CN106957311B - Solvate of raltitrexed and preparation method thereof - Google Patents
Solvate of raltitrexed and preparation method thereof Download PDFInfo
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a solvate of raltitrexed, in particular relates to a raltitrexed methanol hydrate II and a raltitrexed ethanol hydrate III, and discloses preparation methods of the two crystal forms, wherein the two crystal forms have high stability and are key intermediates for preparing raltitrexed monohydrate.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a solvate monohydrate of raltitrexed and a preparation method thereof.
Background
Raltitrexed, a drug developed by the cancer research agency at the Royal Marsden hospital in england in cooperation with Zeneca. It is a thymic synthetase inhibitor, belongs to folic acid derivatives, and is used for treating patients with advanced colorectal cancer. The first time in the uk in 1996, is marketed under the name Tomudex, which has the following structural formula:
at the present stage, few reports are reported on raltitrexed crystal forms, and more reports are disclosed focusing on preparation and refining methods thereof.
The original patent US4992550 discloses a refining method of alkali dissolution and acid precipitation, and finally a powdery solid substance is prepared, which is a monohydrate crystal form and provides related melting point data of 180-. Such a purification method by alkali dissolution and acid precipitation is also industrially used in many cases, but this production method tends to cause sodium chloride residue in the finished product.
CN201210260633.7, CN201110361869.5 and CN201410844732.9 disclose a recrystallization method of raltitrexed dissolved in organic solvent and then washed, wherein CN201210260633.7 also provides a new crystal form of raltitrexed, but the intermediate formed by the above purification method is sticky or forms gel, which is not beneficial to the next filtration process.
Disclosure of Invention
The invention aims to provide a solvate of raltitrexed, which is used as an intermediate product of a refining reaction and provides another path for preparing high-purity raltitrexed.
The invention provides a raltitrexed solvent compound, which is characterized by having the following structure:
r ═ C1-C10 alkyl, where R is preferably one of methyl and ethyl;
preferred raltitrexed methanol hydrate II has characteristic peaks in the X-ray powder diffraction pattern at 2 theta values of 7.9 + -0.2 DEG, 10.2 + -0.2 DEG, 12.9 + -0.2 DEG, 15.2 + -0.2 DEG, 17.0 + -0.2 DEG, 20.4 + -0.2 DEG, 23.2 + -0.2 DEG, 24.00 + -0.2 DEG and 27.6 + -0.2 deg. Preferably, the 2 theta value has characteristic peaks at 7.9 + -0.2 deg., 10.2 + -0.2 deg., 12.9 + -0.2 deg., 15.2 + -0.2 deg., 17.0 + -0.2 deg., 18.9 + -0.2 deg., 19.3 + -0.2 deg., 20.4 + -0.2 deg., 23.2 + -0.2 deg., 24.00 + -0.2 deg., 24.5 + -0.2 deg., 25.3 + -0.2 deg., 27.0 + -0.2 deg., 27.6 + -0.2 deg., 30.8 + -0.2 deg.. More preferably, the XRPD pattern is shown in figure 1.
The Raltitrexed methanol hydrate II provided by the invention has an endothermic peak at 48.2 ℃, 98.2 ℃ and 178.5 ℃ on a Differential Scanning Calorimetry (DSC) curve, loses solvent methanol molecules at 48.2 ℃, loses solvent water molecules at 98.2 ℃, and is a melting peak at 178.5 ℃. The DSC pattern is shown in detail in FIG. 2.
The invention has a water content of 3.46% measured by a Karl Fischer moisture meter and approximately contains one molecule of water.
The raltitrexed methanol hydrate II provided by the invention has the weight loss of 9.5% when the Thermogravimetric (TG) curve is heated to 110 ℃, and one molecule of raltitrexed contains one water molecule and one methanol molecule through thermogravimetric data analysis. The thermogravimetric analysis is shown in FIG. 3.
Furthermore, the invention also provides a single crystal of the raltitrexed methanol hydrate II, which proves that one molecule of raltitrexed in the crystal form II contains one molecule of water and one molecule of methanol, and the single crystal is subjected to single crystal X-ray diffraction analysis, wherein the X-ray single crystal diffraction pattern is shown in figure 4, and is a monoclinic system with axial length
The included angle α is 90 °, β is 91.12 °, and γ is 90 °.
