CN109096161A - A kind of preparation method of N-acetylcystein - Google Patents
A kind of preparation method of N-acetylcystein Download PDFInfo
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- CN109096161A CN109096161A CN201810972373.3A CN201810972373A CN109096161A CN 109096161 A CN109096161 A CN 109096161A CN 201810972373 A CN201810972373 A CN 201810972373A CN 109096161 A CN109096161 A CN 109096161A
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- cysteine
- mother liquor
- acetylcystein
- crude product
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
Abstract
The invention discloses a kind of N-acetylcystein preparation methods.It includes the following steps: at 40~60 DEG C, after acetic anhydride is added in 20~60min and carries out acylation reaction, to keep the temperature after cysteine mother liquor adjusting pH value to 9~12 up to acylated liquid；By in the acylated liquid and after crystallization, obtain N-acetylcystein crude product, after the N-acetylcystein crude product is recrystallized to obtain the final product.Fine work N-acetylcystein can be made using the mother liquor after cysteine hydrochloride production cysteine as raw material in the present invention, reducing production cost, and promotion profit improves enterprise competitiveness in turn on the basis of mitigating environmental pressure.
Description
Technical field
The present invention relates to a kind of methods for preparing N-acetylcystein.
Background technique
N-acetylcystein (N-Acetylcysteine, Ac-Cys), the entitled n-acetyl-L-cysteine of chemistry,
Molecular formula: C5H9NO3S, molecular weight: 163.2, it is white crystalline powder；There is the foul smell of similar garlic, it is sour；Have draw it is moist,
It is soluble easily in water, it is dissolved in ethyl alcohol, does not dissolve in methylene chloride and ether, molecular formula is as follows:
N-acetylcystein is mucolytic agent, causes difficult disease of having difficulty in breathing and cough up phlegm suitable for largely gluing phlegm resistance
Suffer from；Cause sputum viscous for postoperative cough up phlegm difficulty, acute/chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis and pulmonary emphysema etc.
The thick and difficult person that coughs up phlegm.In addition, status is also chiefly used in the treatment of idiopathic interstitial lung.
Cysteine hydrochloride, cysteine and N-acetylcystein are the major product of this field, and industrial one
As using cystine be electrolysed to obtain cysteine hydrochloride, gained cysteine hydrochloride can be used as raw material preparation half Guang of N- acetyl
Propylhomoserin and cysteine.The technique for wherein preparing cysteine is to be added after liquid alkaline neutralizes to obtain after dissolving cysteine hydrochloride
Cysteine is centrifugated to obtain cysteine product and mother liquor, is detected in discovery cysteine mother liquor by iodimetric titration and contains 100
The cysteine of~120g/L, if chloride is extremely difficult to criterion of acceptability in gained cysteine product by mother liquor recycling, if
It is electrolysed to obtain cysteine hydrochloride after mother liquor is oxidized to cystine again as raw material production N-acetylcystein or half Guang
Propylhomoserin not only extends process route, and increases the investment of a large amount of human and material resources, the energy, to enterprise cause economic loss with
And (as shown in FIG. 1, FIG. 1 is prepare cysteine and N- second by cystine in the prior art for the environmental protection pressure of increase wastewater treatment
The process flow chart of acyl cysteine).Therefore, industrial production cysteine mother liquor how is handled, production cost is being reduced, is mitigating
Profit is promoted on the basis of environmental pressure and then improves enterprise competitiveness, is the matter of utmost importance of current industry.
Summary of the invention
To solve the above problems, the present invention provides a kind of N-acetylcystein preparation methods.The preparation method is with half
Cystine mother liquor is that raw material progress acylation reaction obtains N-acetylcystein, and specific reaction equation is as follows.
The present invention solves above-mentioned technical problem by the following technical programs.
The present invention provides a kind of preparation methods of N-acetylcystein comprising following step: by cysteine mother
Liquid adjusts pH value to after 9~12, and at 40~60 DEG C, after acetic anhydride is added in 20~60min and carries out acylation reaction, heat preservation is
Liquid must be acylated；By in the acylated liquid and after crystallization, N-acetylcystein crude product is obtained, by the N-acetylcystein crude product
After recrystallization to obtain the final product.
