CN108558721A - A kind of preparation method of N, N- diacetyl-l-cysteine - Google Patents
A kind of preparation method of N, N- diacetyl-l-cysteine Download PDFInfo
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- CN108558721A CN108558721A CN201810497975.8A CN201810497975A CN108558721A CN 108558721 A CN108558721 A CN 108558721A CN 201810497975 A CN201810497975 A CN 201810497975A CN 108558721 A CN108558721 A CN 108558721A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
Abstract
The invention discloses a kind of N, the preparation methods of N diacetyl L cystines.The raw material that this method uses includes：L cystines, liquid caustic soda, acetic anhydride, hydrochloric acid, ether, methanol etc.；Equipment includes：Reaction kettle, blender, filter, concentration tank, crystallization kettle etc..By acetylization reaction, neutralization, evaporation and concentration, filtering, crystallization and etc. be made sterling.Reaction temperature is controlled at 0 DEG C, the hydrolysis of acetic anhydride is not only reduced, but also avoids L cystine racemizations, reduces the generation of by-product.In addition, the present invention strictly controls reaction condition, such as alkaline concentration, pH value in reaction, using acetic anhydride and alkali alternate dropwise addition, reaction is more abundant, excessive acetic anhydride is not needed, to reduce production cost.The present invention uses methanol purification product, and product purity obtained is high, yield is high.The technique high, simple for process, of low cost, advantages of environment protection with production efficiency.
Description
Technical field
The invention belongs to the technical fields of organic chemical synthesis, and in particular to the life of a kind of N, N- diacetyl-l-cysteine
Production method.
Technical background
Amino acid has extremely extensive purposes, cystine to be in food, medicine, feed, agricultural, daily use chemicals, pesticide etc.
A kind of disulfide, it plays an important role in terms of biochemistry, it can protect cell to inhibit its oxidation, remains thin
The reduction potential of born of the same parents can adjust the metabolism etc. of cell.
N-acetyl-L-cysteine is a kind of well known amino acid derivativges containing sulfydryl, has multiple biological activities, can
As mucolytic agent, for treating respiratory disease, also there is good curative effect to hepatic failure caused by each Hepatitis virus.
N, N- diacetyl-l-cysteine are also a kind of well known amino acid derivativges containing sulfydryl, are N-acetyl-L-cysteines with two
The dimer that sulfide linkage combines has stronger immunostimulation, and the intensity of immunization is N-acetyl-L-cysteine
1000 times, I type anaphylactic types can be stimulated, inhibit IV type delayed allergies.It additionally can prove that N, N- diacetyl-
L-cysteine can be obviously improved the easypro blood function of damaged endothelial cell, but not influence the easypro blood function of normal endothelial cell.Its
Immunocompetence is higher than N-acetyl-L-cysteine, can be used for preparing the drug with immunoregulatory activity, antitumor drug, controls
Treat the drug of immunologic deficiency disease.
Invention content
The purpose of the present invention is to provide a kind of reaction conditions mildly, is simple to operate and friendly to environment, high-purity, high yield
Preparation N, N- diacetyl-l-cysteine method.
The present invention uses following technical scheme：
The preparation method of a kind of N, N- diacetyl-l-cysteine, includes the following steps：
Step 1：L-cysteine solid is added into reaction kettle, 1-2mol/L sodium hydroxide solutions are then added, make solid
It is completely dissolved, pH value of solution 9-11, the weight ratio of l-cysteine and sodium hydroxide solution is 3:1.
Step 2：Under the conditions of 0 DEG C, acetic anhydride is slowly added dropwise dropwise into the solution of step 1 and carries out acetylization reaction,
The weight ratio of mechanical agitation, l-cysteine and acetic anhydride is 1:3-4, while alternate dropwise addition 1mol/L sodium hydroxide solutions are maintained
PH value of solution is 9-11, detects reaction end with thin layer chromatography, ninhydrin is that color developing agent does not develop the color as reaction end, after continuation of insurance
It is 0.5-1 hours warm, it reacts 2-3 hours；
Step 3：1mol/L hydrochloric acid is added into the reaction solution of step 2, adjusting pH is 2-3, and vacuum evaporation obtains
The mixture of N, N- diacetyl-l-cysteine crude product and inorganic salts；
Step 4：Methanol solution, the weight of methanol solution and raw material l-cysteine are added in the mixture obtained to step 3
Amount is than being 4:1, N, N- diacetyl-l-cysteine crude product are dissolved in methanol, and insoluble inorganic salts are filtered to remove with filter, are obtained
To containing N, the methanol solution of N- diacetyl-l-cysteine；
Step 5：Contain N by what step 4 obtained, the methanol solution of N- diacetyl-l-cysteine is carried out true by concentration tank
Sky is concentrated by evaporation, and ether extracts 3 times, and the weight ratio of ether and raw material l-cysteine is 4:1, remaining acetic acid is removed, N is obtained,
The crude product of N- diacetyl-l-cysteine；
Step 6：The crude product that step 5 obtains is put into crystallization kettle, methanol is added and is recrystallized, methanol and raw material L-
The weight ratio of cystine is 3-4:1, it crystallizes 2-3 times, washes, filtering, vacuum evaporation obtains N, N- diacetyl-L- Guang ammonia
The sterling of acid；
Step 7：The product that step 6 obtains is put into dryer, drying temperature is 50 DEG C -60 DEG C, drying time 6-8
Hour, it can be obtained finished product after drying.