The invention also provides raltitrexed ethanol hydrate III, which has characteristic peaks in an X-ray powder diffraction pattern at 2 theta values of 7.7 +/-0.2 degrees, 10.1 +/-0.2 degrees, 12.7 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.7 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.3 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.0 +/-0.2 degrees and 27.2 +/-0.2 degrees. Preferably, the 2 theta value has characteristic peaks at 7.7 + -0.2 °, 8.1 + -0.2 °, 10.1 + -0.2 °, 10.4 + -0.2 °, 10.8 + -0.2 °, 12.7 + -0.2 °, 13.2 + -0.2 °, 14.9 + -0.2 °, 16.7 + -0.2 °, 17.5 + -0.2 °, 19.0 + -0.2 °, 19.8 + -0.2 °, 20.3 + -0.2 °, 22.9 + -0.2 °, 23.8 + -0.2 °, 24.0 + -0.2 °, 27.2 + -0.2 °, 30.6 + -0.2 °, 32.5 + -0.2 °. More preferably, the XRPD pattern is shown in figure 5.
The invention provides a Raltitrexed ethanol hydrate III, wherein a Differential Scanning Calorimetry (DSC) curve of the Raltitrexed ethanol hydrate III has endothermic peaks at 50.0 ℃, 98.2 ℃ and 173.5 ℃, solvent ethanol molecules are lost at 50.0 ℃, solvent water molecules are lost at 98.2 ℃, and a melting peak is at 173.5 ℃. The DSC spectrum is shown in figure 6.
The invention has a water content of 3.50% measured by a Karl Fischer moisture meter and approximately contains one molecule of water.
The raltitrexed ethanol hydrate III provided by the invention has the weight loss of 12.33% when the Thermogravimetric (TG) curve is heated to 140 ℃, and one molecule of raltitrexed contains one water molecule and one ethanol molecule through thermogravimetric data analysis. The thermogravimetric analysis plot is shown in FIG. 7.
On the other hand, the invention also provides a preparation method of the raltitrexed methanol hydrate II, which comprises the following steps: dissolving raltitrexed in a mixed system of water and a methanol solvent, heating for dissolving, heating for pumping, slowly cooling, adding water for separating out, separating and drying to obtain the raltitrexed. Wherein the volume ratio of water to methanol solvent is 1: 1-1: 6.
on the other hand, the invention also provides a preparation method of the raltitrexed ethanol hydrate III, which comprises the following steps: dissolving raltitrexed in a mixed system of water and an ethanol solvent, heating for dissolving, heating for pumping, slowly cooling, adding water for separating out, separating and drying to obtain the raltitrexed. Wherein the volume ratio of water to ethanol solvent is 1: 3-1: 7.
because the raltitrexed powder is difficult to dissolve in water, in general, the addition of water into an organic solvent can reduce the solubility of a crude product, which is also the reason why anhydrous alcohol or ether solvents are adopted in both the comparison documents CN201210260633.7 and CN201110361869.5 to dissolve the crude product of raltitrexed, but the inventor surprisingly found that the solubility of raltitrexed can be remarkably improved after a certain proportion of water is added into an alcohol solvent, and the proportion of water and the alcohol solvent is also important for obtaining a solid intermediate.
The effect of the ratio of water to alcohol on the crystal form of raltitrexed and on its solubility is verified by the following test, which is carried out under the same conditions except for the difference in the ratio of water to alcohol, and the specific test results are detailed in the following table.
Table 1 summary from preliminary small-scale crystallization results
The present invention also finds a process for the preparation of raltitrexed monohydrate using raltitrexed solvates ii, iii as intermediates, by which process substantially pure raltitrexed monohydrate can be prepared, and the monohydrate prepared by this process exhibits more stable properties in long-term stability tests.
The following is the result of small-scale stability test, and the crude product of raltitrexed can be prepared by taking N- [5- (N-methylamino) -2-thenoyl ] -L-glutamic acid diethyl ester and 2-methyl-6-bromomethyl-3-hydrogen-quinazoline-4-ketone as raw materials through condensation and hydrolysis, or the crude product of raltitrexed purchased from the market, the purity is about 95 percent, and the water content is 3 percent.
