Preparation method of intermediate for preparing pemetrexed disodium

Abstract

The invention relates to a preparation method of an intermediate for preparing pemetrexed disodium, which comprises the following steps: mixing and stirring 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrole [2, 3-d] pyrimidine-5-yl) ethyl] methyl benzoate and a sodium hydroxide solution at the stirring temperature of 45-50 DEG C, reacting for 1-3 hours to obtain a reaction solution, continuously adding purified water into the reaction solution, uniformly stirring, filtering, washing, and drying to obtain the pemetrexed disodium. The preparation method comprises the following steps: adding 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidine-5-yl) ethyl] benzoic acid into a reaction kettle, stirring, crystallizing, washing with purified water, collecting a filter cake, and drying the filter cake at 80-90 DEG C under reduced pressure for 8-24 hours to obtain an intermediate for preparing pemetrexed disodium, namely 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidine-5-yl) ethyl] benzoic acid. The invention provides the preparation method for safely producing the intermediate for preparing pemetrexed disodium, and meanwhile, the intermediate which is few in impurity, high in purity and high in content and meets the quality standard is obtained.

Description

Technical Field

[0001] The present invention relates to the technical field of intermediate synthesis, and in particular to a method for preparing an intermediate used in the preparation of pemetrexed disodium. Background Art

[0002] In the synthesis of Pemetrexed disodium, the molecular formula is C 20 H 19 The process of N5Na2O6 requires the participation of many intermediates, among which the intermediate 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid is a key intermediate. Currently, the preparation process of this key intermediate is also recorded in some patent documents.

[0003] A Chinese invention patent (CN 111333658 A) discloses a method for preparing pemetrexed disodium hydrate. The present invention relates to a method for synthesizing pemetrexed disodium hydrate, wherein methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate is used as the starting material, which is hydrolyzed and then directly condensed with L-glutamic acid diethyl ester hydrochloride, hydrolyzed again to obtain a crude product, which is then recrystallized to obtain pemetrexed disodium hydrate, effectively improving the overall yield of the product. The reaction has the advantages of mild reaction conditions, high process efficiency, and environmental friendliness, making it very suitable for industrial production. In its case 2, the preparation process of the key intermediate: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid is described;

[0004] Although the above process obtains an intermediate with high yield and purity, a large amount of anhydrous ethanol needs to be used as a crystallizing agent during its preparation. The large amount of anhydrous ethanol is not conducive to safe production and is extremely harsh on the production environment.

[0005] A Chinese invention patent (CN 102911176 A) discloses a method for preparing pemetrexed disodium. Example 1 thereof describes a process for synthesizing 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, ultimately obtaining an intermediate with a yield of 76.0%. However, not only does the method still use a large amount of ethanol as a crystallizing agent during the production process, but the yield is also relatively low.

[0006] In view of the problems in production safety in the above technical solutions, the crystallization solvents in the above two solutions are now replaced with purified water, and an attempt is made to see whether a key intermediate with less impurities, high purity, and high content that meets quality standards can be prepared without using an organic solvent. The test shows that although the purpose of reducing production safety requirements is achieved by replacing ethanol with purified water according to the above solution, the quality of the intermediate obtained is not ideal.

[0007] Therefore, it is necessary to provide a safe production method for an intermediate used in the preparation of pemetrexed disodium, in which a key intermediate with few impurities, high purity and high content that meets quality standards can be obtained in the absence of an organic solvent during the preparation process. Summary of the Invention

[0008] To solve the above problems, the present invention provides a method for preparing an intermediate for use in the preparation of pemetrexed disodium, which does not involve the participation of organic solvents, thereby achieving the purpose of reducing production safety requirements. At the same time, the intermediate prepared by this preparation method has few impurities, high purity, and high content that meets quality standards.

[0009] To achieve the above object, the technical solution of the present invention provides: a method for preparing an intermediate for use in the preparation of pemetrexed disodium, comprising the following steps:

[0010] S1: Mixing methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and sodium hydroxide solution with stirring at a temperature of 45 to 50° C. for 1 to 3 hours to obtain a reaction solution;

[0011] S2: Continue to add purified water to the reaction solution, stir evenly, control the temperature to 20-30°C, stir to crystallize, wash with purified water and collect the filter cake;

[0012] S3: Dry the filter cake under reduced pressure at 80-90° C. for 8-24 h to obtain an intermediate of pemetrexed disodium, namely 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid.

[0013] As a further improvement, in step S1, the molar ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to the sodium hydroxide solution is 1:2.5-4.

[0014] As a further improvement, in step S1, the molar ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to sodium hydroxide solution is 1:2.5-3.

