CN103965116B - Half 5-flurocytosine salt, its preparation method and application - Google Patents
Half 5-flurocytosine salt, its preparation method and application Download PDFInfo
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- CN103965116B CN103965116B CN201410188289.4A CN201410188289A CN103965116B CN 103965116 B CN103965116 B CN 103965116B CN 201410188289 A CN201410188289 A CN 201410188289A CN 103965116 B CN103965116 B CN 103965116B
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- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/06—Six-membered rings
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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Abstract
The invention discloses a kind of half 5-flurocytosine salt, its preparation method and application. Described salt is acesulfame potassium salt, and it is mainly by 5-flurocytosine cation (FCH+), 5-flurocytosine neutral molecule (FC) and acesulfame potassium anion (AH-) in molar ratio 1:1:1 composition, and the structure cell of described salt belongs to anorthic system, its axial length a=7.2613 (2)? b=10.5289 (3)? c=11.6662 (4)? shaft angle α=66.8180 (11) °, β=82.0220 (12) o, γ=78.5670 (12) o. The problem that half 5-flurocytosine salt prepared by the present invention can be effectively improved the moisture poor stability of 5-flurocytosine, and there is good active drug content and heat stability, and its preparation technology is simple, operate easy, with low cost, remain without toxic solvent, guest molecule component is a kind of sweeting agent simultaneously, the mouthfeel of medicine can be improved, it is adaptable to pharmaceuticals industry.
Description
Technical field
The present invention be more particularly directed to a kind of 5-flurocytosine salt and preparation method thereof, belong to chemical pharmacy field.
Background technology
Drug products more than 80% is applied with solid oral formulations Informal development. Identical crude drug can develop into different solid-state forms, as: polymorphic, hydrate, solvated compounds, salt and eutectic. Different solid-state forms have different physicochemical properties. Medicine becomes salt technology to be widely used in pharmaceuticals industry to improve the physicochemical properties of medicine. According to statistics, the crude drug exceeding half is developed to its salt form.
The molecular formula of 5-flurocytosine is C4H4FN3O, it is a kind of widely used antibacterials, is mainly used in treatment infective endocarditis, urinary tract infection and pulmonary infection etc. 5-flurocytosine self does not have antibiotic effect, but can change into 5-fluorouracil after deamination, and the metabolite of 5-fluorouracil can suppress the synthesis of fungal rna and DNA. Commercially available 5-flurocytosine is its crystal formation I, is at room temperature Thermodynamically stable crystal formation. Louis, DerekA.Tocher et al. report, and 5-flurocytosine can occur hydration to convert at high humidity, generate monohydrate, and preservation and the quality control of such humidity unstability drug bring serious problems. Therefore, it is necessary to improved the moisture stability stability problem of 5-flurocytosine by suitable technological approaches. Although the paid pilot production relevant report becoming salt mode to solve this problem at present, for instance, by by 5-flurocytosine and saccharin, salicylic acid, maleic acid, fumaric acid, oxalic acid and multiple mineral acid (HBr, HI, HNO3) etc. react into salt, but wherein only have the saccharin salt of 5-flurocytosine and oxalates is in the news and has good moisture stability. It is true that also there is not the pharmaceutically acceptable half 5-flurocytosine salt with good moisture stability to be in the news so far.
Summary of the invention
It is an object of the present invention to provide a kind of novel 5-flurocytosine salt, this salt can be effectively improved under 5-flurocytosine high humidity and draw the wet problem occurring hydration to convert.
Further object is that the preparation method that above-mentioned salt is provided.
For reaching foregoing invention purpose, the technical scheme is that
A kind of half 5-flurocytosine salt, it is mainly made up of 5-flurocytosine cation, 5-flurocytosine neutral molecule and acesulfame potassium anion that mol ratio is 1:1:1, and the crystal structure of described salt belongs to anorthic system, its structure cell axial length a=7.2613 (2), b=10.5289 (3), c=11.6662 (4), shaft angle α=66.8180 (11) °, β=82.0220 (12) o, γ=78.5670 (12) o.
Further, described salt is structured with formula:
。
A kind of method preparing aforementioned half 5-flurocytosine salt, including: take 5-flurocytosine and be dissolved in solvent with acesulfame potassium, form supersaturation, saturated or mixed solution close to saturation, and take described mixed solution and carry out crystallization treatment, dividing isolated crystal again, obtained colourless transparent crystal or white powder are end product after drying.
