CN114436973A - Novel fluorouracil crystal form and preparation method and application thereof - Google Patents
Novel fluorouracil crystal form and preparation method and application thereof Download PDFInfo
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- CN114436973A CN114436973A CN202210242942.5A CN202210242942A CN114436973A CN 114436973 A CN114436973 A CN 114436973A CN 202210242942 A CN202210242942 A CN 202210242942A CN 114436973 A CN114436973 A CN 114436973A
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 101
- 239000013078 crystal Substances 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 13
- VMIFBCPINLZNNI-UHFFFAOYSA-N 5-fluoro-2-methoxy-1h-pyrimidin-6-one Chemical compound COC1=NC=C(F)C(=O)N1 VMIFBCPINLZNNI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 11
- 238000004090 dissolution Methods 0.000 claims abstract description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000009466 transformation Effects 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 5
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005034 decoration Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 238000010587 phase diagram Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- UOHPEWIBMAQKCN-UHFFFAOYSA-N 1,3,5,5,6-pentafluoro-1,3-diazinane-2,4-dione Chemical compound FC1C(C(N(C(N1F)=O)F)=O)(F)F UOHPEWIBMAQKCN-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000251511 Holothuroidea Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- 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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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 invention provides a new fluorouracil crystal form, a preparation method and an application thereof, wherein the method comprises the following steps: s1), reacting 2-methoxy-5-fluorouracil with hydrochloric acid, cooling, performing suction filtration, mixing the obtained crude fluorouracil with a refined solvent, performing hot filtration after dissolution, cooling and crystallization, separating solids, mixing the obtained fluorouracil with a crystal transfer solvent, heating, stirring, and filtering to obtain a new fluorouracil crystal form. The method can obtain the new fluorouracil crystal form, is simple, has high yield and purity, reduces the production cost, and is suitable for industrial production. An X-ray powder diffraction pattern of the novel fluorouracil crystal form has diffraction peaks at 2 theta +/-0.2 degrees, wherein the 2 theta is 12.841 degrees, 13.283 degrees, 15.801 degrees, 16.120 degrees, 18.859 degrees, 20.461 degrees, 21.719 degrees, 28.522 degrees, 33.100 degrees, 33.919 degrees and 37.058 degrees.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel fluorouracil crystal form, and a preparation method and application thereof.
Background
Fluorouracil chemical name 5-fluoro-2, 4(1H,3H) -pyrimidinedione, fluorouracil is a sterile solution of 5-fluorouracil in water for injection and sodium hydroxide, the pH of the solution being about 8.9. Fluorouracil is a homologue of uracil, which is a component of ribonucleic acids. The medicine acts with antimetabolite, and after intracellular conversion into effective fluorouracil deoxynucleotide, it interferes with DNA synthesis by blocking the conversion of deoxyribouridylate into thymidylate by intracellular thymidylate synthetase. Fluorouracil can also interfere with RNA synthesis. After intravenous administration, fluorouracil is widely distributed in body fluids and disappears from the blood within 4 hours. It is preferentially taken up by actively dividing tissues and tumors after being converted into nucleotides, and fluorouracil easily enters cerebrospinal fluid. About 20% are excreted from urine as the prototype, with the remainder being metabolized in the liver for the most part by mechanisms typical for uracil metabolism. Pentafluorouracil and 6-mercaptopurine, which were the earliest anticancer drugs, were extracted from sea cucumber.
The published synthetic route of fluorouracil is as follows:
the method is simple to operate, the intermediate is prepared by a one-pot method, the reaction conditions are mild, the method is suitable for industrial production, and the prepared fluorouracil needs to be prepared into a new crystal form so as to be suitable for preparation.
Therefore, a fluorouracil refining process more suitable for industrial production is developed and improved, and a fluorouracil raw material drug is found to be a stable new crystal form used for fluorouracil preparations, and has important practical significance for fluorouracil preparations such as injections, tablets, ointments, microspheres, microemulsions and the like.
Disclosure of Invention
In view of the above, the invention aims to provide a novel fluorouracil crystal form, and a preparation method and application thereof, wherein the novel fluorouracil crystal form can be obtained by the method, and the method is simple, stable in batch consistency of the crystal forms, and high in yield and purity.
