Table 6, Monoether + concentrated sulfuric acid experiment

[0088]

[0089] Based on the experimental data in Table 6 above, and in order to reduce the amount of substances introduced into the reaction system, the optimal conditions for the subsequent monoether conversion to hemiacetal test are monoether + 1% concentrated sulfuric acid at 100°C for reflux reaction for 3.5h.

[0090] Experiment 6: Material treatment experiment after the reaction of monoether + 1% concentrated sulfuric acid

[0091] Four groups of experiments in Experiment 5 (Table 6) were post-processed, and the specific post-processing methods were as follows:

[0092] 1. (Reaction No. 60) To the product of "Reaction No. 60" in Table 6, add 300 g of toluene and 200 ml of 1% NaOH aqueous solution for washing, and then add 200 ml of water and 3.5 g of triethylamine to the organic phase obtained by static separation for washing, and the organic phase obtained by separation is distilled under reduced pressure.

[0093] 2. (Reaction No. 61) To the product of "Reaction No. 61" in Table 6, add 300 g of toluene and 200 ml of 3% NaOH aqueous solution for washing, then add 200 ml of water and 3.5 g of triethylamine to the organic phase obtained by static separation for washing, and the organic phase obtained by separation is distilled under reduced pressure.

[0094] 3. (Reaction No. 65) To the product of "Reaction No. 65" in Table 6, add 300 g of toluene and 200 ml of 3% NaOH aqueous solution for washing, then add 200 ml of water and 3.5 g of triethylamine to the organic phase obtained by static separation for washing, then add 4 g of triethylamine to the organic phase obtained by separation, and then distill under reduced pressure.

[0095] 4. (Reaction No. 66) To the product of "Reaction No. 66" in Table 6, add 300 g of toluene and 200 ml of 3% NaOH aqueous solution for washing, then add 200 ml of water and 3.5 g of triethylamine to the organic phase obtained by static separation for washing, then add 6 g of triethylamine to the organic phase obtained by separation, and then distill under reduced pressure.

[0096] The parameters of the reduced pressure distillation are as follows: vacuum degree -0.098MPa, temperature 170°C.

[0097] The operation may be performed with reference to steps 2 to 5 of Example 1 below.

[0098] The experimental results are shown in Table 7. During the experiment, it was found that the addition of triethylamine in any process would cause the hemiacetal-monoether equilibrium reaction in the system to proceed in the direction of monoether, that is, the hemiacetal was converted back to monoether during the de-evaporation process.

[0099] Table 7, Monoether + 1% concentrated sulfuric acid reaction material treatment experiment 1

[0100] Reaction number 60 61 65 66 Feeding / g 300 300 300 300 Distilled fraction / g 251.4 242.3 287.04 240.3 Fraction ratio / % 83.8 80.77 95.68 80.1 Monoether content of fraction / % 68.54 41.14 55.41 66.6 Acetal content of fraction / % 1.79 5.69 1.85 2.13 Hemiacetal content of fraction / % 23.27 27.19 36.18 26.27

[0101] It can be seen from the experimental data in Table 7 that the introduction of triethylamine into the system after the reaction is completed will cause the equilibrium to proceed to the monoether. It is speculated that the hemiacetal-monoether equilibrium reaction is similar to the enol interconversion, and there are acidic mechanisms and alkaline mechanisms. The driving force of the alkaline mechanism is that the base pulls out the hydrogen on the hemiacetal. Triethylamine is not very alkaline, but it has the ability to pull out hydrogen after reaching a certain concentration. Therefore, a base with the ability to pull out hydrogen, such as triethylamine, provides the conditions for the alkaline mechanism to trigger the equilibrium reaction after entering the system, and the dominant product of the reaction under the alkaline mechanism is the monoether.

[0102] During the invention process, it was found that hemiacetal with a purity of 95% can tolerate a triethylamine concentration of 1% under the condition of 100° C. and normal pressure for 3.5 hours, and the addition of triethylamine exceeding 1% triggers an alkali mechanism equilibrium reaction.

[0103] Experiment 7: Material treatment after the reaction of monoether + 1% concentrated sulfuric acid Experiment 2

[0104] The specific post-processing method is:

[0105] 1. (Reaction No. 59) To the product of "Reaction No. 59" in Table 6, add 300 g of toluene and 200 ml of 3% NaOH aqueous solution for washing, and then add 200 ml of water to the organic phase obtained by static separation for washing, and the organic phase obtained by separation is distilled under reduced pressure.

