Method for recovering acetanilide in chloro-oxytetracycline production by solvent method

Abstract

The invention discloses a method for recovering acetanilide in the production process of chloro oxytetracycline. The method comprises the following steps: after the chlorination reaction is finished and most methanol is recovered, adding an organic solvent which is selected from alcohols or high-boiling-point polar aprotic solvents capable of forming azeotrope with water into the residual liquid; removing residual methanol and moisture by distillation; transferring the obtained organic solvent solution containing acetanilide to a downstream process, adding hot water to dissolve acetanilide, and simultaneously evaporating or extracting to recover the organic solvent; and finally cooling and crystallizing the acetanilide hot water solution to obtain the product. According to the method, the solvent is introduced in the distillation stage, so that the problems of equipment blockage and scaling caused by precipitation of acetanilide, oxytetracycline raw materials and byproducts are effectively prevented, and continuous and stable operation of rectification and subsequent operation is ensured; meanwhile, dangerous and high-energy-consumption links such as high-temperature melt discharging, cooling solidification and mechanical crushing in the prior art are thoroughly avoided, and the safety, economical efficiency and operation efficiency of the process are remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical and pharmaceutical chemical intermediates recovery, and particularly relates to an improved method for efficiently and safely recovering by-product acetanilide in a process for producing chlorotetracycline by using N-chloroacetanilide as a chlorinating agent. BACKGROUND

[0002] In the synthesis process of chlorotetracycline, N-chloroacetanilide is a commonly used chlorinating agent. After the reaction is completed, the by-product acetanilide remains in the reaction system (usually a methanol solvent). The commonly used recovery method in the industry is to first recover the reaction solvent methanol by distillation, then discharge and cool the remaining molten acetanilide, manually or mechanically crush it, then dissolve it in hot water, and finally obtain pure acetanilide product by cooling crystallization.

[0003] The prior art mainly has the following defects:

[0004] 1. Poor production continuity due to equipment blockage: as methanol is evaporated, acetanilide and chlorotetracycline dissolved therein are precipitated, causing blockage

[0005] 2. Poor operation safety: high-temperature molten material discharge operation is dangerous and can cause burns, and the material is exposed to the environment.

[0006] 3. High energy consumption: the material needs to go through phase change processes from molten state to solid state (cooling) and then from solid state to liquid state (hot water dissolution), resulting in high energy consumption.

[0007] 4. Long process flow and high labor intensity: additional steps such as solidification and crushing are involved, the operation is complicated, and dust may be generated during the crushing process.

[0008] 5. Incomplete solvent recovery: after the methanol is evaporated, the small amount of methanol and water remaining in the system may affect the subsequent crystallization purity or require additional treatment.

[0009] Therefore, there is an urgent need in the art for an acetanilide recovery method that overcomes the above-mentioned drawbacks. SUMMARY

[0010] (I) Invention Objectives

[0011] The present application aims to overcome the above-mentioned defects of the prior art and provide an improved method for recovering acetanilide from chlorotetracycline production waste liquid that is safer to operate, has lower energy consumption, and has a more concise process.

[0012] (II) Technical Solution

[0013] To achieve the above-mentioned objectives, the present application adopts the following technical solution:

[0014] A method for recovering acetanilide, for use in the post-reaction treatment of the production of chlorotetracycline using N-chloroacetanilide as chlorinating agent, said method comprising the following steps:

[0015] 1. Selection of the timing of the initial recovery of methanol:

[0016] o The timing of the addition of said organic solvent can be selected from:

[0017] • Scheme A: before distillation of the recovered methanol, i.e. the organic solvent is mixed with the reaction completion liquid and then distilled together. This scheme prevents the precipitation of the material earlier, but attention must be paid to the control of the reflux ratio in the initial distillation stage to prevent the early removal of the added high-boiling organic solvent in small amounts.

[0018] • Scheme B: after distillation of most of the recovered methanol, the organic solvent is added to the remaining residual liquid. This scheme has the advantage of not increasing the difficulty and complexity of the initial recovery of methanol, and the purity of the recovered methanol is easier to guarantee.

[0019] o Said organic solvent is a solvent that can form an azeotrope with water, or a high-boiling polar aprotic solvent, which has good solubility for acetanilide. Preferably, said solvent not only needs to have good azeotrope or mutual solubility with water, but also needs to pay attention to its interaction with methanol, and ideally should not form an azeotrope with methanol that is difficult to separate, in order to facilitate the separate and efficient recovery of methanol.

