CN114989154A - Raltitrexed dimer impurity, synthesis method and application thereof - Google Patents
Raltitrexed dimer impurity, synthesis method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicines, and discloses a raltitrexed dimer impurity, a synthesis method and application thereof. The invention discovers a new raltitrexed dimer impurity accidentally in the production process, and the impurity is difficult to separate and remove in the preparation process of raltitrexed, thereby influencing the product quality. Therefore, the invention directionally synthesizes the impurities by researching the generation path of the impurities. The synthesis process has the advantages of easily available raw materials, short synthesis steps, simple operation, and high yield and purity. The impurities obtained by synthesis can be used as a reference substance for controlling the quality of raltitrexed.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a raltitrexed dimer impurity, a synthesis method and application thereof.
Background
Raltitrexed is a thymidylate synthase inhibitor used for treating patients with advanced colorectal cancer. The chemical name is as follows: (5- (methyl ((2-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) methyl) amino) thiophene-2-carbonyl) -L-glutamic acid, having the structural formula shown in formula V below:
raltitrexed can be prepared by taking a compound shown in a formula VI and L-glutamic acid diethyl ester hydrochloride (shown in a formula VII) as raw materials, performing amide condensation under an alkaline condition to obtain a compound shown in a formula A, and performing Boc removal reaction on the compound A to obtain a compound shown in a formula B. And reacting the compound B with a compound shown in the following formula III to obtain a compound shown in a formula C, and hydrolyzing ester of the compound C under an alkaline condition to obtain raltitrexed.
The synthetic route of raltitrexed is as follows:
raltitrexed impurities are of great importance for the quality studies of raltitrexed, and a number of raltitrexed impurities have now been found, for example: the patent CN201710601520.1 discloses seven raltitrexed impurities A-F, and the structural formula is as follows:
patent CN201710810458.7 discloses raltitrexed impurity G, the structural formula is as follows:
patent CN201710588226.1 discloses an impurity of raltitrexed, the structural formula is as follows:
however, besides the known raltitrexed impurities including the above compounds, there are still some unknown raltitrexed impurities which are difficult to detect or isolate, and in order to further improve the quality of raltitrexed, it is necessary to minimize the content of the unknown impurities in raltitrexed. The applicant finds a new raltitrexed dimer impurity in the production process, the impurity is not reported in any existing literature, and further, the impurity is difficult to remove in the process of preparing the raltitrexed, so that an impurity reference substance is urgently needed for carrying out quality research on the raltitrexed. Therefore, it is necessary to develop a method for synthesizing the impurities simply and efficiently.
Disclosure of Invention
The first technical problem to be solved by the invention is to provide a novel raltitrexed dimer impurity aiming at the current situation that the raltitrexed in the prior art has unknown impurities, and the impurity can provide reference and conditions for the quality research work of the raltitrexed.
The second technical problem to be solved by the present invention is to provide a method for synthesizing the raltitrexed dimer impurity, which is simple and has high yield and purity, aiming at the current situation that the method for synthesizing the raltitrexed dimer impurity is not available in the prior art.
The specific technical scheme of the invention is as follows:
in a first aspect, the present invention provides a raltitrexed dimer impurity, the structural formula of which is shown in formula I:
of the above compounds 1 The H-NMR spectrum parameters are as follows: 1 H NMR(400MHz，DMSO-d6)δ12.39(br，4H)，8.39(d，J＝7.7Hz，1H)，8.00(s，1H)，7.84(s，1H)，7.63(d，J＝8.2Hz，1H)，7.56-7.44(m，4H)，4.31-4.25(m，3H)，4.04(d，J＝6.3Hz，2H)，2.76(s，3H)，2.36(s，6H)，2.30(t，J＝7.4Hz，2H)，2.06-2.02(m，1H)，1.91-1.85(m，1H)。
13 the C-NMR spectrum parameters are as follows: 13 C NMR(101MHz，DMSO-d6)：δ174.2，173.9，162.0，161.8，158.5，155.0，154.6，138.8，135.8，135.4，135.0，130.8，129.7，129.6，126.8，125.7，125.2，120.9，120.8，61.7，52.2，44.8，33.3，30.9，26.4，21.7。ESI-MS m/z＝631.3(M+H + )，629.3(M-H - )。
in a second aspect, the invention provides a method for synthesizing the raltitrexed dimer impurity, which comprises the following steps:
(1) reacting a compound shown as a formula II with a compound shown as a formula III to generate a compound shown as a formula IV:
(2) the compound shown in the formula IV is subjected to ester hydrolysis to obtain raltitrexed dimer impurities shown in the formula I:
preferably, in the step (1), the reaction conditions are as follows: organic solvent (preferably DMF) is used as a reaction medium, and the reaction temperature is 0-50 ℃ in the presence of NaH.
Preferably, in the step (1), the reaction liquid obtained after the reaction is cooled and then quenched by adding water, an organic extractant is used for extraction, and an organic layer is washed by water and is separated and purified to obtain the compound shown as the formula IV.
