CN109096161B - Preparation method of N-acetylcysteine - Google Patents
Preparation method of N-acetylcysteine Download PDFInfo
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- CN109096161B CN109096161B CN201810972373.3A CN201810972373A CN109096161B CN 109096161 B CN109096161 B CN 109096161B CN 201810972373 A CN201810972373 A CN 201810972373A CN 109096161 B CN109096161 B CN 109096161B
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Abstract
The invention discloses a preparation method of N-acetylcysteine. Which comprises the following steps: adjusting the pH value of the cysteine mother liquor to 9-12, adding acetic anhydride at 40-60 ℃ within 20-60 min for acylation reaction, and preserving heat to obtain an acylation liquid; and neutralizing and crystallizing the acylation liquid to obtain a crude N-acetylcysteine product, and recrystallizing the crude N-acetylcysteine product to obtain the compound. According to the invention, the mother liquor obtained after cysteine is produced from cysteine hydrochloride is used as a raw material, so that refined N-acetylcysteine can be prepared, and the profit is improved on the basis of reducing the production cost and relieving the environmental pressure, thereby improving the enterprise competitiveness.
Description
Technical Field
The invention relates to a method for preparing N-acetylcysteine.
Background
N-Acetylcysteine (N-acetyl cysteine, Ac-Cys), the chemical name is N-acetyl-L-cysteine, the molecular formula is as follows: c5H9NO3S, molecular weight: 163.2, which is a white crystalline powder; odor similar to garlic and sour taste; the water-soluble organic silicon compound is hygroscopic, is easily soluble in water, is soluble in ethanol, is insoluble in dichloromethane and diethyl ether, and has the following molecular formula:
n-acetylcysteine is a mucolytic agent and is suitable for the diseases of dyspnea and expectoration difficulty caused by a large amount of viscous phlegm obstruction; can be used for treating postoperative expectoration difficulty, acute and chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis, emphysema, etc. caused by thick sputum and expectoration difficulty. In addition, it is also widely used for the treatment of idiopathic interstitial lung.
Cysteine hydrochloride, cysteine and N-acetylcysteine are all main products in the field, cysteine hydrochloride is generally obtained by electrolyzing cystine in industry, and the obtained cysteine hydrochloride can be used as a raw material to prepare the N-acetylcysteine and the cysteine. The process for preparing the cysteine comprises the steps of dissolving cysteine hydrochloride, adding liquid alkali to neutralize the dissolved cysteine hydrochloride to obtain the cysteine, performing centrifugal separation to obtain a cysteine product and a mother liquor, detecting by an iodometry to find that the cysteine mother liquor contains 100-120 g/L of cysteine, recycling the mother liquor, wherein chloride in the obtained cysteine product hardly reaches a qualified standard, and electrolyzing the mother liquor to obtain the cysteine hydrochloride serving as a raw material to produce the N-acetylcysteine or the cysteine, wherein the cysteine hydrochloride is oxidized into the cystine, so that a process route is prolonged, the investment of a large amount of manpower, material resources and energy is increased, economic loss is caused to enterprises, and the environmental protection pressure of wastewater treatment is increased (as shown in figure 1, and figure 1 is a process flow chart of preparing the cysteine and the N-acetylcysteine from the cystine in the prior art). Therefore, how to treat cysteine mother liquor in industrial production improves profit and further improves enterprise competitiveness on the basis of reducing production cost and environmental pressure, and is the first problem in the industry at present.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of N-acetylcysteine. The preparation method takes cysteine mother liquor as a raw material to carry out acylation reaction to obtain N-acetylcysteine, and the specific reaction formula is shown as follows.
The invention solves the technical problems through the following technical scheme.
