CN114516895A - Azithromycin amine crystallization method - Google Patents
Azithromycin amine crystallization method Download PDFInfo
- Publication number
- CN114516895A CN114516895A CN202011300708.0A CN202011300708A CN114516895A CN 114516895 A CN114516895 A CN 114516895A CN 202011300708 A CN202011300708 A CN 202011300708A CN 114516895 A CN114516895 A CN 114516895A
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- China
- Prior art keywords
- azithromycin
- amine
- crystallizing
- acid
- water
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960004099 azithromycin Drugs 0.000 title claims abstract description 55
- -1 Azithromycin amine Chemical class 0.000 title claims abstract description 49
- 238000002425 crystallisation Methods 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 11
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 239000003651 drinking water Substances 0.000 claims description 3
- 235000020188 drinking water Nutrition 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000007788 liquid Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000011084 recovery Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000012822 chemical development Methods 0.000 abstract description 2
- 238000004886 process control Methods 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a crystallization method of azithromycin amine. The method comprises the steps of firstly preparing an azithromycin amine acid water phase, then reacting ammonia water with the azithromycin amine acid water phase, and carrying out solid-liquid separation by utilizing the water-insoluble characteristic of the generated azithromycin amine to obtain the final azithromycin amine. The crystallization process does not use a solvent, so that the safety coefficient in the generation process is improved while the solvent consumption is reduced, the concept of green chemical development is better met, and the solvent recovery process can be reduced; the production cost is saved, the utilization rate of equipment is improved, the operation and the process control are simpler and more convenient, and the influence of the process operation problem on the product quality is reduced.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a crystallization method of azithromycin amine.
Background
Azithromycin amine, chemical name is 9-deoxy-9 a-aza-9 a-erythromycin A, the structural formula is shown as follows, the azithromycin amine is an intermediate of azithromycin, in the prior art, when preparing the azithromycin amine, a chloroform phase of the azithromycin amine is mainly extracted to a water phase by acid, part of the chloroform phase is dripped into a base solution of acetone and ammonia water, then the ammonia water is added, and finally the rest of an azithromycin amine acid water phase is added until the dripping is finished, and the azithromycin amine is obtained by cooling crystallization and filtration. The whole operation process is complicated, the process is long, the finally prepared azithromycin amine has poor stability, and the degradation speed of the azithromycin amine is high; the acetone used in the process belongs to flammable and explosive tubular reagents, so that the production process is dangerous and difficult to store, and the preparation cost is increased due to the volatile characteristic of the acetone and low recovery rate.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a method for crystallizing azithromycin amine.
The purpose of the invention is realized by the following technical scheme:
a crystallization method of azithromycin amine comprises the following steps:
s1, adding drinking water into the azithromycin amine chloroform phase, and cooling;
s2, dropwise adding acid to adjust the pH value to acidity, stirring, standing, and separating phases to obtain an azithromycin amine acid water phase; the acid is one or more of hydrochloric acid, acetic acid or formic acid.
S3, adding water into the crystallization tank, and heating;
s4, simultaneously dripping an azithromycin amine acid water phase and ammonia water, controlling the temperature, and controlling the pH of the feed liquid to be alkaline in the adding process; the invention adopts the simultaneous dripping to ensure that the pH of the reaction solution is in a stable range. Because azithromycin amine is unstable under the acidic or alkaline condition, the azithromycin amine can be ensured to be rapidly crystallized by dropwise adding in the reaction kettle, and the generation of impurities is reduced.
S5, after the opposite addition is finished, ammonia water is dripped to adjust the pH value to be alkaline so as to ensure that crystallization is more complete;
s6, filtering in a throwing way, and drying the wet product to obtain the finished product of the azithromycin amine.
Preferably, the temperature in the S1 is reduced to 0-10 ℃.
Preferably, to reduce the generation of process wastewater, hydrochloric acid with a concentration of 32% is used in the S2.
Preferably, the pH value in the S2 is adjusted to be 4.5-5.
Preferably, the stirring is carried out for 10-20 min in the S2.
Preferably, the standing time in the S2 is 20-30 min.
Preferably, the temperature in S3 is raised to 55 ℃.
Preferably, in order to ensure the crystallization efficiency of the process and avoid impurities generated in the crystallization process while the reaction is completed, the temperature in the S4 is preferably controlled to be 40-50 ℃.
Preferably, the pH value in the S4 is 9.0-9.2.
Preferably, the pH value in the S5 is 9.5-9.7.
The invention has the beneficial effects that: the crystallization process does not use a solvent, so that the safety coefficient in the generation process is improved while the solvent consumption is reduced, the concept of green chemical development is better met, and the solvent recovery process can be reduced; the process time is saved by 5 hours in batches, the production cost is saved, the equipment utilization rate is improved, the operation and process control are simpler and more convenient, and the influence of the process operation problem on the product quality is reduced.
