阅读说明：本技术 一种药用辅料注射级间甲酚的制备方法 (Preparation method of pharmaceutic adjuvant injection interstage cresol ) 是由 钟祥龙 王宏欣 李培祥 涂敏敏 林艳霞 龙擂 于 2019-10-31 设计创作，主要内容包括：本发明公开了一种药用辅料注射级间甲酚的制备方法,属于化合物精制提纯制备领域。该制备方法包括以下步骤：①将间甲酚粗品和尿素投入反应釜中,匀速搅拌下升温至80～100℃,保温反应40～90min后,滴加溶剂1,得到反应液；②将步骤1得到的反应液低温析晶1～5h,过滤溶液中析出的固体,将固体用溶剂2反复洗涤多次后,真空干燥1～6h,得到络合物固体；③将步骤2得到的络合物固体加入纯水中,25～35℃水浴搅拌20～50min,移至室温搅拌1～2h,离心收集有机层溶液；④将步骤3得到的有机层溶液真空干燥后减压精馏,收集≤75℃馏分,得到注射级间甲酚。本发明原料廉价易得、生产成本低,所得的注射级间甲酚各项指标均满足国内外药典要求。(The invention discloses a preparation method of cresol for pharmaceutical excipients injection, belonging to the field of refining, purifying and preparing compounds. The preparation method comprises the following steps: putting a m-cresol crude product and urea into a reaction kettle, heating to 80-100 ℃ under uniform stirring, carrying out heat preservation reaction for 40-90 min, and then dropwise adding a solvent 1 to obtain a reaction solution; secondly, crystallizing the reaction liquid obtained in the step 1 at a low temperature for 1-5 hours, filtering the precipitated solid in the solution, repeatedly washing the solid with a solvent 2 for multiple times, and drying in vacuum for 1-6 hours to obtain a complex solid; thirdly, adding the complex solid obtained in the step 2 into pure water, stirring in water bath at 25-35 ℃ for 20-50 min, moving to room temperature, stirring for 1-2 h, and centrifuging to collect an organic layer solution; fourthly, the organic layer solution obtained in the step 3 is vacuum dried and then is decompressed and rectified, and fractions with the temperature less than or equal to 75 ℃ are collected to obtain the cresol for injection. The invention has cheap and easily obtained raw materials and low production cost, and all indexes of the obtained cresol for injection grade meet the requirements of pharmacopoeia at home and abroad.)

1. The preparation method of the pharmaceutic adjuvant injection interstage cresol is characterized by comprising the following steps:

step 1: putting the m-cresol crude product and urea into a reaction kettle, heating to 80-100 ℃ under uniform stirring, carrying out heat preservation reaction for 40-90 min, and then dropwise adding a solvent 1 to obtain a reaction solution;

wherein the molar ratio of the urea to the m-cresol is 1: 1-2: 1;

step 2: crystallizing the reaction liquid obtained in the step 1 at a low temperature for 1-5h, filtering the precipitated solid in the solution, repeatedly washing the solid with a solvent 2 for not less than 2 times, and drying in vacuum for 1-6 h to obtain a complex solid;

wherein the solvent 2 is one or more than two of n-hexane, petroleum ether, acetone and ethyl acetate;

and step 3: adding the complex solid obtained in the step 2 into pure water, stirring in a water bath at 25-35 ℃ for 20-50 min, moving to room temperature, stirring for 1-2 h, centrifuging, and collecting an organic layer solution;

and 4, step 4: and (3) carrying out vacuum drying on the organic layer solution obtained in the step (3), carrying out reduced pressure rectification, and collecting fractions at the temperature of less than or equal to 75 ℃ to obtain the cresol for injection.

2. The method for preparing an interstage cresol for pharmaceutical excipients according to claim 1, wherein the solvent 1 in step 1 is any one or more than two of toluene, tetrahydrofuran and N-methylpyrrolidone.

3. The method for preparing a pharmaceutical excipient injectable interstage cresol according to claim 2, wherein the solvent 1 in step 1 is a mixed solution of toluene and N-methylpyrrolidone.