The invention provides a preparation method of N-acetylcysteine, which comprises the following steps: adjusting the pH value of the cysteine mother liquor to 9-12, adding acetic anhydride at 40-60 ℃ within 20-60 min for acylation reaction, and preserving heat to obtain an acylation liquid; and neutralizing and crystallizing the acylation liquid to obtain a crude N-acetylcysteine product, and recrystallizing the crude N-acetylcysteine product to obtain the compound.
In the present invention, the cysteine mother liquor may be a cysteine mother liquor conventional in the art, and is generally prepared by the following steps: performing neutralization reaction on cysteine hydrochloride solution and alkali liquor, cooling and crystallizing, centrifuging, and washing with water to obtain cysteine and the cysteine mother liquor, preferably by the following steps: adjusting the pH value of the cysteine hydrochloride solution to 3.5-5.0 by using alkali liquor, cooling to below 5 ℃ until the crystallization is complete, centrifuging and washing by using water to obtain cysteine and the cysteine mother liquor, wherein the mass volume ratio of the cysteine hydrochloride to the water in the cysteine hydrochloride solution is 600-800 kg: 250-350L.
Among them, the cysteine hydrochloride may be a product conventionally and commercially available in the art. The water is generally purified water commonly used in the chemical industry field. The operations and conditions of the crystallization, the centrifugation, the water washing are all those conventional in the art. The cysteine hydrochloride solution is generally formulated in a reaction tank and the crystallization operation is generally carried out in a crystallization tank.
In the invention, the concentration of cysteine in the cysteine mother liquor is generally 100-120 g/L.
In the present invention, before the pH adjustment operation, the cysteine mother liquor is preferably concentrated under reduced pressure. The operation and conditions of the concentration under reduced pressure may be those conventional in the art, and the end point of the concentration under reduced pressure is preferably: the volume after concentration is 40-60% of the volume before concentration, and more preferably the volume after concentration is 50% of the volume before concentration.
In the present invention, the pH is preferably 9.5 to 11.8, and more preferably 9.5 to 10.5.
In the present invention, the acetic anhydride must be added dropwise at 40 to 60 ℃. If the temperature is lower than 40 ℃, the acylation reaction process is slow, and if the temperature is higher than 60 ℃, side reaction is easy to occur in the acylation reaction process. The dropping temperature of the acetic anhydride is preferably 50 ℃. The dropping time of the acetic anhydride is preferably 40 min.
In the present invention, the molar ratio of cysteine to acetic anhydride in the cysteine mother liquor may be conventional in the art, and is preferably 1: 1-1: 1.5, e.g. 1:1.05 or 1: 1.1.
In the present invention, the operation and conditions for the incubation may be those conventional in the art. The temperature of the heat preservation is preferably 60-70 ℃. The heat preservation time is preferably 10-30 min, and more preferably 20-30 min.
In the present invention, the method for detecting the end point of incubation may be conventional in the art, and is preferably performed by the following steps: taking 1mL of the acylation liquid sample, diluting with water to 100mL, taking 2 mu L of the acylation liquid sample on filter paper, drying, and spraying 2% ninhydrin acetone solution; taking 2 mu L of 0.01% cysteine control solution on filter paper, blowing dry, and spraying 2% ninhydrin acetone solution if the sample solution is weaker than the control solution in color.
In the invention, the pH value of the acylation liquid is generally in the range of 4-7.
In the present invention, the concentration of cysteine in the acylation liquid is preferably less than 0.01% (the above concentration is a mass percentage, that is, 0.01g of cysteine is contained in 100g of water). If the concentration of cysteine in the acylation liquid is more than 0.01%, the acylation reaction is preferably carried out again in the acylation liquid until the concentration of cysteine is less than 0.01%.
In the present invention, the operation and conditions for the neutralization crystallization may be those conventional in the art, and preferably include the following steps: adjusting the pH value to 1.5-2.0 by the acylation liquid, filtering, desalting, discarding the obtained wet salt, cooling and crystallizing the obtained filtrate to obtain crystals, and filtering, washing and drying the crystals to obtain a crude product I of the N-acetylcysteine and an acylation mother liquor I.
