CN109053508A - A kind of preparation method of carbocisteine - Google Patents
A kind of preparation method of carbocisteine Download PDFInfo
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- CN109053508A CN109053508A CN201811090659.5A CN201811090659A CN109053508A CN 109053508 A CN109053508 A CN 109053508A CN 201811090659 A CN201811090659 A CN 201811090659A CN 109053508 A CN109053508 A CN 109053508A
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- carbocisteine
- preparation
- filtrate
- hydrochloric acid
- regulation system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The present invention relates to pharmaceutical fields, more specifically, it is related to a kind of preparation method of carbocisteine, it is formed in the state of the tiny stirring stopping of carbocisteine crystallization based on the prior art, hydrochloric acid is disposably poured into reaction solution by dosage is calculated, after standing by the way of crawl stirring, carry out carbocisteine crystallization, using the means effectively prevent stirring is small formed more than nucleus quantity caused by the childlike problem of crystal, larger crystalline solid is obtained, microscopically observation crystal is up to 100~500 μm, slurry amount reduces 70%, content is increased to percent 99.5% or more by 99%.
Description
Technical field
The present invention relates to pharmaceutical fields, more specifically, are related to a kind of preparation method of carbocisteine.
Background technique
Carbocisteine raw material is amino acids drug, and the secretion of bronchus body of gland is mainly influenced in cellular level, can make to stick
The cystine linkage fracture of mucin in liquid, secretes the saliva mucin of low-viscosity and increases, and the generation of full-bodied rock algae mucin subtracts
It is few, so that making the viscosity of sputum reduces, be conducive to sputum discharge.Raw material is amino acids drug.In its molecular structure simultaneously
Containing carboxyl and amino, thus diluted acid is dissolved in, also dissolves in diluted alkaline, be amphoteric compound, isoelectric point PH=2.8.
Carbocisteine is to complete condensation reaction in the solution of PH=8, obtains target product, salt is then added in the solution
Acid is to PH=2.8, and carbocisteine has minimal solubility at this time, and drug concentration satiety forms crystallization.In the prior art, be
Hydrochloric acid is slowly added dropwise under stirring, the crystallization of formation is fine-powdered crystallization, and microscopically observation partial size is less than 10 μm.It is formed thin
The disadvantage of little crystallization has: 1. the specific surface area of crystalline solid is very big, the impurity in easy adsorbent solution；2. easily in package solution
Chloride, washing is difficult, and water consumption is very big.
Summary of the invention
In the presence of overcoming the shortcomings of the prior art, the present invention provides a kind of preparation method of carbocisteine, solves
The problems such as carbocisteine crystalline solid of existing carbocisteine crystallization processes production is small.
In order to solve the above-mentioned technical problem, the technical scheme adopted by the invention is as follows:
A kind of preparation method of carbocisteine, comprising the following steps:
S1, L-cysteine and monoxone are placed in purified water carry out condensation reaction, control system temperature at 50 DEG C hereinafter, plus
Entering liquefied ammonia regulation system PH is 7.0-7.5；
Hydrochloric acid regulation system PH=6 are added to 60 DEG C in S2, regulation system temperature, and active carbon decoloring is added；
S3, filtering, adjusting filtrate temperature is 45-55 DEG C, and hydrochloric acid is added at one time in filter liquor by metering, is stood；
S4, after 1 hour, crawl stirring, add hydrochloric acid to filtrate PH=2.8；
S5, regulation system temperature are 20 DEG C hereinafter, sediment purifying water washing is obtained qualified carbocisteine by centrifugation.
Further, for the hydrochloric acid being added in the S3 with molar amount, quantity is 0.9 times of L-cysteine mole.
Further, crawl Stirring device gymnastics conduct in the S4: measurement filtrate pH adjusts pH, stirs 1min, stands
10min measures filtrate pH, and so on, until filtrate pH=2.8.
Further, sediment purifying water washing to chloride≤0.15% in the S5.
Compared with prior art, the advantageous effect of present invention is that:
The present invention provides a kind of preparation methods of carbocisteine, form the tiny stirring of carbocisteine crystallization based on the prior art and stop
In the state of only, hydrochloric acid is disposably poured into reaction solution by dosage is calculated, after standing using crawl stirring by the way of, carry out slowly
Carbocisteine large particle crystal is formed, caused by effectively preventing more than the small formation nucleus quantity of stirring using the means
The childlike problem of crystal has obtained larger crystalline solid, and up to 100~500 μm, slurry amount is reduced microscopically observation crystal
70%, content is increased to percent 99.5% or more by 99%.