[0020] 2. Distillation to remove residual alcohol: the mixture obtained in step 1 is subjected to heating distillation to remove trace amounts of residual methanol and water from the system;

[0021] o When said organic solvent is a solvent that can form an azeotrope with water, it is achieved by azeotropic distillation;

[0022] o When said organic solvent is a high-boiling polar aprotic solvent, it is achieved by high-temperature distillation.

[0023] 3. Transfer and purification: the acetanilide-containing organic solvent solution obtained in step 2 is transferred to the crystallization section for purification operation;

[0024] o When said organic solvent is an alcohol solvent that can form an azeotrope with water, hot water is added to the solution to dissolve acetanilide, and at the same time the organic solvent is distilled out and recovered under heating conditions;

[0025] o When said organic solvent is a high-boiling polar aprotic solvent, hot water is added to the solution to dissolve acetanilide, and then the organic solvent is recovered from the aqueous phase by extraction.

[0026] 4. Crystallization and separation: The hot aqueous solution of acetanilide obtained in step 3 is cooled to induce crystallization of acetanilide. After filtration, washing, and drying, the product of acetanilide is obtained.

[0027] 5. Solvent recovery: Collect the organic solvents evaporated or extracted in steps 2 and 3, as well as the methanol recovered in step 1. After purification, they can be recycled.

[0028] (III) Beneficial effects

[0029] Compared with the prior art, the present application has the following significant advantages:

[0030] 1. Safety is greatly improved: The dangerous and tedious steps of high-temperature molten material discharge, operation, and crushing are completely avoided, greatly improving the working environment and reducing safety risks.

[0031] 2. Energy consumption is significantly reduced: The processes of material cooling and solidification and re-heating dissolution are eliminated, and the residual solvent and water are efficiently removed by distillation, significantly reducing overall energy consumption.

[0032] 3. Process flow is simplified and efficiency is improved: Multiple unit operations are integrated, shortening the production cycle, reducing equipment occupation, and improving production efficiency.

[0033] 4. Solvent recovery rate is improved: Through distillation and evaporation / extraction recovery, methanol and organic solvents are more completely recovered, reducing solvent loss and environmental pollution. The addition of auxiliary solubility can improve the recovery efficiency of methanol.

[0034] 5. Product quality is guaranteed: The new process reduces the exposure and pollution of the material, and the distillation process can remove some light impurities, which is beneficial to guarantee the product quality of acetanilide. BRIEF DESCRIPTION OF DRAWINGS

[0035] [ Figure 1 : Process flow diagram of prior art for recovering acetanilide.

[0036] [ Figure 2 : Process flow diagram of the present application for recovering acetanilide (using azeotropic solvent as an example).

[0037] [ Figure 3 : Process flow diagram of the present application for recovering acetanilide (using a high-boiling-point solvent as an example). DETAILED DESCRIPTION

[0038] The present application will be described in detail below through specific examples, but the present application is not limited thereto.

[0039] Example 1 (using azeotropic solvent n-butanol):

[0040] 1. After the typical chlorination reaction of chlorotetracycline is completed, an acetylaniline-containing methanol solution (about 1 L) is obtained. About 80% of the methanol is recovered by distillation first.

[0041] 2. 0.1 L of n-butanol is added to the remaining solution and mixed well by stirring.

[0042] 3. The mixture is heated to boiling and distilled. The distillate (methanol in the early stage and water-butanol azeotrope in the later stage) is collected until the distillation temperature is stabilized at the boiling point of n-butanol (about 117°C) and no distillate is obtained, indicating that the methanol has been substantially removed.

[0043] 4. The remaining acetylaniline-rich n-butanol solution is pumped into a crystallization kettle. 1 L of hot water at 90°C is added to dissolve the acetylaniline completely. At the same time, the n-butanol is distilled off under heating and recovered by condensation.

[0044] 5. The acetylaniline hot water solution in the kettle is slowly cooled to below 30°C and stirred for crystallization for two hours.

[0045] 6. The crystals are filtered, washed with a small amount of cold water, and dried to obtain 80.1 g of white acetylaniline crystals with a purity of 99% (determined by HPLC).

[0046] 7. The recovered n-butanol can be directly reused in step 2.

