CN104529813A - 2-acetyl-2-desaminomethyl tetracycline preparation method - Google Patents
2-acetyl-2-desaminomethyl tetracycline preparation method Download PDFInfo
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- CN104529813A CN104529813A CN201410744314.2A CN201410744314A CN104529813A CN 104529813 A CN104529813 A CN 104529813A CN 201410744314 A CN201410744314 A CN 201410744314A CN 104529813 A CN104529813 A CN 104529813A
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- acetonitrile
- methyl
- tetracycline
- deammoniation
- ethanoyl
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Abstract
The present invention relates to a 2-acetyl-2-desamino methyl tetracycline preparation method. According to the method, an urea double salt mother liquor during a tetracycline hydrochloride production process is subjected to pressure reducing concentrating and then is injected into a high performance liquid chromatograph, a 2-acetyl-2-desaminomethyl tetracycline solution is collected, the pH value of the separated 2-acetyl-2-desaminomethyl tetracycline solution is adjusted to a neutral pH value, sodium chloride is added gradually so as to achieve layering of acetonitrile and water, the 2-acetyl-2-desaminomethyl tetracycline is extracted into the acetonitrile layer, separation is performed to take the acetonitrile layer, an appropriate amount of acetonitrile is added to the water layer, shaking and standing are sequentially performed, separation is performed to take the acetonitrile layer, the acetonitrile layers obtained from the two separations are mixed, the obtained acetonitrile is placed into a freezing chamber of a refrigerator to stand overnight and then is taken out and immediately filtered, the filtrate is taken, and is sequentially subjected to pressure reducing concentrating and drying to obtain the 2-acetyl-2-desamino methyl tetracycline pure product. The preparation method of the present invention has characteristics of simple process, efficiency, rapidness, high recovery rate and the like.
Description
Technical field
The invention belongs to biological pharmacy technical field, particularly relate to a kind of preparation method of 2-ethanoyl-2-deammoniation methyl tsiklomitsin.
Background technology
Tetracycline hydrochloride (Tetracycline hydrochloride) is a kind of tetracycline antibiotics, has good restraining effect to gram-positive microorganism, negative bacterium, rickettsia, filtrable virus, spirochete and protozoon class.Tetracycline hydrochloride is 32 DEG C of fermentations 170 hours by S. aureus, fermented liquid is in pH1.7-1.9 acidification, filter, filtrate regulates pH crystallization to obtain tsiklomitsin, tsiklomitsin and urea reaction generate tetracycline urea double salt, after tetracycline urea double salt adds hydrochloric acid in butanols, reaction generates tetracycline hydrochloride.Impurity can be produced in the preparation process of tetracycline hydrochloride; mainly comprise 4-epitetracycline (4-epitetracycline), 4-epianhydrotetracycline (4-epianhydrotetracycline), dehydration tetracycline (Anhydrotetracycline), terramycin (Oxytetracycline) and 2-ethanoyl-2-deammoniation methyl tsiklomitsin (2-acetyl-2-decarbamoyltetracycline); these impurity toxicity are large, and anti-microbial activity is poor.Wherein 2-ethanoyl-2-deammoniation methyl tsiklomitsin does not all detect in Chinese Pharmacopoeia and American Pharmacopeia, and adopt 4-epitetracycline to do contrast to this impurity in European Pharmacopoeia and detect, limit is≤1.5%.
In recent years, pharmacopoeia of each country is more and more stricter to Control of Impurities in bulk drug, and in this context, preparation 2-ethanoyl-2-deammoniation methyl tsiklomitsin reference substance, qualitative and quantitative to this impurity in tetracycline hydrochloride, seems more and more important.
Summary of the invention
Object of the present invention is just to provide a kind of simple process, and product purity is high, can be used as the preparation method of the 2-ethanoyl-2-deammoniation methyl tsiklomitsin of the qualitative and detection by quantitative reference substance of tetracycline hydrochloride.
Technical scheme taked for achieving the above object is:
A preparation method for 2-ethanoyl-2-deammoniation methyl tsiklomitsin, is characterized in that its processing step is:
Urea double salt mother liquor in tetracycline hydrochloride production process is evaporated to 1/4 of original volume, rear injection high performance liquid chromatograph, collects the solution that 2-ethanoyl-2-deammoniation methyl tsiklomitsin goes out the peak period;
2-ethanoyl-2-deammoniation methyl tetracycline the pH separated is adjusted to neutrality, adds sodium-chlor gradually, until make acetonitrile be separated with water; divide and get acetonitrile layer; add appropriate acetonitrile toward water layer again, jolting, leave standstill; divide and get acetonitrile layer; merge twice acetonitrile layer, at-15 DEG C ~-30 DEG C standing 14-18 hour, after filter immediately; gained filtrate reduced in volume near dry, 58 DEG C ~ 62 DEG C dry 2-ethanoyl-2-deammoniation methyl tsiklomitsin sterlings.