[0015] As a further improvement, in step S1, the concentration of the sodium hydroxide solution is 1 to 3 mol / L.

[0016] As a further improvement, in step S1, the concentration of the sodium hydroxide solution is 2 to 3 mol / L.

[0017] As a further improvement, in the crystallization step of step S2, the feed ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to purified water is 1:8-12.

[0018] As a further improvement, in the crystallization step of step S2, the feed ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to purified water is 1:9-11.

[0019] As a further improvement, the step S2 further includes a pH adjustment step, in which 1N hydrochloric acid solution is added to the reaction solution to adjust the pH to 6-7.

[0020] As a further improvement, the molar ratio of the methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to the 1N hydrochloric acid solution is 1:2-5.

[0021] As a further improvement, in the step S3, the reduced pressure drying temperature is 85 to 90° C. and the time is 10 to 16 hours.

[0022] The above technical solution of the present invention has the following beneficial effects: the present invention achieves the purpose of reducing production safety requirements without the use of organic solvents by synergistically adjusting and controlling the ratio between the reaction materials and the solvent and the parameters of each reaction step, and the intermediate prepared by the preparation method has few impurities, high purity, and high content that meets quality standards, serving as the basis for the subsequent safe production preparation of pemetrexed disodium. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the intermediate synthesis process diagram of the present invention. DETAILED DESCRIPTION

[0024] The following examples further illustrate the present invention, but should not be construed as limiting the present invention. Without departing from the spirit and substance of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention are within the scope of the present invention.

[0025] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

[0026] Pemetrexed disodium, molecular formula C 20 H 19 N5Na2O6 is a folic acid antagonist. It exerts its anti-tumor effects by interfering with folic acid-dependent metabolic processes during cell replication. Studies have shown that pemetrexed produces cytotoxic effects through intracellular polyglutamination, which inhibits several folic acid-dependent enzymes including thymidylate synthase, dihydrofolate reductase, and glycine ribonucleoside formyltransferase.

[0027] In this application, in order to further verify the prior art method for preparing the intermediate of this application, the following experiments (I) and (II) were performed respectively;

[0028] Experiment (1)

[0029] The same preparation method as that described in Case 2 of the Chinese invention patent (CN 111333658 A) for preparing 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid was used, except that anhydrous ethanol was replaced with purified water and the quality test of the prepared intermediate was performed as follows. The specific steps are as follows:

[0030] Purified water (12.00 kg) was added to a 50 L reactor at 20-30 ° C, and stirring was started. Then sodium hydroxide (0.60 kg, 15.00 mol) was added to a 100 L reactor, and the temperature was raised to 30-40 ° C and stirred to dissolve. Under the protection of nitrogen, methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate (1.56 kg, 5.00 mol) was added to 1 00L reactor, maintain the reaction temperature at 50 ° C for 2 hours, add purified water (10.00 kg) and cool to 10-20 ° C, add concentrated hydrochloric acid dropwise to the reaction solution until the pH is 6-7, filter, wash the filter cake with purified water (2.00 kg), and vacuum dry the filter cake for 18 hours (45 ° C, vacuum degree -0.1 MPa) to obtain 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid.

[0031] Experiment 2

[0032] The same preparation method as that described in Case 2 of the Chinese invention patent (CN 111333658 A) for preparing 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid was used, except that anhydrous ethanol was replaced with purified water and the prepared intermediate was subjected to the following quality tests. The specific steps are as follows:

[0033] To a three-necked flask, 58.4 g of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and 200 ml of 2 mol / L sodium hydroxide were added and stirred at 45°C for 3 hours. Then, 200 ml of purified water was added, and the pH of the reaction solution was adjusted to 4 with 5 mol / L hydrochloric acid under cooling. A yellow solid precipitated, which was filtered, washed with 50% purified water, and dried in vacuo at 50°C for 5 hours to obtain 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid as a light yellow solid.

[0034] The quality test results of the intermediates prepared according to the preparation process of Experiment (I) and Experiment (II) are shown in Table 1-1 and Table 1-2

[0035] Table 1-1: Quality test results of intermediates in Experiment (I) and Experiment (II)

[0036]

[0037]

[0038] Experimental results analysis-1:

[0039] The intermediates prepared by the preparation methods of Experiment (1) and Experiment (2) were respectively subjected to quality inspection. In Experiment (1), the reaction temperature and time were appropriately adjusted taking into account the solubility difference between purified water and ethanol. On this basis, after ethanol was replaced with purified water, the purity and yield decreased. In Experiment (2), the intermediate prepared not only had an increase in antimatter content, but also had a certain slight increase in yield, but the purity was far below the quality standard range. It can be seen that simply replacing ethanol in the prior art with purified water cannot directly obtain an intermediate that meets the quality requirements.