In the present invention, the cysteine mother liquor can be the cysteine mother liquor of this field routine, generally pass through following steps
Rapid to be made: after cysteine hydrochloride solution and lye are carried out neutralization reaction, after decrease temperature crystalline, centrifugation, washing obtain half Guang
Propylhomoserin and the cysteine mother liquor are preferably carried out by following step: adjusting the cysteine hydrochloride solution with lye
PH value be 3.5~5.0, being cooled to 5 DEG C, to obtain cysteine and the cysteine female completely, to be centrifuged, wash down toward crystallization
Liquid, wherein the mass volume ratio of cysteine hydrochloride and water is 600~800kg in the cysteine hydrochloride solution:
250~350L.
Wherein, the cysteine hydrochloride can be the available product of this field conventional commercial.The water is generally chemical industry
The common purified water in field.The crystallization, the centrifugation, the operation of the washing and condition be this field routine operation and
Condition.The cysteine hydrochloride solution is generally prepared in reactor tank, and the operation of the crystallization is generally in crystallizing tank
Middle progress.
In the present invention, in the cysteine mother liquor, general semicystinol concentration is 100~120g/L.
In the present invention, before the operation for adjusting pH value, preferably the cysteine mother liquor is concentrated under reduced pressure.Institute
The operation and condition of stating reduced pressure can be the operation and condition of this field routine, and the terminal of the reduced pressure is preferred are as follows: dense
Volume after contracting accounts for the 40~60% of condensate precursor product, and the more preferably volume after concentration accounts for the 50% of condensate precursor product.
In the present invention, the pH value is preferably 9.5~11.8, and further preferred 9.5~10.5.
In the present invention, it is necessary to acetic anhydride need to be added dropwise at 40~60 DEG C.If temperature is lower than 40 DEG C, the process of acylation reaction compared with
Slowly, if temperature is higher than 60 DEG C, side reaction easily occurs during acylation reaction.Preferably 50 DEG C of the dropping temperature of the acetic anhydride.Institute
State the preferred 40min of time for adding of acetic anhydride.
In the present invention, cysteine can be normal for this field with the molar ratio of the acetic anhydride in the cysteine mother liquor
Rule, preferably 1:1~1:1.5, such as 1:1.05 or 1:1.1.
In the present invention, the operation of the heat preservation and condition can be the operation and condition of this field routine.The temperature of the heat preservation
Preferably 60~70 DEG C of degree.The time of the heat preservation is preferably 10~30min, more preferable 20~30min.
In the present invention, the end-point detection method of the heat preservation can be conventional for this field, is preferably carried out: being taken by following step
The sample 1mL of the acylated liquid, water are diluted to 100mL, take 2 μ L in spraying 2% ninhydrin acetone solution on filter paper, after drying；It takes
0.01% cysteine contrast solution, 2 μ L is in spraying 2% ninhydrin acetone solution on filter paper, after drying, if sample solution colour developing is weaker than
Contrast solution.
In the present invention, the pH value of the acylated liquid is generally in 4~7 ranges.
In the present invention, in the acylated liquid, the concentration of cysteine is preferably smaller than 0.01%, and (above-mentioned concentration is quality percentage
Number contains 0.01g cysteine that is, in 100g water).If the concentration of cysteine is greater than 0.01% in the acylated liquid, preferably will
The acylation reaction is carried out in the acylated liquid again until the concentration of cysteine is less than 0.01%.
In the present invention, the operation for neutralizing crystallization and condition can be the operation and condition of this field routine, preferably include
Following steps: through the acylated liquid tune pH value to 1.5~2.0, filtering desalination, and gained wet salt discards, and gained filtrate is tied through cooling
Crystalline substance obtains crystal, and the crystal is filtered to, washed, dried and to obtain N-acetylcystein crude product I and acylated mother liquor I.
During the neutralization crystallization, the regulator of the pH value can be conventional for this field, generally hydrochloric acid.The pH
Value preferably 1.86.It is preferred that the filtrate is cooled to 5~10 DEG C, stir complete to filtrate crystallisation.