During the neutralization crystallization, the pH regulator can be conventional in the art, and is typically hydrochloric acid. The pH is preferably 1.86. Preferably, the temperature of the filtrate is reduced to 5-10 ℃, and the filtrate is stirred until the filtrate is completely crystallized.
Preferably, the acylation mother liquor I is recovered. The recovery method of the acylation mother liquor I can be conventional in the field, and is preferably carried out according to the following steps: adjusting the pH value of the acylation mother liquor I to 4.0-5.0, concentrating under reduced pressure, adjusting the pH value to 1.5-2.0, filtering, desalting, removing the obtained wet salt, cooling and crystallizing the obtained filtrate to obtain crystals, and filtering, washing and drying the crystals to obtain a crude N-acetylcysteine product II and a mother liquor II.
In the recovery method of the acylation mother liquor I, the regulator for regulating the pH value to 4.0-5.0 can be conventional in the field, and is generally sodium hydroxide. The operation and conditions of the reduced pressure concentration can be conventional in the field, and the reduced pressure concentration is generally half of the original volume. The regulator for regulating the pH value to 1.5-2.0 can be conventional in the field, and is generally hydrochloric acid. Preferably, the temperature of the filtrate is reduced to 5-10 ℃, and the filtrate is stirred until the crystallization is complete.
Preferably, the mother liquor II is recovered. The recovery method of the mother liquor II can be conventional in the field, is generally the same as the recovery method of the acylation mother liquor I, and finally can obtain crude N-acetylcysteine III and mother liquor III.
Preferably, the N-acetylcysteine is obtained by recrystallizing the crude N-acetylcysteine I, the crude N-acetylcysteine II and the crude N-acetylcysteine III.
In the present invention, the operation and conditions of the recrystallization may be those conventional in the art, and preferably include the following steps: decolorizing the aqueous solution containing the N-acetylcysteine crude product at 50-60 ℃, filtering for the first time, cooling and crystallizing the obtained filtrate to obtain crystals, and filtering, washing and drying the crystals for the second time.
In the recrystallization, the weight ratio of the crude N-acetylcysteine to the water in the aqueous solution may be conventional in the art, and is preferably 1: (1-1.1). The operation and conditions of the decolorization can be conventional in the art, and preferably, the decolorization is carried out in activated carbon for 10 min. The amount of activated carbon may be as conventional in the art, preferably 0.5 wt% based on the weight of the crude N-acetylcysteine. The temperature for temperature-reducing crystallization can be conventional in the art, and is preferably below 5 ℃. The operations and conditions of the first filtration, the second filtration, the water washing and the drying are all conventional in the art. If the production is continuous, the filtrate obtained by the second filtration needs to be mixed with the cysteine mother liquor.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
according to the invention, the mother liquor obtained after cysteine is produced from cysteine hydrochloride is used as a raw material, so that refined N-acetylcysteine can be prepared, and the profit is improved on the basis of reducing the production cost and relieving the environmental pressure, thereby improving the enterprise competitiveness.
Drawings
FIG. 1 is a flow chart of a prior art process for preparing cysteine and N-acetylcysteine from cystine.
FIG. 2 is a flow chart of the process for preparing N-acetylcysteine from cysteine mother liquor in example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In examples 1 to 4, the cysteine mother liquor was prepared by the following steps: 300L of purified water and 700kg of cysteine hydrochloride (generally commercially available) were put into a reaction tank, and sufficiently stirred and dissolved; transferring into a crystallizing tank, introducing alkali liquor to adjust the pH value to 4.5, and cooling to below 5 ℃ until complete crystallization; centrifuging and washing with water to obtain cysteine and cysteine mother liquor. The concentration of cysteine in the cysteine mother liquor is 120 g/L.
