CN104151186B - The stereoselectivity preparation method of Tigecycline impurity - Google Patents
The stereoselectivity preparation method of Tigecycline impurity Download PDFInfo
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- CN104151186B CN104151186B CN201410391831.6A CN201410391831A CN104151186B CN 104151186 B CN104151186 B CN 104151186B CN 201410391831 A CN201410391831 A CN 201410391831A CN 104151186 B CN104151186 B CN 104151186B
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Abstract
The present invention discloses the stereoselectivity preparation method of a kind of Tigecycline impurity, and it take minocycline hydrochloride as raw material, stirs in low-grade alkane alcohol and liquid acids, after be warming up to 35～45 DEG C, insulation reaction 2-5 hour, cooling, regulate the pH value of mixed solution to 6.5-8.5, precipitate out solid, temperature control reaction 2h, survey pH value again unchanged, filter, with low-grade alkane alcohol solvent wash filter cake, dry, obtaining Tigecycline impurity E, purity can reach more than 98.0%, and receipts rate is greater than 50%.
Description
Technical field
The invention belongs to medical art, specifically, it relates to the preparation method of Tigecycline impurity E.
Background technology
Tigecycline (Tigecycline), chemistry (4S, 4aS by name, 5aR, 12aS) two (the dimethylamino)-9-[(tert-butylamino) acetamido]-3 of-4,7-, 10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a, 5,5a, 6,11,12a-eight hydrogen tetracene-2-methane amide, structural formula is as follows:
Tigecycline is developed by Hui Shi company, and first get permission listing with freeze-dried powder injection type in the U.S. in July, 2005, it is mainly used in treating by leather blue negative and positive pathogenic bacterium, anerobe, methicillin-resistant staphylococcus aureus infects and methicillin-sensitivity staphylococcus aureus infects the complicacy intra-abdominal infection, skin and the skin structure infections that cause, pneumococcal infection etc.
According to standards of pharmacopoeia, having and be no less than 7 kinds of impurity in Tigecycline finished product, wherein, the preparation of impurity E (structural formula is as follows) has no document report.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of Tigecycline impurity E, for finished product detection provides qualitative and quantitative reference substance, thus improve the quality standard of Tigecycline, for its safe medication provides safeguard.
Specifically, the present invention provides the stereoselectivity preparation method of Tigecycline impurity E, comprises the steps:
1) in the mixture of low-grade alkane alcohol and liquid acids, minocycline hydrochloride is added;
2) by step 1) gained mixed solution is warming up to 35-45 DEG C, insulation reaction 2-5h;
3) stopping heating, be cooled to-10～20 DEG C, add alkali, adjust ph is to 6.5-8.5, precipitate out solid, it is incubated 0-5 DEG C of reaction 2h, surveys pH value again unchanged, filter, with low-grade alkane alcohol washing leaching cake at 0-5 DEG C, obtain Tigecycline impurity E, reduced pressure at room temperature 3-6h, obtain impurity E.
In embodiments of the invention, the stereoselectivity preparation method of Tigecycline impurity E provided by the invention, wherein, step 1) and step 3) described in low-grade alkane alcohol, be selected from methyl alcohol, ethanol, propyl alcohol or Virahol one or both, it is most preferable that be methyl alcohol.
In embodiments of the invention, the preparation method of Tigecycline impurity E provided by the invention, wherein, step 1) described in liquid acids, be selected from formic acid, acetic acid, phosphoric acid, hydrochloric acid, sulfurous acid or sulfuric acid, it is most preferable that be acetic acid.
In embodiments of the invention, the stereoselectivity preparation method of Tigecycline impurity E provided by the invention, wherein, step 1) described minocycline hydrochloride, low-grade alkane alcohol, liquid acids ingredient proportion (m:V:V, unit is g:ml:ml) be: 1:10～15:0.8～1.5.
In embodiments of the invention, the stereoselectivity preparation method of Tigecycline impurity E provided by the invention, wherein, step 2) described in warming temperature, it may be preferred that be 40～45 DEG C.
In embodiments of the invention, the stereoselectivity preparation method of Tigecycline impurity E provided by the invention, wherein, step 3) described in be cooled to-10～20 DEG C, it may be preferred that be-5～5 DEG C.
In embodiments of the invention, the stereoselectivity preparation method of Tigecycline impurity E provided by the invention, wherein, step 3) described in alkali be selected from diisopropylethylamine, triethylamine, first amine, ammoniacal liquor, sodium carbonate or sodium bicarbonate, most preferably, it is ammoniacal liquor or triethylamine.
In embodiments of the invention, the stereoselectivity preparation method of Tigecycline impurity E provided by the invention, wherein, step 3) described in pH value, it may be preferred that be 7.5-8.0.
The preparation method of Tigecycline impurity E provided by the invention, products obtained therefrom purity can reach 98%, and receipts rate is greater than 50%.