Advantageous effect：
(1) it uses acetic anhydride and lye alternate dropwise addition, mechanical agitation strictly to control pH value in reaction, is not necessarily to excessive acetic acid acid anhydride
It can fully react, be without the use of a large amount of organic reagents, to reduce production cost, and also it is very friendly to environment.
(2) by thin layer chromatography, ninhydrin is color developing agent, judges reaction end.
(3) it selects methanol to attach most importance to crystalline reagents, N, the sterling of N- diacetyl-l-cysteine can be obtained.
(4) it is high that product purity height, yield is made, up to 90% or more.
(5) reaction step is simple, easy to operate.
Specific implementation mode
Embodiment 1
(1) 24g l-cysteine solids are added into reaction kettle, the sodium hydroxide solution of 100ml2mol/L is then added,
Solid is set to be completely dissolved.
(2) under the conditions of 0 DEG C, 30ml acetic anhydrides are slowly added dropwise dropwise into above-mentioned solution, carry out acetylization reaction, and machine
Tool stirs, while the sodium hydroxide solution of alternate dropwise addition 2mol/L, and it is 9 to keep solution ph, dips reaction solution with capillary, point
On thin layer silica gel plate, color developing agent is made with ninhydrin, is not developed the color as reaction end, continue heat preservation 0.5 hour, reacted 2 hours.
(3) 150ml2mol/L hydrochloric acid is added into the reaction solution of above-mentioned gained, it is 2 to adjust pH, and reaction solution is added and is concentrated
In tank, vacuum evaporation obtains N, the mixture of N- diacetyl-l-cysteine crude product and inorganic salts.
(4) 120ml methanol is added to above-mentioned obtained mixture, solid portion dissolving feeds the mixture into filter
In, insoluble inorganic salts are filtered to remove, obtain containing N, the methanol solution of N- diacetyl-l-cysteine.
(5) will be above-mentioned obtained containing N, the methanol solution of N- diacetyl-l-cysteine injects concentration tank, is evaporated in vacuo
Concentration is extracted with 100ml ether every time, is extracted 3 times, is removed remaining acetic acid, obtain N, the thick production of N- diacetyl-l-cysteine
Product.
(6) above-mentioned obtained crude product is added in crystallization kettle, is recrystallized every time with 100ml methanol, crystallization 3
It is secondary, it washes, filters, be concentrated by evaporation, obtain N, the sterling of N- diacetyl-l-cysteine.
(7) above-mentioned gained sterling is put into dryer, drying temperature is 50 DEG C, and drying time is 8 hours, after drying
Obtain finished product.Yield 81%.
Embodiment 2
(1) 24g l-cysteine solids are added into reaction kettle, the sodium hydroxide solution of 100ml2mol/L is then added,
Solid is set to be completely dissolved.
(2) under the conditions of 0 DEG C, 30ml acetic anhydrides are slowly added dropwise dropwise into above-mentioned solution, carry out acetylization reaction, and machine
Tool stirs, while the sodium hydroxide solution of alternate dropwise addition 2mol/L, and it is 11 to keep solution ph, and reaction solution is dipped with capillary,
Point makees color developing agent with ninhydrin, does not develop the color as reaction end on thin layer silica gel plate, continues heat preservation 0.5 hour, and reaction 3 is small
When.
(3) 150ml2mol/L hydrochloric acid is added into the reaction solution of above-mentioned gained, it is 2 to adjust pH, and reaction solution is added and is concentrated
In tank, vacuum evaporation obtains N, the mixture of N- diacetyl-l-cysteine crude product and inorganic salts.
(4) 120ml methanol is added to above-mentioned obtained mixture, solid portion dissolving feeds the mixture into filter
In, insoluble inorganic salts are filtered to remove, obtain containing N, the methanol solution of N- diacetyl-l-cysteine.
(5) will be above-mentioned obtained containing N, the methanol solution of N- diacetyl-l-cysteine injects concentration tank, is evaporated in vacuo
Concentration is extracted with 100ml ether every time, is extracted 3 times, is removed remaining acetic acid, obtain N, the thick production of N- diacetyl-l-cysteine
Product.