[0106] 2. (Reaction No. 86) To the product of "Reaction No. 86" in Table 6, add 300 g of toluene and 200 ml of 3% NaOH aqueous solution for washing, then add 200 ml of water to the organic phase obtained by static separation for washing, add 6 g of triethanolamine (2% ratio) to the organic phase obtained by separation and perform reduced pressure distillation.

[0107] 3. (Reaction No. 88) To the product of "Reaction No. 88" in Table 6, add 300 g of toluene and 200 ml of 3% NaOH aqueous solution for washing, and then add 200 ml of water to the organic phase obtained by static separation for washing. After distilling the organic phase obtained by separation to remove toluene, add 6 g of triethanolamine (2% ratio) and then distill under reduced pressure.

[0108] The parameters of the reduced pressure distillation are as follows: vacuum degree -0.098MPa, temperature 170°C.

[0109] The operation may be performed with reference to steps 2 to 5 of Example 1 below.

[0110] In table 8, reaction number 59 is a control group, and no substance is added in the post-processing process. Compared with adding triethylamine in the post-processing process, no addition in the post-processing process will also cause the system to react in the steam reduction process. The equilibrium is carried out to the monoether, and the system is weakly acidic. Therefore, post-processing needs to add an appropriate amount of alkaline substances, considering that triethanolamine is a kind of viscous liquid substance with weak alkalinity and does not have the ability to extract hydrogen, and triethanolamine has a high boiling point. The inventor has done a comparative experiment, and the raw material is a high-purity hemiacetal 100g (monoether 0.32% acetal 3.21% hemiacetal 88.38%) of the distillation fraction, and triethanolamine is added to stir 3.5h at 100°C of condensation reflux under normal pressure, and then distilled under reduced pressure to 240°C without fraction, and experiments have shown that triethanolamine is added to the workshop hemiacetal directly to reduce steaming without side reactions and without changing the system reaction equilibrium. Consider using triethanolamine to replace triethylamine to add in the steam reduction process, and the experimental results are shown in table 8, No. 86 and No. 88 experiments.

[0111] Table 8, Monoether + 1% concentrated sulfuric acid reaction material treatment experiment 2

[0112]

[0113]

[0114] The conversion of monoether to hemiacetal can be carried out in both acidic and alkaline conditions, and acidic conditions have more advantages than alkaline hemiacetal structures. Therefore, the experiment adopts the addition of concentrated sulfuric acid or p-toluenesulfonic acid as an acid catalyst. Although p-toluenesulfonic acid is an acid without oxidizing ability, it can reduce the side reactions caused by the strong oxidizing property of concentrated sulfuric acid. However, in the post-treatment process, the introduction of p-toluenesulfonic acid in the reaction process makes the post-treatment process such as alkali washing produce substances that cannot be detected but can affect the reaction equilibrium of the system during the reduction of steam. In the monoether + concentrated sulfuric acid + methanol system, the experiment found that the higher the temperature, the more favorable it is for the thermodynamically controlled equilibrium reaction product hemiacetal. Therefore, the methanol solvent refluxed at high temperature was removed so that the system temperature could be raised to above 100°C. Finally, it was found that directly adding concentrated sulfuric acid to the monoether at high temperature can make the equilibrium reaction reach 1:3 (monoether: hemiacetal), while too high a temperature will lead to side reactions such as concentrated sulfuric acid oxidation or hemiacetal polymerization. Therefore, the reaction at 100°C and normal pressure for 3.5h is currently the best condition.

[0115] The results of post-treatment experiments on the system after the reaction under the above optimal conditions show that the addition of triethanolamine can effectively stabilize the system balance. Triethanolamine provides weak alkalinity to neutralize possible acidic substances and block the occurrence of acid mechanism. Its alkalinity is not enough to extract hydrogen and there is no reaction power of alkaline mechanism.

[0116] Another clever operation is to add 300g toluene and 200ml 3% NaOH aqueous solution to the reaction product for washing, then add 200ml water to the organic phase obtained by static separation for washing, first distill the organic phase obtained by separation to remove toluene, then add 9g triethanolamine (3%), and then perform vacuum distillation. This can effectively achieve the expected effect of the present invention.

