CN103965115B - A kind of 5-flurocytosine salt, its preparation method and application - Google Patents
A kind of 5-flurocytosine salt, its preparation method and application Download PDFInfo
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- CN103965115B CN103965115B CN201410187455.9A CN201410187455A CN103965115B CN 103965115 B CN103965115 B CN 103965115B CN 201410187455 A CN201410187455 A CN 201410187455A CN 103965115 B CN103965115 B CN 103965115B
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- flurocytosine
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- 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
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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 5-flurocytosine salt, its preparation method and application.Described 5-flurocytosine salt is acesulfame potassium salt, and it is primarily of 5-flurocytosine positively charged ion (FCH
+), acesulfame potassium negatively charged ion (AH
-) and water molecules (H
2o) 1:1:0.5 forms in molar ratio, does its structure cell belong to oblique system, its axial length a=26.3596 (11)? b=5.8523 (3)?, c=32.3137 (11)?, shaft angle α=90.00 °, β=105.987 (4) o, γ=90.00o.5-flurocytosine salt of the present invention effectively can improve the problem of 5-flurocytosine moisture poor stability, and there is good thermostability, and can the ordinary method such as lyophilization, solution crystal process prepare, technique is simple, operates easy, with low cost, participate in without noxious solvent, guest molecule is a kind of sweeting agent simultaneously, can improve the mouthfeel of medicine, can be used in 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
Crystal engineering is the interaction understood on the basis of packing of molecules between molecule, and designs new solid-state form on this basis to improve the physicochemical property of raw material.Crystal engineering is widely used in pharmaceutical industry in recent years, and crystal engineering provides possibility by utilizing supramolecule synthon for the solid-state form preparing various different material medicine.The research of medicine solid-state form has great meaning to pharmaceutical industry.Homogeneous raw material medicine can prepare different solid-state forms (polymorphic, hydrate, solvated compounds, salt and eutectic), different solid-state forms has different physicochemical property, as: solubleness, stability, dissolution rate, mechanical property, bioavailability etc.Suitable solid-state form is selected to develop and produce pharmaceutical industry particularly important.Medicine salify is the good approach of physicochemical property improving weak acid/weak base drug.
5-flurocytosine, molecular formula is C
4h
4fN
3o is a kind of widely used antibacterials, is mainly used in treating infective endocarditis, urinary tract infections and pulmonary infection etc.But 5-flurocytosine deposits the problem forming hydrate at high humidity, the preservation of drug brings serious problems.There is the salt of some 5-flurocytosines to prepare at present according to pertinent literature report, comprised asccharin, Whitfield's ointment, toxilic acid, fumaric acid, oxalic acid and multiple mineral acid (HBr, HI, HNO
3) salt.Wherein saccharin salt and oxalate are in the news and can improve hydration problems, but excessive oxalic acid takes in the risk having and cause calculus, and excessive asccharin absorption can affect the normal secretions of gastrointestinal disturbances enzyme, reduce the receptivity of small intestine, make appetite stimulator, and have the record causing experimental animal cancer.
Summary of the invention
Main purpose of the present invention is to provide a kind of novel 5-flurocytosine salt, and this salt draws wet problem hydration occurring and transforms under can effectively improving 5-flurocytosine high humidity.
Another object of the present invention is the preparation method providing above-mentioned salt.
For realizing aforementioned invention object, the technical solution used in the present invention comprises:
A kind of 5-flurocytosine salt, its 5-flurocytosine positively charged ion primarily of mol ratio 1:1:0.5, acesulfame potassium negatively charged ion and water molecules form, and the structure cell of described salt belongs to oblique system, structure cell axial length a=26.3596 (11), b=5.8523 (3), c=32.3137 (11), shaft angle α=90.00 °, β=105.987 (4) o, γ=90.00o.
A kind of method preparing described 5-flurocytosine salt, comprise: get 5-flurocytosine and acesulfame potassium and be dissolved in solvent and form solution, then filter, and at least select solution left standstill, by solution described in any one the mode process among the solvent removing in solution, institute obtains colourless transparent crystal or white powder is final product.
Wherein, described solvent is preferably water.
