CN106496272B - Crystal form A of Yi Zhong oxazolidinone antibacterials magnesium salts and its preparation method and application - Google Patents
Crystal form A of Yi Zhong oxazolidinone antibacterials magnesium salts and its preparation method and application Download PDFInfo
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- CN106496272B CN106496272B CN201610837718.5A CN201610837718A CN106496272B CN 106496272 B CN106496272 B CN 106496272B CN 201610837718 A CN201610837718 A CN 201610837718A CN 106496272 B CN106496272 B CN 106496272B
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- magnesium salts
- oxazolidinone antibacterials
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The characteristic peak that crystal form A the invention discloses an oxazolidinone antibacterials magnesium salts and its preparation method and application, the crystal form A are measured in X x ray diffraction collection of illustrative plates comprising following 2 θ angles of reflection：12.6±0.2°、16.8±0.2°、17.4±0.2°、18.9±0.2°、20.7±0.2°、21.5±0.2°、22.7±0.2°、24.3±0.2°、24.9±0.2°、26.4±0.2°、27.3±0.2°、28.2±0.2°、31.2±0.2°.Crystal form A stability is good, and dissolvent residual is low, available for pharmaceutical composition is prepared, has important application value in antibiotic medicine is prepared.
Description
Technical field
The invention belongs to field of medicaments, and in particular to the crystal form A of Yi Zhong oxazolidinone antibacterials magnesium salts and its preparation
Methods and applications.
Background technology
In recent years, the drug-fast bacteria of all kinds of antibacterials rapid development serious threat to the mankind health, 2011
The World Health Organization will alert the world therefore to enter " rear antibiotic epoch ".Various countries have appreciated that research and development novel antibacterial drug
Importance, the U.S. had approved in 2012《FDA safety and innovation bill》, Part VIII is《Encourage exploitation antibiotic method
Case》(GAIN bills).Country defended 14 ministries and commissions such as planning commission and combined and issues this year《It takes action on containment bacterial resistance country is printed and distributed
Plan the notice of (2016-2020)》, the challenge that reply bacterial resistance is brought is by the height of promotion for the first time to State-level, work
To resist an important measures of bacterial resistance problem, support and encourage the research and development of novel antibacterial drug becomes focus again.
European patent EP 2940024A1 discloses a kind of new oxazolidinones antibacterials, compound structure such as formula (1)
It is shown：
Result of study shows that oxazolidinones antibacterials shown in formula (1) have lives compared with the stronger antibacterial of similar drugs
Property, especially anti-more drug-fast bacteria activity are referred to described in patent EP2940024A1.The medicinal forms of formula (1) drug include free
Sour and its pharmaceutically acceptable salt, such as sodium salt, magnesium salts and calcium salt salt.
It is well known that the generally existing polymorphism in solid drugs, crystal form is to influence drug quality and the weight of curative effect
Want one of factor.In recent years, domestic pharmacy corporation starts gradually to pay attention to the research to drug crystal forms, understands the crystal form of solid drugs
Help to solve following point：Ensure the stability of solid material medicine and preparation in production and transport storage process；Pass through polycrystalline
The effect of bioavilability screening of type drug, enhancement drug；Ensure that the bulk pharmaceutical chemicals of each production batch are consistent with preparation crystal form
Property.
European patent EP 2940024A1 discloses the preparation method of formula (1) free acid and formula (3) sodium salt, but does not disclose
The preparation method and its crystal form of formula (2) magnesium salts (M=Mg).We have found that the free acid and sodium salt that are prepared according to this compound patent
It is amorphous products, and amorphous products dissolvent residual is easily exceeded, stability is relatively poor, it is therefore necessary to develop formula
(1) the crystal form product of officinal salt.
The content of the invention
The present invention provides crystal form A of Yi Zhong oxazolidinone antibacterials magnesium salts and its preparation method and application, the crystalline substance
Type A has better stability compared with unformed, and organic solvent residual is lower.
The present invention is achieved in the following ways：
The crystal form A of Yi Zhong oxazolidinone antibacterials magnesium salts includes following 2 θ angles of reflection in X-ray diffracting spectrum
The characteristic peak of measure：12.6±0.2°、16.8±0.2°、17.4±0.2°、18.9±0.2°、20.7±0.2°、21.5±
0.2°、22.7±0.2°、24.3±0.2°、24.9±0.2°、26.4±0.2°、27.3±0.2°、28.2±0.2°、31.2±
0.2°。
The structural formula such as formula (2) of the crystal form A of Suo Shu oxazolidinone antibacterials magnesium salts：
Stability test and residual solvent detection show to be prepared into according to the method for EP2940024A1 compared with applicant
Dao oxazolidinone antibacterials sodium salts and unformed magnesium salts, the crystal form A of formula (2) magnesium salts have better stability and
Lower dissolvent residual.