Preferably, the acylated mother liquor I is recycled.The recovery method of the acylated mother liquor I can be conventional for this field,
It is preferred that carrying out in the steps below: the acylated mother liquor I is adjusted pH value to 4.0~5.0, is concentrated under reduced pressure, then adjust pH value be 1.5~
2.0, desalination is filtered, gained wet salt discards, and gained filtrate obtains crystal through decrease temperature crystalline, the crystal filtering, washing, dry
N-acetylcystein crude product II and mother liquor II.
In the recovery method of the acylated mother liquor I, the regulator for adjusting pH value to 4.0~5.0 can be normal for this field
Rule, generally sodium hydroxide.The operation of the reduced pressure and condition can be conventional for this field, are generally concentrated under reduced pressure into original volume
Half.The regulator for adjusting pH value to 1.5~2.0 can be conventional for this field, generally hydrochloric acid.It is preferred that by filtering
Liquid is cooled to 5~10 DEG C, stirs complete to filtrate crystallisation.
Preferably, the mother liquor II is recycled.The recovery method of the mother liquor II can be conventional for this field, generally with
The recovery method of the acylated mother liquor I is identical, can finally obtain N-acetylcystein crude product III and mother liquor III.
Preferably, by the N-acetylcystein crude product I, the N-acetylcystein crude product II and the N- acetyl
Cysteine crude product III can obtain the N-acetylcystein after being recrystallized.
In the present invention, the operation of the recrystallization and condition can be the operation and condition of this field routine, preferably include as
Lower step: it at 50~60 DEG C, after the aqueous solution containing N-acetylcystein crude product is decolourized, filters for the first time, institute
It obtains filtrate decrease temperature crystalline and obtains crystal, the crystal is through second of filtering, washing, drying.
In the recrystallization process, in the aqueous solution, the weight ratio of N-acetylcystein crude product and the water can be
This field is conventional, preferably 1:(1~1.1).The operation of the decoloration and condition can be conventional for this field, it is preferable that in active carbon
Decolourize 10min.The dosage of the active carbon can be conventional for this field, the preferably described N-acetylcystein crude product weight
0.5wt%.The temperature of the decrease temperature crystalline can be conventional for this field, and preferably 5 DEG C or less.The first time filtering, second of mistake
Filter, the washing, the operation of the drying and condition are this field routine.If continuous production, second of filtering gained
Filtrate need to be mixed with the cysteine mother liquor.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
Half Guang of fine work N- acetyl can be made using the mother liquor after cysteine hydrochloride production cysteine as raw material in the present invention
Propylhomoserin is reducing production cost, and promotion profit improves enterprise competitiveness in turn on the basis of mitigating environmental pressure.
Detailed description of the invention
Fig. 1 is the process flow chart for preparing cysteine and N-acetylcystein by cystine in the prior art.
Fig. 2 is the process flow chart for preparing N-acetylcystein in embodiment 1 by cysteine mother liquor.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In Examples 1 to 4, cysteine mother liquor used is made by following step: it is pure that 300L is put into reactor tank
Change water and 700kg cysteine hydrochloride (general commercially available), dissolution is sufficiently stirred；It is transferred in crystallizing tank, is passed through lye tune
PH value is saved to 4.5, is cooled to 5 DEG C with complete down toward crystallization；It is centrifuged, washes to obtain cysteine and cysteine mother liquor.Half Guang ammonia
In acid mother liquor, semicystinol concentration is 120g/L.
Embodiment 1
(1) acylation reaction:
1000mL cysteine mother liquor is concentrated under reduced pressure, volume concentration to 500mL stops being concentrated, and concentrate is transferred to reaction
In container, 76g sodium hydroxide is added in concentrate and adjusts pH value to 9.5~10,105.7g acetic acid is added dropwise into reaction vessel
Acid anhydride (molar ratio of cysteine and acetic anhydride is 1:1.05 in reaction system), 40 DEG C of control system temperature, when acetic anhydride is added dropwise
Between be 60min, 20~30min, and sample detection reaction end are kept the temperature at 60~70 DEG C after reaction.Reaction end detection is closed
Acylated liquid is obtained after lattice, it is unqualified, add appropriate acetic anhydride after afterflow.
