CN103965116A - Hemi-5-fluorocytosine salt, as well as preparation method and application thereof - Google Patents
Hemi-5-fluorocytosine salt, as well as preparation method and application thereof Download PDFInfo
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- CN103965116A CN103965116A CN201410188289.4A CN201410188289A CN103965116A CN 103965116 A CN103965116 A CN 103965116A CN 201410188289 A CN201410188289 A CN 201410188289A CN 103965116 A CN103965116 A CN 103965116A
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- salt
- flurocytosine
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- fluorocytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
The invention discloses hemi-5-fluorocytosine salt, as well as a preparation method and application thereof. The salt adopts acesulfame salt, and mainly composed of 5-fluorocytosine cation (FCH+), 5-fluorocytosine neutral molecule (FC) and acesulfame anion (AH-) according to the molar ratio of 1 to 1 to 1, the crystal cell of the salt belongs to an anorthic system, has the axial length a being equal to 7.2613(2)A, b being equal to 10.5289(3)A, and c being equal to 11.6662(4)A, and has the axial angle Alpha being equal to 66.8180(11) degrees, Beta being equal to 82.0220(12) degrees, and Gamma being equal to 78.5670(12) degrees. The hemi-5-fluorocytosine salt provided by the invention can effectively solve the problem of low moisture stability of the 5-fluorocytosine,and has excellent and effective medicine content and heat stability, the preparation technology of the hemi-5-fluorocytosine salt is simple, the operation is easy, the cost is low, poisonous solvent residue is avoided, meanwhile, the object molecule component serves as a sweetener, the medical mouthfeel can be improved, and the hemi-5-fluorocytosine salt is applicable to pharmaceutical 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
Exceed 80% medicament production with solid-state oral preparations form Application and Development.Identical bulk drug can be developed to different solid-state forms, as: polymorphic, hydrate, solvated compounds, salt and eutectic.Different solid-state forms have different physicochemical property.Medicine salify technology is widely used in pharmaceutical industry improves the physicochemical property of medicine.According to statistics, the bulk drug that exceedes half is developed to its salt form.
The molecular formula of 5-flurocytosine is C
4h
4fN
3o, it is a kind of widely used antibacterials, is mainly used in treating infective endocarditis, urinary tract infections and pulmonary infection etc.5-flurocytosine self does not have antibiotic effect, but can change into 5 FU 5 fluorouracil after deamination, and the metabolite of 5 FU 5 fluorouracil can Antifungi RNA and DNA synthetic.Commercially available 5-flurocytosine is its crystal formation I, is at room temperature Thermodynamically stable crystal formation.The people such as Louis, Derek A. Tocher have reported, 5-flurocytosine hydration can occur under high humidity and transforms, and generates monohydrate, and such humidity unstable is brought serious problems to preservation and the quality control of medicine.Therefore, be necessary to improve by suitable technological approaches the moisture stability stability problem of 5-flurocytosine.Although the relevant report that at present paid pilot production addresses this problem by salify mode, for example, by by 5-flurocytosine and asccharin, Whitfield's ointment, toxilic acid, fumaric acid, oxalic acid and multiple mineral acid (HBr, HI, HNO
3) etc. reaction salify, there is good moisture stability but wherein only have the saccharin salt of 5-flurocytosine and oxalate to be in the news.In fact, also there is not so far the pharmaceutically acceptable half 5-flurocytosine salt with good moisture stability to be in the news.
Summary of the invention
One object of the present invention is to provide a kind of novel 5-flurocytosine salt, and this salt can effectively improve the problem of drawing wet generation hydration conversion under 5-flurocytosine high humidity.
Another object of the present invention is to provide the preparation method of above-mentioned salt.
For reaching foregoing invention object, the invention provides following technical scheme:
A kind of half 5-flurocytosine salt, 5-flurocytosine positively charged ion, 5-flurocytosine neutral molecule and acesulfame potassium negatively charged ion that it is mainly 1:1:1 by mol ratio form, and the crystalline structure of described salt belongs to triclinic(crystalline)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 has following structural formula:
。
A kind of method of preparing aforementioned half 5-flurocytosine salt, comprise: get 5-flurocytosine and acesulfame potassium and be dissolved in solvent, form supersaturation, saturated or approach the mixing solutions of state of saturation, and get described mixing solutions and carry out crystallization treatment, divide again isolated crystal, obtain colourless transparent crystal after drying or white powder is final product.
The present invention also provides the application of aforementioned half 5-flurocytosine salt in preparation antibacterials.
