CN101921227A - 5-chloro-4-hydroxyl-2(1H)-pyridone crystal form, preparation method and application thereof - Google Patents
5-chloro-4-hydroxyl-2(1H)-pyridone crystal form, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 5-chloro-4-hydroxyl-2(1H)-pyridone crystal form, a preparation method and application thereof. Intervals of crystal faces d of diffraction peaks in a powder X-ray diffraction diagram of P crystal forms of 5-chloro-4-hydroxyl-2(1H)-pyridone are 5.93, 4.79, 3.46, 3.42, 3.24, 2.97 and 2.77; and relative peak strengths corresponding to the diffraction peaks are 59, 27, 100, 35, 61, 16 and 22. An alkali-solution and acid-isolation crystallizing method is adopted in the preparation method of the P crystal forms. The crystal forms can be used as a dihydropyrimidine dehydrogenase inhibitor for preparing a drug for treating cancers. The crystal forms have the advantages of better thermodynamic stability, dissolution and bioavailability. The preparation method is simple and easy and suitable for industrialization application.
Description
The application is to be on April 3rd, 2007 applying date, and application number is 200710020907.4, and denomination of invention is the dividing an application of application of 5-chloro-4-hydroxyl-2 (1H)-pyridone crystal formation and its production and application.
Technical field
The present invention relates to the crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone, the invention still further relates to the preparation method of 5-chloro-4-hydroxyl-2 (1H)-pyridone crystal formation.
Background technology
People such as Kolder (nineteen fifty-three, 1954) had once reported preparation method (Rec.trav.chim.1953, the 72:285 of 5-chloro-4-hydroxyl-2 (1H)-pyridone; Rec.trav.chim.1954,73:704).(Heterocycles 1993,36:145) disclose the preparation method that 5-chloro-4-hydroxyl-2 (1H)-pyridone is new for Japanese Patent JP 0578324 (1993), JP 0539241 (1993) and document.International Patent Application WO 9221345 (1992), U.S. Patent application US5525603 (1996) disclose Tegafur (Tegafur) and (have claimed Ao Telaxi again with compound 5-chloro-4-hydroxyl-2 (1H)-pyridone, Oteracil Potassium, Potassium Oxonate, Oteracil) three forms compound, is used for the treatment of cancers such as cancer of the stomach, incidence cancer, colorectal carcinoma, carcinoma of the pancreas, mammary cancer and nonsmall-cell lung cancer.
5-chloro-4-hydroxyl-2 (1H)-pyridone (formula I or formula II) is the dihydroxy-pyridine ketone compounds, is the reversibly-competitive inhibitor of a kind of dihydropyrimidine dehydrogenase (DPD).5-chloro-4-hydroxyl-2 (1H)-pyridone itself does not have antitumor action.
Formula I. formula II.
Tegafur is the derivative of 5 FU 5 fluorouracil (5-FU), is to use wider miazines antitumor drug at present.The Tegafur effect is identical with 5-FU, in vivo can interference, blocking dna, RNA and proteinic synthetic.The toxicity of Tegafur has only 1/7～1/4 of 5-FU; Chemotherapeutic index is 2 times of 5-FU.The Tegafur oral administration changes 5-FU into after entering in the body under the effect of liver microsomes cytochrome P-450 enzyme system, the performance antitumor action.The active metabolite 5-FU of Tegafur is extremely unstable in vivo, is easily degraded (reaching more than 85%) and inactivation fast by the dihydropyrimidine dehydrogenase (DPD) of normal organ and tumor tissues generation.Suppress the DPD in the tumor tissues, can prolong the antitumor action time of fluorouracil drug.5-chloro-4-hydroxyl-2 (1H)-active ability of pyridone inhibition DPD is 180 times of uridylic.5-chloro-4-hydroxyl-2 (1H)-pyridone can effectively suppress the degraded of 5-FU, and the decomposition rate of the 5-FU that slows down makes the 5-FU long period in blood plasma that is produced by Tegafur keep the high density level.Can make the sour high density that continues of phosphorylation meta-bolites 5-floxuridine (FUDR) of 5-FU in the body like this, can reach the antitumous effect that the DNA that strengthens in the 5-FU inhibition tumor tissues is synthetic and block the RNA function, reduce the Tegafur toxic side effect.Inhibition can reduce the dosage individual difference that the 5-FU side effect causes to the body tissue of 5-FU sensitivity such as the DPD in gastrointestinal wall and the marrow; Suppress the DPD in the tumor tissues, can prolong the action time of 5-FU class medicine.DPD in tumor tissues is active to be increased, and the degradation capability of 5-FU is increased when producing resistance, also can eliminate resistance by 5-chloro-4-hydroxyl-2 (1H)-pyridone inhibition DPD.
