Fine baking ladle purification method of raltitrexed
By using organic solvents such as N-methylpyrrolidone or tetrahydrofuran for thermal filtration and cooling crystallization, the problems of chloride residues and esterified impurities in ratitrexed purification were solved, high purity and stability were achieved, and operation was simplified. Reduced costs and is suitable for industrial production.
Patent Information
- Application Number
- CN202411376273.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-30
- Publication Date
- 2024-12-20
AI Technical Summary
In the existing ratetrexed purification method, alkali-soluble acidolysis method produces sodium chloride residues, and alcohol solvent method leads to esterified impurities and gel formation, affecting purification quality and stability.
Organic solvents such as N-methylpyrrolidone or tetrahydrofuran dissolve the crude product of ratitroxet, heat filtration, cooling crystallization, washing and vacuum drying, avoiding the production of chlorides and esterification of impurities, and improving purification stability and quality.
The high purity (over 99.9%) purification of lytetrexed is achieved, which avoids impurity formation and gel problems, simplifies operations, reduces costs, and is suitable for industrial production.
Smart Images
Figure CN119161333A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of drug purification, and in particular to a method for purifying a refined baking package of raltitrexed. Background Art
[0002] Raltitrexed, chemical name is N-[5-[N-methyl-N-(2-methyl-4-oxo-3,4-dihydroquinazoline-6-methyl)amino]thiophene-2-carbonyl]-L-glutamic acid, the structural formula is as follows:
[0003]
[0004] Raltitrexed is a quinazoline folate analog. Raltitrexed is currently used as a new water-soluble thymidylate synthase inhibitor, which can cause DNA breakage and cell death by inhibiting thymidylate synthase. Compared with 5-fluorouracil, raltitrexed has stronger selectivity and can replace fluorouracil in the treatment of advanced colorectal cancer. It has become a first-line drug for the treatment of advanced colorectal cancer.
[0005] There are currently two ways to purify raltitrexed:
[0006] Method 1: Alkaline dissolution and acid precipitation are used to obtain raltitrexed monohydrate. However, this method will produce a large amount of sodium chloride, resulting in residual sodium chloride, which needs to be removed by multiple pulping processes during post-treatment.
[0007] Method 2: A purification method is adopted in which the crude product of raltitrexed is dissolved in an alcohol solvent and then cooled to crystallize. However, alcohol reagents are easy to form esters with the crude product of raltitrexed to form impurities, and methanol residues during the stability period will also react with the crude product to form corresponding methyl ester impurities, affecting the quality. In addition, the raltitrexed intermediate formed during the purification method is easy to become sticky or form a gel, which affects the subsequent product filtration and the purification of raltitrexed.
[0008] It should be noted that the information disclosed in the above background technology section is only used to enhance the understanding of the background of the present disclosure, and therefore may include information that does not constitute the prior art known to ordinary technicians in the field. Summary of the invention
[0009] In view of the deficiencies in the prior art, the present invention discloses a method for purifying raltitrexed by fine baking.
[0010] The technical solution adopted by the present invention is as follows:
[0011] A method for purifying a refined baking package of raltitrexed comprises the following steps:
[0012] Step S1, heating and dissolving the crude product of raltitrexed with an organic solvent;
[0013] Step S2, hot filtering the dissolved solution to obtain a filtrate;
[0014] Step S3, cooling the filtrate, adding purified water dropwise to the filtrate system, cooling and crystallizing to obtain a reaction solution;
[0015] Step S4: centrifuging the reaction solution, washing it, and finally drying it to obtain the finished product of raltitrexed.
[0016] Furthermore, in step S1, the weight ratio of the crude raltitrexed to the organic solvent is 1:(35-40).
[0017] Further, in step S1, the organic solvent includes N-methylpyrrolidone and tetrahydrofuran.
[0018] Furthermore, in step S1, the heating temperature ranges from 30 to 40°C.
[0019] Furthermore, in step S1, the heating time ranges from 30 to 45 minutes.
[0020] Furthermore, in step S3, the weight ratio of crude raltitrexed to purified water is 1:(150-180).
[0021] Furthermore, in step S3, the crystallization temperature is lowered to 0-10°C.
[0022] Furthermore, in step S3, the cooling and crystallization time is 1 to 1.5 hours.
[0023] Furthermore, in step S4, purified water is used for washing, the weight ratio of crude raltitrexed to purified water is 1:(2-5), and the washing times are 3-5 times.