Preferably, the X-ray diffracting spectrum of the crystal form A is as shown in Figure 1.
The present invention also provides the preparation method of the crystal form A of Shu oxazolidinone antibacterials magnesium salts Shang Ru a kind of, including
Following steps：
1) it is oxazolidinone antibacterials sodium salt is soluble in water, and organic solvent diluting is added in, obtain solution I；It is described
Organic solvent for acetone, acetonitrile, tetrahydrofuran, dioxane, C1~C3One kind in alkylol；
2) solution II is obtained by inorganic magnesium salt is soluble in water, solution II is added in solution I, stand crystallization, it is filtering, dry
It is dry, obtain the crystal form A.
Wherein, Suo Shu oxazolidinone antibacterials sodium salts may be referred to the preparation in European patent EP 2940024A1
Method is prepared, shown in structural formula such as formula (3)：
The reaction equation of the preparation method is as follows：
If we by the study found that dicyandiamide solution be simple water, obtained magnesium salts be amorphous products, crystal form A
Product can only obtain in the mixed system of water and organic solvent, and organic solvent and water must be controlled certain in solution I
In proportion, otherwise sodium salt is easily precipitated or obtains the amorphous products of magnesium salts.
Preferably, Suo Shu oxazolidinone antibacterials sodium salts enantiomeric purity is more than 99%, 6 contained are non-right
The impurity summation reflected including isomers is less than 1%.
Preferably, Suo Shu oxazolidinone antibacterials sodium salts enantiomeric purity is more than 99.5%.
Preferably, the organic solvent I is methanol.
Preferably, the volume ratio of organic solvent and water is 0.5~3 in the solution I.
Preferably, the inorganic magnesium salt is magnesium sulfate or magnesium chloride, can be anhydride or hydrate.
Crystal form A the present invention also provides Shu oxazolidinone antibacterials magnesium salts Shang a kind of Ru is preparing antibiotic medicine
In application.
Preferably, the crystal form A and one or more of the drug Bao Han oxazolidinone antibacterials magnesium salts can
Medicinal inert non-toxic carrier.The inert non-toxic carrier can be selected according to the existing knowledge of those skilled in the art
It selects, including diluent pharmaceutically used, flavouring agent, solubilizer, lubricant and coating agent etc., such as magnesium phosphate, smoothers sugar,
Lactose, pectin, starch and gelatin etc..
Compared with the existing technology the crystal form A of the , oxazolidinone antibacterials magnesium salts is very stable in ambient enviroment, and
Solvent residual amount is small, can be used for preparing pharmaceutical composition；In the process parameters range described in the preparation method, repeat multiple
Batch, reappearance are fabulous.
Description of the drawings
Fig. 1 is the X-ray diffracting spectrum for the crystal form A that embodiment 1 prepares oxazolidinone antibacterials magnesium salts；
Fig. 2 is the X-ray diffracting spectrum that embodiment 7 prepares oxazolidinone antibacterials magnesium salts amorphous products.
Specific embodiment
Illustrating the particular embodiment of the present invention with reference to the following example, these embodiments are to illustrate the present invention, and
It is non-to limit the invention in any way.
(3) oxazolidinone antibacterials sodium salts are synthesized formula by European patent EP 2940024A1.
Embodiment 1
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL) at room temperature, adds methanol (25mL) stirring.
Magnesium sulfate (2.41g, 0.02mol) is dissolved in water (50mL), is added in above-mentioned sodium salt solution.Static crystallization filters, vacuum
Dry, obtained solid carries out powder x-ray diffraction, and the results are shown in Figure 1.
Embodiment 2
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL), 60 DEG C is warming up to, adds methanol
(150mL) is stirred.Magnesium sulfate 7 hydrate (4.93g, 0.02mol) is dissolved in water (50mL), is added to above-mentioned sodium salt solution
In, when 60 DEG C of stirring heat preservations 1 are small.Cooling, static crystallization filter, and vacuum drying, obtained solid carries out powder x-ray diffraction.