4. The method for preparing the pharmaceutical adjuvant injection interstage cresol according to claim 3, wherein the volume ratio of the toluene and the N-methyl pyrrolidone is 1: 5-1: 1.

5. The method for preparing a pharmaceutical adjuvant injectable interstage cresol according to claim 1, wherein the low temperature crystallization temperature in step 2 is-10 to-20 ℃.

6. The method for preparing a pharmaceutical excipient injectable interstage cresol according to claim 1, wherein the solvent 2 in step 2 is a mixed solution of petroleum ether and ethyl acetate.

7. The method for preparing the pharmaceutical adjuvant injection interstage cresol according to claim 6, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 8-1: 2.

8. The method for preparing a pharmaceutical excipient injectable interstage cresol according to claim 1, wherein the mass ratio of the complex solid and the purified water in the step 3 is 1: 1-1: 5.

Technical Field

The invention belongs to the field of refining, purifying and preparing compounds, and particularly relates to a preparation method of cresol for injection stages.

Technical Field

Of the three cresol isomers, m-cresol has the lowest toxicity, and can be used as a disinfection antiseptic drug auxiliary material, can be used as an antibacterial antiseptic for intramuscular, subcutaneous and intradermal injections under certain concentration, and can also be used as a bacteriostatic agent and a disinfectant in a local drug preparation. High-purity m-cresol in fine chemical industry is always a hot topic in the chemical field, people continuously research how to obtain high-purity m-cresol, however, at present, high-purity m-cresol only stays at an industrial level and a raw material medicine level, and the m-cresol cannot meet the requirements of pharmaceutic adjuvants.

Industrial grade m-cresol production: firstly, toluene is taken as a raw material and is synthesized by sulfonation alkali fusion; the other is the isopropyl toluene process with co-production of acetone. In the process of producing vitamin E, the content of p-cresol in the raw material medicament grade m-cresol is required to be not more than 0.2 percent, and the content of m-cresol is required to be not less than 99.8 percent. The generated m-cresol is unknown in the aspects of impurity conditions, solvent residues, ignition residues and the like, and the standard of the pharmaceutical adjuvant injection-grade cresol is far higher than the industrial grade and the raw material medicine grade. In order to meet the requirement of auxiliary material standard meeting the injection grade, the medical grade product is not simply sterilized to remove endotoxin. Especially, the organic auxiliary materials such as m-cresol are more complex and toxic in impurities possibly brought in the process. For the application of m-cresol in injection highly sensitive to impurities, the purity requirement is very high (Chinese pharmacopoeia solvent requirements: N-hexane is less than 0.029%, petroleum ether is not limited temporarily, ethyl acetate is less than 0.5%, toluene is less than 0.089%, tetrahydrofuran is less than 0.072%, and N-methylpyrrolidone is less than 0.053%).

At present, in domestic markets, more m-cresol pharmaceutic adjuvant suppliers distribute products by adopting a method of split charging after purchasing from foreign original manufacturers. Although the original producer of the auxiliary materials can control the indexes of the product according to the relevant standards, the product still ensures the original quality without pollution after the secondary subpackaging is difficult to ensure. The subpackaging process of many enterprises does not meet the standard conditions of GMP factory production, and the use safety of the auxiliary materials for the injection can not be ensured to the maximum extent after subpackaging. Therefore, a method for preparing m-cresol of pharmaceutical adjuvant injection grade is urgently needed.

Disclosure of Invention

In order to solve the problems that the preparation method of the pharmaceutical adjuvant injection interstage cresol is not standard and the quality of the m-cresol is difficult to guarantee in the existing domestic market, the invention provides a method for preparing the pharmaceutical adjuvant injection interstage cresol. The invention can realize the purification from the existing industrial grade m-cresol and meet the standard requirements of pharmaceutical grade auxiliary materials.