Reaction end detection method is: taking acylated liquid 1mL, water is diluted to 100mL, takes 2 μ L on filter paper, sprays after drying
2% ninhydrin acetone soln；0.01% cysteine contrast solution, 2 μ L is taken with method, if sample solution colour developing is weaker than contrast solution
?.
(2) crystallization is neutralized
199g Nacl acid for adjusting pH value is added into acylated liquid to 1.86, filters desalination, wet salt discards, filtrate cooling knot
Crystalline substance, is cooled to 5~10 DEG C, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washing, dry N- mucolyticum
Acid crude 94.2g and acylated mother liquor I.
(3) disposing mother liquor
Acylated mother liquor I is recycled: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts acylated mother liquor I, is concentrated under reduced pressure, it is dense
It is reduced to the half of about original volume, processing industry hydrochloric acid tune pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to
In crystallisation vessel, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washes, dry
It is dry to obtain N-acetylcystein crude product II30g and mother liquor II.
The method of mother liquor II recycling: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts mother liquor II, is concentrated under reduced pressure, is concentrated into
The about half of original volume, processing industry salt acid for adjusting pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to knot
In brilliant container, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring is complete to material crystallization.Filtering, washing, dry 10g N- acetyl
Cysteine crude product III and mother liquor III.
(4) it recrystallizes
In decoloration container, crude product, crude product II, crude product III is added, amounts to 134.2g, and 140g purified water is added.Stirring
50~60 DEG C of dissolutions are heated to, 0.5% active carbon decoloring 10min of crude product total amount, decolorization filtering, filtrate cooling knot is added
Crystalline substance, filtrate are cooled to 5 DEG C or less and stir and is precipitated completely to crystal, filtering washing, dry N-acetylcystein fine work 107g.
Filtrate essence mother, which can return in first step acylation process, when continuous production is concentrated.
Fig. 2 is the process flow chart for preparing N-acetylcystein in embodiment 1 by cysteine mother liquor.
Embodiment 2
(1) acylation reaction:
1000mL cysteine mother liquor is concentrated under reduced pressure, volume concentration to 500mL stops being concentrated, and concentrate is transferred to reaction
In container, 70g sodium hydroxide is added in concentrate and adjusts pH value 9.5~10.0,111.4g acetic acid is added dropwise into reaction vessel
Acid anhydride (molar ratio of cysteine and acetic anhydride is 1:1.10 in reaction system), control system temperature 60 C, when acetic anhydride is added dropwise
Between 20min, keep the temperature 20~30 minutes for 60~70 DEG C after reaction, and sample detection reaction end.Reaction end detection is qualified
After obtain acylated liquid, it is unqualified, add appropriate acetic anhydride after afterflow.
Reaction end detection method is same as Example 1.
(2) crystallization is neutralized
199g Nacl acid for adjusting pH value is added into acylated liquid to 1.86, filters desalination, wet salt discards, filtrate cooling knot
Crystalline substance, is cooled to 5~10 DEG C, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washing, dry N- mucolyticum
Acid crude 106.6g and acylated mother liquor I.
(3) disposing mother liquor
Acylated mother liquor I is recycled: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts acylated mother liquor I, is concentrated under reduced pressure, it is dense
It is reduced to the half of about original volume, processing industry hydrochloric acid tune pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to
In crystallisation vessel, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washes, dry
It is dry to obtain N-acetylcystein crude product II29g and mother liquor II.
The method of mother liquor II recycling: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts mother liquor II, is concentrated under reduced pressure, is concentrated into
The about half of original volume, processing industry salt acid for adjusting pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to knot
In brilliant container, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring is complete to material crystallization.Filtering, washing, dry 8.2g N- acetyl
Cysteine crude product III and mother liquor III.