[0040] Table 1-2: Quality test results of intermediates in Experiment (I) and Experiment (II)

[0041]

[0042] Analysis of experimental results:

[0043] The intermediates prepared by the preparation methods of Experiment (1) and Experiment (2) were subjected to quality tests. The results showed that multiple indicators in the relevant substance tests exceeded the standards, which further demonstrated that simply replacing the ethanol in the prior art with purified water cannot directly produce an intermediate that meets the quality requirements.

[0044] Example 1

[0045] The intermediates were prepared using the materials and process conditions shown in Table 1.

[0046] Table 1: List of materials used in the synthesis of intermediates

[0047]

[0048] To a 200 L enameled reactor, 8.74 kg of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and 35 L of 1N sodium hydroxide solution were added. The temperature was controlled to 45 °C and stirred for 1 h. The reaction progress was monitored by TLC.

[0049] After the reaction is completed, 70 L of purified water is added and stirred evenly. The temperature is lowered to 20 ° C and about 56 L of 1N hydrochloric acid solution is slowly added to adjust the pH of the system to 6-7. The mixture is stirred at 20 ° C for crystallization for 0.5 h, filtered, and the filter cake is washed with an appropriate amount of purified water. The filter cake is collected and dried under reduced pressure at 80 ° C for 10 h to obtain the intermediate.

[0050] Example 2

[0051] The same preparation method as in Example 1 was used, except that the materials and amounts shown in Table 2 were used.

[0052] Table 2: List of materials used in the synthesis of intermediates

[0053]

[0054] Example 3

[0055] The same preparation method as in Example 1 was used, except that the materials and amounts shown in Table 3 were used.

[0056] Table 3: List of materials used in the synthesis of intermediates

[0057]

[0058] Example 4

[0059] The same preparation method as in Example 2 was used, except that methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and sodium hydroxide solution were added, and the reaction was stirred at 48°C for 2 hours. The temperature was lowered to 25°C, and the pH was adjusted by slowly adding methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate. The reaction was then dried under reduced pressure at 85°C for 11 hours.

[0060] Example 5

[0061] The same preparation method as in Example 2 was used, except that methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and sodium hydroxide solution were added, and the reaction was stirred at 50°C for 3 hours. The temperature was lowered to 30°C, and the pH was adjusted by slowly adding methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate. The reaction was then dried under reduced pressure at 90°C for 16 hours.

[0062] Comparative Example 1

[0063] The same preparation method as in Example 4 was used, except that the materials and amounts shown in Table 4 were used.

[0064] Table 4: List of materials used in the synthesis of intermediates

[0065]

[0066] Comparative Example 2

[0067] The same preparation method as in Example 4 was used, except that the materials and amounts shown in Table 5 were used.

[0068] Table 5: List of materials used in the synthesis of intermediates

[0069]

[0070] Comparative Example 3

[0071] The same preparation method as in Example 4 was used, except that the same preparation method as in Example 2 was used, except that methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and sodium hydroxide solution were added, and the temperature was controlled to 30°C and stirred for 1 hour. The temperature was lowered to 15°C, and the pH was slowly adjusted by adding 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate. The reaction was then dried under reduced pressure at 45°C for 20 hours.

[0072] Comparative Example 4

[0073] The same preparation method as in Example 4 was used, except that the same preparation method as in Example 2 was used, except that methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and sodium hydroxide solution were added, and the temperature was controlled to 55°C and stirred for 2 hours. The temperature was lowered to 15°C, and the pH was slowly adjusted by adding 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate. The reaction was then dried under reduced pressure at 80°C for 18 hours.

[0074] Test Example 1: Investigation of intermediate purity and yield

[0075] The intermediates prepared by the preparation methods of Examples 1-5 and Comparative Examples 1-4 were sampled and tested for relevant substances, purity and yield. The test results are shown in Table 6.

[0076] Table 6: Results of investigation on the amount of reaction solvent (intermediates)

[0077]

[0078] Note: ① The yield calculation formula is as follows:

[0079] Yield (%) = weight of intermediate IV × content / theoretical yield of intermediate IV × 100%;

[0080] Analysis of the test results: It can be seen from the above results that the intermediates prepared according to the preparation methods of Examples 1-5 show fewer related impurities, higher purity and yield in terms of relevant substance detection. Among them, Example 4, based on the coordinated adjustment of the ratio of reaction materials and reaction conditions, has better detection results than Comparative Examples 1-4 and other Examples in terms of control of relevant substances, yield and purity.