[0117] Experiment 8: Purification of the hemiacetal obtained after the reaction of monoether + 1% concentrated sulfuric acid for the synthesis of cyclized pyrimidines

[0118] Three batches of monoether + 1% concentrated sulfuric acid were reacted and purified to obtain the hemiacetal, which was used in the experiment of synthesizing cyclized pyrimidines. The experimental results are shown in Table 9.

[0119] Add butyrimidine hydrochloride to an appropriate amount of sodium methoxide methanol solution for dissociation, then reduce the pressure and heat to an internal temperature of 50°C, keep warm for 1 hour, then preheat three batches of experimental hemiacetal and workshop hemiacetal to 80°C, then add the dissociated butyrimidine dropwise over about 0.5 hours, keep warm at 80°C for 1 hour after the addition, then add 100g of 30% sodium hydroxide aqueous solution for hydrolysis and keep warm at 100°C for 3 hours, then add 325g of water, and finally use 300g of chloroform for extraction and separation to obtain the organic phase for analysis.

[0120] Table 9. Hemiacetal purified from monoether + 1% concentrated sulfuric acid for use in the synthesis of cyclized pyrimidines

[0121]

[0122]

[0123]

[0124] From the cyclization test results in Table 9, the content of cyclized pyrimidine obtained after the hemiacetal obtained in the experiment was fed according to the workshop feed ratio was above 88%, which is basically consistent with the yield of the existing process.

[0125] Example 1: A method for preparing hemiacetal from monoether, wherein the raw monoether is a byproduct of producing hemiacetal and is obtained by vacuum distillation, wherein the monoether content is 95.2%, the hemiacetal content is 1.26%, the low-boiling substance content is 2.16%, and the rest is other impurities. The above % is mass %.

[0126] See also Figure 1 , follow these steps in order:

[0127] 1) 840 kg of monoether (monoether content: 95.2%) was put into a reactor, and 8.4 kg of concentrated sulfuric acid (98%) was added. After stirring for 15 min, steam was passed to raise the temperature of the material in the reactor to 100±2° C., and an isomerization reaction was carried out for 5 h to obtain a reaction mixture containing monoether and hemiacetal;

[0128] The reaction mixture containing monoether and hemiacetal obtained in step 1) was analyzed, and the content of monoether was 16.42%, hemiacetal was 72.37%, acetal was 1.26%, low boiling point was 3.78%, and the rest was impurities.

[0129] 2) Cooling the reaction mixture containing monoether and hemiacetal obtained in step 1) to about 80°C, then adding 500 kg of toluene and 500 kg of a 3% sodium hydroxide aqueous solution, alkali washing and extraction for 30 min under stirring, then turning off the stirring, and allowing the mixture to stand for stratification to obtain 1330 kg of organic phase I and 518.4 kg of saline wastewater (mainly containing sodium hydroxide, sodium sulfate, tar and water);

[0130] 3) Add 500 kg of water (satisfying the standard of conventional production water) to the organic phase I, stir and wash for 30 minutes, and then stand still to separate the layers, to obtain 1316 kg of organic phase II and 514 kg of saline wastewater (mainly containing sodium hydroxide, sodium sulfate, tar and water);

[0131] 4) The organic phase II obtained in step 3) is distilled at atmospheric pressure (distillation temperature is 105-115°C) to remove toluene therein, and about 849 kg of crude hemiacetal is obtained. The crude hemiacetal contains 15.23% monoether, 70.46% hemiacetal, 1.34% acetal, 5.26% toluene, and the rest is impurities. The above % is mass %.

[0132] The toluene can be collected and used in step 2).

[0133] 5) Add 25 kg of weak base protective agent (triethanolamine) to 849 kg of crude hemiacetal obtained by atmospheric distillation in step 4) and perform vacuum distillation.

[0134] The temperature of the distillation tower bottom does not exceed 170°C, the vacuum degree is 5-10Kpa, the reflux ratio is 4:1 (i.e., the volume ratio of the fraction returned to the distillation tower bottom: the fraction discharged), and the fractions are collected in sections according to the tower top temperature:

[0135] The top temperature was in the range of 10-50°C, and 98.2 kg of fraction Ⅰ (main components were toluene and unknown low-boiling impurities) were collected;

[0136] In the top temperature section of 50-80°C, 128.1 kg of fraction II (mainly monoether, monoether content of 97.13%) was collected and returned to step 1) for recycling;

[0137] The top temperature is in the range of 80-110°C, and 610.5 kg of fraction III is collected (the main component is hemiacetal, with a monoether content of 0.82%, a hemiacetal content of 98.03%, an acetal content of 0.23%, and the rest are impurities), which meets the quality requirements of raw materials for the production of amprolium hydrochloride;

[0138] The residual liquid at the bottom of the distillation tower is treated as hazardous waste and disposed of harmlessly.