Batch 1: preparing raltitrexed monohydrate according to the method disclosed in US4992550 (abbreviation' 550);
batch 2: recrystallizing the crude product of raltitrexed to generate raltitrexed methanol hydrate II, and drying the raltitrexed methanol hydrate II in vacuum at the temperature of between 40 and 60 ℃ for 6 to 8 hours to obtain raltitrexed monohydrate.
Batch 3: recrystallizing the crude product of raltitrexed to generate raltitrexed ethanol hydrate III, and drying the raltitrexed ethanol hydrate III in vacuum at 50-65 ℃ for 6-8h to obtain raltitrexed monohydrate.
A comparative analysis of the' 550 method and the method of the present application is provided below, and the specific differences are detailed in the following table
TABLE 2 comparative analysis of refining methods
As can be seen from the above table, the refining method directly avoids the generation of NaCl compared with the method disclosed in' 550, and the overproof chloride ion is a difficult point for controlling the production quality of the variety. Therefore, the method is simple to operate and is more suitable for industrial operation.
Meanwhile, the method prepared according to the present application resulted in higher stability of the final product compared to the preparation method disclosed in' 550, which was confirmed by the stability test below.
The stability of the 3 batches of products is checked in a constant temperature and humidity cabinet for 30 days, and the test conditions are as follows: 60 ℃/92.5% Relative Humidity (RH), under the condition of illumination of 4000lx, standing for 10 days, respectively for 0 day, 5 days and 10 days, sampling, and carrying out product purity and impurity inspection.
TABLE 3 results of stability tests for batches 1-3
From the data, the triptoresin monohydrate prepared by directly drying the solvate serving as the intermediate to obtain a refined product is superior to the long-term stability.
Drawings
FIG. 1 XRPD pattern of raltitrexed methanol hydrate II;
FIG. 2 DSC spectrum of raltitrexed methanol hydrate II;
FIG. 3 a TGA profile of Raltitrexed methanol hydrate II;
FIG. 4 is a single crystal spatial structure diagram of Raltitrexed methanol hydrate II;
FIG. 5 an XRPD pattern for raltitrexed ethanol hydrate III;
FIG. 6 DSC profile of raltitrexed ethanol hydrate III;
FIG. 7 a TGA profile of raltitrexed ethanol hydrate III;
figure 8 an amorphous XRPD pattern of raltitrexed;
figure 9 HPLC profile of raltitrexed monohydrate prepared in example 9;
figure 10 HPLC profile of raltitrexed monohydrate prepared in example 10.
Detailed Description
The following examples are provided to further illustrate the technical solutions of the present invention, but not to limit the present invention.
The crude product of raltitrexed can be prepared by taking N- [5- (N-methylamino) -2-thenoyl ] -L-diethyl glutamate and 2-methyl-6-bromomethyl-3-hydrogen-quinazoline-4-ketone as raw materials through condensation and hydrolysis, or the crude product of raltitrexed purchased from the market, the purity is about 95.0 percent, and the water content is 3 percent.
The invention discloses an instrument for detecting the crystal structure and the performance of a medicament, which comprises the following parts:
1. the single crystal structure was measured by an X-ray single crystal diffractometer, manufacturer, Enraf Noius & Enraf Noius, netherlands, instrument model: CAD 4/PC.
2. The powder diffractometer was manufactured by ARL of Switzerland, manufacturer, instrument type X' TRA, Cu-K α
The tube voltage is 40KV, the tube current is 30mA, and the scanning speed is 8 DEG/min.
3. Differential scanning calorimetry and thermogravimetry curves were produced by PerKinElmer, USA, with instrument models: pyris1DSC in nitrogen atmosphere at a temperature rise rate of 10 ℃/min.