Example 1
(1) Acylation reaction:
concentrating 1000mL of cysteine mother liquor under reduced pressure, concentrating the volume to 500mL, stopping concentrating, transferring the concentrated solution into a reaction container, adding 76g of sodium hydroxide into the concentrated solution to adjust the pH value to 9.5-10, dropwise adding 105.7g of acetic anhydride into the reaction container (the molar ratio of cysteine to acetic anhydride in the reaction system is 1: 1.05), controlling the temperature of the system to be 40 ℃, dropwise adding acetic anhydride for 60min, preserving the temperature at 60-70 ℃ for 20-30 min after the reaction is finished, and sampling to detect the reaction end point. And obtaining acylation liquid after the reaction end point detection is qualified, and continuously adding a proper amount of acetic anhydride when the reaction end point detection is unqualified.
The reaction end point detection method comprises the following steps: diluting the acylation liquid with water to 100mL, placing 2 μ L on filter paper, drying, and spraying 2% ninhydrin acetone solution; in the same way, 2 μ L of 0.01% cysteine control solution is used, if the color development of the sample solution is weaker than that of the control solution.
(2) Neutralization crystallization
Adding 199g of industrial hydrochloric acid into the acylation liquid to adjust the pH value to 1.86, filtering for desalination, discarding wet salt, cooling filtrate for crystallization, cooling to 5-10 ℃, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain 94.2g of crude N-acetylcysteine and acylation mother liquor I.
(3) Recovery of mother liquor
And (3) recovering the acylation mother liquor I: adjusting the pH value of the acylation mother liquor I to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using hydrochloric acid in the processing industry. Filtering and desalting while hot, discarding wet salt, transferring the filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain a crude product II30g of N-acetylcysteine and a mother solution II.
And (3) a method for recovering mother liquor II: adjusting the pH value of the mother liquor II to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using industrial hydrochloric acid. Filtering and desalting while hot, discarding wet salt, transferring filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, and stirring until the material is completely crystallized. Filtering, washing and drying to obtain 10g N-acetylcysteine crude product III and mother liquor III.
(4) Recrystallization
In the decolourisation vessel, 134.2g of crude product, crude product II, crude product III in total, and 140g of purified water are added. Stirring and heating to 50-60 ℃ for dissolution, adding active carbon accounting for 0.5% of the total amount of the crude product for decolorization for 10min, decolorizing and filtering, cooling the filtrate for crystallization, cooling the filtrate to below 5 ℃ and stirring until the crystals are completely separated out, filtering, washing with water, and drying 107g of refined N-acetylcysteine. During continuous production, the filtrate, namely the spermatozoa, can be returned to the first acylation process for concentration.
FIG. 2 is a flow chart of the process for preparing N-acetylcysteine from cysteine mother liquor in example 1.
Example 2
(1) Acylation reaction:
concentrating 1000mL of cysteine mother liquor under reduced pressure, concentrating the cysteine mother liquor to 500mL in volume, stopping concentrating, transferring the concentrated solution into a reaction container, adding 70g of sodium hydroxide into the concentrated solution to adjust the pH value to be 9.5-10.0, dropwise adding 111.4g of acetic anhydride into the reaction container (the molar ratio of cysteine to acetic anhydride in the reaction system is 1: 1.10), controlling the temperature of the system to be 60 ℃, dropwise adding acetic anhydride for 20min, preserving heat for 20-30 min at 60-70 ℃ after the reaction is finished, and sampling to detect the reaction end point. And obtaining acylation liquid after the reaction end point detection is qualified, and continuously adding a proper amount of acetic anhydride when the reaction end point detection is unqualified.
The reaction end point detection method was the same as in example 1.
(2) Neutralization crystallization
Adding 199g of industrial hydrochloric acid into the acylation liquid to adjust the pH value to 1.86, filtering for desalination, discarding wet salt, cooling filtrate for crystallization, cooling to 5-10 ℃, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain 106.6g of crude N-acetylcysteine and acylation mother liquor I.