Compared with prior art, advantage of the present invention comprises: a kind of half novel 5-flurocytosine salt is provided, it is half salt that uses sweeting agent acesulfame potassium to form, medicine effective content for example, far above the 5-flurocytosine salt of having reported (salt of asccharin and 5-flurocytosine), there is sweet taste mouthfeel and excellent wet fastness, for example, 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 formation purity high.
brief description of the drawings
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 X-ray RD collection of illustrative plates of half 5-flurocytosine salt in embodiment 1;
Fig. 3 is half 5-flurocytosine salt in embodiment 2
13c solid-state nuclear magnetic resonance collection of illustrative plates;
Fig. 4 is half 5-flurocytosine salt in embodiment 2
15n solid-state nuclear magnetic resonance collection of illustrative plates;
Fig. 5 is the single crystal structure figure of half 5-flurocytosine salt in embodiment 3;
Fig. 6 is means of differential scanning calorimetry (DSC) curve of half 5-flurocytosine salt and raw materials (, 5-flurocytosine and acesulfame potassium) in the present invention.
Embodiment
In view of the defect of prior art, this case contriver, through studying for a long period of time and putting into practice, is known technical scheme of the present invention, and it is mainly by the novel salify mode of one, has obtained a kind of half 5-flurocytosine salt with good moisture stability and pharmaceutical use.
Further say, half 5-flurocytosine salt of the present invention is acesulfame potassium salt, and it is mainly by 5-flurocytosine positively charged ion (FCH
+), 5-flurocytosine neutral molecule (FC) and acesulfame potassium negatively charged ion (AH
-) 1:1:1 composition in molar ratio, and its structure cell belongs to triclinic(crystalline)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, half 5-flurocytosine salt of the present invention has the molecular structure shown in following formula 1.
Formula 1
Further, the powder X-ray ray powder diffraction pattern (for example, source of radiation 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 have a characteristic peak.
Further, described salt
13c solid-state nuclear magnetic resonance spectrum (for example,, with tetramethylsilane calibration, 0 ppm) has characteristic peak at 171.9,163.2,158.0,155.2,151.5,140 ~ 131,128.9,102.4,19.7 ppm places.
Further, described salt
15n solid-state nuclear magnetic resonance spectrum (with glycine calibration ,-347 ppm) has characteristic peak at-186.5 ,-199.3 ,-231.8 ,-243.3 ,-246.0 ,-283.6 ,-287.3 ppm places.
Among embodiments more of the present invention, the preparation method of described salt can comprise the steps:
(1) under certain temperature, 5-flurocytosine and acesulfame potassium are dissolved in solvent completely according to certain mol proportion example, form supersaturation, saturated or approach state of saturation;
(2) above-mentioned mixing solutions lowered the temperature, leave standstill or solvent evaporates, separate out the crystal of salt;
(3), by the crystal vacuum-drying of obtaining, obtain colourless transparent crystal or white powder is final product.
Further, aforementioned solvents can be selected but a kind of or its arbitrary proportion of being not limited in the middle of water, methyl alcohol, ethanol, acetic acid obtains mixed solvent.
Among a preferred embodiment, the solvent 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, is especially preferably 2:1.
Among a preferred embodiment, if use cooling or standing mode crystallization, Tc is 4 ° of C ~ room temperatures.
Among a preferred embodiment, if use solvent evaporates crystallization, Tc is room temperature ~ 80 ° C.
Preparation method of the present invention is simple, mild condition, and can to make water be solvent, avoid the use of organic solvent, reduce environmental pollution, simultaneously, its crystallization parameters final condition is wide, and repeatability is high, can the be convenient stable product that obtains, and show through powder X-ray RD and DSC test, obtained product crystal formation purity is high, and without obvious raw material impurity and residual solvent, it has excellent wet fastness, under 95% relative humidity, drawing wet weightening finish is 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): take 0.2 mmol 5-flurocytosine and 0.1 mmol acesulfame potassium, 40 ° of C are dissolved in 20 mL methyl alcohol, filter rear 25 ° of C volatilization, obtain lenticular salt, productive rate 95%, XRD figure is composed as shown in Figure 2.
embodiment 2the preparation of salt: take 1 mmol 5-flurocytosine and 0.5 mmol acesulfame potassium, room temperature is dissolved in 15 mL water, filters rear 60 ° of C volatilization, obtains lenticular salt, productive rate 84%, and its solid-state nuclear magnetic resonance dactylogram is as Fig. 3, shown in 4.
embodiment 3single crystal preparation: take 0.1 mmol 5-flurocytosine and 0.1 mmol acesulfame potassium, 60 ° of C are dissolved in 15 mL methyl alcohol, after filtering, room temperature volatilization, obtains lenticular salt, carries out monocrystalline test in 153K condition, and structure is as shown in Figure 5.
embodiment 4the water absorbability of salt is measured: the salt that goes embodiment 1-3 to obtain, use Dynamic Water adsorption-desorption instrument to carry out water absorbability test, 25 ± 0.1 ° of C of experimental temperature, relative humidity drops to again 0% from 0% rises to 95%, step-length is 5%, every step tension metrics be the differentiate of weight relative time change be less than 0.01% or starting time exceed 120 minutes.As shown in Figure 1: the water regain of 5-flurocytosine salt is starkly lower than bulk drug.In water adsorption process, the water regain of pure bulk drug is 13.8%, is transformed into monohydrate, and the water regain of salt is only 0.55 %.