4. Karl fischer moisture tester model: mettler Toledo V30 Volumeric KF Titrator
Example 1 preparation of powder of Raltitrexed methanol monohydrate II
Dissolving 1g of raltitrexed in a mixed solvent of 40ml of methanol and 10ml of water, heating to 50 ℃ for dissolving, heating to pump out, naturally and slowly cooling to 35 ℃, separating out crystals, slowly dripping 110ml of water, separating out crystals for 2 hours at a low temperature of 5 ℃, filtering and drying to obtain white green crystal powder of a crystal form II. The sample was characterized by XRPD, DSC and TG, and the results are shown in FIGS. 1-3.
EXAMPLE 2 preparation of a Single Crystal of Raltitrexed methanol monohydrate II
Dissolve 1g raltitrexed powder in water: filtering undissolved solid through 0.45 mu m filter paper in a mixed solvent of methanol (volume ratio is 1: 3), sealing the obtained saturated filtrate with a perforated film, slowly volatilizing until the solid is separated out, filtering, drying in vacuum, and collecting the solid to obtain the crystal form II. The single crystal was subjected to X-ray single crystal diffraction, and the results are shown in fig. 4.
Example 3 preparation of powder of Raltitrexed ethanol monohydrate III
Dissolving 1g of raltitrexed in a mixed solvent of 60ml of ethanol and 10ml of water, heating to 50 ℃ for dissolving, heat pumping, naturally and slowly cooling to 40 ℃, adding raltitrexed ethanol monohydrate III seed crystal, separating out crystals, naturally cooling to 35 ℃, slowly dripping 170ml of water, crystallizing at the low temperature of 5 ℃ for 2 hours, filtering and drying to obtain crystal powder of crystal form III.
EXAMPLE 4 preparation of amorphous form in pure organic solvent
Dissolving 1g of raltitrexed in 40ml of methanol, heating to 50 ℃ for dissolving, heating to pump, naturally and slowly cooling to 35 ℃, separating out crystals, slowly dripping 110ml of water, separating out crystals at 5 ℃ for 2h, filtering and drying to obtain yellow green powder, wherein XRD powder diffraction of the yellow green powder is amorphous as shown in figure 8.
Example 5 preparation according to the method disclosed in CN201110001785.0
0.20g (0.38mmol) of diethyl N- [5- [ N- [ (3, 4-dihydro-2-methyl-4-oxo-6-quinazolinyl) methyl ] -N-methylamino ] -2-thenoyl ] -L-glutamate was dissolved in 10mL of ethanol and 10mL of acetone, and 14mL of 3 mol. L-1 aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for reaction for 3 hours. Distilling under reduced pressure to remove ethanol and acetone, adjusting pH to 4 with 2 mol. L-1 hydrochloric acid, filtering to obtain brown yellow solid, and recrystallizing with methanol-anhydrous ether to obtain light yellow solid Raltitrexed 0.14g with yield of 80.1%. It was detected as an amorphous powder.
Example 6 preparation according to the method disclosed in CN201210260633.7
To 480ml of a 1N NaOH solution at 0 ℃ was added 52.8g N- [5- [ N-methyl-N- (2-methyl-4-oxo-3, 4-dihydroquinazolinyl-6-methyl) amino ] in portions]Thiophene-2-formyl radicals]diethyl-L-glutamate (ca. 0.1mol) was 97% pure, stirring was continued for 2 hours and filtered. The filtrate was extracted with dichloromethane (500 ml. times.2) to remove organic phase impurities, then the remaining organic phase impurities were re-extracted with ethyl acetate (500 ml. times.2), and the pH of the aqueous layer was adjusted to about 3.0 with 1N hydrochloric acid under stirring (0- -5 ℃ C.), whereupon a large amount of solid was precipitated. Stirring at 0 deg.C for 1 hr, filtering, washing the product with purified water until the filtrate is free of Cl-Ion residue is measured by 0.1NAgNO 3), the solution is pumped to be dry as much as possible to obtain 138 g of crude and wet raltitrexed product, 13.8g of the crude raltitrexed product is taken to be added into 600ml of anhydrous methanol, the mixture is stirred for 0.5 hour at room temperature, a small amount of insoluble substances exist in the test product, the filtration is carried out at the room temperature, the filtrate is concentrated and crystallized at the temperature of 28-35 ℃, the test product is placed in a refrigerator at the temperature of 4 ℃ for 3 hours, the filtration is carried out, the product is washed by a small amount of purified water, andin the course of time, 3.2g of an almost white crystalline solid was obtained and was detected as an amorphous powder.