[0081] Comparative Example 1 adjusted the ratio between the reaction materials on the basis of Example 4. The purpose of this comparison is to examine whether the ratio of the reaction materials added can affect the purity and yield of the intermediate. The results show that the preparation method of Comparative Example 1 not only causes insufficient reaction resulting in an increase in related substances, but also fails to achieve the yield and purity of the intermediate prepared by any one of the preparation methods in Examples 1-5. The effect is quite different. This shows that the ratio of the reaction materials added can affect the purity and yield of the intermediate.

[0082] Comparative Example 2 adjusted the types of reaction materials based on Example 4. Specifically, the purified water in the reaction materials was replaced with methanol, and tetrahydrofuran was used as a crystallizing agent. Compared with Examples 1-5, the results showed that except for a slight increase in the maximum single impurity, the yield and purity were not significantly affected. However, due to the toxicity, strong volatility, and flammability of methanol, even if the slightly increased impurities are not considered, the use of the above reaction materials should be avoided for the sake of production environment requirements and production safety considerations.

[0083] Comparative Examples 3-4, the reaction conditions were adjusted on the basis of Example 4. The results showed that the purity and yield of the intermediates in Comparative Examples 3-4 were significantly reduced, which shows that the reaction conditions of the materials can affect the yield and purity of the intermediates.

[0084] Test Example 2: Test on the quality standard of intermediates

[0085] The intermediates prepared by the preparation methods of Examples 1-5 and Comparative Examples 1-4 were respectively subjected to quality inspections. The inspection indicators and test results are shown in Table 7.

[0086] Table 7: Test results of intermediate IV

[0087]

[0088]

[0089] Analysis of test results:

[0090] The above results show that the intermediates prepared according to the preparation methods of Examples 1-5 have lower contents of various impurities in the quality standard inspection, among which the test results of Example 4 are better than those of Comparative Examples 1-4 and other Examples.

[0091] Comparative Example 1 failed to meet the quality standards in terms of both the relevant substances and the content determination in the quality standard inspection test, which also shows that the ratio conditions of the added reaction materials can affect the quality of the intermediates and thus cannot be used in the preparation of pemetrexed disodium.

[0092] After adjusting the reaction conditions on the basis of Example 4, the moisture content index of Comparative Example 3-4 exceeded the quality standard requirement range in the quality standard inspection test, and the content determination of Comparative Example 4 did not meet the standard, which shows that adjusting the reaction conditions between the materials can affect the quality of the intermediate.

[0093] The impurity information of the intermediates in this application is shown in Table 8;

[0094] Table 8: Structural formula of intermediate organic impurities

[0095]

[0096] The above-described embodiments are merely descriptions of preferred implementations of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A method for preparing an intermediate for use in the preparation of pemetrexed disodium, characterized in that: The steps include: S1: Mixing methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate and sodium hydroxide solution with stirring at a temperature of 45 to 50° C. for 1 to 3 hours to obtain a reaction solution; S2: Continue to add purified water to the reaction solution, stir evenly, control the temperature to 20-30°C, stir to crystallize, wash with purified water and collect the filter cake; S3: Dry the filter cake under reduced pressure at 80-90° C. for 8-24 h to obtain an intermediate for the preparation of pemetrexed disodium, namely 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid.

2. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, wherein: In the step S1, the molar ratio of the methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to the sodium hydroxide solution is 1:2.5-4.

3. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, characterized in that: In step S1, the molar ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to the sodium hydroxide solution is 1:2.5-3.

4. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, wherein: In step S1, the concentration of the sodium hydroxide solution is 1 to 3 mol / L.

5. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, characterized in that: In step S1, the concentration of the sodium hydroxide solution is 2-3 mol / L.

6. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, characterized in that: In the crystallization step of step S2, the feed ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to purified water is 1:8-12.

7. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, characterized in that: In the crystallization step of step S2, the feed ratio of methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to purified water is 1:9-11.

8. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, characterized in that: The step S2 further includes a pH adjustment step, in which 1N hydrochloric acid solution is added to the reaction solution to adjust the pH to 6-7.

9. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 8, characterized in that: The molar ratio of the methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate to the 1N hydrochloric acid solution is 1:2-5.

10. The method for preparing an intermediate for use in the preparation of pemetrexed disodium according to claim 1, characterized in that: In the step S3, the reduced pressure drying temperature is 85 to 90° C. and the time is 10 to 16 hours.

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