5-chloro-4-hydroxyl-2 (1H)-pyridone effect is the antitumor action that strengthens Tegafur.Be that (it mainly acts on is optionally to act on orotate phosphoribosyl-transferase at gi tract with Tegafur, Oteracil Potassium during use, blocked the 5-FU phosphorylation, alleviate the gastrointestinal side effect that FT causes, as diarrhoea, appetite stimulator etc.) form compound, make solid orally ingestible.
The solid material medicine if adopt different recrystallization solvents and process for refining, may make the crystal of same medicine have two or more space structure and lattice constant in preparation process, promptly produces the polymorphism of medicine.The polymorphic problem of solid orally ingestible bulk drug may directly have influence on the absorption and the curative effect of medicine stability, solvability and medicine, and then causes the difference of clinical drug curative effect.Therefore, the polymorphic problem of research solid orally ingestible bulk drug just seems extremely important.
In the process of development 5-chloro-4-hydroxyl-2 (1H)-pyridone, the contriver finds that 5-chloro-4-hydroxyl-2 (1H)-pyridone has 2 kinds of crystal formations at least.5-chloro-4-hydroxyl-2 (the 1H)-pyridone of different crystal forms may there are differences at aspects such as stability, solubleness, dissolution rate, fusing point, outward appearance and biological effectivenesses, thereby influences the performance of stability of drug, bioavailability and drug effect.Do not see the polymorphous research report of relevant 5-chloro-4-hydroxyl-2 (1H)-pyridone.
Summary of the invention
The purpose of this invention is to provide 5-chloro-4-hydroxyl-2 (1H)-pyridone crystal formation.
Another object of the present invention provides the preparation method of 5-chloro-4-hydroxyl-2 (1H)-pyridone crystal formation.
A further object of the invention is the application of 5-chloro-4-hydroxyl-2 (1H)-pyridone crystal formation in preparation medicine for treating tumor thing.
The contriver finds the crystal formation that it has two kinds of 5-chloro-4-hydroxyls-2 (1H)-pyridone at least when research 5-chloro-4-hydroxyl-2 (1H)-pyridone (formula I or formula II) process for purification and crystallization condition, the one, the P crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone (to call the P crystal formation in the following text), another is the L crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone (to call the L crystal formation in the following text).
Formula I. formula II.
The spacing d value and the relative intensity (I/I0) of diffraction peak see Table 1 in the x-ray diffractogram of powder spectrum of P crystal formation;
Table 1.P crystal form X ray powder diffraction data
The absorption peak that comprises in its infrared spectra is 2802 (br), 1869,1812,1617 (br), 1433,1374,1260,1221,676 and 628cm
-1Endotherm(ic)peak in the differential scanning calorimetric analysis is 277.9 ℃.
Further, the spacing d value and the relative intensity (I/I0) of diffraction peak sees Table 2 in the x-ray diffractogram of powder of this P crystal formation spectrum; The absorption peak that comprises in the infrared spectra be 2802 (3268～2100, br), 1869,1812,1648,1617 (br), 1489,1456,1433,1374,1260,1221,1091,986,970,917,860,839,789,676,628 and 534cm
-1Endotherm(ic)peak in the differential scanning calorimetric analysis is 277.9 ℃.