Detailed description of the invention
Fig. 1 is the micro- microgram of carbocisteine prepared by embodiment 2；
Fig. 2 is the micro- microgram of carbocisteine of comparative example preparation；
Fig. 3 is carbocisteine liquid chromatogram prepared by embodiment 2；
Fig. 4 is the carbocisteine liquid chromatogram of comparative example preparation.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
Embodiment 1
A kind of preparation method of carbocisteine, comprising the following steps:
S1, L-cysteine and 60kg monoxone are placed in purified water carry out condensation reaction, control system temperature 50 DEG C with
Under, addition liquefied ammonia regulation system pH is 7.0-7.5；
Hydrochloric acid regulation system PH=6 are added to 60 DEG C in S2, regulation system temperature, and active carbon decoloring is added；
S3, filtering, adjusting filtrate temperature is 45-55 DEG C, and the hydrochloric acid for being 0.9 times of L-cysteine mole by mole is disposable
It is added in filter liquor, stands；
S4, after 1 hour, filtrate pH is measured, salt acid for adjusting pH is added dropwise, stir 1min, stand 10min, measure filtrate pH, until filter
Liquid pH is 2.8；
S5, regulation system temperature are 20 DEG C hereinafter, centrifugation, sediment is closed with purifying water washing to chloride≤0.15%
The carbocisteine of lattice.
Embodiment 2
A kind of preparation method of carbocisteine, comprising the following steps:
S1, it 100kg L-cysteine and monoxone is placed in purified water carries out condensation reaction, control system temperature is at 50 DEG C
Hereinafter, it is 7.0-7.5 that liquefied ammonia regulation system pH, which is added,；
Hydrochloric acid regulation system pH=6 are added to 60 DEG C in S2, regulation system temperature, and active carbon decoloring is added；
S3, filtering, adjusting filtrate temperature is 45-55 DEG C, and the hydrochloric acid that the mass concentration of 69kg is 30% is added at one time filter liquor
In, it stands；
S4, after 1 hour, filtrate pH is measured, salt acid for adjusting pH is added dropwise, stir 1min, stand 10min, measure filtrate pH, until filter
Liquid pH is 2.8；
S5, regulation system temperature are 20 DEG C hereinafter, centrifugation, sediment is closed with purifying water washing to chloride≤0.15%
The carbocisteine of lattice.
As shown in Figure 1, crystal is up to 100~500 μm in the micro- microgram of carbocisteine manufactured in the present embodiment.
As shown in figure 3, there are two impurity in carbocisteine liquid chromatogram manufactured in the present embodiment, content is respectively less than
0.1%, chromatographic peak the results are shown in Table 1:
Table 1
| Title | Retention time | Area | % area | Highly (micro- shape) | USP separating degree | USP hangover | USP theoretical cam curve | |
| 1 | 6.402 | 3285 | 0.020 | 192 | 0.823 | 3969 | ||
| 2 | 9.365 | 14689 | 0.092 | 1035 | 7.404 | 1.220 | 10260 | |
| 3 | 11.267 | 8178 | 0.051 | 524 | 4.724 | 1.144 | 11723 | |
| 4 | 15.388 | 16017657 | 99.837 | 444258 | 5.384 | 2.572 | 3142 |
Comparative example
A kind of preparation method of carbocisteine, comprising the following steps:
S1, L-cysteine and monoxone are placed in purified water carry out condensation reaction, control system temperature at 50 DEG C hereinafter, plus
Entering liquefied ammonia regulation system pH is 7.0-7.5；
Active carbon decoloring is added to 60 DEG C in S2, regulation system temperature；
S3, filtering, take filtrate, and adjusting temperature is 45-55 DEG C, be added under stirring hydrochloric acid to filtrate pH be 2.8；
S4, regulation system temperature are 20 DEG C hereinafter, centrifugation, sediment is closed with purifying water washing to chloride≤0.15%
The carbocisteine of lattice.
As shown in Fig. 2, the micro- microgram of carbocisteine manufactured in the present embodiment.
As shown in figure 4, there are three impurity for carbocisteine liquid chromatogram manufactured in the present embodiment, content is 0.2%-
0.5%, chromatographic peak the results are shown in Table 2:
Table 2
| Title | Retention time | Area | % area | Highly (micro- shape) | USP separating degree | USP hangover | USP theoretical cam curve | |
| 1 | 6.202 | 8306 | 0.051 | 494 | 1.905 | 368 | ||
| 2 | 8.181 | 10864 | 0.067 | 578 | 4.393 | 1.032 | 4309 | |
| 3 | 9.309 | 9218 | 0.057 | 659 | 2.567 | 1.279 | 10427 | |
| 4 | 11.149 | 74985 | 0.464 | 4666 | 4.520 | 1.173 | 11269 | |
| 5 | 15.189 | 16002439 | 98.943 | 447697 | 5.285 | 2.535 | 3114 | |
| 6 | 37.942 | 67616 | 0.418 | 1637 | 20.507 | 0.978 | 18586 |
Only presently preferred embodiments of the present invention is explained in detail above, but the present invention is not limited to above-described embodiment,
Within the knowledge of a person skilled in the art, it can also make without departing from the purpose of the present invention each
Kind variation, various change should all be included in the protection scope of the present invention.