The invention provides a new fluorouracil crystal form, wherein an X-ray powder diffraction pattern of the new fluorouracil crystal form has diffraction peaks at 2 theta +/-0.2 degrees, and the 2 theta is 12.841 degrees, 13.283 degrees, 15.801 degrees, 16.120 degrees, 18.859 degrees, 20.461 degrees, 21.719 degrees, 28.522 degrees, 33.100 degrees, 33.919 degrees and 37.058 degrees. The diffraction peak is a characteristic powder diffraction peak of the new fluorouracil crystal form, and the detection precision is +/-1 degrees.
In the invention, the 2 theta of the new fluorouracil crystal form is 12.841 degrees, 13.283 degrees, 15.801 degrees, 16.120 degrees, 17.821 degrees, 18.859 degrees, 20.461 degrees, 21.719 degrees, 23.683 degrees, 25.299 degrees, 26.902 degrees, 28.522 degrees, 31.998 degrees, 33.100 degrees, 33.919 degrees, 37.058 degrees and 39.181 degrees.
The invention provides a preparation method of a new fluorouracil crystal form, which comprises the following steps:
s1), reacting 2-methoxy-5-fluorouracil with hydrochloric acid, cooling, and separating to obtain crude fluorouracil;
s2), mixing the crude fluorouracil obtained in the step S1) with a refined solvent, carrying out hot filtration after dissolution, cooling and crystallizing, and separating solids to obtain fluorouracil;
s3), mixing the fluorouracil obtained in the step S2) with a crystal transformation solvent, heating, stirring, and filtering to obtain a novel fluorouracil crystal form.
The preparation method of the new fluorouracil crystal form provided by the invention is environment-friendly and strong, the operation of preparing the new fluorouracil crystal form by adopting the method is simpler, the yield is higher, the production cost is reduced, and the method is more suitable for industrial production and is green and pollution-free.
In the invention, the 2-methoxy-5-fluorouracil has a structure shown in a formula I:
in the invention, the reaction temperature is 50-60 ℃ and the reaction time is 1-3 h. The method of separation is not particularly limited in the present invention, and separation methods known to those skilled in the art may be used, including but not limited to suction filtration.
And (4) mixing the fluorouracil obtained in the step S2) with a crystal transfer solvent, and heating to 70-80 ℃.
In the invention, the mass ratio of the volume of the hydrochloric acid to the 2-methoxy-5-fluorouracil is 1: 1-3: 1;
the mass ratio of the volume of the crystal transformation solvent to the fluorouracil is 1.8-2.2: 1.
In the present invention, the refining solvent is selected from DMF and/or DMSO; the ratio of the mass of the crude fluorouracil to the volume of the purified solvent is preferably 1/8 m/v, more preferably 1/6 m/v. The invention preferably preheats the refined solvent to 60-65 ℃, and then mixes the refined solvent with the crude fluorouracil. The invention preferably dissolves under stirring; the dissolving temperature is 60-70 ℃; the filtering temperature is 60-70 ℃.
In the invention, the cooling crystallization temperature is preferably 10-25 ℃; the cooling and crystallizing time is 1-3 h.
The crystal transformation solvent is water. The invention adopts green pollution-free water as the crystal transformation solvent, realizes green production and is more suitable for industrial production. The temperature of the crystal transformation is 70-80 ℃, and the time of the crystal transformation is preferably 11-13 h, more preferably 12 h.
The purity of the obtained new fluorouracil crystal form reaches the use standard of fluorouracil preparations such as injection, tablets, ointment, microspheres, microemulsion and the like through detection, and the new fluorouracil crystal form can be directly used as a raw material medicament.
The novel fluorouracil crystal form provided by the invention has the characteristics of good batch-to-batch consistency, good stability under storage conditions, high dissolution speed, reduction of degradation risk in the production process of a preparation and the like, and is more suitable for the use of the preparation.
The invention provides an application of the new fluorouracil crystal form in the technical scheme or the new fluorouracil crystal form prepared by the preparation method in the technical scheme in preparation of a medicament for treating digestive tract tumors.
The invention provides a pharmaceutical preparation, which comprises the new fluorouracil crystal form of the technical scheme or the new fluorouracil crystal form prepared by the preparation method of the technical scheme;
and pharmaceutically acceptable adjuvants.