(4) it recrystallizes
In decoloration container, crude product, crude product II, crude product III is added, amounts to 142.8g, and 145g purified water is added.Stirring
50~60 DEG C of dissolutions are heated to, 0.5% active carbon decoloring 10min of crude product total amount, decolorization filtering, filtrate cooling knot is added
Crystalline substance, filtrate are cooled to 5 DEG C or less and stir and is precipitated completely to crystal, filtering washing, dry N-acetylcystein fine work
119.9g.Filtrate essence mother, which can return in first step acylation process, when continuous production is concentrated.
Embodiment 3
(1) acylation reaction:
1000mL cysteine mother liquor is concentrated under reduced pressure, volume concentration to 500mL stops being concentrated, and concentrate is transferred to reaction
In container, 70g sodium hydroxide is added in concentrate and adjusts pH value to 9.5~10.0,116.8g second is added dropwise into reaction vessel
Acid anhydrides (molar ratio of cysteine and acetic anhydride is 1:1.15 in reaction system), control system temperature 50 C, acetic anhydride is added dropwise
Time 40min, after reaction 60~70 DEG C of 20~30min of heat preservation, and sample detection reaction end.Reaction end detection is qualified
After obtain acylated liquid, it is unqualified, add appropriate acetic anhydride after afterflow.
Reaction end detection method is same as Example 1.
(2) crystallization is neutralized
199g Nacl acid for adjusting pH value is added into acylated liquid to 1.86, filters desalination, wet salt discards, filtrate cooling knot
Crystalline substance, is cooled to 5~10 DEG C, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washing, dry N- mucolyticum
Acid crude 110.1g and acylated mother liquor I.
(3) disposing mother liquor
Acylated mother liquor I is recycled: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts acylated mother liquor I, is concentrated under reduced pressure, it is dense
It is reduced to the half of about original volume, processing industry hydrochloric acid tune pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to
In crystallisation vessel, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washes, dry
It is dry to obtain N-acetylcystein crude product II27g and mother liquor II.
The method of mother liquor II recycling: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts mother liquor II, is concentrated under reduced pressure, is concentrated into
The about half of original volume, processing industry salt acid for adjusting pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to knot
In brilliant container, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring is complete to material crystallization.Filtering, washing, dry 7.5g N- acetyl
Cysteine crude product III and mother liquor III.
(4) it recrystallizes
In decoloration container, crude product, crude product II, crude product III is added, amounts to 144.6g, and 145g purified water is added.Stirring
50~60 DEG C of dissolutions are heated to, 0.5% active carbon decoloring 10min of crude product total amount, decolorization filtering, filtrate cooling knot is added
Crystalline substance, filtrate are cooled to 5 DEG C or less and stir and is precipitated completely to crystal, filtering washing, dry N-acetylcystein fine work 115g.
Filtrate essence mother, which can return in first step acylation process, when continuous production is concentrated.
Embodiment 4
(1) acylation reaction:
1000mL cysteine mother liquor is concentrated under reduced pressure, volume concentration to 500mL stops being concentrated, and concentrate is transferred to reaction
In container, 88.4g sodium hydroxide is added in concentrate and adjusts pH value to 11.8,111.0g acetic anhydride is added dropwise into reaction vessel
(molar ratio of cysteine and acetic anhydride is 1:1.15 in reaction system), control system temperature 50 C, acetic anhydride time for adding
40min, after reaction 60~70 DEG C of 20~30min of heat preservation, and sample detection reaction end.After reaction end detection is qualified
It is unqualified to acylated liquid, add appropriate acetic anhydride after afterflow.
Reaction end detection method is same as Example 1.
(2) crystallization is neutralized
243.9g Nacl acid for adjusting pH value is added into acylated liquid to 1.86, filters desalination, wet salt discards, filtrate cooling
Crystallization, is cooled to 5~10 DEG C, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washing, dry half Guang of N- acetyl
Propylhomoserin crude product 101.33g and acylated mother liquor I.
(3) disposing mother liquor
Acylated mother liquor I is recycled: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts acylated mother liquor I, is concentrated under reduced pressure, it is dense
It is reduced to the half of about original volume, processing industry hydrochloric acid tune pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to
In crystallisation vessel, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring to material crystallization completely, obtains crystal, by crystal filtering, washes, dry
It is dry to obtain N-acetylcystein crude product II18g and mother liquor II.