In order to realize the aim of the invention, the invention provides a preparation method of pharmaceutical adjuvant injection interstage cresol, which comprises the following steps:

step 1: putting the m-cresol crude product and urea into a reaction kettle, heating to 80-100 ℃ under uniform stirring, carrying out heat preservation reaction at the temperature of 40-90 min, and then dropwise adding a solvent 1 to obtain a reaction solution; wherein the molar ratio of the urea to the m-cresol is 1.20-1.50: 1;

step 2: crystallizing the reaction liquid obtained in the step 1 at a low temperature for 1-5h, filtering the precipitated solid in the solution, repeatedly washing the solid with a solvent 2 for at least 2h, and drying in vacuum for 1-6 h to obtain a complex solid;

wherein the solvent 2 is one or more than two solvents selected from n-hexane, petroleum ether, acetone and ethyl acetate;

and step 3: adding the complex solid obtained in the step 2 into pure water, stirring in a water bath at 25-35 ℃ for 20-50 min, moving to room temperature, stirring for 1-2 h, centrifuging, and collecting an organic layer solution;

and 4, step 4: and (3) carrying out vacuum drying on the organic layer solution obtained in the step (3), carrying out reduced pressure rectification, and collecting fractions at the temperature of less than or equal to 75 ℃ to obtain the cresol for injection.

Wherein the solvent 1 in the step 1 is any one or more than two solvents selected from toluene, tetrahydrofuran and N-methylpyrrolidone. Preferably, the solvent 1 is a mixture of toluene and N-methylpyrrolidone. Further preferably, the volume ratio of toluene to N-methylpyrrolidone is 1:5 to 1: 1.

At 80-100 deg.C, m-cresol is fully complexed with urea, and p-cresol and o-cresol are in free state. After heating and heat preservation are carried out for 40-90 minutes, the solvent 1 is dripped to ensure that the m-cresol-urea complex and impurities are dispersed in the solvent, thereby providing better conditions for removing the impurities in the subsequent steps. Toluene, tetrahydrofuran and N-methyl pyrrolidone can control the isomer impurity of m-cresol below 0.1%.

Preferably, the temperature of the low-temperature crystallization in the step 2 is-10 to-20. Preferably, the solvent 2 in step 2 is a mixed solution of petroleum ether and ethyl acetate. Further preferably, the volume ratio of the ethyl acetate to the petroleum ether is 1:8 to 1: 2.

And the crystallization is carried out for 1-5h at low temperature, so that the m-cresol-urea complex is fully separated out, and the yield of the finished product is ensured. Crystallization is carried out at the temperature of minus 10 to minus 20 ℃, and the yield of the finished product is highest. The m-cresol isomers, i.e., p-cresol and o-cresol, are fully removed after the complex solid is filtered and repeatedly washed by the solvent 2, so that the quality of a finished product is ensured. In the washing process, residual solvent 1 in step 1 can be effectively removed by using low-boiling-point solvents such as n-hexane, petroleum ether, acetone and ethyl acetate, and the low-boiling-point solvents are removed by vacuum drying, so that the quality of finished products is ensured.

Preferably, the mass ratio of the complex solid in the step 3 to the purified water is 1: 1-1: 5. Under the condition, the solid of the complex compound is hydrolyzed fully, and the loss of m-cresol is minimum.

The m-cresol-urea complex exists in the presence of hydrogen bond acting force, water is a solvent which can destroy hydrogen bonds well, and after the complex is hydrolyzed, urea is dissolved in water, and m-cresol is separated out to obtain crude m-cresol. The m-cresol is slightly soluble in water, and the loss of the m-cresol can be reduced through centrifugal treatment.

The invention removes the solvent and the moisture by vacuum drying, and reduces the risk of difficult solvent and moisture removal in the vacuum rectification step. By controlling the fraction temperature, the control on the residual urea is improved, the quality of the finished product is ensured, and the injection grade requirement of the pharmaceutic adjuvant is met.