Present invention also offers the application in preparation antibacterials of the aforementioned half 5-flurocytosine salt.
Compared with prior art, the invention have the advantages that and provide a kind of half novel 5-flurocytosine salt, it is half salt using sweeting agent acesulfame potassium to be formed, medicine effective content is far above the 5-flurocytosine salt (salt of such as saccharin and 5-flurocytosine) reported, there is sweet taste mouthfeel and excellent moisture-proof, such as, under 95% relative humidity, drawing wet weightening finish is lower than 0.6%, simultaneously, its preparation technology is simple, mild condition, environmental protection, repeatability is high, good stability, and obtained product also has crystal form purity high.
Accompanying drawing explanation
Fig. 1 is dynamic moisture adsorption-desorption (DVS) curve of 5-flurocytosine and half 5-flurocytosine salt in the present invention;
Fig. 2 is the Powder XRD pattern of half 5-flurocytosine salt in embodiment 1;
Fig. 3 is half 5-flurocytosine salt in embodiment 213C solid-state nuclear magnetic resonance collection of illustrative plates;
Fig. 4 is half 5-flurocytosine salt in embodiment 215N solid-state nuclear magnetic resonance collection of illustrative plates;
Fig. 5 is the mono-crystalline structures figure of half 5-flurocytosine salt in embodiment 3;
Fig. 6 is half 5-flurocytosine salt and prepare means of differential scanning calorimetry (DSC) curve of raw material (that is, 5-flurocytosine and acesulfame potassium) in the present invention.
Detailed description of the invention
In view of the defect of prior art, inventor, through studying for a long period of time and putting into practice, is known technical scheme, and it is mainly by a kind of novel one-tenth salt mode, it is thus achieved that a kind of half 5-flurocytosine salt with good moisture stability and medical value.
Further saying, the half 5-flurocytosine salt of the present invention is acesulfame potassium salt, and it is mainly by 5-flurocytosine cation (FCH+), 5-flurocytosine neutral molecule (FC) and acesulfame potassium anion (AH-) in molar ratio 1:1:1 composition, and its structure cell belongs to anorthic system, its axial length a=7.2613 (2), b=10.5289 (3), c=11.6662 (4), shaft angle α=66.8180 (11) °, β=82.0220 (12) o, γ=78.5670 (12) o.
Further, the half 5-flurocytosine salt of the present invention has the molecular structure shown in following formula 1.
Formula 1
Further, the powder X-ray diffraction figure (such as, radiation source is CuK α) of described salt in angle of diffraction 2 θ=8.29,14.47,15.31,16.48,17.14,18.17,19.49,19.86,23.00,23.70,24.78,25.11,27.04,27.69,28.40,28.67,29.76,31.06,31.49,31.87,32.52,33.13,34.59,36.50,36.87,38.66,39.03 degree there is characteristic peak.
Further, described salt13C solid-state nuclear magnetic resonance spectrum (such as, calibrates with tetramethylsilane, 0ppm) 171.9,163.2,158.0,155.2,151.5,140 ~ 131,128.9,102.4,19.7ppm place there is characteristic peak.
Further, described salt15N solid-state nuclear magnetic resonance spectrum (calibrates with glycine ,-347ppm)-186.5 ,-199.3 ,-231.8 ,-243.3 ,-246.0 ,-283.6 ,-287.3ppm place there is characteristic peak.
Among some embodiments of the present invention, the preparation method of described salt may include steps of:
(1) under uniform temperature, 5-flurocytosine and acesulfame potassium are dissolved completely in solvent according to certain mol proportion example, form supersaturation, saturated or close to saturation;
(2) undertaken above-mentioned mixed solution lowering the temperature, standing or solvent volatilization, precipitate out the crystal of salt;
(3) the crystal vacuum drying that will obtain, obtains colourless transparent crystal or white powder is end product.
Further, aforementioned solvents can be selected for but is not limited to the one in the middle of water, methanol, ethanol, acetic acid or its arbitrary proportion obtains mixed solvent.