(6) above-mentioned obtained crude product is added in crystallization kettle, is recrystallized every time with 100ml methanol, crystallization 3
It is secondary, it washes, filters, be concentrated by evaporation, obtain N, the sterling of N- diacetyl-l-cysteine.
(7) above-mentioned gained sterling is put into dryer, drying temperature is 60 DEG C, and drying time is 6 hours, after drying
Obtain finished product.Yield 78%.
Embodiment 3
(1) 24g l-cysteine solids are added into reaction kettle, the sodium hydroxide solution of 200ml1mol/L is then added,
Solid is set to be completely dissolved.
(2) under the conditions of 0 DEG C, 40ml acetic anhydrides are slowly added dropwise dropwise into above-mentioned solution, carry out acetylization reaction, and machine
Tool stirs, while the sodium hydroxide solution of alternate dropwise addition 2mol/L, and it is 10 to keep solution ph, and reaction solution is dipped with capillary,
Point makees color developing agent with ninhydrin, does not develop the color as reaction end on thin layer silica gel plate, continues heat preservation 0.5 hour, and reaction 2 is small
When.
(3) 200ml1mol/L hydrochloric acid is added into the reaction solution of above-mentioned gained, it is 2 to adjust pH, and reaction solution is added and is concentrated
In tank, vacuum evaporation obtains N, the mixture of N- diacetyl-l-cysteine crude product and inorganic salts.
(4) 120ml methanol is added to above-mentioned obtained mixture, solid portion dissolving feeds the mixture into filter
In, insoluble inorganic salts are filtered to remove, obtain containing N, the methanol solution of N- diacetyl-l-cysteine.
(5) will be above-mentioned obtained containing N, the methanol solution of N- diacetyl-l-cysteine injects concentration tank, is evaporated in vacuo
Concentration is extracted with 100ml ether every time, is extracted 3 times, is removed remaining acetic acid, obtain N, the thick production of N- diacetyl-l-cysteine
Product.
(6) above-mentioned obtained crude product is added in crystallization kettle, is recrystallized every time with 120ml methanol, crystallization 2
It is secondary, it washes, filtering, vacuum evaporation obtains N, the sterling of N- diacetyl-l-cysteine.
(7) above-mentioned gained sterling is put into dryer, drying temperature is 60 DEG C, and drying time is 6 hours, after drying
Obtain finished product, yield 85%.
Embodiment 4
(1) 24g l-cysteine solids are added into reaction kettle, the onium hydroxide solution of 200ml1mol/L is then added, makes
Solid is completely dissolved.
(2) under the conditions of 0 DEG C, 40ml acetic anhydrides are slowly added dropwise dropwise into above-mentioned solution, carry out acetylization reaction, and machine
Tool stirs, while the sodium hydroxide solution of alternate dropwise addition 1mol/L, and it is 11 to keep solution ph, and reaction solution is dipped with capillary,
Point makees color developing agent with ninhydrin, does not develop the color as reaction end on thin layer silica gel plate, continues heat preservation 0.5 hour, and reaction 3 is small
When.
(3) 200ml1mol/L hydrochloric acid is added into the reaction solution of above-mentioned gained, it is 2 to adjust pH, and reaction solution is added and is concentrated
In tank, vacuum evaporation obtains N, the mixture of N- diacetyl-l-cysteine crude product and inorganic salts.
(4) 120ml methanol is added in above-mentioned obtained mixture, solid portion dissolving feeds the mixture into filter
In, inorganic salts not are filtered to remove, obtain containing N, the methanol solution of N- diacetyl-l-cysteine.
(5) will be above-mentioned obtained containing N, the methanol solution of N- diacetyl-l-cysteine injects concentration tank, is evaporated in vacuo
Concentration is extracted with 100ml ether every time, is extracted 3 times, is removed remaining acetic acid, obtain N, the thick production of N- diacetyl-l-cysteine
Product.
(6) above-mentioned obtained crude product is added in crystallization kettle, is recrystallized every time with 120ml methanol, crystallization 3
It is secondary, it washes, filters, be concentrated by evaporation, obtain N, the sterling of N- diacetyl-l-cysteine.
(7) above-mentioned gained sterling is put into dryer, drying temperature is 60 DEG C, and drying time is 6 hours, after drying
Obtain finished product, yield 95%.
Claims (1)
1. the preparation method of a kind of N, N- diacetyl-l-cysteine, it is characterised in that include the following steps：
Step 1：L-cysteine solid is added into reaction kettle, 1-2mol/L sodium hydroxide solutions are then added, keep solid complete
The weight ratio of dissolving, pH value of solution 9-11, l-cysteine and sodium hydroxide solution is 3:1.