The invention has cheap and easily obtained raw materials and low production cost, the content of the obtained product m-cresol is more than or equal to 99.8 percent, the content of the obtained product p-cresol is controlled to be less than or equal to 0.05 percent, the total impurities are less than or equal to 0.1 percent, no solvent residue is left, and the evaporation residue is less than or equal to 0.05 percent. The indexes of the product all meet the requirements of domestic and foreign pharmacopoeia (wherein, the European pharmacopoeia requires that the content of p-cresol and o-cresol is less than 0.5%, other monohetero is less than 0.1%, total hetero is less than 1.0%, evaporation residue is less than or equal to 0.1%, the United states pharmacopoeia requires that the content of p-cresol and o-cresol is 98.0% -102.0%, both p-cresol and o-cresol is less than 0.5%, other monohetero is less than 0.1%, total hetero is less than 1.0%, evaporation residue is less than or equal to 0.1%, the Chinese pharmacopoeia requires that N-hexane is less than 0.029%, petroleum ether has no limit temporarily, ethyl acetate is less than 0.5%, toluene is less than 0.089%, tetrahydrofuran is less than 0.072%, N-methyl pyrrolidone is less than 0.053%), the toxicity of the used solvent is low, and can be recycled, thereby realizing zero discharge of waste liquid, reducing the pollution to the environment and having higher practical application value.

Drawings

FIG. 1 is a gas chromatogram of cresol between injection stages of example 9;

FIG. 2 is an enlarged view of the gas chromatogram of cresol between injection stages of example 9.

Detailed Description

The present invention will be described in further detail with reference to specific examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

EXAMPLE 1 preparation of solid Complex

Weighing industrial grade cresol (2500g) and urea (1388.48g), putting into a (10L) three-neck bottle, placing into an oil bath pan at 80-100 ℃, and reacting for 1h under heat preservation. And (3) after the reaction is finished, moving the reaction device out of the oil bath pot, adding a burette, and filling a mixed solvent into the burette, wherein the mixed solvent is as follows: toluene/N-methylpyrrolidone 1/5 (toluene 834ml,/N-methylpyrrolidone 4166ml), and the solvent was added dropwise with stirring. After 5L of the solvent is dripped, the burette is taken down, and a rubber plug with a thermometer is additionally arranged to close the side opening.

And (3) moving the reaction bottle into low-temperature cooling liquid, mechanically stirring at a constant speed, starting refrigeration, and timing and crystallizing for about 4 hours when the temperature of the cooling liquid is reduced to-15 ℃. The reaction flask was removed, filtered and the solid collected. The solid was washed with petroleum ether/ethyl acetate 5/1 (petroleum ether 584ml, ethyl acetate 2917ml) and filtered 3 times. The collected solid was placed in a stainless steel tray and dried in a vacuum oven for about 2 h. 2934g of the complex solid are obtained.

EXAMPLE 2 preparation of solid Complex

Weighing industrial grade cresol (2500g) and urea (2776.96g), putting into a (10L) three-neck bottle, placing into an oil bath pan at 80-100 ℃, and reacting for 1h under heat preservation. And (3) after the reaction is finished, moving the reaction device out of the oil bath pot, adding a burette, and filling a mixed solvent into the burette, wherein the mixed solvent is as follows: toluene/N-methylpyrrolidone 1/1 (3000 ml toluene,/3000 ml N-methylpyrrolidone), and the solvent was added dropwise with stirring. After 6L of the solvent is dripped, the burette is taken down, and a rubber plug with a thermometer is additionally arranged to close the side opening.

And (3) moving the reaction bottle into low-temperature cooling liquid, mechanically stirring at a constant speed, starting refrigeration, and timing and crystallizing for about 4 hours when the temperature of the cooling liquid is reduced to-15 ℃. The reaction flask was removed, filtered and the solid collected. The solid was washed with petroleum ether/ethyl acetate 2/1 (petroleum ether 2333ml, ethyl acetate 1167ml) and filtered 4 times. The collected solid was placed in a stainless steel tray and dried in a vacuum oven for about 2 h. 4176g of complex solid were obtained.