Postscript, then get salt and raw materials used (being 5-flurocytosine, acesulfame potassium) in embodiment 1-3, obtained and test, its means of differential scanning calorimetry (DSC) all can be consulted Fig. 6.
Half 5-flurocytosine salt prepared by the present invention can effectively improve the problem of the moisture poor stability of 5-flurocytosine, and there is good thermostability, and described salt can be produced by the common technology such as solvent evaporation method and lowering temperature crystallization, technique is simple, operation is row easily, with low cost, residual without noxious 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 so far the report being detrimental to health, the food that its country checks and approves adds limitation high (daily intaking amount of FDA approval is 0 ~ 15mg/kg), can improve the mouthfeel of medicine simultaneously, and there is good active drug content, be applicable to pharmaceutical industry.
Should be appreciated that the above the present invention specifically implements example for showing essence novelty of the present invention, is not that content of the present invention is further limited.All employing equivalents or equivalence are replaced and the technical scheme of formation; or use that other crystallization conditions are prepared according to the technical scheme that is subject to this invention patent protection taking 5-flurocytosine as active medicine; taking acesulfame potassium as proton donor; the two with 2:1 mole of metering than the relevant achievement that has and have the related product fingerprint characteristic of the present invention, within all belonging to protection domain of the present invention.
Claims (10)
1. one and half 5-flurocytosine salt, it is characterized in that 5-flurocytosine positively charged ion, 5-flurocytosine neutral molecule and acesulfame potassium negatively charged ion that described salt is mainly 1:1:1 by mol ratio form, and the crystalline structure of described salt belongs to triclinic(crystalline)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.
2. half 5-flurocytosine salt according to claim 1, is characterized in that described salt has following structural formula:
。
3. the preparation method of half 5-flurocytosine salt described in any one in claim 1-2, it is characterized in that comprising: get 5-flurocytosine and acesulfame potassium and be dissolved in solvent, form supersaturation, saturated or approach the mixing solutions of state of saturation, and get described mixing solutions and carry out crystallization treatment, divide again isolated crystal, obtain colourless transparent crystal after drying or white powder is final product.
4. the preparation method of half 5-flurocytosine salt according to claim 3, is characterized in that comprising: under the temperature condition of room temperature ~ 80 ° C, 5-flurocytosine and acesulfame potassium are dissolved in solvent, form described mixing solutions.
5. according to the preparation method of half 5-flurocytosine salt described in any one in claim 3-4, the initial molar ratio that it is characterized in that described 5-flurocytosine and acesulfame potassium is 4:1 ~ 1:2.
6. according to the preparation method of half 5-flurocytosine salt described in any one in claim 3-5, it is characterized in that described solvent comprises any one or the two or more mixed solvent mixing in any proportion among water, methyl alcohol, ethanol, acetic acid.
7. according to the preparation method of half 5-flurocytosine salt described in any one in claim 3-6, it is characterized in that comprising: at least select cooling, leave standstill and solvent evaporates in any method realize the crystallization treatment to described mixing solutions.
8. the preparation method of half 5-flurocytosine salt according to claim 7, is characterized in that comprising:
If adopt cooling or standing mode to carry out crystallization treatment, Tc is 4 ° of C ~ room temperatures;
Or if adopt solvent evaporates mode to carry out crystallization treatment, Tc is room temperature ~ 80 ° C.
9. according to the preparation method of half 5-flurocytosine salt described in any one in claim 3-8, it is characterized in that comprising: the crystal of separating out is carried out to vacuum drying treatment, obtain described final product.
10. the application of half 5-flurocytosine salt in preparation antibacterials described in any one in claim 1-9.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11718594B2 (en) | 2016-09-21 | 2023-08-08 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| US11724994B2 (en) | 2016-09-21 | 2023-08-15 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| US11724993B2 (en) | 2016-09-21 | 2023-08-15 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| US11731948B2 (en) | 2016-09-21 | 2023-08-22 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| CN117003702A (en) * | 2023-08-04 | 2023-11-07 | 广东中科半导体微纳制造技术研究院 | Fluocytosine-orotate and preparation method and application thereof |
| CN117003701A (en) * | 2023-08-04 | 2023-11-07 | 广东中科半导体微纳制造技术研究院 | Fluocytosine-isostearate 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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2014
- 2014-05-06 CN CN201410188289.4A patent/CN103965116B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| 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 |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11718594B2 (en) | 2016-09-21 | 2023-08-08 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| US11724994B2 (en) | 2016-09-21 | 2023-08-15 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| US11724993B2 (en) | 2016-09-21 | 2023-08-15 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| US11731948B2 (en) | 2016-09-21 | 2023-08-22 | Celanese International Corporation | Acesulfame potassium compositions and processes for producing same |
| CN117003702A (en) * | 2023-08-04 | 2023-11-07 | 广东中科半导体微纳制造技术研究院 | Fluocytosine-orotate and preparation method and application thereof |
| CN117003701A (en) * | 2023-08-04 | 2023-11-07 | 广东中科半导体微纳制造技术研究院 | Fluocytosine-isostearate and preparation method and application thereof |
| 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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