Among a preferred embodiment, the solution temperature of the raw materials such as aforementioned 5-flurocytosine and acesulfame potassium is room temperature ~ 80 ° C.
Among a preferred embodiment, the initial molar ratio of aforementioned 5-flurocytosine and acesulfame potassium is 4:1 ~ 1:2, it is particularly preferred that for 2:1.
Among a preferred embodiment, if using cooling or standing mode crystallization, then crystallization temperature is 4 ° of C ~ room temperatures.
Among a preferred embodiment, if using solvent volatilization crystallization, then crystallization temperature is room temperature ~ 80 ° C.
The preparation method of the present invention is simple, mild condition, and can to use water be solvent, avoid the use of organic solvent, reduce environmental pollution, simultaneously, its crystallization parameters boundary condition width, repeatability is high, can convenient stable acquisition product, and show through powder X-ray RD and DSC test, obtained product crystal form purity is high, and without obvious raw material impurity and residual solvent, it has the moisture-proof of excellence, under 95% relative humidity, draw wet weightening finish for lower than 0.6%.
Below in conjunction with specific embodiment and accompanying drawing, the innovation essence of technical solution of the present invention is described further:
Embodiment 1The preparation of salt (half 5-flurocytosine salt, lower same): weighing 0.2mmol5-flucytosine and 0.1mmol acesulfame potassium, 40 ° of C are dissolved in 20mL methanol, filter rear 25 ° of C volatilization, obtain lenticular salt, productivity 95%, and XRD figure is composed as shown in Figure 2.
Embodiment 2The preparation of salt: weigh 1mmol5-flucytosine and 0.5mmol acesulfame potassium, room-temperature dissolution, in 15mL water, filters rear 60 ° of C volatilization, obtains lenticular salt, productivity 84%, and its solid-state nuclear magnetic resonance dactylogram such as Fig. 3, shown in 4.
Embodiment 3Single crystal preparation: weigh 0.1mmol5-flucytosine and 0.1mmol acesulfame potassium, 60 ° of C are dissolved in 15mL methanol, and after filtration, room temperature volatilization, obtains lenticular salt, carry out monocrystalline test in 153K condition, and structure is as shown in Figure 5.
Embodiment 4The hygroscopicity of salt measures: remove the salt that embodiment 1-3 obtains, Dynamic Water adsorption-desorption instrument is used to carry out hygroscopicity test, 25 ± 0.1 ° of C of experimental temperature, relative humidity drops to again 0% after rising to 95% from 0%, step-length is 5%, and often step tension metrics is that weight relative time derivation changes less than 0.01% or equilibration time was more than 120 minutes. As shown in Figure 1: the water absorption of 5-flurocytosine salt is significantly lower than crude drug.In water adsorption process, the water absorption of pure crude drug is 13.8%, is transformed into monohydrate, and the water absorption of salt is only 0.55%.
Postscript, then the salt obtained in Example 1-3 and raw materials used (i.e. 5-flurocytosine, acesulfame potassium) test, its means of differential scanning calorimetry (DSC) all see Fig. 6.
The problem that half 5-flurocytosine salt prepared by the present invention can be effectively improved the moisture poor stability of 5-flurocytosine, and there is good heat stability, and described salt can be produced by the common technology such as solvent evaporation method and lowering temperature crystallization, technique is simple, operate easy, with low cost, remain without toxic solvent, guest molecule is a kind of sweeting agent simultaneously, molecular weight is little, there is not metabolism in human body, non-absorbent feature, there is not the report being detrimental to health so far, the food that its country checks and approves adds limitation high (daily intaking amount of FDA approval is 0 ~ 15mg/kg), the mouthfeel of medicine can be improved simultaneously, and there is good active drug content, suitable in pharmaceuticals industry.
Should be appreciated that present invention described above is embodied as example for showing the essence novelty of the present invention, be not that present invention is further limited. The technical scheme that all employing equivalents or equivalence are replaced and formed; or use other crystallization conditions according to the technical scheme by this invention patent protection prepare with 5-flurocytosine for active medicine; with acesulfame potassium for proton donor; the two than existence and has the related ends of product fingerprint characteristic involved by the present invention with 2:1 mole of metering, all belongs within scope.