EXAMPLE 3 preparation of solid Complex

Weighing industrial grade cresol (2500g) and urea (2082.72g), putting into a (10L) three-neck bottle, placing into an oil bath pan at 80-100 ℃, and reacting for 1h under heat preservation. And (3) after the reaction is finished, moving the reaction device out of the oil bath pot, adding a burette, and filling a mixed solvent into the burette, wherein the mixed solvent is as follows: toluene/N-methylpyrrolidone 1/3 (toluene 1250ml,/N-methylpyrrolidone 3750ml), and the solvent was added dropwise with stirring. After 5L of the solvent is dripped, the burette is taken down, and a rubber plug with a thermometer is additionally arranged to close the side opening.

And (3) moving the reaction bottle into low-temperature cooling liquid, mechanically stirring at a constant speed, starting refrigeration, and timing and crystallizing for about 4 hours when the temperature of the cooling liquid is reduced to-15 ℃. The reaction flask was removed, filtered and the solid collected. The solid was washed with petroleum ether/ethyl acetate 5/1 (2917 ml, ethyl acetate 583ml) and filtered 3 times. The collected solid was placed in a stainless steel tray and dried in a vacuum oven for about 2 h. 3483g of complex solid are obtained.

EXAMPLE 4 preparation of solid Complex

Weighing industrial grade cresol (2500g) and urea (2776.96g), putting into a (10L) three-neck bottle, placing into an oil bath pan at 80-100 ℃, and reacting for 1h under heat preservation. And (3) after the reaction is finished, moving the reaction device out of the oil bath pot, adding a burette, and filling a mixed solvent into the burette, wherein the mixed solvent is as follows: tetrahydrofuran (3.7L) was added dropwise with stirring. After 3.7L of the solvent is dripped, the burette is taken down, and a rubber plug with a thermometer is additionally arranged to close the side opening.

And (3) moving the reaction bottle into low-temperature cooling liquid, mechanically stirring at a constant speed, starting refrigeration, and timing and crystallizing for about 4 hours when the temperature of the cooling liquid is reduced to-15 ℃. The reaction flask was removed, filtered and the solid collected. The solid was washed with n-hexane (3500ml) and filtered 2 times. The collected solid was placed in a stainless steel tray and dried in a vacuum oven for about 2 h. 4176g of complex solid were obtained.

EXAMPLE 5 preparation of solid Complex

Weighing industrial grade cresol (2500g) and urea (1388.48g), putting into a (10L) three-neck bottle, placing into an oil bath pan at 80-100 ℃, and reacting for 1h under heat preservation. And (3) after the reaction is finished, moving the reaction device out of the oil bath pot, adding a burette, and filling a mixed solvent into the burette, wherein the mixed solvent is as follows: 7.5L of N-methylpyrrolidone, and the solvent was added dropwise with stirring. After 7.5L of solvent is dripped, the burette is taken down, and a rubber plug with a thermometer is additionally arranged to close the side opening.

And (3) moving the reaction bottle into low-temperature cooling liquid, mechanically stirring at a constant speed, starting refrigeration, and timing and crystallizing for about 4 hours when the temperature of the cooling liquid is reduced to-15 ℃. The reaction flask was removed, filtered and the solid collected. The solid was washed with acetone (3500ml) and filtered 5 times. The collected solid was placed in a stainless steel tray and dried in a vacuum oven for about 2 h. 2933g of the complex solid are obtained.

EXAMPLE 6 preparation of solid Complex

Weighing industrial grade cresol (2500g) and urea (1944.1g), putting into a (10L) three-neck bottle, placing into an oil bath pan at 80-100 ℃, and reacting for 1h under heat preservation.

And (3) after the reaction is finished, moving the reaction device out of the oil bath pot, adding a burette, and filling a mixed solvent into the burette, wherein the mixed solvent is as follows: toluene/N-methylpyrrolidone 1/1 (toluene 2500ml,/N-methylpyrrolidone 2500ml), and the solvent was added dropwise with stirring. After 5L of the solvent is dripped, the burette is taken down, and a rubber plug with a thermometer is additionally arranged to close the side opening.