The method of mother liquor II recycling: it is 4.0~5.0 with the pH value that sodium hydroxide adjusts mother liquor II, is concentrated under reduced pressure, is concentrated into
The about half of original volume, processing industry salt acid for adjusting pH value to 1.5~2.0.Desalination is filtered while hot, and wet salt is discarded, and filtrate is transferred to knot
In brilliant container, filtrate is cooled to 5~10 DEG C of crystallizations, and stirring is complete to material crystallization.Filtering, washing, dry 6.5g N- acetyl
Cysteine crude product III and mother liquor III.
(4) it recrystallizes
In decoloration container, crude product, crude product II, crude product III is added, amounts to 125.83g, and 100g purified water is added.It stirs
It mixes and is heated to 50~60 DEG C of dissolutions, 0.5% active carbon decoloring 10min of crude product total amount, decolorization filtering, filtrate cooling knot is added
Crystalline substance, filtrate are cooled to 5 DEG C or less and stir and is precipitated completely to crystal, filtering washing, dry N-acetylcystein fine work
100.66g.Filtrate essence mother, which can return in first step acylation process, when continuous production is concentrated.
PH is adjusted to 11.8 before embodiment 4 will be acylated, and piece base amount increases by 20.8%, and hydrochloric acid dosage increases 18.4%, not only
Soda acid dosage is increased, while increasing reaction solution volume.Although impurity C, the more other mother liquors of amount of impurity D are low in two mothers,
Yield does not significantly improve.
Comparative example 1
In addition to operations described below condition, other operating conditions are same as Example 1.
Acylated mother liquor I is recycled: acylated mother liquor I is concentrated under reduced pressure, and is concentrated into the half of about original volume, and filtering is de- while hot
Salt, wet salt is discarded, and filtrate is transferred in crystallisation vessel, and filtrate is cooled to 5~10 DEG C of crystallizations, and stirring to material crystallization completely, obtains brilliant
Body, by crystal filtering, washing, dry N-acetylcystein crude product II and mother liquor II.
Effect example 1
Fine work obtained by Examples 1 to 4 is detected, the inspection including related substances, specific rotation, transmitance, content, pH
It surveys, wherein the testing result of related substances (HPLC) is shown in Table 1, and specific rotation, transmitance, content, the testing result of pH are shown in Table 2.Its
In, the detecting instrument model Hitachi L2420 of 1 data of table is detected according to EP8 in relation to the chromatographic condition of substance；2 data of table
Detecting instrument model Hitachi L2420, detected according to Japanese aginomoto AJI97 standard.
The HPLC testing result of fine work obtained by 1 Examples 1 to 4 of table
In table, A is cystine, and B is cysteine, C N, N- diacetyl cystine, D N, S- diacetyl cysteine.
The conventional detection result of fine work obtained by 2 Examples 1 to 4 of table
By table 1,2 it is found that fine work obtained by Examples 1 to 4 meets Japanese aginomoto AJI97 standard.Examples 1 to 4 institute
Obtaining specific rotation in fine work, between 25.4 °~26.4 °, transmitance is in 98.7% or more, N-acetylcystein content
99.3% or more, pH value is in 2.4~2.6 ranges.
Method that pH is directly concentrated is not adjusted when recycling simultaneously using mother I as comparative example (other techniques are same as Example 1),
The concentration of impurity in mother liquor is detected by the way of HPLC, testing result is shown in Table 3.
The HPLC testing result of the mother liquor II of 3 Examples 1 to 4 of table, comparative example 1
In table, A is cystine, and B is cysteine, C N, N- diacetyl cystine, D N, S- diacetyl cysteine.
As shown in Table 3, the acylated mother liquor I of the present invention is carried out in removal process, and concentration front and back regulation system pH value can effectively press down
The generation of impurity D in mother liquor II processed.
Fine work yield obtained by Examples 1 to 4 is as shown in table 4, and yield is mass yield, yield=fine work quality/half Guang ammonia
Cysteine quality * 100% in acid mother liquor.