Example 7 was prepared according to the method disclosed in CN201410844732.9
Adding 5g of crude raltitrexed into a reaction bottle, adding 15ml of methanol, heating in a water bath, refluxing and stirring to completely dissolve, refluxing for 0.5h, cooling the solution to 40 ℃, keeping the temperature at 40 ℃ and standing for 1h, filtering to remove impurities, slowly cooling the solution to 15 ℃ within 4 h, keeping the temperature for 7h, and separating out solids. It was detected as an amorphous powder.
Example 8 preparation according to the method disclosed in CN20110361869.5
Placing the crude product in a 1000ml reaction bottle, adding 600ml methanol, heating and refluxing to clarify, filtering, cooling the filtrate to 5-10 deg.C, slowly adding about 4200ml purified water, stirring for crystallization, filtering, and washing the solid with purified water to obtain light yellow solid. Vacuum drying at 40 deg.c for 24 hr to obtain light yellow refined product 30.3g in 85 mol% yield. HPLC purity 99.8%. It was detected as an amorphous powder.
Example 9 long term stability test studies were conducted on amorphous, monohydrate, and solvate compounds.
Amorphous raltitrexed, monohydrate, solvates ii, iii were subjected to a stability test in a constant temperature and humidity cabinet for 6 months. The test conditions were: sampling at 25 deg.C/75% Relative Humidity (RH) for 0, 1, 2, 3, and 6 months respectively, and performing purity and impurity inspection.
TABLE 4 stability test results for different crystal forms
As can be seen from the data in the table above, the methanol hydrate and the ethanol hydrate of raltitrexed showed higher stability than the amorphous form in the long-term stability test, and the stability was not inferior to that of the monohydrate.
Example 10
2g of the raltitrexed methanol hydrate obtained in example 1 were taken and dried in vacuum at 40-60 ℃ for 6-8 hours to obtain raltitrexed monohydrate with a yield of 86%, a purity of 99.94% and a maximum single impurity of 0.04%, and its HPLC chromatogram is shown in detail in FIG. 9.
Example 11
3g of the raltitrexed ethanol hydrate obtained in the example 3 is taken and dried in vacuum at 50-65 ℃ for 6-8h to obtain the raltitrexed monohydrate, the yield is 83%, the purity is 99.84%, the maximum single impurity is 0.06%, and the HPLC (high performance liquid chromatography) spectrum is shown in figure 10 in detail.
Claims (10)
1. A solvate of raltitrexed, which is characterized in that the solvate is raltitrexed methanol monohydrate II, and has characteristic peaks in the positions of 2 theta values of 7.9 +/-0.2 degrees, 10.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 15.2 +/-0.2 degrees, 17.0 +/-0.2 degrees, 20.4 +/-0.2 degrees, 23.2 +/-0.2 degrees, 24.00 +/-0.2 degrees and 27.6 +/-0.2 degrees in an X-ray powder diffraction pattern.
2. The solvate of raltitrexed according to claim 1, characterized by an X-ray powder diffraction pattern having characteristic peaks at 2 Θ values of 7.9 ± 0.2 °, 10.2 ± 0.2 °, 12.9 ± 0.2 °, 15.2 ± 0.2 °, 17.0 ± 0.2 °, 18.9 ± 0.2 °, 19.3 ± 0.2 °, 20.4 ± 0.2 °, 23.2 ± 0.2 °, 24.00 ± 0.2 °, 24.5 ± 0.2 °, 25.3 ± 0.2 °, 27.0 ± 0.2 °, 27.6 ± 0.2 °, 30.8 ± 0.2 °, and a Differential Scanning Calorimetry (DSC) curve having endothermic peaks at 48.2 DSC °, 98.2 ℃, 178.5 ℃, as shown in fig. 2, and a TGA as shown in fig. 3.