The chromatographic condition of described high performance liquid chromatography is:
Moving phase: volume ratio is the 0.05% phosphoric acid solution-acetonitrile solution of 80 ~ 85:20 ~ 15;
Chromatographic column: Sinochrom ODS-AP 10um;
Flow rate of mobile phase: 20-30ml/min;
Determined wavelength: 254nm.
Described concentrating under reduced pressure condition is: pressure 0.06 ~ 0.09MPa, heats in 58 DEG C ~ 62 DEG C water-baths.
Above-mentioned extraction process, after adding sodium-chlor, makes acetonitrile and water stratification, and 2-ethanoyl-2-deammoniation methyl tsiklomitsin is extracted in acetonitrile layer, and continuous extraction twice, makes water layer close to colourless.Make to be dissolved in micro-salt crystallization in acetonitrile-15 DEG C ~-30 DEG C standing objects.
In above-mentioned system, acetonitrile layer after concentrating under reduced pressure drying, the high purity 85% of gained 2-ethanoyl-2-deammoniation methyl tsiklomitsin.
The invention has the advantages that: 1,2-ethanoyl-2-deammoniation methyl tsiklomitsin sterling can be prepared by present method; using it as 2-ethanoyl-2-deammoniation methyl tsiklomitsin reference substance qualitatively, thus solve analyst's this impurity orientation problem in analytic process.2, present invention process is easy, has the features such as efficient, quick.
Embodiment
For a better understanding of the present invention, do to carry out a step explanation to the present invention below by embodiment, but illustrated embodiment does not limit the scope of the invention.
Urea double salt mother liquor in following embodiment in tetracycline hydrochloride production process is the waste liquid after tsiklomitsin and urea reaction generate urea double salt, and wherein the impurity such as 4-epitetracycline, 2-ethanoyl-2-deammoniation methyl tsiklomitsin is more.
embodiment 1
Chromatographic condition: chromatographic column: Sinochrom ODS-AP 10um; Moving phase: with 0.05% phosphoric acid solution-acetonitrile (85:15); Flow velocity: 24 ml/min; Determined wavelength: 254nm.
INSTRUMENT MODEL: Dalian Yi Lite P230 preparative liquid chromatograph.
Preparation method:
By the urea double salt mother liquor in tetracycline hydrochloride production process through 0.08MPa, 60 DEG C be evaporated to 1/4 of original volume after, inject preparative high-performance liquid chromatographic instrument, collect the solution that 2-ethanoyl-2-deammoniation methyl tsiklomitsin goes out the peak period.
2-ethanoyl-2-deammoniation methyl tetracycline the acetic acid separated is adjusted to neutrality, add solid sodium chloride gradually and stir, until make acetonitrile and water stratification, divide and get acetonitrile layer, equal-volume acetonitrile is added again toward water layer, jolting, leave standstill, divide and get acetonitrile layer, merge twice acetonitrile, put-15 DEG C ~-30 DEG C standing 14-18 hour, filter immediately after taking-up, get filtrate at 0.07MPa, be evaporated near dry under 58 DEG C ~ 62 DEG C water bath condition, and 58 DEG C ~ 62 DEG C dryings, obtain 2-ethanoyl-2-deammoniation methyl tsiklomitsin sterling, after measured, content is 85.6%, 87.4%.
Embodiment 2
Chromatographic condition: chromatographic column: Sinochrom ODS-AP 10um; Moving phase: with 0.05% phosphoric acid solution-acetonitrile (85:20); Flow velocity: 20 ml/min; Determined wavelength: 254nm.
INSTRUMENT MODEL: Dalian Yi Lite P230 preparative liquid chromatograph.
Preparation method:
By the urea double salt mother liquor in tetracycline hydrochloride production process through 0.06MPa, 58 DEG C be evaporated to 1/4 of original volume after, inject preparative high-performance liquid chromatographic instrument, collect the solution that 2-ethanoyl-2-deammoniation methyl tsiklomitsin goes out the peak period.
2-ethanoyl-2-deammoniation methyl tetracycline the acetic acid separated is adjusted to neutrality, add solid sodium chloride gradually and stir, until make acetonitrile and water stratification, divide and get acetonitrile layer, equal-volume acetonitrile is added again toward water layer, jolting, leave standstill, divide and get acetonitrile layer, merge twice acetonitrile, put-15 DEG C ~-30 DEG C standing 14-18 hour, filter immediately after taking-up, get filtrate at 0.09MPa, be evaporated near dry under 58 DEG C ~ 62 DEG C water bath condition, and 58 DEG C ~ 62 DEG C dryings, obtain 2-ethanoyl-2-deammoniation methyl tsiklomitsin sterling, after measured, content is 86.2%, 85.3%.
Embodiment 3
Chromatographic condition: chromatographic column: Sinochrom ODS-AP 10um; Moving phase: with 0.05% phosphoric acid solution-acetonitrile (85:20); Flow velocity: 20 ml/min; Determined wavelength: 254nm.