And (3) moving the reaction bottle into low-temperature cooling liquid, mechanically stirring at a constant speed, starting refrigeration, and timing and crystallizing for about 4 hours when the temperature of the cooling liquid is reduced to-15 ℃. The reaction flask was removed, filtered and the solid collected. The solid was washed with n-hexane (3500ml) and filtered 3 times. The collected solid was placed in a stainless steel tray and dried in a vacuum oven for about 2 h. 3895g of a solid complex are obtained.

EXAMPLE 7 preparation of injectable interstage cresols

After controlling the temperature of the jacket water bath of the reaction kettle to 35 ℃ and the temperature to 20L, 2940ml of purified water and 2934g of the complex solid in example 1 were sequentially added to the reaction kettle (20L), and the mixture was stirred at a constant speed for 40 minutes. The water bath was removed and the reaction solution was stirred at room temperature for 1.5 hours, after which stirring was stopped and centrifugation was started. After centrifugation, the lower layer was an organic layer (oil) and the upper layer was an aqueous layer. The aqueous layer was discarded and all organic phases were combined. Adding the organic phase into a 2L single-mouth bottle, adding magnetons, stirring in a water bath at 30 ℃, and drying in vacuum for about 3 hours to obtain the m-cresol organic liquid. And (3) carrying out reduced pressure rectification on the organic liquid obtained in the previous step, controlling the steam temperature to be less than or equal to 75 ℃, collecting fractions, and subpackaging the fractions in an aseptic environment to obtain the cresol for injection, wherein the gas chromatography is similar to that in figure 1.

EXAMPLE 8 preparation of injectable interstage cresols

The temperature of the jacket water bath of the reaction kettle is controlled to be 35 ℃, then 25L of purified water and 4176g of the complex solid in example 2 are added into the reaction kettle (20L) in sequence, and the mixture is stirred at a constant speed for 40 minutes. The water bath was removed and the reaction solution was stirred at room temperature for 1.5 hours, after which stirring was stopped and centrifugation was started. After centrifugation, the lower layer was an organic layer (oil) and the upper layer was an aqueous layer. The aqueous layer was discarded and all organic phases were combined. Adding the organic phase into a 2L single-mouth bottle, adding magnetons, stirring in a water bath at 30 ℃, and drying in vacuum for about 3 hours to obtain the m-cresol organic liquid.

And (3) carrying out reduced pressure rectification on the organic liquid obtained in the previous step, controlling the steam temperature to be less than or equal to 75 ℃, collecting fractions, and subpackaging the fractions in an aseptic environment to obtain the cresol for injection, wherein the gas chromatography is similar to that in figure 1.

EXAMPLE 9 preparation of injectable interstage cresols

The temperature of the jacket water bath of the reaction kettle is controlled to be 35 ℃, then 17L of purified water and 3483g of complex solid in example 3 are added into the reaction kettle (20L) in sequence, and the mixture is stirred at a constant speed for 40 minutes. The water bath was removed and the reaction solution was stirred at room temperature for 1.5 hours, after which stirring was stopped and centrifugation was started. After centrifugation, the lower layer was an organic layer (oil) and the upper layer was an aqueous layer. The aqueous layer was discarded and all organic phases were combined. Adding the organic phase into a 2L single-mouth bottle, adding magnetons, stirring in a water bath at 30 ℃, and drying in vacuum for about 3 hours to obtain the m-cresol organic liquid.

Vacuum rectifying the organic liquid obtained in the above step, controlling steam temperature to be less than or equal to 75 deg.C, collecting fraction, subpackaging the fraction in sterile environment, and injecting cresol into the stage by equal injection, wherein gas chromatogram is shown in figure 1, and the enlarged view is shown in figure 2.