Step 2：Under the conditions of 0 DEG C, acetic anhydride is slowly added dropwise dropwise into the solution of step 1 and carries out acetylization reaction, machinery
The weight ratio of stirring, l-cysteine and acetic anhydride is 1:3-4, while alternate dropwise addition 1mol/L sodium hydroxide solutions maintain solution
PH is 9-11, detects reaction end with thin layer chromatography, ninhydrin is that color developing agent does not develop the color as reaction end, continues to keep the temperature
It 0.5-1 hours, reacts 2-3 hours；
Step 3：1mol/L hydrochloric acid is added into the reaction solution of step 2, adjusting pH is 2-3, and vacuum evaporation obtains N, N-
The mixture of diacetyl-l-cysteine crude product and inorganic salts；
Step 4：Methanol solution, the weight ratio of methanol solution and raw material l-cysteine are added in the mixture obtained to step 3
It is 4:1, N, N- diacetyl-l-cysteine crude product are dissolved in methanol, and insoluble inorganic salts are filtered to remove with filter, are contained
The methanol solution of N, N- diacetyl-l-cysteine；
Step 5：Contain N by what step 4 obtained, the methanol solution of N- diacetyl-l-cysteine carries out vacuum steaming by concentration tank
Hair concentration, ether extract 3 times, and the weight ratio of ether and raw material l-cysteine is 4:1, remaining acetic acid is removed, N, N- bis- are obtained
The crude product of acetyl-l-cysteine；
Step 6：The crude product that step 5 obtains is put into crystallization kettle, methanol is added and is recrystallized, methanol and raw material L- Guang ammonia
The weight ratio of acid is 3-4:1, it crystallizes 2-3 times, washes, filtering, vacuum evaporation obtains N, N- diacetyl-l-cysteine
Sterling；
Step 7：The product that step 6 obtains is put into dryer, drying temperature is 50 DEG C -60 DEG C, and drying time is that 6-8 is small
When, it can be obtained finished product after drying.
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| CN201810497975.8A CN108558721A (en) | 2018-05-23 | 2018-05-23 | A kind of preparation method of N, N- diacetyl-l-cysteine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110344077A (en) * | 2019-07-01 | 2019-10-18 | 吉林大学 | A method of by l-cysteine electrochemistry formated n-acetyl-L-cysteine |
| CN111072537A (en) * | 2019-12-20 | 2020-04-28 | 南京德尔诺医药科技有限公司 | Preparation method and application of diacetylated-L-cystine |
| WO2021219377A1 (en) * | 2020-04-28 | 2021-11-04 | Unilever Ip Holdings B.V. | Process of making n,n-diacetyl-l-cystine disodium salt from cystine and acetyl chloride in methanol in the presence of sodium hydroxide |
| CN115461325A (en) * | 2020-04-28 | 2022-12-09 | 联合利华知识产权控股有限公司 | Process for preparing N, N' -diacetyl-L-cystine |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1733717A (en) * | 2005-07-20 | 2006-02-15 | 江苏正大天晴药业股份有限公司 | N,N'-biacetylcysteine-diarginine salt isomer and its uses |
-
2018
- 2018-05-23 CN CN201810497975.8A patent/CN108558721A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1733717A (en) * | 2005-07-20 | 2006-02-15 | 江苏正大天晴药业股份有限公司 | N,N'-biacetylcysteine-diarginine salt isomer and its uses |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110344077A (en) * | 2019-07-01 | 2019-10-18 | 吉林大学 | A method of by l-cysteine electrochemistry formated n-acetyl-L-cysteine |
| CN111072537A (en) * | 2019-12-20 | 2020-04-28 | 南京德尔诺医药科技有限公司 | Preparation method and application of diacetylated-L-cystine |
| CN111072537B (en) * | 2019-12-20 | 2021-11-19 | 南京德尔诺医药科技有限公司 | Preparation method and application of diacetylated-L-cystine |
| WO2021219377A1 (en) * | 2020-04-28 | 2021-11-04 | Unilever Ip Holdings B.V. | Process of making n,n-diacetyl-l-cystine disodium salt from cystine and acetyl chloride in methanol in the presence of sodium hydroxide |
| CN115461326A (en) * | 2020-04-28 | 2022-12-09 | 联合利华知识产权控股有限公司 | Process for the preparation of N, N' -diacetyl-L-cystine disodium salt from cystine and acetyl chloride in methanol in the presence of sodium hydroxide |
| CN115461325A (en) * | 2020-04-28 | 2022-12-09 | 联合利华知识产权控股有限公司 | Process for preparing N, N' -diacetyl-L-cystine |
| 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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Inventor after: Lin Haibo Inventor after: Zuo Tingting Inventor after: Huang Weimin Inventor before: Huang Weimin Inventor before: Zuo Tingting |
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Application publication date: 20180921 |