The preparation method of the Stereoselective synthesis Tigecycline impurity E of the present invention; achieve and mass-producing can prepare this impurity on the one hand; this preparation method's product rate height of another aspect, stereoselectivity are good; only Minocycline HCl 4-hydroxyl configuration reversal, and do not affect the hydrogen atom of 4a, 5a, 12a position, the configuration change of hydroxyl. Therefore, the method for stereoselective syntheses Tigecycline impurity E provided by the invention, is possible not only to the quality control into product and provides foundation, and may be used for the Qualitative and quantitative analysis of impurity in Tigecycline production, thus improve the quality of Tigecycline finished product.
Embodiment
Embodiment 1
1L reaction flask adds 500ml methyl alcohol, 40ml acetic acid, under stirring, adds 40g minocycline hydrochloride (source: Huabei Pharmaceutic Co., Ltd, lower same). It is warming up to 40 DEG C, insulation reaction 3h, stops heating, lowering the temperature-5～5 DEG C, control this temperature and drip and add triethylamine, adjust ph is to 7.5-8.0, precipitating out faint yellow solid, temperature control 0-5 DEG C stirs 2h, surveys pH value again unchanged, filter, methanol wash filter cake, after in reduced pressure at room temperature 4h, obtain Tigecycline impurity E 19.4g, purity 98.2%, receipts rate 52.5%.
The HPLC method detection condition of Tigecycline impurity E purity and method (lower with) be:
Chromatographic column: ODS-BPC18 (4.6 × 250mm5 μm);
Moving phase: acetonitrile 0.05mol/L ammonium dihydrogen phosphate (adds triethylamine 30ml/L, adjust pH to 6.7 ± 0.1 with phosphoric acid, add disodium ethylene diamine tetraacetate 0.5g/L) (20:80);
Thinner: get dipotassium hydrogen phosphate 4.35g and sodium bisulfite 0.5g, be dissolved in water and be diluted to 1000ml, with 1.0mol/L potassium hydroxide solution adjust pH to 8.0 ± 0.2;
Determined wavelength: 248nm
Flow velocity: 1.0ml/min;
Post temperature: 35 DEG C;
Sample size: 20 μ l;
Acquisition time: 40min
Method: get this product and be about 25mg, accurately weighed, put in 50ml measuring bottle, add thinner and dissolve and be diluted to scale, shake even. As need testing solution. Get need testing solution and enter sample, calculate impurity E content by area normalization method.
1H-NMR (500MHz, DMSO-d6) δ: 1.334-1.409 (1H, q); (2.122-2.180 2H, m); (2.42 1H, m); 2.52 (6H, s), 2.578 (6H, s); (2.616-2.728 1H, m); (3.204-3.242 1H, dd); (4.036-4.042 1H, d); (6.773-6.790 1H, d); (7.343-7.392 1H, d); (8.453 1H, s); (9.065-9.139 1H, s).
13C-NMR (100MHz, DMSO-d6) δ: 27.374; 30.165; 31.783; 42.295; 44.141; 44.406; 64.082; 75.968; 97.951; 107.543; 115.388; 116.177; 128.096; 136.830; 142.853; 157.153; 172.710; 176.533; 191.279; 192.859.
Embodiment 2
1L reaction flask adds 500ml methyl alcohol, 38ml formic acid, under stirring, adds 40g minocycline hydrochloride. It is warming up to 40 DEG C, insulation reaction 3h, stops heating, lowering the temperature-5～5 DEG C, control this temperature and drip and add first amine, adjust ph is to 7.5-8.0, precipitating out faint yellow solid, temperature control 0-5 DEG C stirs 2h, surveys pH value again unchanged, filter, methanol wash filter cake, after in reduced pressure at room temperature 4h, obtain Tigecycline impurity E 20g, purity 98.5%, receipts rate 54.2%.
Embodiment 3
1L reaction flask adds 500ml ethanol, 40ml formic acid, under stirring, adds 40g minocycline hydrochloride. It is warming up to 40 DEG C, insulation reaction 3h, stops heating, lowering the temperature-5～5 DEG C, control this temperature and add sodium carbonate, adjust ph is to 7.6-8.0, precipitating out faint yellow solid, temperature control 0-5 DEG C stirs 2h, surveys pH value again unchanged, filter, washing with alcohol filter cake, after in reduced pressure at room temperature 4h, obtain Tigecycline impurity E 19.6g, purity 98.2%, receipts rate 53%.