Detailed Description
The technical scheme of the invention is specifically illustrated by the following embodiments, and the invention discloses a method for crystallizing azithromycin amine. Firstly, preparing an azithromycin amino acid water phase, then carrying out a reaction between ammonia water and the azithromycin amino acid water phase, and carrying out solid-liquid separation by utilizing the water-insoluble characteristic of the generated azithromycin amine. The reaction formula is shown as follows:
the crystallization step is specifically described below:
adding 2300L of drinking water into the azithromycin amine chloroform phase, and cooling to 0-10 ℃; dropwise adding 32% hydrochloric acid to adjust the pH value to 4.5-5, stirring for 10-20 min, standing for 20-30 min, and separating an azithromycin amine acid water phase; 3000L of water was added to the crystallizer and the temperature was raised to 55 ℃. In order to ensure that the pH of the reaction liquid is in a stable range and reduce the generation of impurities under the condition that the azithromycin amine dropped into the reaction kettle can be rapidly crystallized, the azithromycin amine is unstable under the acidic or alkaline condition, an azithromycin amine acid water phase and ammonia water are dropped simultaneously, the temperature is controlled to be 40-50 ℃, and the pH of the addition process is controlled to be 9.0-9.2; after the addition is finished, ammonia water is dripped to adjust the pH value to 9.5-9.7; filtering, and drying the wet product at 45 ℃ to obtain the finished product of azithromycin amine. Of course, other low concentrations of hydrochloric acid, or other acids such as acetic acid or formic acid, may be used as the hydrochloric acid in the present invention.
The invention utilizes the crystallization principle that azithromycin amine reacts with hydrochloric acid through acid extraction to generate azithromycin amine hydrochloride which is dissolved in a water phase, and the azithromycin amine hydrochloride in the water phase reacts with ammonia water to produce azithromycin amine and ammonium chloride. The azithromycin amine is insoluble in water, solid is separated out in the water, and the azithromycin amine solid is obtained through solid-liquid separation.
There are, of course, many other specific embodiments of the invention and these are not to be considered as limiting. All technical solutions formed by using equivalent substitutions or equivalent transformations fall within the scope of the present invention.
Claims (10)
1. A crystallization method of azithromycin amine is characterized in that: the method comprises the following steps:
s1, adding drinking water into the azithromycin amine chloroform phase, and cooling;
s2, dropwise adding acid to adjust the pH value to acidity, stirring, standing, and separating phases to obtain an azithromycin amine acid water phase;
s3, adding water into the crystallization tank, and heating;
s4, simultaneously dripping an azithromycin amine acid water phase and ammonia water, controlling the temperature, and controlling the pH to be alkaline in the addition process;
s5, after the pair addition is finished, ammonia water is dripped to adjust the pH value to be alkaline;
s6, filtering in a throwing way, and drying the wet product to obtain the finished product of the azithromycin amine.
2. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: and cooling to 0-10 ℃ in the S1.
3. A method for crystallizing azithromycin amine, according to claim 1, wherein: the acid in the S2 is hydrochloric acid with the concentration of 32%.
4. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: and adjusting the pH value to 4.5-5 in the S2.
5. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: and stirring in the S2 for 10-20 min.
6. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: and the standing time in the S2 is 20-30 min.
7. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: the temperature in S3 was raised to 55 ℃.
8. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: and controlling the temperature in the S4 to be 40-50 ℃.
9. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: the pH value of the S4 is 9.0-9.2.
10. A method of crystallizing azithromycin amine, as claimed in claim 1, wherein: the pH value of the S5 is 9.5-9.7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011300708.0A CN114516895A (en) | 2020-11-19 | 2020-11-19 | Azithromycin amine crystallization method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011300708.0A CN114516895A (en) | 2020-11-19 | 2020-11-19 | Azithromycin amine crystallization method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114516895A true CN114516895A (en) | 2022-05-20 |
Family
ID=81594442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011300708.0A Pending CN114516895A (en) | 2020-11-19 | 2020-11-19 | Azithromycin amine crystallization method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114516895A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6703372B1 (en) * | 1999-06-29 | 2004-03-09 | Biochemie S.A. | Macrolides |
| CN1625560A (en) * | 2002-04-03 | 2005-06-08 | 韩美药品株式会社 | Preparation method of azithromycin and crystal 9-deoxidation-9a-aza-9a-homoilotycin A hydrate used therein |
| CN105001283A (en) * | 2015-07-09 | 2015-10-28 | 北京红太阳药业有限公司 | Azithromycin refining method |
-
2020
- 2020-11-19 CN CN202011300708.0A patent/CN114516895A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6703372B1 (en) * | 1999-06-29 | 2004-03-09 | Biochemie S.A. | Macrolides |
| CN1625560A (en) * | 2002-04-03 | 2005-06-08 | 韩美药品株式会社 | Preparation method of azithromycin and crystal 9-deoxidation-9a-aza-9a-homoilotycin A hydrate used therein |
| CN105001283A (en) * | 2015-07-09 | 2015-10-28 | 北京红太阳药业有限公司 | Azithromycin refining method |
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