Fine work yield obtained by 4 Examples 1 to 4 of table
Claims (10)
1. a kind of preparation method of N-acetylcystein, which is characterized in that it includes the following steps: cysteine mother liquor tune
PH value is saved to after 9~12, at 40~60 DEG C, after acetic anhydride is added in 20~60min and carries out acylation reaction, is kept the temperature up to acyl
Change liquid；By in the acylated liquid and after crystallization, N-acetylcystein crude product is obtained, the N-acetylcystein crude product is tied again
After crystalline substance to obtain the final product.
2. preparation method as described in claim 1, which is characterized in that the cysteine mother liquor is made by following step:
After cysteine hydrochloride solution and lye are carried out neutralization reaction, after decrease temperature crystalline, centrifugation, washing obtain cysteine and institute
State cysteine mother liquor, preferably pass through following step and carry out: with the pH value that lye adjusts cysteine hydrochloride solution be 3.5~
5.0,5 DEG C are cooled to completely, to be centrifuged down toward crystallization, wash to obtain cysteine and the cysteine mother liquor；
In the preparation method of the cysteine mother liquor, in the cysteine hydrochloride solution, cysteine hydrochloride and water
Mass volume ratio be preferably 600~800kg:250~350L；The cysteine hydrochloride solution preferably in reactor tank into
Row is prepared, and the operation of the crystallization carries out preferably in crystallizing tank；
And/or in the cysteine mother liquor, semicystinol concentration is 100~120g/L.
3. preparation method as described in claim 1, which is characterized in that before the operation for adjusting pH value, by half Guang
Propylhomoserin mother liquor is concentrated under reduced pressure；The terminal of the reduced pressure is preferred are as follows: the volume after concentration account for condensate precursor product 40~
60%, the more preferably volume after concentration accounts for the 50% of condensate precursor product；
And/or the pH value is 9.5~11.8, preferably 9.5~10；
And/or the molar ratio of cysteine and the acetic anhydride is 1:1~1:1.5 in the cysteine mother liquor, preferably 1:
1.05,1:1.15 or 1:1.1；
And/or 50 DEG C of the dropping temperature of the acetic anhydride；
And/or the time for adding of the acetic anhydride is 40min.
4. preparation method as described in claim 1, which is characterized in that the temperature of the heat preservation is 60~70 DEG C；
And/or the time of the heat preservation is 10~30min, preferably 20~30min；
And/or the end-point detection method of the heat preservation is carried out by following step: taking the sample 1mL of the acylated liquid, water dilution
To 100mL, take 2 μ L in spraying 2% ninhydrin acetone solution on filter paper, after drying；Take 0.01% cysteine contrast solution, 2 μ L in filter
2% ninhydrin acetone solution is sprayed on paper, after drying, if sample solution colour developing is weaker than contrast solution.
5. preparation method as described in claim 1, which is characterized in that the pH value of the acylated liquid is 4~7；
And/or in the acylated liquid, for the concentration of cysteine less than 0.01%, above-mentioned concentration is mass percent.
6. preparation method as described in claim 1, which is characterized in that it is described neutralize crystallization operation include the following steps: through
The acylated liquid tune pH value is to 1.5~2.0, and filtering, gained filtrate obtains crystal through decrease temperature crystalline, by the filtering of gained crystal, water
It washes, dry to obtain N-acetylcystein crude product I and acylated mother liquor I；
During the neutralization crystallization, the regulator of the pH value is preferably hydrochloric acid；The pH value is preferably 1.86；It is preferred that will
The filtrate is cooled to 5~10 DEG C, stirs complete to filtrate crystallisation.
7. preparation method as claimed in claim 6, which is characterized in that recycle the acylated mother liquor I；It is described acylated female
The recovery method of liquid I carries out in the steps below: the acylated mother liquor I is adjusted pH value to 4.0~5.0, is concentrated under reduced pressure, then adjust pH
Value is 1.5~2.0, filtering, and gained filtrate obtains crystal through decrease temperature crystalline, the filtering of gained crystal, washing, dry N- acetyl half
Cystine crude product II and mother liquor II；
In the recovery method of the acylated mother liquor I, the regulator for adjusting pH value to 4.0~5.0 is preferably sodium hydroxide；Institute
The terminal for stating reduced pressure is preferably concentrated under reduced pressure into the 40~60% of original volume；The adjusting for adjusting pH value to 1.5~2.0
Agent is preferably hydrochloric acid；It is preferred that cooling the filtrate to 5~10 DEG C, stir complete to filtrate crystallisation.