[0139] Example 2: A method for preparing hemiacetal from monoether. The raw monoether is a by-product of producing hemiacetal and is obtained by vacuum distillation. The monoether content is 90.6%, hemiacetal is 1.83%, low-boiling substances are 4.21%, and the rest are other impurities.

[0140] The following steps are included in sequence:

[0141] 1) 885 kg of monoether (monoether content: 90.6%) was put into a reactor, and 8.85 kg of concentrated sulfuric acid (98%) was added. After stirring for 15 min, steam was passed to raise the temperature of the material in the reactor to 100 ± 2 ° C, and an isomerization reaction was carried out for 5 h to obtain a reaction mixture containing monoether and hemiacetal;

[0142] The reaction mixture containing monoether and hemiacetal obtained in step 1) was analyzed to have a monoether content of 16.23%, hemiacetal 67.91%, acetal 1.53%, low boiling point substances 4.53%, and the rest being impurities.

[0143] 2) Cooling the reaction mixture containing monoether and hemiacetal obtained in step 1) to about 80° C., then adding 500 kg of toluene and 500 kg of 3% sodium hydroxide aqueous solution, alkali washing and extraction for 30 min under stirring, then turning off the stirring, and allowing the layers to stand to separate, to obtain 1362 kg of organic phase I and 531.85 kg of saline wastewater;

[0144] 3) Add 500 kg of production water to the organic phase I, stir and wash for 30 minutes, and then stand still to separate the layers, to obtain 1347 kg of organic phase II and 515 kg of saline wastewater;

[0145] 4) The organic phase II obtained in step 3) is distilled at normal pressure to remove toluene therein, and about 932 kg of crude hemiacetal is obtained. The crude hemiacetal contains 16.31% monoether, 69.53% hemiacetal, 1.45% acetal, 4.87% toluene, and the rest is impurities.

[0146] 5) Add 28 kg of weak base protective agent (triethanolamine) to 932 kg of crude hemiacetal obtained by atmospheric distillation in step 4) and perform vacuum distillation.

[0147] The temperature of the distillation tower kettle does not exceed 170℃, the vacuum degree is 5-10Kpa, the reflux ratio is 4:1, and the fractions are collected in sections according to the tower top temperature:

[0148] The top temperature was in the range of 10-50°C, and 103.7 kg of fraction Ⅰ (main components were toluene and unknown low-boiling impurities) were collected;

[0149] In the top temperature section of 50-80°C, 131.2 kg of fraction II (mainly monoether, monoether content of 96.11%) was collected and returned to step 1) for recycling;

[0150] The top temperature is in the range of 80-110°C, and 608.4 kg of fraction III is collected (the main component is hemiacetal, with a monoether content of 0.89%, a hemiacetal content of 97.23%, an acetal content of 0.36%, and the rest are impurities), which meets the quality requirements of raw materials for the production of amprolium hydrochloride;

[0151] The residual liquid at the bottom of the distillation tower is treated as hazardous waste and disposed of harmlessly.

[0152] Example 3: A method for preparing hemiacetal from monoether, wherein the raw monoether is a by-product of producing hemiacetal and is obtained by vacuum distillation, wherein the content of monoether is 95.2%, hemiacetal is 1.26%, low-boiling substances are 2.16%, and the rest are other impurities.

[0153] The following steps are included in sequence:

[0154] 1) 128.1 kg of fraction II (containing 97.13% monoether) collected from the distillation of step 5) of Example 1 in the section with a top temperature of 50-80°C, 131.2 kg of fraction II (containing 96.11% monoether) collected from the distillation of step 2 in the section with a top temperature of 50-80°C, and 577 kg of monoether (containing 95.2% monoether) were put into a reactor, and 8.36 kg of concentrated sulfuric acid (98%) was added. After stirring for 15 min, steam was passed to increase the temperature of the material in the reactor to 100±2°C, and an isomerization reaction was carried out for 5 h to obtain a reaction mixture containing monoether and hemiacetal;

[0155] The reaction mixture containing monoether and hemiacetal obtained in step 1) was analyzed, and the content of monoether was 16.59%, hemiacetal was 72.24%, acetal was 1.17%, low boiling point was 3.55%, and the rest was impurities.