Table 2.P crystal form X ray powder diffraction data
The spacing d value and the relative intensity (I/I of diffraction peak in the L crystal formation x-ray diffractogram of powder spectrum
0) see Table 3;
Table 3.L crystal form X ray powder diffraction data
Further, the spacing d value and the relative intensity (I/I of diffraction peak in this L crystal formation x-ray diffractogram of powder spectrum
0) see Table 4; The absorption peak that comprises in the infrared spectra is 3095,2990,2826,2537,1676,1618,1494,1449,1421,1342,1317,1277,1219,1199,1094,857,823,813,786,681,534 and 438cm
-1Endotherm(ic)peak in the differential scanning calorimetric analysis is 280.6 ℃.
Table 4.L crystal form X ray powder comes diffraction data
Above-mentioned powder x-ray diffraction test condition is:
The instrument model: ARL X ' TRA type changes the target x-ray diffractometer
Test condition: pipe is pressed: 30KV; Pipe stream: 50mA; Target type: Cu
Sweep velocity: 10 °/min; 3 ° of scanning initial angles, 50 ° of scanning end angles;
Stepped intervals: 0.02 °
The test condition of infrared spectra:
Instrument model: VECTOR 22 type infrared spectrometers
Test condition: KBr pressed disc method
The test condition of differential scanning calorimetric analysis:
Instrument model: Perkin ElmerPyris 1DSC type
Test condition: 10 ℃/min of heat-up rate; Temperature range 50-300 ℃
The contriver prepares the P crystal formation by " alkali molten-acid out " crystallization process, and this preparation method may further comprise the steps:
I) 5-chloro-4-hydroxyl-2 (1H)-pyridone is dissolved in the basic solution;
Ii) keep mixing solutions at 10～12 ℃, add the acidic solution neutralization, regulator solution pH to 4.0～4.5;
Iii) solution is placed 10～12h, crystallization in 18～20 ℃;
Iv) fractional crystallization promptly obtains the P crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone from this pH=4.0～4.5 solution.
Described preparation method's neutral and alkali solution is selected from one or more in sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, the solution of potassium carbonate; Preferred concentration is 10% sodium hydroxide solution; Acidic solution can be hydrochloric acid soln, sulphuric acid soln; Preferred concentration is that 5% hydrochloric acid soln, concentration are 5% sulphuric acid soln;
The present invention passes through recrystallization with an organic solvent, be controlled at crystallization under certain temperature condition and the schedule of operation, can obtain the L crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone, organic solvent can be one or more in methyl alcohol, ethanol, acetone, the ethyl acetate, particular methanol or ethanol.The crystallization condition optimization: first room temperature is placed 8h, and the back moves into refrigerator and places the 48h crystallization for 0～4 ℃.
A kind of pharmaceutical composition, it contains P crystal formation (or L crystal formation), Oteracil Potassium and and the pharmaceutically acceptable carrier of Tegafur, 5-chloro-4-hydroxyl-2 (1H)-pyridone.
In the described pharmaceutical composition, the P crystal formation (or L crystal formation) of Tegafur, 5-chloro-4-hydroxyl-2 (1H)-pyridone, the mol ratio of Oteracil Potassium are 1: 0.4: 1.
Described pharmaceutical composition, its formulation are tablet, capsule, granule, orally disintegrating tablet, powder, pill, suspensoid; Be preferably tablet, capsule.
Described pharmaceutical composition can be used as the medicine of cancers such as treatment cancer of the stomach, incidence cancer, colorectal carcinoma, carcinoma of the pancreas, mammary cancer and nonsmall-cell lung cancer.
The application in preparation treatment cancer drug of described 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation or L crystal formation.
Described application be 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation or L crystal formation in the treatment cancer drug of preparation as the dihydropyrimidine dehydrogenase inhibitor.These cancers comprise cancer of the stomach, incidence cancer, colorectal carcinoma, carcinoma of the pancreas, mammary cancer or nonsmall-cell lung cancer.
Beneficial effect of the present invention:
1, P crystal formation provided by the invention and L crystal formation have good thermodynamic stability
(1) thermogravimetric analysis (TGA) analytical results of P crystal formation (see figure 9) and L crystal formation (see figure 10) shows, 30～200 ℃ of scopes, collection of illustrative plates is close to and is horizontal linear, and almost no change does not have weightless.P crystal formation and L crystal formation are stable in 30～200 ℃ of scopes.