EXAMPLE 10 preparation of injectable interstage cresol

The temperature of the jacket water bath of the reaction kettle was controlled at 35 ℃ and then 20.8L of purified water and the solid complex (4176g) of example 4 were added to the reaction kettle (20L) in this order, and the mixture was stirred at a constant speed for 40 minutes. The water bath was removed and the reaction solution was stirred at room temperature for 1.5 hours, after which stirring was stopped and centrifugation was started. After centrifugation, the lower layer was an organic layer (oil) and the upper layer was an aqueous layer. The aqueous layer was discarded and all organic phases were combined. Adding the organic phase into a 2L single-mouth bottle, adding magnetons, stirring in a water bath at 30 ℃, and drying in vacuum for about 3 hours to obtain the m-cresol organic liquid.

And (3) carrying out reduced pressure rectification on the organic liquid obtained in the previous step, controlling the steam temperature to be less than or equal to 75 ℃, collecting fractions, and subpackaging the fractions in an aseptic environment to obtain the cresol for injection, wherein the gas chromatography is similar to that in figure 1.

EXAMPLE 11 preparation of injectable interstage cresol

After controlling the temperature of the jacket water bath of the reaction kettle to 35 ℃ and the temperature to 20L, 8.8L of purified water and 2933g of the complex solid in example 5 were sequentially added to the reaction kettle (20L), and the mixture was stirred at a constant speed for 40 minutes. The water bath was removed and the reaction solution was stirred at room temperature for 1.5 hours, after which stirring was stopped and centrifugation was started. After centrifugation, the lower layer was an organic layer (oil) and the upper layer was an aqueous layer. The aqueous layer was discarded and all organic phases were combined. Adding the organic phase into a 2L single-mouth bottle, adding magnetons, stirring in a water bath at 30 ℃, and drying in vacuum for about 3 hours to obtain the m-cresol organic liquid.

And (3) carrying out reduced pressure rectification on the organic liquid obtained in the previous step, controlling the steam temperature to be less than or equal to 75 ℃, collecting fractions, and subpackaging the fractions in an aseptic environment to obtain the cresol for injection, wherein the gas chromatography is similar to that in figure 1.

EXAMPLE 12 preparation of injectable interstage cresols

The temperature of the jacket water bath of the reaction kettle is controlled to be 35 ℃, then 11.7L of purified water and 3895g of the complex solid in example 6 are added into the reaction kettle (20L) in sequence, and the mixture is stirred for 40 minutes at a constant speed. The water bath was removed and the reaction solution was stirred at room temperature for 1.5 hours, after which stirring was stopped and centrifugation was started. After centrifugation, the lower layer was an organic layer (oil) and the upper layer was an aqueous layer. The aqueous layer was discarded and all organic phases were combined. Adding the organic phase into a 2L single-mouth bottle, adding magnetons, stirring in a water bath at 30 ℃, and drying in vacuum for about 3 hours to obtain the m-cresol organic liquid.

And (3) carrying out reduced pressure rectification on the organic liquid obtained in the previous step, controlling the steam temperature to be less than or equal to 75 ℃, collecting fractions, and subpackaging the fractions in an aseptic environment to obtain the cresol for injection, wherein the gas chromatography is similar to that in figure 1.

EXAMPLE 13 detection of impurities

Chromatographic conditions and system applicability of gas chromatography experiments: adopts a direct sample introduction system program heating method. The chromatographic column is 30m × 250 μm, 0.5 μm coating Of G7; the temperature of a sample inlet is 200 ℃; the temperature of the hydrogen flame ion detector is 220 ℃; temperature programming: the initial temperature is 90 ℃, the temperature is kept for 2min, the temperature is increased to 120 ℃ at the speed of 30 ℃/min, and the temperature is kept for 10 min; finally, the temperature was raised to 200 ℃ at a rate of 3 ℃/min and held for 3 minutes. Nitrogen gas is used as carrier gas, and air: hydrogen gas: 300 parts of nitrogen: 30: 30, the split ratio is 40: 1, flow rate of 1.8ml per minute. Taking a proper amount of m-cresol, o-cresol and p-cresol, dissolving and diluting with methanol to prepare solutions containing 5mg in each 1ml as system adaptive solutions; precisely sucking 1 mul of the mixture to inject into a gas chromatograph, and requiring that the separation degree between the paracresol and the metacresol is not less than 1.4.