[0156] 2) Cooling the reaction mixture containing monoether and hemiacetal obtained in step 1) to about 80° C., then adding 500 kg of toluene and 500 kg of 3% sodium hydroxide aqueous solution, alkali washing and extraction for 30 min under stirring, then turning off the stirring, and allowing the layers to stand to separate, to obtain 1305 kg of organic phase I and 539.66 kg of saline wastewater;

[0157] 3) Add 500 kg of production water to the organic phase I, stir and wash for 30 minutes, and then stand still to separate the layers, to obtain 1292 kg of organic phase II and 513 kg of saline wastewater;

[0158] 4) The organic phase II obtained in step 3) is distilled under normal pressure to remove toluene therein, and about 882 kg of crude hemiacetal is obtained. The crude hemiacetal contains 15.72% monoether, 68.47% hemiacetal, 1.36% acetal, 5.02% toluene, and the rest are impurities.

[0159] 5) Add 26.5 kg of weak base protective agent (triethanolamine) to 882 kg of crude hemiacetal obtained by atmospheric distillation in step 4) and perform vacuum distillation.

[0160] The temperature of the distillation tower kettle does not exceed 170℃, the vacuum degree is 5~10Kpa, the reflux ratio is 4:1, and the fractions are collected in sections according to the tower top temperature:

[0161] The top temperature was in the range of 10-50°C, and 101.3 kg of fraction Ⅰ (main components were toluene and unknown low-boiling impurities) were collected;

[0162] In the top temperature section of 50-80°C, 133.7 kg of fraction II (mainly monoether, monoether content of 96.42%) was collected and returned to step 1) for recycling;

[0163] The top temperature is in the range of 80-110°C, and 611.4 kg of fraction III is collected (the main component is hemiacetal, with a monoether content of 0.71%, a hemiacetal content of 97.80%, an acetal content of 0.31%, and the rest are impurities), which meets the quality requirements of raw materials for the production of amprolium hydrochloride;

[0164] The residual liquid at the bottom of the distillation tower is treated as hazardous waste and disposed of harmlessly.

[0165] Example 4

[0166] The hemiacetals obtained in Example 1, Example 2 and Example 3 were used as raw materials for the synthesis of amprolium hydrochloride, and were subjected to a cyclization reaction with butyrimidine hydrochloride to prepare cyclized pyrimidines. The hemiacetals synthesized normally were used as comparisons to verify whether the hemiacetals obtained in the present invention met the raw material quality requirements for the synthesis of amprolium hydrochloride.

[0167] 1) Weigh 130 kg of butyrimidine hydrochloride (content 97.32%), put it into a reactor, then put 177 kg of sodium methoxide methanol solution (sodium methoxide content 30.21%) into the reactor for freeing, then pass hot water to raise the temperature, remove methanol from the reaction system until the internal temperature reaches 50°C, and then reduce the temperature to room temperature to obtain free butyrimidine hydrochloride;

[0168] 2) Weigh the hemiacetal obtained in Example 1 (content 98.03%), Example 2 (content 97.23%), Example 3 (content 97.80%) and the workshop hemiacetal (content 97.10%) respectively and put them into the reactor, and preheat the hemiacetal to 80±2° C.;

[0169] Description: Workshop hemiacetal: monoether content is 0.82%, hemiacetal content is 97.10%, acetal content is 0.37%, and the rest are impurities.