The invention provides a pharmaceutical composition, which comprises the new fluorouracil crystal form of the technical scheme or the new fluorouracil crystal form prepared by the preparation method of the technical scheme;
and digestive tract tumor medicines.
The invention provides a preparation method of a new fluorouracil crystal form, which comprises the following steps: s1), reacting 2-methoxy-5-fluorouracil with hydrochloric acid, cooling, and performing suction filtration to obtain a crude product of fluorouracil; s2), mixing the crude fluorouracil obtained in the step S1) with a refined solvent, carrying out hot filtration after dissolution, cooling for crystallization, and separating solid to obtain fluorouracil; s3), mixing the fluorouracil obtained in the step S2) with a crystal transformation solvent, heating, stirring, and filtering to obtain a novel fluorouracil crystal form. The method can obtain the new fluorouracil crystal form, is simple, has high yield, reduces the production cost, and is suitable for industrial production.
Drawings
FIG. 1 is a powder diffraction pattern of a crystalline form of fluorouracil prepared in example 1 of the present invention;
FIG. 2 is a liquid phase diagram of a fluorouracil crystalline form prepared in example 1 of the present invention;
FIG. 3 is a C-NMR of fluorouracil crystal form prepared in example 1 of the present invention;
FIG. 4 is a H-NMR of fluorouracil crystal form prepared in example 1 of the present invention;
FIG. 5 is LC-MS of fluorouracil crystalline form prepared in example 1 of the present invention;
FIG. 6 is a powder diffraction pattern of the fluorouracil crystalline form prepared in example 2 of the present invention;
figure 7 is a liquid phase diagram of the fluorouracil crystalline form prepared in example 2 of the present invention.
Detailed Description
In order to further illustrate the present invention, the following examples are provided to describe a new fluorouracil crystal form and its preparation method and application in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
2-methoxy-5-fluorouracil and dilute hydrochloric acid (V) are added into a reaction bottleDilute hydrochloric acid: m 2-methoxy-5-fluorouracil ═ 6.0: 1; preparing dilute hydrochloric acid: concentrated hydrochloric acid (12 mol/L)/water is 1:2), and the temperature is controlled to be 55 ℃ to react for 3h until the reaction is finished. Cooling to 5-15 deg.C, centrifuging, mixing water and ethanol (V)Water (W)：VAnhydrous ethanol1:1) the mixture was washed to pH5-6, filtered to dryness under suction and dried in vacuo at 40 ℃To obtain a solid.
Adding DMF (V) to the obtained solidDMF：mCrude product1) heating to 60-70 ℃, dissolving the solid, then carrying out hot filtration, cooling the filtrate to 10-20 ℃, stirring for 30min, carrying out suction filtration, leaching the filter cake with a small amount of anhydrous ethanol, and carrying out vacuum drying at 45 ℃ to obtain the fluorouracil.
The obtained fluorouracil was added to water (V)Water (W)：mFluorouracilStirring and heating to 70-80 ℃ in a ratio of 2:1), stirring for 12h to complete fluorouracil crystal transformation, and performing suction filtration to obtain the transformed fluorouracil with the purity of 99.927% and the yield of 75.00%.
The product is characterized by powder diffraction, liquid chromatography, NMR and LC-MS, and the results are shown in figures 1-5, which shows that the obtained compound is fluorouracil and new fluorouracil crystal form.
Example 2
2-methoxy-5-fluorouracil and dilute hydrochloric acid (V) are added into a reaction bottleDilute hydrochloric acid: m 2-methoxy-5-fluorouracil ═ 6.0: 1; preparing dilute hydrochloric acid: concentrated hydrochloric acid (12 mol/L)/water is 1:2), and the temperature is controlled to be 55 ℃ to react for 3h until the reaction is finished. Cooling to 5-15 deg.C, centrifuging, mixing water and ethanol (V)Water (W)：VAnhydrous ethanol1:1) the mixture was washed to pH5-6, filtered to dryness with suction and dried in vacuo at 40 ℃ to give a solid.
The resulting solid was added DMSO (V)DMSO：mCrude productHeating to 60-70 ℃, dissolving the solid, performing hot filtration, cooling the filtrate to 20-25 ℃, stirring for 30min, performing suction filtration, leaching the filter cake with a small amount of anhydrous ethanol, and performing vacuum drying at 45 ℃ to obtain fluorouracil.