INSTRUMENT MODEL: Dalian Yi Lite P230 preparative liquid chromatograph.
Preparation method:
By the urea double salt mother liquor in tetracycline hydrochloride production process through 0.09MPa, 62 DEG C be evaporated to 1/4 of original volume after, inject preparative high-performance liquid chromatographic instrument, collect the solution that 2-ethanoyl-2-deammoniation methyl tsiklomitsin goes out the peak period.
2-ethanoyl-2-deammoniation methyl tetracycline the acetic acid separated is adjusted to neutrality, add solid sodium chloride gradually and stir, until make acetonitrile and water stratification, divide and get acetonitrile layer, equal-volume acetonitrile is added again toward water layer, jolting, leave standstill, divide and get acetonitrile layer, merge twice acetonitrile, put-15 DEG C ~-30 DEG C standing 14-18 hour, filter immediately after taking-up, get filtrate at 0.06MPa, be evaporated near dry under 58 DEG C ~ 62 DEG C water bath condition, and 58 DEG C ~ 62 DEG C dryings, obtain 2-ethanoyl-2-deammoniation methyl tsiklomitsin sterling, after measured, content is 85.5%, 87.0%.
Claims (3)
1. a preparation method for 2-ethanoyl-2-deammoniation methyl tsiklomitsin, is characterized in that its processing step is:
Urea double salt mother liquor in tetracycline hydrochloride production process is evaporated to 1/4 of original volume, rear injection high performance liquid chromatograph, collects the solution that 2-ethanoyl-2-deammoniation methyl tsiklomitsin goes out the peak period;
2-ethanoyl-2-deammoniation methyl tetracycline the pH separated is adjusted to neutrality, adds sodium-chlor gradually, until make acetonitrile be separated with water; divide and get acetonitrile layer; add appropriate acetonitrile toward water layer again, jolting, leave standstill; divide and get acetonitrile layer; merge twice acetonitrile layer, at-15 DEG C ~-30 DEG C standing 14-18 hour, after filter immediately; gained filtrate reduced in volume near dry, 58 DEG C ~ 62 DEG C dry 2-ethanoyl-2-deammoniation methyl tsiklomitsin sterlings.
2., according to the preparation method of 2-ethanoyl-2-deammoniation methyl tsiklomitsin according to claim 1, it is characterized in that the chromatographic condition of described high performance liquid chromatography is:
Moving phase: volume ratio is the 0.05% phosphoric acid solution-acetonitrile solution of 80 ~ 85:20 ~ 15;
Chromatographic column: Sinochrom ODS-AP 10um;
Flow rate of mobile phase: 20-30ml/min;
Determined wavelength: 254nm.
3., according to the preparation method of 2-ethanoyl-2-deammoniation methyl tsiklomitsin according to claim 1, it is characterized in that described concentrating under reduced pressure condition is: pressure 0.06 ~ 0.09MPa, heat in 58 DEG C ~ 62 DEG C water-baths.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410744314.2A CN104529813B (en) | 2014-12-09 | 2014-12-09 | A kind of 2-acetyl group-2-goes the preparation method of amide groups tetracycline |
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| CN201410744314.2A CN104529813B (en) | 2014-12-09 | 2014-12-09 | A kind of 2-acetyl group-2-goes the preparation method of amide groups tetracycline |
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| CN104529813B CN104529813B (en) | 2016-11-23 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456217A (en) * | 2018-12-12 | 2019-03-12 | 宁夏启元药业有限公司 | A kind of preparation method of dehydration tetracycline |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3022347A (en) * | 1960-03-28 | 1962-02-20 | Pfizer & Co C | Antibiotics and processes |
| CN103553960A (en) * | 2013-10-31 | 2014-02-05 | 宁夏启元药业有限公司 | Method for preparing 4-epitetracycline from tetracycline urea double salt crystallization mother solution |
-
2014
- 2014-12-09 CN CN201410744314.2A patent/CN104529813B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3022347A (en) * | 1960-03-28 | 1962-02-20 | Pfizer & Co C | Antibiotics and processes |
| CN103553960A (en) * | 2013-10-31 | 2014-02-05 | 宁夏启元药业有限公司 | Method for preparing 4-epitetracycline from tetracycline urea double salt crystallization mother solution |
Non-Patent Citations (2)
| Title |
|---|
| MILLER, MAX W. ET AL.: "Isolation and characterization of two new tetracycline antibiotics", 《JOURNAL OF ORGANIC CHEMISTRY》, 31 December 1962 (1962-12-31), pages 2525 - 8 * |
| 李十中等: "高纯度土霉素碱制备工艺研究Ⅱ.土霉素新产品中2-乙酰-2-去酰胺土霉素的去除", 《中国抗生素杂志》, vol. 26, no. 6, 31 December 2001 (2001-12-31), pages 437 - 439 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456217A (en) * | 2018-12-12 | 2019-03-12 | 宁夏启元药业有限公司 | A kind of preparation method of dehydration tetracycline |
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