(2) P crystal formation and L crystal formation grind 30min respectively, and infrared spectra detects collection of illustrative plates does not all have considerable change.
(3) P crystal formation and L crystal formation are at 105 ℃ of heating 4h, and outward appearance is almost without any variation, and content does not reduce, and impurity is not seen increase.
Concrete test method: 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation, L crystal formation (respectively by the embodiment of the invention 1,2 preparations) are heated 4h at 105 ℃, content and the impurity of measuring its heating front and back with high performance liquid chromatography (HPLC) change, and observe the thermodynamic stability of P crystal formation, L crystal formation.Table 5 and Figure 11 are preceding high-efficient liquid phase chromatogram and the corresponding data of P crystal formation heating; Table 6 and Figure 12 are preceding high-efficient liquid phase chromatogram and the corresponding data of L crystal formation heating; Table 7 and Figure 13 are high-efficient liquid phase chromatogram and corresponding data after the P crystal formation heating; Table 8 and Figure 14 are high-efficient liquid phase chromatogram and corresponding data after the L crystal formation heating.
Table 5.P crystal formation (before the heating) high-efficient liquid phase chromatogram (HPLC) number
Table 6.L crystal formation (before the heating) high-efficient liquid phase chromatogram (HPLC) data
Table 7.P crystal formation (heating 105 ℃, behind the 4h) high-efficient liquid phase chromatogram (HPLC) data
Table 8.L crystal formation (heating 105 ℃, behind the 4h) high-efficient liquid phase chromatogram (HPLC) data
The result shows that the P crystal formation before and after being heated, L crystal formation are almost without any variation, and content does not reduce, and impurity is not seen increase.Conclusion: the thermodynamic property of P crystal formation, L crystal formation is stable.
2, P crystal formation provided by the invention or L crystal formation and Tegafur, Oteracil Potassium and suitable pharmaceutical excipient are made medicinal compositions (as capsule), and P crystal formation, L crystal formation all have good stripping behavior (the 20min dissolution rate all 〉=92%)
Concrete test method:
(1) instrument and test drug
Agilent 1100 type high performance liquid chromatographs (U.S. Agilent company); AG285 type electronic balance (plum Teller-Tuo benefit Shanghai company limited); ZRS-4 type intelligence dissolution rate tester (Radio Factory of Tianjin Univ.).5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation reference substance (contriver prepares according to embodiment 1 method, lot number: 040517, content is 99.6%); L crystal formation reference substance (contriver prepares according to embodiment 2 methods, lot number: 040525, content is 99.8%); Lactose (Shanghai Hua Mao milk-product company limited, lot number: 050311); Sodium lauryl sulphate (on the grand chemical industry company limited that transports by sea, lot number: 050421); Magnesium Stearate (Distributions in Liaocheng of Shandong Province pharmaceutical factory, lot number: 050408).
(2) capsular preparation
Take by weighing Tegafur 2.00g, 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation (or L crystal formation) 0.58g, Oteracil Potassium 1.96g, lactose 6.00g, sodium lauryl sulphate 0.40g, crossing 80 mesh sieves mixes, make softwood in right amount with the 1% HPMC aqueous solution, 24 mesh sieves are granulated, 60 ℃ of air seasonings, the whole grain of 20 mesh sieves, add Magnesium Stearate 0.15g, abundant mixing, promptly get particle, chemical examination and definite loading amount, can makes and contains Tegafur, 100 of the compound capsules of 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation (or L crystal formation) and 3 kinds of medicines of Oteracil Potassium.
(3) dissolution determination method
Getting above-mentioned capsule, according to dissolution method [two appendix XC first methods of version Chinese Pharmacopoeia in 2005] operation, is dissolution medium with water 1000ml, and rotating speed is 100r/min, measures in accordance with the law, and it is an amount of to get solution after 45 minutes, filters, and gets subsequent filtrate as need testing solution; It is an amount of that other gets 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation (or L crystal formation) reference substance, accurate claims surely, is dissolved in water and quantitatively is diluted to the solution that contains 5-chloro-4-hydroxyl-2 (1H)-pyridone 6 μ g among the 1ml approximately, product solution in contrast.According to the HPLC content determination, calculate the stripping quantity of 5-chloro-4-hydroxyl-2 (1H)-pyridone in every capsules.