[0024] Furthermore, in step S4, the drying method is vacuum drying, the drying temperature is 50° C., and the drying time is 1 hour.
[0025] The beneficial effects of the present invention are as follows:
[0026] 1. Compared with the method of obtaining raltitrexed monohydrate by alkali dissolution and acid precipitation, the method of purifying the crude raltitrexed by using an organic solvent avoids the generation of chlorides during the purification process; compared with the use of alcohol solvents, no new esterified impurities are generated on the basis of the crude product, which greatly improves the stability and quality of the purified raltitrexed. The purity of the obtained raltitrexed is as high as 99.9% or more, and the maximum single impurity is less than 0.03% (area normalization method).
[0027] 2. The raltitrexed finished product obtained by the purification method is an off-white powder, which will not become sticky or form a gel during the purification process, and will not cause the product to be difficult to filter, making it easier to filter and perform subsequent purification operations.
[0028] 3. The method is simple to operate, has high yield, low cost, low requirements on reaction conditions, and no toxic or harmful by-products will appear in the reaction, which is beneficial to environmental protection and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1 The HPLC detection spectrum of Example 1 is shown.
[0030] Figure 2 This is the XRD detection spectrum of Example 1.
[0031] Figure 3 It is the HPLC detection spectrum of Comparative Example 1.
[0032] Figure 4 This is the XRD detection spectrum of Comparative Example 1.
[0033] Figure 5 This is the HPLC detection spectrum of Comparative Example 2.
[0034] Figure 6 This is the XRD detection spectrum of Comparative Example 2. DETAILED DESCRIPTION
[0035] The specific implementation of the present invention will be described below in conjunction with the accompanying drawings.
[0036] Embodiment 1:
[0037] A method for purifying a refined baking package of raltitrexed comprises the following steps:
[0038] Step S1, prepare crude raltitrexed, the crude raltitrexed is hydrolyzed with N-[5-[N-methyl-N-(2-methyl-4-oxo-3,4-dihydroquinazoline-6-methyl)amino]thiophene-2-carbonyl]-L-glutamic acid diethyl ester to prepare crude raltitrexed, the purity of which is about 98.0%, and the water content is 4%. Add 1.3 kg of crude raltitrexed into a 100L glass-lined reactor, add 46.1 kg of N-methylpyrrolidone, heat to 35°C, stir for 40 minutes, and dissolve.
[0039] Step S2: hot-filter the clear solution to remove solid residues and solid impurities to obtain a filtrate.
[0040] Step S3, transfer the filtrate to a 300L glass-lined reactor, cool it to 5°C, add 210.0kg of purified water at 0-10°C, and stir at 0-10°C for 1 hour to obtain a reaction solution.
[0041] Step S4, the reaction solution was centrifuged, and the filter cake was washed with purified water for 5 times, 4 L each time, and vacuum dried at 50°C for 24 hours to obtain 1.22 kg of raltitrexed finished product with a yield of 93.8% and a purity of 99.91%.
[0042] The finished product of raltitrexed was subjected to HPLC and XRD testing. The HPLC test spectrum of the finished product of raltitrexed is as follows: Figure 1 As shown, the XRD detection spectrum is as follows Figure 2 shown.
[0043] The X-ray powder diffraction pattern of the finished product of raltitrexed has characteristic peaks at 2θ values of 8.09±0.2°, 10.42±0.2°, 12.76±0.2°, 14.83±0.2°, 15.44±0.2°, 17.52±0.2°, 19.12±0.2°, 20.91±0.2°, 23.2±0.2°, 24.05±0.2°, 28.28±0.2°, and 33.43±0.2°.
[0044] Embodiment 2:
[0045] The difference from Example 1 is that N-methylpyrrolidone is replaced by tetrahydrofuran.
[0046] Step S1: Add 1.5 g of crude raltitrexed into a 100 ml reaction bottle, add 53.4 g of N-methylpyrrolidone, heat to 35° C., stir for 40 minutes, and dissolve.
[0047] Step S2: hot-filter the clear solution to remove solid residues and solid impurities to obtain a filtrate.
[0048] Step S3, transfer the filtrate to a 500 ml glass-lined reactor, cool it to 5°C, add 240 g of purified water at 0-10°C, and stir at 0-10°C for 1 hour to obtain a reaction solution.