[0170] Table 10. Comparative experiment of different hemiacetals for synthesizing cyclized pyrimidines (dosage table)

[0171]

[0172] 3) The freed butyrimidine hydrochloride obtained in step 1) is added dropwise to the hemiacetal in step 2) at a uniform rate, and the reaction is carried out by natural temperature rise (the reaction temperature is between 80-95° C.), the dropping time is 30 min, and after the dropping is completed, the temperature is kept at 80° C. for 1 h;

[0173] 4) Add 100 kg of 30% sodium hydroxide solution to the system after the reaction and insulation in step 3) for hydrolysis at a temperature of 100 ± 2 ° C for 3 hours;

[0174] 5) Add 300 kg of production water to the hydrolyzed material in step 4), lower the temperature to 10-15°C, add 600 kg (extracted three times, 300 kg for the first time, 150 kg for the second time, and 150 kg for the third time) of organic solvent chloroform to extract and separate the liquids, and combine the organic phases obtained from the three extractions;

[0175] 6) The organic phase obtained in step 5) was subjected to reduced pressure distillation to recover the organic solvent chloroform to obtain the cyclized pyrimidine, which was measured and analyzed. The results are shown in Table 11:

[0176] Table 11 Comparative experiment of different hemiacetals for synthesizing cyclized pyrimidines (experimental results)

[0177]

[0178] From the cyclization test results in Table 11, there is no difference in quality between the hemiacetal obtained by the present invention and the hemiacetal produced normally, both meet the production requirements of amprolium hydrochloride, and the product yield and product quality are basically the same.

[0179] Comparative Example 1-1: 8.4 kg of concentrated sulfuric acid (98%, 84 mol of H2SO4) in Example 1 was replaced with the same molar amount of hydrochloric acid, i.e., 17 kg of hydrochloric acid (36%, 168 mol of HCl);

[0180] And change step 1) accordingly:

[0181] 840 kg of monoether (monoether content of 95.2%) was put into a reactor, and 17 kg of hydrochloric acid (36%, 168 mol of HCl) was added. After stirring for 15 minutes, steam was passed to increase the temperature of the material in the reactor to 100±2° C., and an isomerization reaction was carried out for 5 hours to obtain a reaction mixture containing monoether and hemiacetal;

[0182] The reaction mixture containing monoether and hemiacetal obtained in step 1) was analyzed to have a monoether content of 67.57%, hemiacetal 6.52%, acetal 15.36%, low boiling point substances 2.16%, and the rest impurities.

[0183] According to Comparative Example 1-1, it is known that the desired result of the present invention cannot be obtained by replacing sulfuric acid with an equal mole of hydrochloric acid, and the hemiacetal content in the material after the reaction is only 6.52%.

[0184] Comparative Example 1-2: The 8.4 kg of concentrated sulfuric acid (98%, 84 mol of H2SO4) in Example 1 was replaced with the same molar amount of nitric acid, i.e., 17.64 kg of nitric acid (60%, 168 mol of HNO3);

[0185] And change step 1) accordingly:

[0186] 840 kg of monoether (monoether content of 95.2%) was put into a reactor, and 17.64 kg of nitric acid (60%, 168 mol of HNO3) was added. After stirring for 15 min, steam was passed to increase the temperature of the material in the reactor to 100±2°C, and an isomerization reaction was carried out for 5 h to obtain a reaction mixture containing monoether and hemiacetal;

[0187] The reaction mixture containing monoether and hemiacetal obtained in step 1) is analyzed to have a monoether content of 46.57%, hemiacetal 9.42%, acetal 18.77%, low-boiling substances 6.16%, and the rest are impurities. The material is viscous.

[0188] According to Comparative Example 1-2, it is known that the desired result of the present invention cannot be obtained by replacing sulfuric acid with an equal molar amount of nitric acid, and the hemiacetal content in the material after the reaction is only 9.42%, and the material after the reaction is viscous, indicating that there are many side reactions.

[0189] Comparative Example 2: The "500 Kg toluene" in step 2) of Example 1 was replaced with xylene, and the amount remained unchanged, still 500 Kg.

[0190] 1) Same as step 1) of Example 1;

[0191] 2) Cooling the reaction mixture containing monoether and hemiacetal obtained in step 1) to about 80°C, then adding 500 kg of xylene and 500 kg of 3% sodium hydroxide aqueous solution, alkali washing and extraction for 30 min under stirring, then turning off the stirring, and allowing the mixture to stand for stratification to obtain 1323 kg of organic phase I and 525.4 kg of saline wastewater (mainly containing sodium hydroxide, sodium sulfate, tar and water);

[0192] 3) Add 500 kg of water (satisfying the standard of conventional production water) to the organic phase I, stir and wash for 30 minutes, and then stand still to separate the layers, to obtain 1312 kg of organic phase II and 511 kg of saline wastewater (mainly containing sodium hydroxide, sodium sulfate, tar and water);

[0193] 4) The organic phase II obtained in step 3) is distilled at atmospheric pressure (distillation temperature is 105-115°C), but xylene cannot be distilled out, so the temperature is raised to 135-145°C, and xylene is removed therefrom to obtain about 856 kg of crude hemiacetal. The crude hemiacetal contains 32.53% monoether, 48.46% hemiacetal, 4.34% acetal, 8.26% xylene, and the rest are impurities. The above % are mass %.