Preferably, in the step (1), the organic extractant is dichloromethane, and the separation and purification is separation and purification by a silica gel column.
Preferably, in the step (2), the reaction conditions are as follows: water is used as a reaction medium in the presence of alkali.
Preferably, in step (2), the base is sodium hydroxide.
Preferably, in the step (2), after the reaction is finished, acid is added to adjust the pH value to precipitate a solid, and after suction filtration, the obtained filter cake is dried to obtain the raltitrexed dimer impurity.
Preferably, in the step (2), acid is added to adjust the pH value to 3-4.
In a third aspect, the invention provides the use of the raltitrexed dimer impurity as an impurity reference substance in the quality detection of raltitrexed.
Compared with the prior art, the invention has the beneficial effects that: the team of the invention accidentally finds a new raltitrexed dimer impurity in the production process, and the impurity is difficult to separate and remove in the preparation process of raltitrexed, so that the product quality is influenced. Therefore, the invention directionally synthesizes the impurities by researching the generation path of the impurities. The synthesis process has the advantages of easily available raw materials, short synthesis steps, simple operation, and high yield and purity. The impurities obtained by synthesis can be used as a reference substance for controlling the quality of raltitrexed.
Drawings
FIG. 1 shows Raltitrexed dimer impurity of formula I in example 1 of the present invention 1 H NMR spectrum (400MHz, DMSO-d 6);
FIG. 2 shows Raltitrexed dimer impurity of formula I in example 1 of the present invention 13 C NMR spectrum (101MHz, DMSO-d 6);
FIG. 3 is an ESI-MS spectrum of the Raltitrexed dimer impurity of formula I shown in example 1 of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples.
General examples
A raltitrexed dimer impurity having the structural formula shown in formula I:
a synthetic method of raltitrexed dimer impurities comprises the following steps:
(1) reacting a compound shown as a formula II with a compound shown as a formula III to generate a compound shown as a formula IV:
in the step (1), the reaction conditions are as follows: organic solvent (preferably DMF) is used as a reaction medium, and the reaction temperature is 0-50 ℃ in the presence of NaH. Cooling the reaction liquid obtained after the reaction, adding water for quenching, extracting by using an organic extracting agent (preferably dichloromethane), washing an organic layer by using water, and separating and purifying by using a silica gel column to obtain the compound shown as the formula IV.
(2) The compound shown in the formula IV is subjected to ester hydrolysis to obtain raltitrexed dimer impurities shown in the formula I:
in the step (2), the reaction conditions are as follows: water is used as reaction medium in the presence of a base, preferably sodium hydroxide. And after the reaction is finished, adding acid to adjust the pH value to 3-4, precipitating a solid, and after suction filtration, drying the obtained filter cake to obtain the raltitrexed dimer impurity.
The raltitrexed dimer impurity can be used as an impurity reference substance in the quality detection of raltitrexed.
Example 1
The synthetic route for the raltitrexed dimer impurity is as follows:
the specific synthesis method is as follows:
(1) adding 100mL of DMF and 10.0g of compound II into a 250mL reaction bottle in sequence, cooling the solution to 0 ℃ after uniformly stirring, adding 1.5g of NaH (60%) in batches, controlling the temperature to 30 ℃ for reaction for 1 hour, then adding 16.0g of compound III, reacting overnight at 50 ℃, cooling the reaction solution to 25 ℃, adding water to quench the reaction solution, then adding dichloromethane for extraction, washing an organic phase with water, concentrating the organic phase, carrying out reaction column chromatography purification, taking dichloromethane to methanol as an eluent according to the volume ratio of 40: 1, collecting a target component, concentrating and drying to obtain 10.1g of a white-like solid IV with the yield of 70%.
(2) Adding 50mL of water and 1.5g of sodium hydroxide into a 250mL reaction bottle in sequence, stirring to dissolve, adding 10.0g of compound IV, reacting for 4 hours at 25 ℃, slowly dropwise adding dilute hydrochloric acid, adjusting the pH value to 3-4, separating out a solid, performing suction filtration, and drying a filter cake in vacuum to obtain 7.0g of light yellow solid raltitrexed impurity I with the yield of 80%. The characterization data of the compound I are shown in figures 1-3.
Example 2
(1) Adding 100mL of DMA and 12g of compound II into a 250mL reaction bottle in sequence, cooling the solution to 0 ℃ after uniformly stirring, adding 2g of NaH (60%) in batches, controlling the temperature to 30 ℃ for reaction for 2 hours, then adding 19.2g of compound III, reacting for 28 hours at 45 ℃, cooling the reaction solution to 25 ℃, adding water to quench the reaction solution, then adding toluene for extraction, washing the organic phase with water, concentrating the organic phase, performing reaction column chromatography purification, collecting target components by using dichloromethane to methanol volume ratio of 40: 1 as eluent, concentrating and drying to obtain 9.9g of quasi-white solid IV, wherein the yield is 69%.
