CN103524577B - A kind of synthetic method of Etimicin sulfate intermediate (3,2 ', 6 '-three-N-ethanoyl Gentamicin C1a) - Google Patents
A kind of synthetic method of Etimicin sulfate intermediate (3,2 ', 6 '-three-N-ethanoyl Gentamicin C1a) Download PDFInfo
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Abstract
The present invention relates to a kind of Etimicin sulfate intermediate (3,2 ', 6 '-three-N-ethanoyl gentamicinC
1a) synthetic method, comprise the following steps: a, at the temperature of 29 DEG C, in 50L there-necked flask, add the methyl alcohol of 20L, the gentamicinC of 2.70kg
1aand the Glacial acetic acid zinc of 3.21kg, stir dissolving in 1.5 hours, obtain gentamicinC
1a-Zn title complex.B, in step a, drip the acetylize of 2.55L acetic anhydride.After c, reaction terminate, concentrated by step b reaction solution, concentrated solution passes into loading in chromatographic separation post, and salt-free water is rinsed, and aqueous ethanolic solution is resolved, and collects effective constituent.Concentrated, dry to obtain P1 finished product 3.29kg.Yield is 95.3%, and purity is 96.1%.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of aminoglycoside antibiotics intermediate 3,2 ', 6 '-three-N-ethanoyl gentamicinC
1asynthetic method.
Background technology
Etimicin sulfate (Etimicinsulfate) is that China scientific research personnel develops voluntarily, having the semi-synthetic aminoglycoside antibiotics of efficient, low toxicity, antimicrobial agent a new generation of independent intellectual property right, is the anti-infectives uniquely obtaining first class national new drug certificate.
At present, for intermediate 3, (be called for short: P1), Chinese patent literature successively discloses three kinds of preparation methods to 2 ', 6 '-three-N-ethanoyl Gentamicin C1a.
Chinese patent 93112412.3 describes following methods:
At room temperature, 10gGMC1a lyophilized powder is under agitation dissolved in 40ml water, adds 360ml dimethyl formamide, then add 20gCoAc24H2O and dissolve.Stir 1 hour, drip 56ml freshly prepared M acetic anhydride tetrahydrofuran solution.Speed 1ml/min, drips rear continuation stirring 1 hour, and reaction terminates.Reaction solution double water mixing, pass into 500m1732 (H+) resin column absorption.Resolve with 2NH3H2O after washing.With YPR-II resin column (40 × 500mm) purifying after desorbed solution concentrating under reduced pressure.With the ethanol concentration gradient wash-out of 6%-30%, collect the elutriant of 10%-15% alcohol concn, merge concentrated rear freeze-drying and obtain 9.5g3,2 ', 6 '-triacetyl GMC1a.Yield 95%.
Chinese patent 201010132460.1 describes following methods:
At the temperature of 15 DEG C ~ 25 DEG C, Gentamicin C1a and zinc acetate are carried out coordination reaction in methanol solvate, form Gentamicin C1a-Zn title complex.Then 0 DEG C ~ 10 DEG C are cooled the temperature to; stir and drip the mixed solution be made up of diacetyl oxide, triethylamine and tetrahydrofuran (THF) down; drip off rear continuation stirring reaction 1h ~ 2h; then add water, underpressure distillation obtains containing 3; 2 ＇, the concentrated solution of 6 ＇-three-N-ethanoyl Gentamicin C1a-Zn title complexs.Concentrated solution is passed into loading in chromatographic separation post; then rinse by purified water; resolve with aqueous ethanolic solution again; collect the effective constituent of chromatography separator column outlet, will collect liquid concentrating under reduced pressure, last lyophilize obtains 3; 2 ＇; 6 ＇-three-N-ethanoyl Gentamicin C1as, yield 93.9%, purity 92%.
Chinese patent 201010132961.X describes following methods:
1. at the temperature of 15 DEG C ~ 25 DEG C, Gentamicin C1a and zinc acetate are carried out coordination reaction in methanol solvate, form Gentamicin C1a-Zn title complex; 2. then the temperature of step system is 1. down to 0 DEG C ~ 10 DEG C, stir and drip down the mixed solution that is made up of diacetyl oxide, triethylamine and tetrahydrofuran (THF) and generation 3 occurs, 2 ＇, the acylation reaction of 6 ＇-three-N-ethanoyl Gentamicin C1a-Zn title complexs, drip off rear continuation stirring reaction 1h ~ 2h, then add water, underpressure distillation obtains containing 3,2 ＇, the concentrated solution of 6 ＇-three-N-ethanoyl Gentamicin C1a-Zn title complexs; 3. the concentrated solution 2. obtained step carries out aftertreatment and obtains 3,2 ＇, 6 ＇-three-N-ethanoyl Gentamicin C1a finished products.Yield 94.9%, purity 92%.
In above-mentioned patent, employ the solvent of tetrahydrofuran (THF) as acylating reagent, cause difficulty to the purifying of end product.
In above-mentioned patent, after prepared by Gentamicin C1a-Zn, need to reduce the temperature to 0 DEG C ~ 10 DEG C and drip acetic anhydride generation acetylization reaction again, bring difficulty to operation.
In above-mentioned patent, 3,2 ＇, the purity of 6 ＇-three-N-ethanoyl Gentamicin C1a finished products only has 92%, bringing more impurity, causing purification difficult to preparing Etimicin sulfate further.