[0194] 5) Add 25 kg of weak base protective agent (triethanolamine) to 856 kg of crude hemiacetal obtained by atmospheric distillation in step 4) and perform vacuum distillation.

[0195] The temperature of the distillation tower bottom does not exceed 170°C, the vacuum degree is 5-10Kpa, the reflux ratio is 4:1 (i.e., the volume ratio of the fraction returned to the distillation tower bottom: the fraction discharged), and the fractions are collected in sections according to the tower top temperature:

[0196] The top temperature was in the range of 10-50°C, and 16.43 kg of fraction Ⅰ (main components were xylene and unknown low-boiling impurities) were collected;

[0197] In the top temperature range of 50-80°C, 360.72 kg of fraction II (main component is monoether, monoether content is 77.13%) was collected;

[0198] The top temperature was in the range of 80-110°C, and 394.2 kg of fraction III was collected (the main component was hemiacetal, with a monoether content of 2.36%, a hemiacetal content of 95.43%, an acetal content of 0.53%, and the rest being impurities), which did not meet the quality requirements for raw materials for the production of amprolium hydrochloride;

[0199] The residual liquid at the bottom of the distillation tower is treated as hazardous waste and disposed of harmlessly.

[0200] The defect of Comparative Example 2 relative to Example 1 is that: due to the excessively high temperature during the atmospheric pressure distillation of xylene in step 4), the hemiacetal is isomerized and part of the hemiacetal is converted into monoether.

[0201] Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by a person skilled in the art should be considered as the protection scope of the present invention.

Claims

1. A method for preparing hemiacetal from monoether, characterized in that The following steps are involved: 1) Using monoether as raw material, in the presence of a catalyst, an isomerization reaction is carried out at a high temperature of 100±5°C for 3 to 5 hours to obtain a reaction mixture containing monoether and hemiacetal; The catalyst is concentrated sulfuric acid, and the catalyst is 0.8-1.2% by weight of the monoether; 2) first cooling the reaction mixture containing monoether and hemiacetal obtained in step 1) to 80±10° C., then adding toluene and sodium hydroxide aqueous solution for alkali washing and extraction, and obtaining an organic phase I through layering; The mass ratio of toluene to sodium hydroxide aqueous solution is 1:0.9-1.1; The mass concentration of the sodium hydroxide aqueous solution is 2.5-3.5%; Toluene: monoether in step 1) = 1:1.6-1.8 weight ratio; 3) Wash the organic phase I with water, and let it stand for stratification to obtain the organic phase II; 4) The organic phase II is distilled at normal pressure to separate toluene to obtain a crude hemiacetal; 5) adding a weak base protective agent to the crude hemiacetal product to carry out vacuum distillation to obtain monoether and hemiacetal respectively; The weak alkaline protective agent is triethanolamine, and the triethanolamine is 2.5-3.5% of the weight of the crude hemiacetal; The monoether is The hemiacetal is 2. The method for preparing hemiacetal from monoether according to claim 1, characterized in that: The monoether obtained in step 5) is returned to step 1) for recycling as a raw material.

3. The method for preparing hemiacetal from monoether according to claim 1 or 2, characterized in that: The mass ratio of water in step 3) to toluene in step 2) is 1:0.9-1.

1.

4. The method for preparing hemiacetal from monoether according to claim 3, characterized in that: In step 5), vacuum distillation is carried out in a distillation tower, the temperature of the distillation tower kettle does not exceed 170°C, the vacuum degree is 5-10Kpa, the reflux ratio is 3.5-4.5:1, and the fractions are collected in sections according to the tower top temperature: The fraction with a top temperature of 50-80° C., whose main component is monoether, is returned to step 1) for recycling; The fraction with a top temperature of 80-110°C is hemiacetal as a product.

5. The method for preparing hemiacetal from monoether according to claim 4, characterized in that: The fraction with a top temperature of 10 to 50°C is mainly toluene and low-boiling impurities.

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