8. preparation method as claimed in claim 7, which is characterized in that the mother liquor II is recycled, the mother liquor II's
Recovery method is identical as the recovery method of the acylated mother liquor I, obtains N-acetylcystein crude product III and mother liquor III.
9. preparation method as claimed in claim 8, which is characterized in that by the N-acetylcystein crude product I, the N- second
The acyl cysteine crude product II and N-acetylcystein crude product III can obtain N-acetylcystein after being recrystallized.
10. the preparation method as described in claim 1 or 9, which is characterized in that the operation of the recrystallization includes the following steps:
It at 50~60 DEG C, after the aqueous solution containing N-acetylcystein crude product is decolourized, filters for the first time, gained filtrate drop
Temperature crystallizes to obtain crystal, and gained crystal is through second of filtering, washing, drying；
In the recrystallization process, in the aqueous solution, the preferred 1:(1 of the weight ratio of N-acetylcystein crude product and the water
~1.1)；The operation of the decoloration is preferably decolourized in active carbon 10min；The dosage of the active carbon is preferably the N- acetyl
The 0.5wt% of cysteine crude product weight；Preferably 5 DEG C or less of the temperature of the decrease temperature crystalline.
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| CN110344077A (en) * | 2019-07-01 | 2019-10-18 | 吉林大学 | A method of by l-cysteine electrochemistry formated n-acetyl-L-cysteine |
| CN111718287A (en) * | 2020-06-12 | 2020-09-29 | 吉林大学 | Electrodialysis extraction method of N-acetyl-L-cysteine |
| CN112245412A (en) * | 2020-09-28 | 2021-01-22 | 山西国润制药有限公司 | Acetylcysteine solution for inhalation and preparation method and application thereof |
| CN113461580A (en) * | 2021-06-25 | 2021-10-01 | 浙江金华康恩贝生物制药有限公司 | N-acetyl-L-cysteine synthesis method |
| CN113461581A (en) * | 2021-03-02 | 2021-10-01 | 杭州浙中医药科技有限公司 | Environment-friendly high-yield method for synthesizing acetylcysteine |
| CN114989055A (en) * | 2022-07-06 | 2022-09-02 | 浙江金华康恩贝生物制药有限公司 | Preparation method of N-acetyl-L-cysteine |
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| CN110344077A (en) * | 2019-07-01 | 2019-10-18 | 吉林大学 | A method of by l-cysteine electrochemistry formated n-acetyl-L-cysteine |
| CN111718287A (en) * | 2020-06-12 | 2020-09-29 | 吉林大学 | Electrodialysis extraction method of N-acetyl-L-cysteine |
| CN111718287B (en) * | 2020-06-12 | 2022-02-18 | 吉林大学 | Electrodialysis extraction method of N-acetyl-L-cysteine |
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| CN113461581A (en) * | 2021-03-02 | 2021-10-01 | 杭州浙中医药科技有限公司 | Environment-friendly high-yield method for synthesizing acetylcysteine |
| CN113461580A (en) * | 2021-06-25 | 2021-10-01 | 浙江金华康恩贝生物制药有限公司 | N-acetyl-L-cysteine synthesis method |
| CN113461580B (en) * | 2021-06-25 | 2023-08-15 | 浙江金华康恩贝生物制药有限公司 | N-acetyl-L-cysteine synthesis method |
| CN114989055A (en) * | 2022-07-06 | 2022-09-02 | 浙江金华康恩贝生物制药有限公司 | Preparation method of N-acetyl-L-cysteine |
| CN115772104A (en) * | 2022-11-15 | 2023-03-10 | 广东百澳药业有限公司 | Preparation method of N-acetyl-L-cysteine |
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