The obtained fluorouracil was added to water (V)Water (W)：mFluorouracilStirring and heating to 70-80 ℃ in a ratio of 2:1), stirring for 12h to complete fluorouracil crystal transformation, and performing suction filtration to obtain the transformed fluorouracil with the purity of 99.916% and the yield of 80.00%.
The product is characterized by powder diffraction and liquid chromatography, and the results are shown in figures 6-7, which shows that the new fluorouracil crystal form is obtained.
The embodiment shows that the invention provides a preparation method of a new fluorouracil crystal form, which comprises the following steps: s1), reacting 2-methoxy-5-fluorouracil with hydrochloric acid, cooling, and performing suction filtration to obtain a crude product of fluorouracil; s2), mixing the crude fluorouracil obtained in the step S1) with a refined solvent, carrying out hot filtration after dissolution, cooling and crystallizing, and separating solids to obtain fluorouracil; s3), mixing the fluorouracil obtained in the step S2) with a crystal transformation solvent, heating, stirring, and filtering to obtain a novel fluorouracil crystal form. The method can obtain the new fluorouracil crystal form, is simple, has high yield, reduces the production cost, and is suitable for industrial production.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A new fluorouracil crystal form is characterized in that an X-ray powder diffraction pattern of the new fluorouracil crystal form has diffraction peaks at 2 theta +/-0.2 degrees, wherein the 2 theta is 12.841 degrees, 13.283 degrees, 15.801 degrees, 16.120 degrees, 18.859 degrees, 20.461 degrees, 21.719 degrees, 28.522 degrees, 33.100 degrees, 33.919 degrees and 37.058 degrees.
2. The novel fluorouracil crystal form according to claim 1, characterized in that 2 θ of the novel fluorouracil crystal form is 12.841 °, 13.283 °, 15.801 °, 16.120 °, 17.821 °, 18.859 °, 20.461 °, 21.719 °, 23.683 °, 25.299 °, 26.902 °, 28.522 °, 31.998 °, 33.100 °, 33.919 °, 37.058 °, 39.181 °.
3. A method for preparing a novel fluorouracil crystal form according to any one of claims 1 to 2, comprising the following steps:
s1), reacting 2-methoxy-5-fluorouracil with hydrochloric acid, cooling, and separating to obtain crude fluorouracil;
s2), mixing the crude fluorouracil obtained in the step S1) with a refined solvent, carrying out hot filtration after dissolution, cooling and crystallizing, and separating solids to obtain fluorouracil;
s3), mixing the fluorouracil obtained in the step S2) with a crystal transformation solvent, heating, stirring, and filtering to obtain a novel fluorouracil crystal form.
4. The preparation method according to claim 3, wherein the reaction temperature is 50-60 ℃ and the reaction time is 1-3 h;
and (4) mixing the fluorouracil obtained in the step S2) with a crystal transfer solvent, and heating to 70-80 ℃.
5. The preparation method according to claim 3, wherein the mass ratio of the volume of the hydrochloric acid to the 2-methoxy-5-fluorouracil is 1: 1-3: 1;
the mass ratio of the volume of the crystal transformation solvent to the fluorouracil is 1.8-2.2: 1.
6. the method according to claim 3, wherein the refining solvent is selected from DMF and/or DMSO;
the crystal transformation solvent is water.
7. The application of the novel fluorouracil crystal form according to any one of claims 1 to 2 or the novel fluorouracil crystal form prepared by the preparation method according to any one of claims 3 to 6 in preparation of drugs for treating digestive tract tumors.
8. A pharmaceutical formulation comprising a novel crystalline form of fluorouracil according to any one of claims 1 to 2 or prepared by a process according to any one of claims 3 to 6;
and pharmaceutically acceptable adjuvants.
9. A pharmaceutical composition, which comprises the novel fluorouracil crystal form according to any one of claims 1 to 2 or the novel fluorouracil crystal form prepared by the preparation method according to any one of claims 3 to 6;
and digestive tract tumor drugs.
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| 陈小林;: "一种高纯度5-氟尿嘧啶合成工艺研究", 科技视界, no. 26, pages 1204 - 24 * |
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