(4) dissolution determination result
(lot number 040706-1 contains the P crystal formation to take the capsule of different crystal forms 5-chloro-4-hydroxyl-2 (1H)-pyridone preparation respectively; 040706-2 contains the L crystal formation), according to dissolution determination method, respectively at 5,10,20,30,45,60 minutes sampling and measuring stripping quantities.The stripping of different crystal forms 5-chloro-4-hydroxyl-2 (1H)-pyridone the results are shown in Table 9 in the two batches of capsule samples, and stripping curve is seen Figure 15.
The stripping curve measurement result of different crystal forms 5-chloro-4-hydroxyl-2 (1H)-pyridone in table 9. capsule preparations
(5) conclusion
With the compound capsule of different crystal forms 5-chloro-4-hydroxyl-2 (1H)-pyridone preparation, 5-chloro-4-hydroxyl-2 (1H) in the 20min-dissolution rate of pyridone in water all can reach more than 97.0%, all has good stripping behavior; 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation and L crystal formation stripping quantity no significant difference in the identical time.
3, P crystal formation provided by the invention and L crystal formation are irritated gastric motility and pharmacokinetic parameter thereof in the rat body
Rat oral gavage (i.g) is respectively behind administration 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation and the L crystal formation 10mg/kg, and the transformation period that records is respectively 2.15 ± 0.40 and 1.88 ± 0.13h, AUC
0 → 8Be respectively 4.30 ± 0.51 and 4.11 ± 0.60 μ g.h/ml.Be respectively 1.77 ± 0.23 and 1.63 ± 0.22 μ g/ml to peak concentration of drug, the administration peak time is respectively 0.86 ± 0.13 and 0.88 ± 0.14 μ g/m.
Concrete test method:
1) instrument, test drug and laboratory animal
Tianjin, instrument island LC-10Avp high performance liquid chromatograph, LC-10ADvp pump, CTO-10Avp column oven, RF-10AXL fluorimetric detector, HW-2000 chromatographic working station; Thermo IEC supercentrifuge (Micromax RF); Eppendorf 5432 vortex mixers (Netheler+HinzGmbH).
Animal SD rat, body weight 190～220g, male.Provide conformity certification number by Shanghai west pul-Bi Kai laboratory animal company limited: SCXK (Shanghai) 2003-0002.
Reagent methyl alcohol (chromatographically pure) is Fisher Scientific company product; Perchloric acid is Shanghai gold deer chemical industry company limited product; All the other reagent are commercially available analytical pure.
Test drug 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation (lot number CD040608P) and L crystal formation (lot number CD040608L), the Jiangsu Province Medicine Primary Institute provides.The capacity that the filling stomach is pressed the 1ml/100g rat body weight with medicine is converted the administration volume, makes suspension with 0.5%CMC-Na.
2) experimentation on animals grouping and process
Get 14 of rats, body weight 202.7 ± 5.6g.Be divided into 2 groups at random, 7 every group.Fasting but after can freely drinking water 10 hours, ig 10mg/kg P crystal formation or L crystal formation respectively.After administration 0.083,0.25,0.50,0.75,1,2,3,4,6 and 8h, the eye socket vein is got blood 0.25ml in the heparinization test tube, and is centrifugal, gets blood plasma 90 μ l and is used for the HPLC-ultra-violet analysis.After getting blood, replenish the physiological saline of equivalent at every turn.
3) result
(1) records Plasma Concentration-time data behind Plasma Concentration rat i.g 10mg/kg P crystal formation or the L crystal formation and list in table 10, table 11 and Figure 16 respectively.