The determination method comprises the following steps: an appropriate amount of the interstage cresols obtained in examples 7, 8, 9, 10, 11 and 12 was weighed out precisely and diluted quantitatively with methanol to give a solution containing 10mg per 1ml as a test solution. Precisely sucking the above diluent (methanol) and sample solution 1 μ l each, injecting into gas chromatograph, and recording chromatogram. Calculated by an area normalization method, o-cresol is not more than 0.1%, RRT0.98 (p-cresol + impurity F + impurity G) is not more than 0.3%, other single impurities are not more than 0.1%, and the total impurities are not more than 0.5%. The results are shown in Table 1.

EXAMPLE 14 examination of content

Chromatographic conditions and system applicability of gas chromatography experiments: adopts a direct sample introduction system program heating method. The chromatographic column is 30m × 250 μm, 0.5 μm coating Of G7; the temperature of a sample inlet is 200 ℃; the temperature of the hydrogen flame ion detector is 220 ℃; temperature programming: the initial temperature was 90 deg.C, held for 2min, ramped up to 150 deg.C at 30 deg.C/min, held for 0min, ramped up to 200 deg.C at 20 deg.C/min, and held for 5 min. Nitrogen gas is used as carrier gas, and air: hydrogen gas: 300 parts of nitrogen: 30: 30, the split ratio is 40: 1, flow rate of 1.8ml per minute. Taking a proper amount of phenol, o-cresol, p-cresol and m-cresol, dissolving and diluting the phenol, o-cresol, p-cresol and m-cresol by using methanol to prepare a solution containing 1mg of phenol, 5mg of o-cresol, 5mg of p-cresol and 5mg of m-cresol in each 1ml of solution as a system adaptive solution; in a system adaptive solution map, the front and back separation degrees of phenol, o-cresol, p-cresol and m-cresol are all more than 1.4.

The determination method comprises the following steps: taking a proper amount of phenol, adding methanol to dissolve the phenol to prepare a solution containing 1mg of phenol in each 1ml of the solution as an internal standard solution; taking a proper amount of m-cresol reference substance, and quantitatively diluting with an internal standard solution to prepare a solution containing 1mg in each 1ml as a reference substance solution. An appropriate amount of the interstage cresols obtained in examples 7, 8, 9, 10, 11 and 12 was precisely weighed and quantitatively diluted with an internal standard solution to give a solution containing 1mg per 1ml as a test solution. Precisely measuring 1 μ l of each of the reference solution and the sample solution, injecting into a gas chromatograph, and recording chromatogram. Calculating according to the peak area by an internal standard method to obtain the product. The results are shown in Table 1.

Example 15 detection of residual solvent

An appropriate amount of the interstage cresols obtained in examples 7, 8, 9, 10, 11 and 12 was quantitatively diluted with methanol to give a solution containing 100mg of cresol per 1ml as a test solution. An appropriate amount of the solvent 1/2 used in the examples was weighed out precisely and diluted quantitatively with methanol to give a solution containing an appropriate amount of 1mg of the solvent 1/2 used in the examples per 1ml, as a control solution. Precisely sucking 1 μ l each of the above diluent (methanol), reference solution and sample solution, injecting into gas chromatograph, measuring according to impurity detection method, and recording chromatogram. The product contained 1/2 solvent used in the examples, which was calculated as peak area by external standard method, not more than 1%. The results are shown in Table 1.

EXAMPLE 16 detection of non-volatile matter

2.0g of the cresol obtained in examples 7, 8, 9, 10, 11 and 12 was taken out between injections, placed in an evaporation dish of constant weight at 105 ℃ and heated on a water bath to volatilize, and dried at 105 ℃ for 1 hour, leaving no more than 2mg of residue. The results are shown in Table 1.

TABLE 1