Embodiment 3
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL) at room temperature, adds tetrahydrofuran (35mL)
Stirring.Magnesium chloride (1.91g, 0.02mol) is dissolved in water (50mL), is added in above-mentioned sodium salt solution.Static crystallization is taken out
Filter, vacuum drying, obtained solid carry out powder x-ray diffraction.
Embodiment 4
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL), is warming up to 70 DEG C, adds acetonitrile (75mL)
Stirring.Magnesium chloride hexahydrate (4.07g, 0.02mol) is dissolved in water (50mL), is added in above-mentioned sodium salt solution, 70 DEG C
When stirring heat preservation 1 is small.Cooling, static crystallization filter, and vacuum drying, obtained solid carries out powder x-ray diffraction.
Embodiment 5
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL) at room temperature, adds dioxane (30mL)
Stirring.Magnesium sulfate (2.41g, 0.02mol) is dissolved in water (50mL), is added in above-mentioned sodium salt solution.Static crystallization is taken out
Filter, vacuum drying, obtained solid carry out powder x-ray diffraction.
Embodiment 6
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL) at room temperature, adds ethyl alcohol (50mL) stirring.
Magnesium sulfate 7 hydrate (4.93g, 0.02mol) is dissolved in water (50mL), is added in above-mentioned sodium salt solution.Static crystallization,
It filters, vacuum drying, obtained solid carries out powder x-ray diffraction.
Embodiment 7
Formula (3) sodium salt (10.43g, 0.02mol) is dissolved in water (50mL) at room temperature.Again by magnesium sulfate (2.41g,
It 0.02mol) is dissolved in water (50mL), is added in above-mentioned sodium salt solution.Static crystallization, filter, vacuum drying, obtained solid into
Row powder x-ray diffraction, the results are shown in Figure 2.
Performance test 1X- ray Powder Diffraction patterns：
Determining instrument：EMPYREAN type diffractometers, PANALYTICAL
Determination condition：
Fig. 1 is the X-ray diffracting spectrum for the crystal form A that embodiment 1 prepares oxazolidinone antibacterials magnesium salts, is measured
Data are listed in table 1.
The X- diffraction data of the crystal form A of 1 oxazolidinone antibacterials magnesium salts of table
The X-ray diffracting spectrum and Fig. 1 of the crystal form A of oxazolidinones antibacterials magnesium salts prepared by embodiment 2~6
It is identical.Fig. 2 is the unformed X-ray diffracting spectrum that embodiment 7 prepares oxazolidinone antibacterials magnesium salts.
The crystal form A and magnesium salts of 2 oxazolidinone antibacterials magnesium salts of performance test are unformed and by European patent
The quality of the oxazolidinone antibacterials sodium salt of EP2940024A1 synthesis compares
According to four general rule ＜ of Chinese Pharmacopoeia version in 2015,0861 residual solvent measuring method ＞ and 9001 bulk pharmaceutical chemicals of guideline ＜
Object is with preparation stability test direction principle ＞ relevant regulations to the crystalline substance of 1 get oxazolidinones antibacterials magnesium salts processed of embodiment
It 7 get oxazolidinones antibacterials magnesium salts processed of type A and embodiment unformed and is synthesized by European patent EP 2940024A1
Oxazolidinone antibacterials sodium salt carries out dissolvent residual detection and accelerated test, as a result such as table 2：
2 magnesium salts crystal form A of table and magnesium salts is unformed and the quality of sodium salt compares
Result of the test shows magnesium salts crystal form A that the present processes obtain no matter in terms of stability or dissolvent residual,
Effect is all substantially improved.
Claims (10)
1. the crystal form A of Yi Zhong oxazolidinone antibacterials magnesium salts, which is characterized in that comprising following in X-ray diffracting spectrum
The characteristic peak that 2 θ angles of reflection measure：12.6±0.2°、16.8±0.2°、17.4±0.2°、18.9±0.2°、20.7±0.2°、
21.5±0.2°、22.7±0.2°、24.3±0.2°、24.9±0.2°、26.4±0.2°、27.3±0.2°、28.2±0.2°、
31.2±0.2°；
The structural formula such as formula (2) of Suo Shu oxazolidinone antibacterials magnesium salts：
2. according to the crystal form A of claim 1 Suo Shu oxazolidinone antibacterials magnesium salts, which is characterized in that the crystal form A
X-ray diffracting spectrum as shown in Figure 1.