[0047] Example 2 (using high-boiling solvent DMF):

[0048] 1. After the same reaction as in Example 1 is completed, most of the methanol is recovered.

[0049] 2. An equal volume of DMF is added to the remaining solution and mixed by stirring.

[0050] 3. The system is heated to 120°C and high-temperature distillation is performed to remove the remaining methanol. The system temperature is stabilized and no distillate is obtained.

[0051] 4. The remaining acetylaniline-rich DMF solution is transferred to a crystallization kettle, 1 L of hot water at 90°C is added to dissolve the acetylaniline completely, and a DMF aqueous solution is obtained.

[0052] 5. Chloroform is then added to the aqueous solution in two portions, each being about one time the volume of the aqueous solution, and extraction is performed. After mixing well, the layers are separated. The organic phase (containing DMF) is separated, and the aqueous phase is subjected to subsequent crystallization.

[0053] 6. The aqueous phase is cooled to below 30°C and stirred for crystallization for two hours. After filtration, washing, and drying, 76 g of acetylaniline product is obtained with a purity of 97%.

[0054] 7. The collected organic phase (chloroform and DMF) is separated by distillation, and the recovered DMF and chloroform can be recycled.

[0055] Comparative Example (conventional method):

[0056] The same batch of reaction solution is treated according to the prior art: the melt is discharged after the methanol is distilled out, and is cooled and crushed, and then is dissolved in hot water and cooled to crystallize. Finally, 76 g of acetanilide is obtained, with a purity of 98%. The whole process takes 6 hours, and has many operation steps and high labor intensity.

[0057] Through comparison, the embodiment of the present application has obvious advantages in product yield, purity, operation time, safety, etc.

Claims

1. A method for recovering acetanilide during the production of chlorooxytetracycline, wherein the chlorooxytetracycline is prepared by reacting N-chloroacetanilide as a chlorinating agent in a methanol solvent, characterized in that, The method includes the following steps: (a) Distillation of the reaction liquid to recover most of the methanol; (b) Add an organic solvent to the residual liquid obtained in step (a), wherein the organic solvent is selected from solvents that can form an azeotrope with water but not with methanol, or high-boiling-point polar aprotic solvents. (c) Distill the mixture obtained in step (b) to remove residual methanol and water from the system; (d) The organic solvent solution containing acetanilide obtained in step (c) is purified to separate and recover acetanilide; (e) Optionally, the solvents obtained in steps (a), (c) and (d) are recovered and recycled.

2. The method according to claim 1, characterized in that, The solvent that can form an azeotrope with water but not with methanol in step (b) is selected from one or more of methyl isobutyl ketone (MIBK), n-butanol, isobutanol, and isoamyl alcohol.

3. The method according to claim 1, characterized in that, The high-boiling-point polar aprotic solvent mentioned in step (b) is selected from one or more of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).

4. The method according to claim 1, characterized in that, The organic solvent in step (b) is added after most of the methanol has been recovered by distillation.

5. The method according to claim 1, characterized in that, The organic solvent in step (b) is added before the methanol is recovered by distillation, and a high reflux ratio is used in the initial distillation stage of step (a) to prevent the organic solvent from being carried out.

6. The method according to claim 1, characterized in that, The purification operation described in step (d) includes: (d1) When the organic solvent is a solvent that can form an azeotrope with water, hot water is added to the organic solvent solution containing acetanilide to dissolve acetanilide, while the organic solvent is evaporated and recovered under heating conditions, and then the resulting aqueous solution of acetanilide is cooled to crystallize. (d2) When the organic solvent is a high-boiling-point polar aprotic solvent, hot water is added to the organic solvent solution containing acetanilide to dissolve acetanilide, and then the organic solvent is recovered from the aqueous phase by extraction, and the aqueous phase is cooled to crystallize.

7. The method according to claim 6, characterized in that, The extraction method uses chloroform, dichloromethane, or dichloroethane as the extractant.

8. The method according to claim 1, characterized in that, The amount of organic solvent added in step (b) is 0.5 to 5 times the volume of the residual liquid.

9. The method according to claim 6, characterized in that, In the hot water dissolution step, the temperature of the hot water is between 50°C and 100°C.

10. The method according to claim 1, characterized in that, The distillation temperature described in step (c) is 70°C to the boiling point of the added organic solvent.

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