(3) Recovery of mother liquor
And (3) recovering the acylation mother liquor I: adjusting the pH value of the acylation mother liquor I to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using hydrochloric acid in the processing industry. Filtering and desalting while hot, discarding wet salt, transferring the filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain a crude product II29g of N-acetylcysteine and a mother solution II.
And (3) a method for recovering mother liquor II: adjusting the pH value of the mother liquor II to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using industrial hydrochloric acid. Filtering and desalting while hot, discarding wet salt, transferring filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, and stirring until the material is completely crystallized. Filtering, washing and drying to obtain 8.2g N-acetylcysteine crude product III and mother liquor III.
(4) Recrystallization
In the decolourisation vessel, 142.8g of crude, crude II, crude III in total and 145g of purified water were added. Stirring and heating to 50-60 ℃ for dissolution, adding active carbon accounting for 0.5% of the total amount of the crude product for decolorization for 10min, decolorizing and filtering, cooling the filtrate for crystallization, cooling the filtrate to below 5 ℃ and stirring until the crystals are completely separated out, filtering and washing, and drying 119.9g of refined N-acetylcysteine. During continuous production, the filtrate, namely the spermatozoa, can be returned to the first acylation process for concentration.
Example 3
(1) Acylation reaction:
concentrating 1000mL of cysteine mother liquor under reduced pressure, concentrating the volume to 500mL, stopping concentrating, transferring the concentrated solution into a reaction container, adding 70g of sodium hydroxide into the concentrated solution to adjust the pH value to 9.5-10.0, dropwise adding 116.8g of acetic anhydride into the reaction container (the molar ratio of cysteine to acetic anhydride in the reaction system is 1: 1.15), controlling the temperature of the system to be 50 ℃, dropwise adding the acetic anhydride for 40min, preserving the temperature at 60-70 ℃ for 20-30 min after the reaction is finished, and sampling to detect the reaction end point. And obtaining acylation liquid after the reaction end point detection is qualified, and continuously adding a proper amount of acetic anhydride when the reaction end point detection is unqualified.
The reaction end point detection method was the same as in example 1.
(2) Neutralization crystallization
Adding 199g of industrial hydrochloric acid into the acylation liquid to adjust the pH value to 1.86, filtering for desalination, discarding wet salt, cooling filtrate for crystallization, cooling to 5-10 ℃, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain 110.1g of crude N-acetylcysteine and acylation mother liquor I.
(3) Recovery of mother liquor
And (3) recovering the acylation mother liquor I: adjusting the pH value of the acylation mother liquor I to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using hydrochloric acid in the processing industry. Filtering and desalting while hot, discarding wet salt, transferring the filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain a crude product II27g of N-acetylcysteine and a mother solution II.
And (3) a method for recovering mother liquor II: adjusting the pH value of the mother liquor II to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using industrial hydrochloric acid. Filtering and desalting while hot, discarding wet salt, transferring filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, and stirring until the material is completely crystallized. Filtering, washing and drying to obtain 7.5g N-acetylcysteine crude product III and mother liquor III.
(4) Recrystallization
In a decolourisation vessel, 144.6g of crude, crude II, crude III in total and 145g of purified water are added. Stirring and heating to 50-60 ℃ for dissolution, adding active carbon accounting for 0.5% of the total amount of the crude product for decolorization for 10min, decolorizing and filtering, cooling the filtrate for crystallization, cooling the filtrate to below 5 ℃ and stirring until the crystals are completely separated out, filtering, washing with water, and drying 115g of refined N-acetylcysteine. During continuous production, the filtrate, namely the spermatozoa, can be returned to the first acylation process for concentration.