[0049] Step S4, the reaction solution was centrifuged, and the filter cake was washed with purified water for 5 times, 400 ml each time, and vacuum dried at 50°C for 24 hours to obtain 1.36 g of raltitrexed finished product, with a yield of 90.5% and a purity of 99.83%.
[0050] Comparative Example 1, alkaline hydrolysis and acid precipitation method:
[0051] Follow the steps below:
[0052] S1. Add 20.5 g of crude raltitrexed to a 2 L glass reaction bottle. Add 200.5 g of purified water and cool to 0-10°C.
[0053] S2. Add the prepared sodium hydroxide solution (6.35 g sodium hydroxide dissolved in 102.5 g purified water) dropwise into the system at 0-10°C, and stir until the solution is clear.
[0054] S3. The clarified solution is filtered, transferred to a reaction bottle, and cooled to 0-10°C.
[0055] S4. Add hydrochloric acid solution (22.1 g of concentrated hydrochloric acid added to 575 g of purified water) at 0-10 °C, adjust Ph to 2-3, a large amount of solid precipitates, and crystallize for 1 hour.
[0056] S5, suction filtration (the filter cake is in gel form and difficult to be suction filtered), vacuum drying at 50°C for 24 hours to obtain 18.14 g of raltitrexed finished product. Yield 88.49%, purity 99.86%, chloride mixed. HPLC detection spectrum of raltitrexed finished product is as follows Figure 3 As shown, the XRD detection spectrum is as follows Figure 4 Shown (amorphous).
[0057] Comparative Example 2, using alcohol reagents:
[0058] Follow the steps below:
[0059] Add 5g of crude raltitrexed to a 100ml reactor, then add 15ml of methanol, heat in a water bath, reflux and stir to completely dissolve it, reflux for 0.5 hours, cool the solution to 40°C, keep it at 40°C for 1 hour, and filter to remove impurities. Slowly cool the filtrate to 15°C within 4 hours, keep it at this temperature for 7 hours, and solid will precipitate. Then filter, rinse the obtained solid with ice methanol to remove impurities on the surface or inside the solid, and then dry it under reduced pressure at 80°C for 24 hours to obtain 4.35g of raltitrexed fine product, with a yield of 87.0% and a purity of 99.8% (impurity content caused by methanol is 0.125%). The HPLC detection spectrum of the finished raltitrexed is shown below: Figure 5 As shown, the XRD detection spectrum is as follows Figure 6 Shown (amorphous).
[0060] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0061] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.
Claims
1. A method for purifying raltitrexed by fine baking, characterized in that: The following steps are involved: Step S1, heating and dissolving the crude product of raltitrexed with an organic solvent; Step S2, hot filtering the dissolved solution to obtain a filtrate; Step S3, cooling the filtrate, adding purified water dropwise to the filtrate system, cooling and crystallizing to obtain a reaction solution; Step S4: the reaction solution is centrifuged, then washed, and finally dried to obtain the raltitrexed finished product.
2. The method for purifying raltitrexed by fine baking according to claim 1, characterized in that: In step S1, the weight ratio of crude raltitrexed to the organic solvent is 1:(35-40).
3. The method for purifying raltitrexed by fine baking according to claim 2, characterized in that: In step S1, the organic solvent includes N-methylpyrrolidone and tetrahydrofuran.
4. The method for purifying raltitrexed by fine baking according to claim 1, characterized in that: In step S1, the heating temperature ranges from 30 to 40°C.
5. The method for purifying raltitrexed by fine baking according to claim 4, characterized in that: In step S1, the heating time ranges from 30 to 45 minutes.
6. The method for purifying raltitrexed by fine baking according to claim 1, characterized in that: In step S3, the weight ratio of crude raltitrexed to purified water is 1:(150-180).
7. The method for purifying raltitrexed by fine baking according to claim 6, characterized in that: In step S3, the crystallization temperature is lowered to 0-10°C.
8. The method for purifying raltitrexed by fine baking according to claim 7, characterized in that: In step S3, the temperature reduction and crystallization time is 1 to 1.5 hours.
9. The method for purifying raltitrexed by fine baking according to claim 1, characterized in that: In step S4, purified water is used for washing, the weight ratio of crude raltitrexed to purified water is 1:(2-5), and the washing times are 3-5 times.
10. The method for purifying raltitrexed by fine baking according to claim 1, characterized in that: In step S4 drying, the drying method is vacuum drying, the drying temperature is 50° C., and the drying time is 1 hour.