The present invention finds unexpectedly, after Gentamicin C1a-Zn complexing is complete, directly drips acetic anhydride generation acetylization reaction, can improve the yield of this reaction.Do not use triethylamine and tetrahydrofuran (THF) as solvent, be conducive to environmental protection, improve product purity simultaneously, carry out acetylization reaction at ambient temperature, simplify operation.
Summary of the invention
The object of the present invention is on existing basis, provides a kind of easy and simple to handle, and energy-conserving and environment-protective also can with higher yield synthesis Etimicin sulfate intermediate P1(3,2 ', 6 '-three-N-ethanoyl gentamicinC
1a) method.
Realize technical scheme of the present invention as follows: the synthetic method of a kind of Etimicin sulfate intermediate P1, has following steps:
A, at the temperature of 20 DEG C, in 50L there-necked flask, add the methyl alcohol of 20L, the gentamicinC of 2.70kg
1aand the Glacial acetic acid zinc of 3.21kg, stir dissolving in 1.5 hours, obtain gentamicinC
1a-Zn title complex.
B, in step a, drip the acetylize of 2.55L acetic anhydride.
After c, reaction terminate, concentrated by step b reaction solution, concentrated solution passes into loading in chromatographic separation post, and salt-free water is rinsed, and aqueous ethanolic solution is resolved, and collects effective constituent.Concentrated, dry to obtain P1 finished product 3.29kg.Yield is 95.3%, and purity is 96.1%.
Of the present invention benefiting is: whole process is almost reacted at ambient temperature, reduces energy consumption; Tetrahydrofuran (THF) is not used, the creationary use decreasing poisonous and hazardous solvent in chemicals synthesis, cost-saving emissions reduction in acetylation.This synthetic method reduces the pressure in environment protection in sum.
Embodiment
Embodiment 1
A, at the temperature of 20 DEG C, in 50L there-necked flask, add the methyl alcohol of 20L, the gentamicinC of 2.70kg
1aand the Glacial acetic acid zinc of 3.21kg, stir dissolving in 1.5 hours, obtain gentamicinC
1a-Zn title complex.
B, in step a, drip the acetylize of 2.55L acetic anhydride.
After c, reaction terminate, concentrated by step b reaction solution, concentrated solution passes into loading in chromatographic separation post, and salt-free water is rinsed, and aqueous ethanolic solution is resolved, and collects effective constituent.Concentrated, dry to obtain P1 finished product 3.29kg.Yield is 95.3%, and purity is 96.1%.
Comparative example:
1, embodiment 1 method and prior art yield and purity compare, in table 1
Table 1
| Yield (%) | Purity (%) | |
| Embodiment 1 | 95.3 | 96.1 |
| Prior art | 94.9 | 92 |
2, the screening of diacetyl oxide temperature is dripped:
Synthetic method and the embodiment 1 of each comparative example are basically identical, and difference is: in step b, acetylizad temperature is different, and experimental result is as table 2
Table 2
| ? | Drip the system temperature (DEG C) during diacetyl oxide | Yield (%) | Purity (%) |
| Embodiment 1 | 20 | 95.3 | 96.1 |
| Comparative example 2 | 0 | 95.4 | 95.9 |
| Comparative example 3 | 5 | 93.3 | 95.8 |
| Comparative example 4 | 10 | 95.1 | 96.1 |
| Comparative example 5 | 30 | 94.8 | 95.5 |
Reducing temperature as shown in Table 2 improves not obvious to reaction yield, and improve acetylization reaction temperature within the specific limits, experimental result can accept.Consider energy-saving and emission-reduction preferred embodiment 1.
Claims (1)
1. Etimicin sulfate intermediate 3,2 ', 6 '-three-N-ethanoyl gentamicinC
1asynthetic method, comprise the following steps:
A, at the temperature of 20 DEG C, in 50L there-necked flask, add the methyl alcohol of 20L, the gentamicinC of 2.70kg
1aand the Glacial acetic acid zinc of 3.21kg, stir dissolving in 1.5 hours, obtain gentamicinC
1a-Zn title complex;
B, in the reaction mixture in step a, drip the acetylize of 2.55L acetic anhydride;
After c, reaction terminate, concentrated by step b reaction solution, concentrated solution passes into loading in chromatographic separation post, and salt-free water is rinsed, and aqueous ethanolic solution is resolved, and collects effective constituent, concentrated, dries to obtain finished product.
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| CN109096347B (en) * | 2018-09-20 | 2022-03-08 | 无锡济煜山禾药业股份有限公司 | Method for purifying high-purity 3,2 ', 6' -tri-N-acetyl gentamicin C1a alkali (P1) |
| CN111825732A (en) * | 2020-07-18 | 2020-10-27 | 无锡济煜山禾药业股份有限公司 | Method for preparing etimicin sulfate by ultrasonic wave |
| CN113960183A (en) * | 2020-12-28 | 2022-01-21 | 常州方圆制药有限公司 | Method for detecting acetylation impurities in etimicin intermediate |
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| CN101928309A (en) * | 2010-03-26 | 2010-12-29 | 常州方圆制药有限公司 | 3,2',6'-tri-N-acetyl gentamicin C1asynthesis method |
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Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Patentee after: Wuxi Jiyu Shanhe Pharmaceutical Co., Ltd Patentee after: JINGXI JIMIN KEXIN GROUP Co.,Ltd. Address before: 214028 No. 12 Changjiang South Road, New District, Jiangsu, Wuxi Patentee before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. Patentee before: JINGXI JIMIN KEXIN GROUP Co.,Ltd. |