Table 10. rat i.g 10mg/kg P crystal formation (CD040608P) back blood plasma Chinese traditional medicine concentration (μ g/ml)
Table 11. rat i.g 10mg/kg L crystal formation (CD040608L) back blood plasma Chinese traditional medicine concentration (μ g/ml)
(2) pharmacokinetic parameter by table 10,11 as seen, the 8h Plasma Concentration reaches the 1/10-1/20 of peak concentration after administration, asks by the statistical moment method with the 0-8h data and calculates corresponding pharmacokinetic parameter, the results are shown in Table 12,13, C
Max, T
MaxBe measured value.
Table 12. rat i.g 10mg/kg P crystal formation (CD040608P) back pharmacokinetic parameter
Table 13. rat i.g 10mg/kg L crystal formation (CD040608L) back pharmacokinetic parameter
Pharmacokinetic parameter relatively behind table 14. rat i.g 10mg/kg P crystal formation and the L crystal formation
By table 14 as seen, behind rat i.g 10mg/kg 5-chloro-4-hydroxyl-2 (1H)-two kinds of crystal formations of pyridone (CD040608P, CD040608L), the transformation period of estimation is respectively 2.15 ± 0.40 and 1.88 ± 0.13h, AUC
0 → 8Be respectively 4.30 ± 0.51 and 4.11 ± 0.60 μ g.h/ml.Survey to such an extent that be respectively 1.77 ± 0.23 and 1.63 ± 0.22 μ g/ml to peak concentration of drug, survey to such an extent that the administration peak time is respectively 0.86 ± 0.13 and 0.88 ± 0.14 μ g/ml, learn check by statistics, behind 5-chloro-4-hydroxyl-2 (the 1H)-pyridone of rat oral gavage kind crystal formation, 5-chloro-4-hydroxyl-2 (1H)-pyridone absorption dynamics parameter does not have significant difference (p＞0.05), and prompting 5-chloro-4-hydroxyl-2 (1H)-two kinds of crystal formations of pyridone pharmacokinetics behavior in the rat body is similar.
Description of drawings
Fig. 1 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal form X ray powder diffraction pattern.
Fig. 2 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal form X ray powder diffraction data.
Fig. 3 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal form X ray powder diffraction pattern.
Fig. 4 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal form X ray powder diffraction data.
Fig. 5 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal formation infrared spectrogram.
Fig. 6 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal formation infrared spectrogram.
Fig. 7 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal formation differential scanning calorimetric thermogram.
Fig. 8 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal formation differential scanning calorimetric thermogram.
Fig. 9 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal formation thermogravimetric analysis figure.
Figure 10 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal formation thermogravimetric analysis figure.
Figure 11 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal formation (before the heating) high-efficient liquid phase chromatogram (HPLC).
Figure 12 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal formation (before the heating) high-efficient liquid phase chromatogram (HPLC).
Figure 13 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal formation (heating 105 ℃, behind the 4h) high-efficient liquid phase chromatogram (HPLC).
Figure 14 is 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone L crystal formation (heating 105 ℃, behind the 4h) high-efficient liquid phase chromatogram (HPLC).
Figure 15 is the stripping curve of 5-chloro-4-hydroxyl-2 of the present invention (1H)-pyridone P crystal formation and L crystal formation in the compound capsule.
Figure 16 is rat i.g 10mg/kg P crystal formation (CD040608P) or L crystal formation (CD040608L) blood plasma Chinese traditional medicine concentration-time curve (Mean ± SD).
Embodiment
The invention will be further elaborated by the following examples.
Reference example 1
The preparation of 5-chloro-4-hydroxyl-2 (1H)-pyridone
In the 500ml reaction flask, add 5-chloro-3-cyano group-4-methoxyl group-2 (1H)-pyridone 30.0g (0.163mol), 48% Hydrogen bromide 150ml (1.33mol).Heating reflux reaction, TLC detection reaction terminal point.In reactant impouring 500ml frozen water, with 10% sodium hydroxide solution (about 600ml) regulator solution pH to 9～10.Add the 6g gac, stirring at room 10min filters, and filtrate is carefully regulated pH to 4.0～4.5 with 5% hydrochloric acid (about 140ml), and a large amount of white solids are separated out.Suction filtration, washing filter cake several, drying gets white solid (5-chloro-4-hydroxyl-2 (1H)-pyridone crude product) 19.7 grams, yield 83%.