Example 4
(1) Acylation reaction:
concentrating 1000mL of cysteine mother liquor under reduced pressure, concentrating the volume to 500mL, stopping concentrating, transferring the concentrated solution into a reaction container, adding 88.4g of sodium hydroxide into the concentrated solution to adjust the pH value to 11.8, dropwise adding 111.0g of acetic anhydride into the reaction container (the molar ratio of cysteine to acetic anhydride in the reaction system is 1: 1.15), controlling the temperature of the system to be 50 ℃, dropwise adding acetic anhydride for 40min, preserving the temperature at 60-70 ℃ for 20-30 min after the reaction is finished, and sampling to detect the reaction end point. And obtaining acylation liquid after the reaction end point detection is qualified, and continuously adding a proper amount of acetic anhydride when the reaction end point detection is unqualified.
The reaction end point detection method was the same as in example 1.
(2) Neutralization crystallization
Adding 243.9g of industrial hydrochloric acid into the acylation liquid to adjust the pH value to 1.86, filtering and desalting, discarding wet salt, cooling the filtrate to crystallize, cooling to 5-10 ℃, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain 101.33g of crude N-acetylcysteine and acylation mother liquor I.
(3) Recovery of mother liquor
And (3) recovering the acylation mother liquor I: adjusting the pH value of the acylation mother liquor I to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using hydrochloric acid in the processing industry. Filtering and desalting while hot, discarding wet salt, transferring the filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain a crude product II18g of N-acetylcysteine and a mother solution II.
And (3) a method for recovering mother liquor II: adjusting the pH value of the mother liquor II to 4.0-5.0 by using sodium hydroxide, concentrating under reduced pressure to about half of the original volume, and adjusting the pH value to 1.5-2.0 by using industrial hydrochloric acid. Filtering and desalting while hot, discarding wet salt, transferring filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, and stirring until the material is completely crystallized. Filtering, washing and drying to obtain 6.5g N-acetylcysteine crude product III and mother liquor III.
(4) Recrystallization
In the decolourisation vessel, 125.83g total of crude II, crude III were added and 100g purified water was added. Stirring and heating to 50-60 ℃ for dissolution, adding active carbon accounting for 0.5% of the total amount of the crude product for decolorization for 10min, decolorizing and filtering, cooling the filtrate for crystallization, cooling the filtrate to below 5 ℃ and stirring until the crystals are completely separated out, filtering and washing, and drying 100.66g of refined N-acetylcysteine. During continuous production, the filtrate, namely the spermatozoa, can be returned to the first acylation process for concentration.
Example 4 the pH before acylation was adjusted to 11.8, the amount of caustic soda flakes was increased by 20.8%, and the amount of hydrochloric acid was increased by 18.4%, which not only increased the amount of acid and base, but also increased the volume of the reaction solution. Although the amounts of impurities C and D in the two mother liquors are lower than those in the other mother liquors, the yield is not significantly improved.
Comparative example 1
The operating conditions were the same as in example 1 except for the following operating conditions.
And (3) recovering the acylation mother liquor I: and (2) concentrating the acylation mother liquor I under reduced pressure, concentrating to about half of the original volume, filtering for desalting while hot, discarding wet salt, transferring the filtrate into a crystallization container, cooling the filtrate to 5-10 ℃ for crystallization, stirring until the material is completely crystallized to obtain crystals, and filtering, washing and drying the crystals to obtain a crude product II of the N-acetylcysteine and a mother liquor II.
Effect example 1
And (3) detecting the refined products obtained in the embodiments 1-4, including detection of related substances, specific rotation, transmittance, content and pH, wherein detection results of the related substances (HPLC) are shown in table 1, and detection results of the specific rotation, the transmittance, the content and the pH are shown in table 2. Wherein, the type of the detecting instrument of the data in the table 1 is Hitachi L2420, and the detection is carried out according to the chromatographic conditions of related substances in EP 8; the data in Table 2 were obtained by a measurement instrument model of Hitachi L2420, and measured according to the Japanese AJI97 standard.