Of the present invention additionally provide any one 5-flurocytosine salt aforementioned preparation antibacterials in application.
Compared with prior art, advantage of the present invention comprises:
(1) show through powder X-ray RD and DSC test, institute's 5-flurocytosine salt crystal form purity that obtains is high, without obvious raw material impurity and residual solvent.
(2) preparation method is simple, mild condition, and crystallization parameters final condition is wide, and repeatability is high, can convenient stable acquisition product;
(3) preferably use water to be solvent, avoid the use of organic solvent, reduce environmental pollution;
(4) obtain 5-flurocytosine salt there is excellent wet fastness, under 95% relative humidity, drawing wet weightening finish lower than 4wt%.
Accompanying drawing explanation
Fig. 1 is dynamic moisture adsorption-desorption (DVS) curve of 5-flurocytosine salt of the present invention and 5-flurocytosine;
Fig. 2 be the embodiment of the present invention 1 obtain the Powder XRD pattern of 5-flurocytosine salt;
Fig. 3 be the embodiment of the present invention 2 obtain 5-flurocytosine salt
13c solid-state nuclear magnetic resonance collection of illustrative plates;
Fig. 4 be the embodiment of the present invention 2 obtain 5-flurocytosine salt
15n solid-state nuclear magnetic resonance collection of illustrative plates;
Fig. 5 be the embodiment of the present invention 3 obtain the single crystal structure figure of 5-flurocytosine salt;
Fig. 6 is means of differential scanning calorimetry (DSC) graphic representation of 5-flurocytosine salt of the present invention and its raw materials.
Embodiment
In view of 5-flurocytosine and existing salt thereof are unfavorable for the defect of preservation, inventor is through studying for a long period of time and putting into practice in a large number, propose technical scheme of the present invention, it is mainly active medicine with 5-flurocytosine, take acesulfame potassium as proton donor, and with the water molecules of specific quantity, define a kind of novel 5-flurocytosine salt, it has outstanding representation in wet fastness etc., is suitable for applying in preparation broad-spectrum antibacterials.
Specifically, 5-flurocytosine salt of the present invention has the chemical structure shown in following formula 1, and it is primarily of 5-flurocytosine positively charged ion (FCH
+), acesulfame potassium negatively charged ion (AH
-) and water molecules 1:1:0.5 composition in molar ratio.
Formula 1
Further, the structure cell of 5-flurocytosine salt of the present invention belongs to oblique system, its structure cell axial length a=26.3596 (11), b=5.8523 (3), c=32.3137 (11), shaft angle α=90.00 °, β=105.987 (4) o, γ=90.00o.
Further, in the X-ray powder diffraction figure of 5-flurocytosine salt of the present invention, (source of radiation is CuK α) is in angle of diffraction 2 θ=5.60, 6.98, 7.68, 10.07, 11.29, 13.48, 14.75, 15.97, 16.17, 16.53, 16.99, 18.16, 18.41, 18.66, 18.87, 19.07, 20.19, 20.91, 21.46, 22.73, 23.14, 23.60, 23.85, 24.97, 26.44, 27.05, 27.87, 28.23, 28.73, 29.64, 31.48, 31.98, 33.20, 33.52, 34.22, 34.83, 35.24, there is characteristic peak at 36.10 degree of places.
Further, 5-flurocytosine salt of the present invention
13c solid-state nuclear magnetic resonance spectrum (with tetramethylsilane calibration, 0ppm) 174.2,166.9,164.9,156.8,155.7,149.3,140 ~ 134,132.3,130.6,102.6,20.9,18.9ppm place has characteristic peak.
Further, 5-flurocytosine salt of the present invention
15n solid-state nuclear magnetic resonance spectrum (with glycine calibration ,-347ppm)-195.7 ,-198.8 ,-232.7 ,-236.0 ,-253.2 ,-254.6 ,-273.4 ,-280.6ppm place has characteristic peak.
The exemplary manufacturing process of 5-flurocytosine salt of the present invention comprises solution crystallization or lyophilization.
Further, this preparation method can comprise: get 5-flurocytosine and acesulfame potassium and be dissolved in solvent and form solution, then filter, and at least select solution left standstill, by solution described in any one the mode process among the solvent removing in solution, institute obtains colourless transparent crystal or white powder is final product.