Claims (9)
1. one and half 5-flurocytosine salt, it is characterised in that described salt is made up of 5-flurocytosine cation, 5-flurocytosine neutral molecule and the acesulfame potassium anion that mol ratio is 1:1:1, and the crystal structure of described salt belongs to anorthic system, its structure cell axial lengthShaft angle α=66.8180 (11) °, β=82.0220 (12) °, γ=78.5670 (12) °; And described salt is structured with formula:
2. the preparation method of half 5-flurocytosine salt described in claim 1, it is characterized in that including: take 5-flurocytosine and be dissolved in solvent with acesulfame potassium, form supersaturation, saturated or mixed solution close to saturation, and take described mixed solution and carry out crystallization treatment, dividing isolated crystal again, obtained colourless transparent crystal or white powder are end product after drying.
3. the preparation method of half 5-flurocytosine salt according to claim 2, it is characterised in that including: under the temperature conditions of room temperature～80 DEG C, is dissolved in solvent by 5-flurocytosine and acesulfame potassium, forms described mixed solution.
4. the preparation method of half 5-flurocytosine salt according to any one of claim 2-3, it is characterised in that the initial molar ratio of described 5-flurocytosine and acesulfame potassium is 4:1～1:2.
5. the preparation method of half 5-flurocytosine salt according to any one of claim 2-3, it is characterised in that described solvent includes any one or the two or more mixed solvent mixed in any proportion among water, methanol, ethanol, acetic acid.
6. the preparation method of half 5-flurocytosine salt according to claim 2, it is characterised in that including: at least select cooling, stand and any one method in solvent volatilization realizes the crystallization treatment to described mixed solution.
7. the preparation method of half 5-flurocytosine salt according to claim 6, it is characterised in that including:
Carry out crystallization treatment according to cooling or standing mode, then crystallization temperature is 4 DEG C～room temperature;
Or, carrying out crystallization treatment according to solvent volatilization mode, then crystallization temperature is room temperature～80 DEG C.
8. the preparation method of half 5-flurocytosine salt according to claim 2 or 6, it is characterised in that including: the crystal precipitated out is carried out vacuum drying treatment, it is thus achieved that described end product.
9. the application in preparation antibacterials of the half 5-flurocytosine salt described in claim 1.
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| RS59840B1 (en) | 2016-09-21 | 2020-02-28 | Celanese Int Corp | Acesulfame potassium compositions and processes for producing same |
| DK3319948T3 (en) | 2016-09-21 | 2021-09-27 | Celanese Int Corp | Acesulfame-potassium compositions and methods for their preparation |
| JP6912582B2 (en) | 2016-09-21 | 2021-08-04 | セラニーズ・インターナショナル・コーポレーション | Acesulfame potassium composition and its production method |
| SI3319949T1 (en) | 2016-09-21 | 2020-11-30 | Celanese International Corporation, | Acesulfame potassium compositions and processes for producing same |
| CN117003701B (en) * | 2023-08-04 | 2024-02-13 | 广东中科半导体微纳制造技术研究院 | Fluocytosine-isostearate and preparation method and application thereof |
| CN117003702B (en) * | 2023-08-04 | 2024-02-13 | 广东中科半导体微纳制造技术研究院 | Fluocytosine-orotate and preparation method and application thereof |
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| CN1723215A (en) * | 2002-12-09 | 2006-01-18 | 霍夫曼-拉罗奇有限公司 | Anhydrous crystalline azido cytosine hemisulfate derivative |
| CN101085355A (en) * | 2007-06-20 | 2007-12-12 | 山东大学 | 5-flucytosine/hydrotalcite-like nano hybrid compound and preparation method thereof |
| US20100226943A1 (en) * | 2004-02-17 | 2010-09-09 | University Of Florida | Surface topographies for non-toxic bioadhesion control |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1723215A (en) * | 2002-12-09 | 2006-01-18 | 霍夫曼-拉罗奇有限公司 | Anhydrous crystalline azido cytosine hemisulfate derivative |
| US20100226943A1 (en) * | 2004-02-17 | 2010-09-09 | University Of Florida | Surface topographies for non-toxic bioadhesion control |
| CN101085355A (en) * | 2007-06-20 | 2007-12-12 | 山东大学 | 5-flucytosine/hydrotalcite-like nano hybrid compound and preparation method thereof |
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