TABLE 1 HPLC TEST RESULTS OF FINES OBTAINED IN EXAMPLES 1-4
In the table, A is cystine, B is cysteine, C is N, N-diacetylcystine, and D is N, S-diacetylcysteine.
Table 2 general test results of the top-quality products obtained in examples 1 to 4
As is clear from tables 1 and 2, the products of examples 1 to 4 all meet the Japanese AJI97 standard. The specific rotation degree of the refined product obtained in the examples 1 to 4 is 25.4-26.4 DEG, the transmittance is more than 98.7%, the content of N-acetylcysteine is more than 99.3%, and the pH value is within the range of 2.4-2.6.
Meanwhile, the method of directly concentrating the mother liquor without adjusting pH during the recovery of the mother liquor I is taken as a comparative example (other processes are the same as the example 1), the concentration of impurities in the mother liquor is detected by adopting an HPLC mode, and the detection results are shown in Table 3.
TABLE 3 HPLC TEST RESULTS OF STORAGE SOLUTION II OF EXAMPLES 1-4 AND COMPARATIVE EXAMPLE 1
In the table, A is cystine, B is cysteine, C is N, N-diacetylcystine, and D is N, S-diacetylcysteine.
As can be seen from Table 3, in the recovery process of the acylated mother liquor I, the generation of the impurity D in the mother liquor II can be effectively inhibited by adjusting the pH value of the system before and after concentration.
The yields of the purified products obtained in examples 1 to 4 are shown in table 4, and the yields are mass yields, i.e., the mass of the purified product per 100% by mass of cysteine in the cysteine mother liquor.
TABLE 4 yields of the fine products obtained in examples 1 to 4
Claims (24)
1. A preparation method of N-acetylcysteine is characterized by comprising the following steps: adjusting the pH value of the cysteine mother liquor to 9-12, adding acetic anhydride at 40-60 ℃ within 20-60 min for acylation reaction, and preserving heat to obtain an acylation liquid; neutralizing and crystallizing the acylation liquid;
the operation of neutralization crystallization comprises the following steps: adjusting the pH value to 1.5-2.0 by the acylation liquid, filtering, cooling and crystallizing the obtained filtrate to obtain crystals, filtering, washing and drying the obtained crystals to obtain a crude product I of N-acetylcysteine and an acylation mother liquor I;
recovering the acylation mother liquor I; the recovery method of the acylation mother liquor I comprises the following steps: adjusting the pH value of the acylation mother liquor I to 4.0-5.0, concentrating under reduced pressure, adjusting the pH value to 1.5-2.0, filtering, cooling and crystallizing the obtained filtrate to obtain crystals, filtering, washing and drying the obtained crystals to obtain a crude N-acetylcysteine product II and a mother liquor II;
recovering the mother liquor II, wherein the recovery method of the mother liquor II is the same as that of the acylation mother liquor I, so as to obtain a crude product III of N-acetylcysteine and a mother liquor III;
recrystallizing the crude N-acetylcysteine I, the crude N-acetylcysteine II and the crude N-acetylcysteine III to obtain N-acetylcysteine;
wherein the mol ratio of cysteine to acetic anhydride in the cysteine mother liquor is 1: 1-1: 1.5.
2. the method of claim 1, wherein the cysteine mother liquor is prepared by: performing neutralization reaction on the cysteine hydrochloride solution and alkali liquor, cooling and crystallizing, centrifuging, and washing with water to obtain cysteine and the cysteine mother liquor;
and/or the concentration of cysteine in the cysteine mother liquor is 100-120 g/L.
3. The method of claim 2, wherein the cysteine mother liquor is prepared by: adjusting the pH value of the cysteine hydrochloride solution to 3.5-5.0 by using an alkali solution, cooling to below 5 ℃ until the cysteine hydrochloride solution is completely crystallized, centrifuging, and washing with water to obtain cysteine and the cysteine mother solution.