The preparation of 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation
In the 500ml reaction flask, add 10% sodium hydroxide solution 210ml, add in batches and treat refining 5-chloro-4-hydroxyl-2 (1H)-pyridone 21g, stirring at room to sample all dissolves.Filter, Dropwise 5 % hydrochloric acid neutralization is down stirred in filtrate ice bath to 10～12 ℃, to pH value of solution to 4.0, places 10h, crystallization in 18～20 ℃.Suction filtration, with the distilled water wash filter cake for several times.Drying gets white solid 19g, yield 90%, and content 〉=99.0% (HPLC normalization method) is the P crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone after measured, and determination data is seen Fig. 1,2,5,7 and 9, and condition determination is described consistent with the summary of the invention part.
The preparation of 5-chloro-4-hydroxyl-2 (1H)-pyridone polymorphic L type
In the 1L reaction flask, add the P crystal formation 9.0g of 5-chloro-4-hydroxyl-2 (1H)-pyridone, dehydrated alcohol 600ml, reflux dissolving, filtered while hot.The filtrate room temperature is placed 8h, moves into refrigerator and places the 48h crystallization for 0～4 ℃.Suction filtration, with the absolute ethanol washing filter cake for several times.Drying gets white solid 5.9g, yield 65%, and content 〉=99.0% (HPLC normalization method) is the L crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone after measured, and determination data is seen Fig. 3,4,6,8 and 10, and condition determination is described consistent with the summary of the invention part.
The preparation of 5-chloro-4-hydroxyl-2 (1H)-pyridone P crystal formation
In the 500ml reaction flask, add 5% solution of potassium carbonate 160ml, add in batches and treat refining 5-chloro-4-hydroxyl-2 (1H)-pyridone 16g, stirring at room to sample all dissolves.Filter, Dropwise 5 % sulfuric acid neutralization is down stirred in filtrate ice bath to 10～12 ℃, to pH value of solution to 4.0, places 10h, crystallization in 18～20 ℃.Suction filtration, with the distilled water wash filter cake for several times.Drying gets white solid 13.6g, yield 85%, and content 〉=99.0% (HPLC normalization method) is the P crystal formation of 5-chloro-4-hydroxyl-2 (1H)-pyridone after measured.
Preparation of pharmaceutical compositions
Take by weighing Tegafur 20.0g, 5-chloro-4-hydroxyl-2 (1H)-pyridone P type 5.8g, Oteracil Potassium 19.6g, lactose 60g, sodium lauryl sulphate 4g, crossing 80 mesh sieves mixes, make softwood in right amount with the 1% HPMC aqueous solution, 24 mesh sieves are granulated, 60 ℃ of air seasonings, the whole grain of 20 mesh sieves, add Magnesium Stearate 1.5g, fully mixing promptly gets particle, chemical examination and definite loading amount make about 1000 of capsule.Measure the dissolution rate of 5-chloro-4-hydroxyl-2 (1H)-pyridone according to two appendix XC first methods of Chinese Pharmacopoeia version in 2005.20min stripping 5-chloro-4-hydroxyl-2 (1H)-pyridone can reach 92.5～100.2%.Contain Tegafur (C in every capsules
8H
9FN
2O
3), 5-chloro-4-hydroxyl-2 (1H)-pyridone (C
5H
4ClNO
2) and Oteracil Potassium (C
4H
2KN
3O
4) all reach 90.0%～110.0% of labelled amount.
With the P crystal formation among the L crystal formation replacement embodiment 4 of 5-chloro-4-hydroxyl-2 (1H)-pyridone, the gained preparation compositions can get equifinality.
Claims (10)
1. the P N-type waferN of structural formula 5-chloro-4-hydroxyl-2 (the 1H)-pyridone that is formula I or formula II is characterized in that 2 θ, crystal face d-spacing and the relative intensity of diffraction peak in the x-ray diffractogram of powder spectrum of described P N-type waferN is as follows:
Formula I. formula II.