Embodiment 4
1L reaction flask adds 500ml ethanol, 32ml hydrochloric acid (concentration 15 weight %), under stirring, adds 40g minocycline hydrochloride. It is warming up to 40 DEG C, insulation reaction 3h, stops heating, lowering the temperature-5～5 DEG C, control this temperature and drip and add triethylamine, adjust ph is to 7.8-8.0, precipitating out faint yellow solid, temperature control 0-5 DEG C stirs 2h, surveys pH value again unchanged, filter, washing with alcohol filter cake, after in reduced pressure at room temperature 4h, obtain Tigecycline impurity E 20.2g, purity 98.8%, receipts rate 54.5%.
Embodiment 5
1L reaction flask adds 500ml methyl alcohol, 40ml acetic acid, under stirring, adds 40g minocycline hydrochloride. It is warming up to 42 DEG C, insulation reaction 3h, stops heating, lowering the temperature 0～5 DEG C, control this temperature and drip and add ammoniacal liquor, adjust ph is to 7.8-8.0, precipitating out faint yellow solid, temperature control 0-5 DEG C stirs 2h, surveys pH value again unchanged, filter, methanol wash filter cake, after in reduced pressure at room temperature 4h, obtain Tigecycline impurity E 20.5g, purity 98.6%, receipts rate 55.4%.
Embodiment 6
1L reaction flask adds 500ml methyl alcohol, 50ml acetic acid, under stirring, adds 40g minocycline hydrochloride. It is warming up to 45 DEG C, insulation reaction 3h, stops heating, lowering the temperature-2～5 DEG C, control this temperature and drip and add triethylamine, adjust ph is to 7.6-7.8, precipitating out faint yellow solid, temperature control 0-5 DEG C stirs 2h, surveys pH value again unchanged, filter, methanol wash filter cake, after in reduced pressure at room temperature 4h, obtain Tigecycline impurity E 20g, purity 98.2%, receipts rate 54.1%.
Claims (10)
1. the stereoselectivity preparation method of Tigecycline impurity E, comprises the steps:
1) in the mixture of low-grade alkane alcohol and liquid acids, minocycline hydrochloride is added;
2) by step 1) gained mixed solution is warming up to 35-45 DEG C, insulation reaction 2-5h;
3) stopping heating, be cooled to-10～20 DEG C, add alkali, adjust ph is to 6.5-8.5, precipitate out solid, it is incubated 0-5 DEG C of reaction 2h, surveys pH value again unchanged, filter, with low-grade alkane alcohol washing leaching cake at 0-5 DEG C, obtain Tigecycline impurity E, reduced pressure at room temperature 3-6h, obtain impurity E;
Here, the structural formula of described Tigecycline impurity E is:
Wherein, step 1) and step 3) described in low-grade alkane alcohol, be selected from methyl alcohol, ethanol or Virahol one or both.
2. preparation method as claimed in claim 1, wherein, step 1) and step 3) described in low-grade alkane alcohol be methyl alcohol.
3. preparation method as claimed in claim 1, wherein, step 1) described in liquid acids, be selected from formic acid, acetic acid, phosphoric acid, hydrochloric acid, sulfurous acid or sulfuric acid.
4. preparation method as claimed in claim 3, wherein, step 1) described in liquid acids be acetic acid.
5. preparation method as claimed in claim 1, wherein, step 1) described minocycline hydrochloride, low-grade alkane alcohol, liquid acids ingredient proportion m:V:V be: 1g:10ml～15ml:0.8ml～1.5ml.
6. preparation method as claimed in claim 1, wherein, step 2) described in warming temperature be 40～45 DEG C.
7. preparation method as claimed in claim 1, wherein, step 3) described in be cooled to-5～5 DEG C.
8. preparation method as claimed in claim 1, wherein, step 3) described in alkali be selected from diisopropylethylamine, triethylamine, first amine, ammoniacal liquor, sodium carbonate or sodium bicarbonate.
9. preparation method as claimed in claim 8, wherein, step 3) described in alkali be ammoniacal liquor or triethylamine.
10. preparation method as claimed in claim 1, wherein, wherein, step 3) described in pH value be 7.5-8.0.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101679218A (en) * | 2007-02-23 | 2010-03-24 | 霍维奥恩联合有限公司 | Crystalline minocycline base and preparation method thereof |
| PT105199A (en) * | 2007-02-23 | 2011-02-10 | Hovione Farmaciencia S A | MINORCYCLE PREPARATION PROCESS AMORFA |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101679218A (en) * | 2007-02-23 | 2010-03-24 | 霍维奥恩联合有限公司 | Crystalline minocycline base and preparation method thereof |
| PT105199A (en) * | 2007-02-23 | 2011-02-10 | Hovione Farmaciencia S A | MINORCYCLE PREPARATION PROCESS AMORFA |
Non-Patent Citations (1)
| Title |
|---|
| Assay and purity control of minocycline by thin-layer chromatography using UV and fluorescence densitometry-A comparison with liquid chromatography;Weng Naidong等;《Journal of Pharmaceutical and Biomedical Analysis》;19950630;第13卷(第7期);第905-910页 * |
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