4. The preparation method according to claim 3, wherein in the preparation method of the cysteine mother liquor, the mass-to-volume ratio of the cysteine hydrochloride to the water in the cysteine hydrochloride solution is 600 to 800 kg: 250-350L.
5. The method according to claim 3, wherein the cysteine hydrochloride solution is prepared in a reaction tank.
6. The process according to claim 3, wherein the crystallization is carried out in a crystallizer in the process for preparing the mother solution of cysteine.
7. The method according to claim 1, wherein the cysteine mother liquor is concentrated under reduced pressure before the pH adjustment;
and/or the pH value is 9.5-11.8;
and/or the molar ratio of cysteine to acetic anhydride in the cysteine mother liquor is 1:1.05, 1:1.15 or 1: 1.1;
and/or the dropping temperature of the acetic anhydride is 50 ℃;
and/or the dripping time of the acetic anhydride is 40 min.
8. The method of claim 7, wherein the reduced pressure concentration ends at: the volume after concentration accounts for 40-60% of the volume before concentration;
and/or the pH value is 9.5-10.
9. The method of claim 8, wherein the reduced pressure concentration ends at: the volume after concentration was 50% of the volume before concentration.
10. The preparation method according to claim 1, wherein the temperature of the heat preservation is 60-70 ℃;
and/or the heat preservation time is 10-30 min;
and/or the heat-preservation end point detection method is carried out by the following steps: taking 1mL of the acylation liquid sample, diluting with water to 100mL, taking 2 mu L of the acylation liquid sample on filter paper, drying, and spraying 2% ninhydrin acetone solution; taking 2 mu L of 0.01% cysteine control solution on filter paper, blowing dry, and spraying 2% ninhydrin acetone solution if the sample solution is weaker than the control solution in color.
11. The method according to claim 10, wherein the holding time is 20 to 30 min.
12. The method according to claim 1, wherein the pH of the acylation liquid is 4 to 7;
and/or the concentration of cysteine in the acylation liquid is less than 0.01 percent, and the concentration is the mass percentage.
13. The method according to claim 1, wherein the pH regulator is hydrochloric acid during the neutralization crystallization.
14. The method according to claim 1, wherein the pH is 1.86 during the neutralization crystallization.
15. The preparation method of claim 1, wherein in the neutralization and crystallization process, the temperature of the filtrate is reduced to 5-10 ℃, and the filtrate is stirred until crystallization is completed.
16. The method according to claim 1, wherein the pH adjusting agent is sodium hydroxide, and the mother liquid I is a sodium hydroxide solution.
17. The method according to claim 1, wherein the end point of the vacuum concentration in the method for recovering the acylation mother liquor I is vacuum concentration to 40 to 60% of the original volume.
18. The method according to claim 1, wherein the pH adjusting agent is hydrochloric acid in the recovery method of the acylation mother liquor I, wherein the pH adjusting agent is hydrochloric acid in the range of 1.5-2.0.
19. The preparation method according to claim 1, wherein in the recovery method of the acylation mother liquor I, the temperature of the filtrate is reduced to 5-10 ℃, and the filtrate is stirred until the crystallization is complete.
20. The method of claim 1, wherein said recrystallization step comprises the steps of: decolorizing the aqueous solution containing the N-acetylcysteine crude product at 50-60 ℃, filtering for the first time, cooling and crystallizing the obtained filtrate to obtain crystals, and filtering, washing and drying the obtained crystals for the second time.
21. The method according to claim 20, wherein in the recrystallization, the weight ratio of crude N-acetylcysteine to water in the aqueous solution is 1: (1-1.1).
22. The method according to claim 20, wherein the decolorization is performed in activated carbon for 10min during the recrystallization.
23. The method of claim 22, wherein the activated carbon is used in an amount of 0.5 wt% based on the crude N-acetylcysteine during the recrystallization.
24. The method according to claim 20, wherein the temperature of the temperature-decreasing crystallization is 5 ℃ or lower during the recrystallization.
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