2. the P N-type waferN of 5-chloro-4-hydroxyl-2 according to claim 1 (1H)-pyridone is characterized in that the absorption peak that comprises in the infrared spectra of described P N-type waferN is 2802 (br), 1869,1812,1617 (br), 1433,1374,1260,1221,676 and 628cm
-1Endotherm(ic)peak in the differential scanning calorimetric analysis is 277.9 ℃.
3. the P N-type waferN of 5-chloro-4-hydroxyl-2 according to claim 1 (1H)-pyridone, it is characterized in that the absorption peak that comprises in the infrared spectra of described P N-type waferN be 2802 (3268～2100, br), 1869,1812,1648,1617 (br), 1489,1456,1433,1374,1260,1221,1091,986,970,917,860,839,789,676,628 and 534cm
-1Endotherm(ic)peak in the difference formula scanning calorimetric analysis is 277.9 ℃; 2 θ, crystal face d-spacing and the relative intensity of diffraction peak are as follows in the x-ray diffractogram of powder spectrum:
One kind to prepare according to each described structural formula among the claim 1-3 be the method for P N-type waferN of 5-chloro-4-hydroxyl-2 (1H)-pyridone of formula I or formula II, it is characterized in that described method comprises the steps:
I) 5-chloro-4-hydroxyl-2 (1H)-pyridone is dissolved in the basic solution;
Ii) keep mixing solutions at 10～12 ℃, add the acidic solution neutralization, regulator solution pH to 4.0～4.5;
Iii) solution is placed 10～12h, crystallization in 18～20 ℃;
Iv) fractional crystallization from this pH=4.0～4.5 solution obtains the P N-type waferN of 5-chloro-4-hydroxyl-2 (1H)-pyridone.
5. method according to claim 4 is characterized in that described basic solution is selected from one or more in sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution and the solution of potassium carbonate, and preferred concentration is 10% sodium hydroxide solution; Acidic solution is hydrochloric acid soln or sulphuric acid soln, and preferred concentration is 5% hydrochloric acid soln.
6. pharmaceutical composition, it comprises P N-type waferN, Tegafur, Oteracil Potassium and pharmaceutically acceptable carrier according to each described 5-chloro-4-hydroxyl-2 (1H)-pyridone among the claim 1-3.
7. pharmaceutical composition according to claim 6 is characterized in that the P N-type waferN of Tegafur, 5-chloro-4-hydroxyl-2 (1H)-pyridone, the mol ratio of Oteracil Potassium are 1: 0.4: 1;
8. pharmaceutical composition according to claim 6, the formulation that it is characterized in that described pharmaceutical composition is tablet, capsule, granule, orally disintegrating tablet, powder, pill or suspensoid, preferred tablet or capsule.
According to each described 5-chloro-4-hydroxyl-2 (1H)-pyridone P N-type waferN among the claim 1-3 as the application of dihydropyrimidine dehydrogenase inhibitor in the medicine of preparation treatment cancer.
10. application according to claim 9 is characterized in that described cancer is cancer of the stomach, incidence cancer, colorectal carcinoma, the rectum cancer, carcinoma of the pancreas, mammary cancer or nonsmall-cell lung cancer.
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| CN102746244A (en) * | 2012-07-27 | 2012-10-24 | 南京正大天晴制药有限公司 | Refining method of oteracil potassium |
| CN109280074A (en) * | 2017-07-20 | 2019-01-29 | 歌礼药业（浙江）有限公司 | Dan Nuoruiwei sodium crystal and preparation method thereof |
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| JP2614164B2 (en) * | 1991-05-27 | 1997-05-28 | 大鵬薬品工業株式会社 | Composition for enhancing antitumor effect and for treating tumor |
| CN1915976B (en) * | 2006-09-08 | 2010-05-12 | 中国药科大学 | Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102746244A (en) * | 2012-07-27 | 2012-10-24 | 南京正大天晴制药有限公司 | Refining method of oteracil potassium |
| CN102746244B (en) * | 2012-07-27 | 2014-06-25 | 南京正大天晴制药有限公司 | Refining method of oteracil potassium |
| CN109280074A (en) * | 2017-07-20 | 2019-01-29 | 歌礼药业（浙江）有限公司 | Dan Nuoruiwei sodium crystal and preparation method thereof |
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