3. The solvate of raltitrexed according to claim 1, characterized by an XRPD pattern as shown in figure 1 and a Differential Scanning Calorimetry (DSC) curve with endothermic peaks at 48.2 ℃, 98.2 ℃ and 178.5 ℃, a DSC pattern as shown in figure 2 and a TGA pattern as shown in figure 3.
4. The solvate of raltitrexed according to claim 1, which is monoclinic and has an axial length
The included angle α is 90 °, β is 91.12 °, γ is 90 °, and the X single crystal diffraction pattern is shown in fig. 4.
5. The method for preparing a solvate compound of raltitrexed according to claims 1 to 4, characterized by comprising the following steps: dissolving raltitrexed in a mixed system of water and a methanol solvent, heating for dissolving, hot pumping, slowly cooling, adding water for separating out, separating and drying to obtain the raltitrexed, wherein the volume ratio of the water to the methanol solvent is 1: 1-1: 6.
6. a solvate of raltitrexed, which is characterized in that the solvate is raltitrexed ethanol monohydrate III, and has characteristic peaks in the positions of 2 theta values of 7.7 +/-0.2 degrees, 10.1 +/-0.2 degrees, 12.7 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.7 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.3 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.0 +/-0.2 degrees and 27.2 +/-0.2 degrees in an X-ray powder diffraction pattern.
7. The solvate compound of raltitrexed according to claim 6, characterized by an X-ray powder diffraction pattern having characteristic peaks at 2 θ values of 7.7 ± 0.2 °, 8.1 ± 0.2 °, 10.1 ± 0.2 °, 10.4 ± 0.2 °, 10.8 ± 0.2 °, 12.7 ± 0.2 °, 13.2 ± 0.2 °, 14.9 ± 0.2 °, 16.7 ± 0.2 °, 17.5 ± 0.2 °, 19.0 ± 0.2 °, 19.8 ± 0.2 °, 20.3 ± 0.2 °, 22.9 ± 0.2 °, 23.8 ± 0.2 °, 24.0 ± 0.2 °, 27.2 ± 0.2 °, 30.6 ± 0.2 °, 32.5 ± 0.2 °.
8. The solvate of raltitrexed of claim 6, having an XRPD pattern as shown in figure 5 and a Differential Scanning Calorimetry (DSC) curve with endothermic peaks at 50.0 ℃, 98.2 ℃ and 173.5 ℃, a DSC pattern as shown in figure 6 and a TGA pattern as shown in figure 7.
9. The method of claim 6, comprising the steps of: dissolving raltitrexed in a mixed system of water and an ethanol solvent, heating for dissolving, hot pumping, slowly cooling, adding water for separating out, separating and drying to obtain the raltitrexed, wherein the volume ratio of the water to the ethanol solvent is 1: 3-1: 7.
10. a solvate of raltitrexed according to any of claims 1-4 or 6-8 for use in the preparation of raltitrexed monohydrate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992550A (en) * | 1986-03-27 | 1991-02-12 | Imperial Chemical Industries Plc | Anti-tumour agents |
| CN103570702A (en) * | 2012-07-26 | 2014-02-12 | 南京优科生物医药有限公司 | Method for industrial preparation of raltitrexed and novel raltitrexed crystal form for pharmacy |
| CN104447724A (en) * | 2014-12-31 | 2015-03-25 | 四川峨嵋山药业股份有限公司 | Refining method of raltitrexed |
| CN105111197A (en) * | 2015-08-26 | 2015-12-02 | 上海鼎雅药物化学科技有限公司 | Synthesis methods of raltitrexed |
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- 2016-12-29 CN CN201611244886.XA patent/CN106957311B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992550A (en) * | 1986-03-27 | 1991-02-12 | Imperial Chemical Industries Plc | Anti-tumour agents |
| CN103570702A (en) * | 2012-07-26 | 2014-02-12 | 南京优科生物医药有限公司 | Method for industrial preparation of raltitrexed and novel raltitrexed crystal form for pharmacy |
| CN104447724A (en) * | 2014-12-31 | 2015-03-25 | 四川峨嵋山药业股份有限公司 | Refining method of raltitrexed |
| CN105111197A (en) * | 2015-08-26 | 2015-12-02 | 上海鼎雅药物化学科技有限公司 | Synthesis methods of raltitrexed |
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