3. a kind of such as claim 1 or the preparation method of the crystal form A of 2 Shu oxazolidinone antibacterials magnesium salts, feature
It is, comprises the following steps：
1) it is oxazolidinone antibacterials sodium salt is soluble in water, and organic solvent diluting is added in, obtain solution I；Described has
Solvent is acetone, one kind in acetonitrile, tetrahydrofuran, dioxane, C1~C3 alkylols；
2) solution II is obtained by inorganic magnesium salt is soluble in water, solution II is added in solution I, stand crystallization, it is filtering, dry,
Obtain the crystal form A.
4. according to the preparation method of the crystal form A of claim 3 Suo Shu oxazolidinone antibacterials magnesium salts, which is characterized in that
Suo Shu oxazolidinone antibacterials sodium salts enantiomeric purity is miscellaneous including 6 diastereoisomers contained more than 99%
Matter summation is less than 1%.
5. according to the preparation method of the crystal form A of claim 4 Suo Shu oxazolidinone antibacterials magnesium salts, which is characterized in that
Suo Shu oxazolidinone antibacterials sodium salts enantiomeric purity is more than 99.5%.
6. according to the preparation method of the crystal form A of claim 3 Suo Shu oxazolidinone antibacterials magnesium salts, which is characterized in that
The organic solvent is methanol.
7. according to the preparation method of the crystal form A of claim 3 Suo Shu oxazolidinone antibacterials magnesium salts, which is characterized in that
The volume ratio of organic solvent and water is 0.5~3 in the solution I.
8. according to the preparation method of the crystal form A of claim 3 Suo Shu oxazolidinone antibacterials magnesium salts, which is characterized in that
The inorganic magnesium salt is magnesium sulfate or magnesium chloride.
It is 9. a kind of if the crystal form A of claim 1 or 2 Shu oxazolidinone antibacterials magnesium salts is in antibiotic medicine is prepared
Application.
10. according to the crystal form A of claim 9 Suo Shu oxazolidinone antibacterials magnesium salts answering in antibiotic medicine is prepared
With, which is characterized in that the crystal form A and one or more of the drug Bao Han oxazolidinone antibacterials magnesium salts are pharmaceutically acceptable
Inert non-toxic carrier.
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|---|---|---|---|---|
| CN1749256A (en) * | 2004-09-16 | 2006-03-22 | 中国科学院上海药物研究所 | One class Xin De oxazolidone derivative, Preparation Method And The Use |
| CN102260277A (en) * | 2010-05-24 | 2011-11-30 | 中国科学院上海药物研究所 | Novel benzoxazine oxazolidinone compound as well as preparation method thereof and purpose thereof |
| CN103896963A (en) * | 2012-12-26 | 2014-07-02 | 中国科学院上海药物研究所 | Benzoxazine oxazolidinone compounds, preparation method and applications thereof |
| CN106632481A (en) * | 2016-09-09 | 2017-05-10 | 优胜美特制药有限公司 | Oxazolidinone antibacterial drug crystal A and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1749256A (en) * | 2004-09-16 | 2006-03-22 | 中国科学院上海药物研究所 | One class Xin De oxazolidone derivative, Preparation Method And The Use |
| CN102260277A (en) * | 2010-05-24 | 2011-11-30 | 中国科学院上海药物研究所 | Novel benzoxazine oxazolidinone compound as well as preparation method thereof and purpose thereof |
| CN103896963A (en) * | 2012-12-26 | 2014-07-02 | 中国科学院上海药物研究所 | Benzoxazine oxazolidinone compounds, preparation method and applications thereof |
| CN106632481A (en) * | 2016-09-09 | 2017-05-10 | 优胜美特制药有限公司 | Oxazolidinone antibacterial drug crystal A and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Solubility-Driven Optimization of (Pyridin-3-yl)Benzoxazinyl-oxazolidinones Leading to a Promising Antibacterial Agent;Bin Guo et al.;《Journal of Medicinal Chemistry》;20130221;第2642-2650页 * |
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Effective date of registration: 20180727 Address after: 201203 555 Zhangjiang Road, Zhangjiang, Pudong New Area, Shanghai Patentee after: Shanghai Institute of Materia Medica, Chinese Academy of Sciences Address before: 322118 Jiangnan Road, Hengdian Industrial Zone, Dongyang, Jinhua, Zhejiang 519 Patentee before: Zhejiang Puluo Debang Pharmaceutical Co., Ltd. |
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