In this preparation method, the molar ratio of 5-flurocytosine and acesulfame potassium is preferably 1:1 ~ 1:8,1:3 ~ 1:8 or 1:1.
In this preparation method, solvent is preferably water.
In one comparatively specific embodiment, the preparation method of 5-flurocytosine salt of the present invention 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 unsaturated solution;
2) after filtering, by solution at a certain temperature leave standstill or solvent flashing carry out crystallization, crystallize out;
3) filter and obtain above-mentioned crystal, carry out vacuum-drying, obtain colourless transparent crystal or white powder is final product.
Abovementioned steps 1) in, solvent temperature is preferably room temperature ~ 80 ° C.
Abovementioned steps 2) in, Tc is preferably 4 ° of C ~ 40 ° C.
In this preparation method, the molar ratio of 5-flurocytosine and acesulfame potassium is preferably 1:3 ~ 1:8.
In another comparatively specific embodiment, the preparation method of 5-flurocytosine salt of the present invention can comprise the steps:
1), under room temperature, 5-flurocytosine and acesulfame potassium are dissolved in the water completely according to certain mol proportion example, form saturated or unsaturated solution;
2) after filtering, use liquid nitrogen by after solution quick freeze;
3) scars are put into Freeze Drying Equipment and carry out lyophilize, obtain white powder and be final product.
In this preparation method, the molar ratio of 5-flurocytosine and acesulfame potassium is preferably 1:1.
Abovementioned steps 3) in, freeze temperature is preferably-60 ° of C.
Abovementioned steps 3) in, freeze-drying time is preferably 24h ~ 72h.
5-flurocytosine salt of the present invention is a kind of new sweet taste salt form, effectively can improve the problem of the moisture poor stability of 5-flurocytosine, there is good thermostability, and preparation technology's simple operations is easy, with low cost, 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 the report be 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, be applicable to pharmaceutical industry.
Below in conjunction with specific examples and accompanying drawing, technical scheme of the present invention is described further:
embodiment 1:the preparation of salt (that is, 5-flurocytosine salt, lower same): take 0.2mmol5-flucytosine and 0.2mmol acesulfame potassium, be successively dissolved in 10mL ultrapure water, put into liquid nitrogen after filtration freezing, freeze-drying 72h, obtain salt 46.8mg.Productive rate 80.1%.XRD figure spectrum as shown in Figure 2.
embodiment 2:the preparation of salt: take 0.4mmol5-flucytosine and 0.4mmol acesulfame potassium, is successively dissolved in 20mL ultrapure water, puts into liquid nitrogen freezing after filtration, freeze-drying 72h, obtain salt 94.0mg.Productive rate 80.5%.Its solid-state nuclear magnetic resonance dactylogram as Fig. 3, shown in 4.
embodiment 3:single crystal preparation: take 1mmol5-flucytosine and 4mmol acesulfame potassium, add 4.5mL ultrapure water, after water-bath 60 ° of C dissolve, room temperature leaves standstill 3h, obtains the single crystal samples of salt.Resolve and obtain structure as shown in Figure 5.
embodiment 4:the water absorbability of salt measures
The salt obtained in Example 1-3, Dynamic Water adsorption-desorption instrument is used to carry out water absorbability test, experimental temperature 25 ± 0.1 ° of C, relative humidity drops to 0% again after rising to 95% from 0%, step-length is 5%, often walk tension metrics be the differentiate of weight relative time change be less than 0.01% or starting time more than 120 minutes, experimental result is all as shown in Figure 1.Thus known, previous embodiment of the present invention obtain 5-flurocytosine salt water regain be all starkly lower than bulk drug.In water adsorption process, the water regain of bulk drug is 13.8%, and the water regain of salt is only 3.84%, and water absorbability is starkly lower than bulk drug.Therefore, after salify, the hygroscopicity problems of bulk drug obviously improves.
Postscript, then the salt obtained in Example 1-3 and raw materials used (i.e. 5-flurocytosine, acesulfame potassium) are tested, its means of differential scanning calorimetry (DSC) all can consult Fig. 6.