Claims (4)
1. a kind of preparation method of carbocisteine, which comprises the following steps:
S1, L-cysteine and monoxone are placed in purified water carry out condensation reaction, control system temperature at 50 DEG C hereinafter, plus
Entering liquefied ammonia regulation system pH is 7.0-7.5；
S2, regulation system temperature are added hydrochloric acid regulation system PH=6, add active carbon decoloring to 60 DEG C；
S3, filtering, adjusting filtrate temperature is 45-55 DEG C, and hydrochloric acid is added at one time in filter liquor by metering, is stood；
S4, after 1 hour, crawl stirring, add hydrochloric acid to filtrate PH=2.8；
S5, regulation system temperature are 20 DEG C hereinafter, sediment purifying water washing is obtained qualified carbocisteine by centrifugation.
2. a kind of preparation method of carbocisteine according to claim 1, it is characterised in that: the hydrochloric acid being added in the S3
With molar amount, quantity is 0.9 times of L-cysteine mole.
3. a kind of preparation method of carbocisteine according to claim 1, it is characterised in that: crawl Stirring device in the S4
Gymnastics conduct: measurement filtrate pH adjusts pH, stirs 1min, stand 10min, measures filtrate pH, and so on, until filtrate pH=
It is 2.8.
4. a kind of preparation method of carbocisteine according to claim 1, it is characterised in that: sediment is with pure in the S5
Change water washing to chloride≤0.15%.
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| CN201811090659.5A CN109053508B (en) | 2018-09-19 | 2018-09-19 | Preparation method of carbocisteine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452142A (en) * | 2019-09-10 | 2019-11-15 | 云鹏医药集团有限公司 | A kind of preparation method of high-purity S- (carboxymethyl)-cysteine |
| CN111138326A (en) * | 2019-12-31 | 2020-05-12 | 宁波市远发生物工程有限公司 | Preparation method of S-carboxymethyl-L-cysteine |
| WO2021102918A1 (en) * | 2019-11-29 | 2021-06-03 | 武汉远大弘元股份有限公司 | Method for preparing carbocisteine |
| CN115160197A (en) * | 2021-04-01 | 2022-10-11 | 广东众生药业股份有限公司 | Preparation method of carbocisteine bulk drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083673A (en) * | 2016-06-29 | 2016-11-09 | 罗江晨明生物制品有限公司 | A kind of preparation technology of carbocisteine |
| CN108191725A (en) * | 2018-01-05 | 2018-06-22 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of S- (carboxymethyl)-L-cysteine ammonium anhydrous crystal forms, preparation method and its usage |
-
2018
- 2018-09-19 CN CN201811090659.5A patent/CN109053508B/en active Active
Patent Citations (2)
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| CN106083673A (en) * | 2016-06-29 | 2016-11-09 | 罗江晨明生物制品有限公司 | A kind of preparation technology of carbocisteine |
| CN108191725A (en) * | 2018-01-05 | 2018-06-22 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of S- (carboxymethyl)-L-cysteine ammonium anhydrous crystal forms, preparation method and its usage |
Non-Patent Citations (1)
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| 张克旭: "等电点法提取谷氨酸", 《发酵科技通讯》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452142A (en) * | 2019-09-10 | 2019-11-15 | 云鹏医药集团有限公司 | A kind of preparation method of high-purity S- (carboxymethyl)-cysteine |
| WO2021102918A1 (en) * | 2019-11-29 | 2021-06-03 | 武汉远大弘元股份有限公司 | Method for preparing carbocisteine |
| CN114746399A (en) * | 2019-11-29 | 2022-07-12 | 武汉远大弘元股份有限公司 | Preparation method of carbocisteine |
| CN114746399B (en) * | 2019-11-29 | 2024-05-24 | 武汉远大弘元股份有限公司 | Preparation method of carbocisteine |
| CN111138326A (en) * | 2019-12-31 | 2020-05-12 | 宁波市远发生物工程有限公司 | Preparation method of S-carboxymethyl-L-cysteine |
| CN115160197A (en) * | 2021-04-01 | 2022-10-11 | 广东众生药业股份有限公司 | Preparation method of carbocisteine bulk drug |
| CN115160197B (en) * | 2021-04-01 | 2023-07-25 | 广东众生药业股份有限公司 | Preparation method of carbocisteine bulk drug |
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