But it should be noted that, be only specific embodiment of the invention example in sum, these descriptions are not be further limited content of the present invention.The technical scheme that all employing equivalents or equivalence are replaced and formed; or what use other solvents to prepare according to the technical scheme by this invention patent protection take 5-flurocytosine as active medicine; take acesulfame potassium as proton donor; the two and water molecules exist with 1:1:0.5 mole of metering ratio and have the related ends of product fingerprint characteristic involved by the present invention, all belong within scope.
Claims (10)
1. a 5-flurocytosine salt, it is characterized in that described salt is made up of the 5-flurocytosine positively charged ion of mol ratio 1:1:0.5, acesulfame potassium negatively charged ion and water molecules, and the structure cell of described salt belongs to oblique system, structure cell axial length
shaft angle α=90.00 °, β=105.987 (4) °, γ=90.00 °;
And in angle of diffraction 2 θ=5.60 in the X-ray powder diffraction figure of described salt, 6.98, 7.68, 10.07, 11.29, 13.48, 14.75, 15.97, 16.17, 16.53, 16.99, 18.16, 18.41, 18.66, 18.87, 19.07, 20.19, 20.91, 21.46, 22.73, 23.14, 23.60, 23.85, 24.97, 26.44, 27.05, 27.87, 28.23, 28.73, 29.64, 31.48, 31.98, 33.20, 33.52, 34.22, 34.83, 35.24, there is characteristic peak at 36.10 degree of places.
2. 5-flurocytosine salt according to claim 1, is characterized in that described salt
13c solid-state nuclear magnetic resonance spectrum 174.2,166.9,164.9,156.8,155.7,149.3,140 ~ 134,132.3,130.6,102.6,20.9,18.9ppm place has characteristic peak.
3. 5-flurocytosine salt according to claim 1, is characterized in that described salt
15n solid-state nuclear magnetic resonance spectrum-195.7 ,-198.8 ,-232.7 ,-236.0 ,-253.2 ,-254.6 ,-273.4 ,-280.6ppm place has characteristic peak.
4. the preparation method of 5-flurocytosine salt according to any one of claim 1-3, it is characterized in that comprising: get 5-flurocytosine and acesulfame potassium and be dissolved in solvent and form solution, then filter, and at least select solution left standstill, by solution described in any one the mode process among the solvent removing in solution, institute obtains colourless transparent crystal or white powder is final product.
5. the preparation method of 5-flurocytosine salt according to claim 4, is characterized in that comprising:
Under the temperature condition of room temperature ~ 80 DEG C, 5-flurocytosine and acesulfame potassium are dissolved in solvent completely, form supersaturation, saturated or unsaturated solution, then filter, again by solution under the temperature condition of 4 DEG C ~ 40 DEG C leave standstill or solvent flashing carry out crystallization, isolate the crystal of precipitation afterwards, after vacuum-drying, obtain final product;
Or, at room temperature 5-flurocytosine and acesulfame potassium are dissolved in solvent completely, form saturated or unsaturated solution, then filter, then by solution quick freeze, afterwards by scars lyophilize, obtain final product.
6. the preparation method of 5-flurocytosine salt according to any one of claim 4-5, is characterized in that described solvent is water.
7. the preparation method of 5-flurocytosine salt according to any one of claim 4-5, is characterized in that the molar ratio of described 5-flurocytosine and acesulfame potassium is 1:1 ~ 1:8.
8. the preparation method of 5-flurocytosine salt according to any one of claim 4-5, is characterized in that the molar ratio of described 5-flurocytosine and acesulfame potassium is 1:3 ~ 1:8 or 1:1.
9. the preparation method of 5-flurocytosine salt according to claim 5, is characterized in that comprising: by the solution after filtering with liquid nitrogen quick freeze, then by scars lyophilize, obtain final product.
10. the application of 5-flurocytosine salt according to any one of claim 1-3 in preparation antibacterials.
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| 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 |
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| CN1723251A (en) * | 2003-03-07 | 2006-01-18 | 马斯公司 | Water-based inks for printing on confectionery |
| 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 |
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| CN1723251A (en) * | 2003-03-07 | 2006-01-18 | 马斯公司 | Water-based inks for printing on confectionery |
| 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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