(2) Adding 45mL of water and 1.4g of potassium hydroxide into a 250mL reaction bottle in sequence, stirring to dissolve, adding 9.9g of compound IV, reacting for 3 hours at 35 ℃, slowly dropwise adding dilute hydrochloric acid, adjusting the pH value to 3-4, separating out a solid, performing suction filtration, and drying a filter cake in vacuum to obtain 6.8g of light yellow solid raltitrexed impurity I with the yield of 81%.
Example 3
(1) Adding 80mL of DMF and 7.0g of compound II into a 250mL reaction bottle in sequence, uniformly stirring, cooling the solution to-5 ℃, adding 2g of NaH (60%) in batches, controlling the temperature to 30 ℃ for reaction for 1 hour, then adding 11.2g of compound III, reacting for 20 hours at 45 ℃, cooling the reaction solution to room temperature, adding water to quench the reaction solution, then adding toluene for extraction, washing the organic phase with water, concentrating the organic phase, carrying out reaction column chromatography purification, taking dichloromethane to methanol volume ratio of 40: 1 as eluent, collecting target components, concentrating and drying to obtain 6.6g of similar white solid IV with the yield of 65%.
(2) Adding 40mL of water and 1.4g of lithium hydroxide into a 250mL reaction bottle in sequence, stirring to dissolve, adding 6.5g of a compound IV, reacting for 2 hours at 40 ℃, slowly dropwise adding dilute hydrochloric acid, adjusting the pH value to 3-4, separating out a solid, performing suction filtration, and drying a filter cake in vacuum to obtain 4.5g of a light yellow solid raltitrexed impurity I with the yield of 79%.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modifications, alterations and equivalent changes made to the above embodiment according to the technical spirit of the present invention still belong to the protection scope of the technical solution of the present invention.
Claims (10)
1. A raltitrexed dimer impurity characterized by: the structural formula is shown in formula I:
2. a method of synthesizing the raltitrexed dimer impurity of claim 1, characterized by comprising the steps of:
(1) reacting a compound shown as a formula II with a compound shown as a formula III to generate a compound shown as a formula IV:
(2) the compound shown in the formula IV is subjected to ester hydrolysis to obtain raltitrexed dimer impurities shown in the formula I:
3. the method of synthesis of claim 2, wherein: in the step (1), the reaction conditions are as follows: an organic solvent is used as a reaction medium, and the reaction temperature is 0-50 ℃ in the presence of NaH.
4. A method of synthesis as claimed in claim 2 or 3, wherein: in the step (1), cooling the reaction liquid obtained after the reaction, adding water for quenching, extracting by using an organic extracting agent, washing an organic layer by using water, and separating and purifying to obtain the compound shown as the formula IV.
5. The method of synthesis of claim 4, wherein: in the step (1), the organic extracting agent is dichloromethane, and the separation and purification is separation and purification through a silica gel column.
6. The method of synthesis of claim 2, wherein: in the step (2), the reaction conditions are as follows: water is used as a reaction medium in the presence of alkali.
7. The method of synthesis of claim 6, wherein: in the step (2), the alkali is sodium hydroxide.
8. The method of synthesis of claim 2 or 6, wherein: in the step (2), after the reaction is finished, adding acid to adjust the pH value to precipitate a solid, and after suction filtration, drying the obtained filter cake to obtain the raltitrexed dimer impurity.
9. The method of synthesis of claim 8, wherein: in the step (2), adding acid to adjust the pH value to 3-4.
10. Use of the raltitrexed dimer impurity of claim 1 or the raltitrexed dimer impurity obtained by the synthetic method of any one of claims 2-9 as an impurity control in the quality detection of raltitrexed.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115772165A (en) * | 2022-12-03 | 2023-03-10 | 山东百诺医药股份有限公司 | Key impurity of raltitrexed and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107129492A (en) * | 2017-07-19 | 2017-09-05 | 南京普氟生物检测技术有限公司 | A kind of Raltitrexed is condensed the preparation method of impurity |
| CN107400109A (en) * | 2017-09-11 | 2017-11-28 | 南京正大天晴制药有限公司 | The impurity A of Raltitrexed and its preparation and application |
| CN107400110A (en) * | 2017-09-11 | 2017-11-28 | 南京正大天晴制药有限公司 | The impurity B of Raltitrexed and its preparation and application |
| CN107721995A (en) * | 2017-09-11 | 2018-02-23 | 南京正大天晴制药有限公司 | The relevant material G of Raltitrexed and its preparation and application |
| CN109280052A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | The related substance F of Raltitrexed and its preparation and application |
| CN109280044A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | Raltitrexed impurity C and its preparation and application |
| CN115772165A (en) * | 2022-12-03 | 2023-03-10 | 山东百诺医药股份有限公司 | Key impurity of raltitrexed and preparation method thereof |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107129492A (en) * | 2017-07-19 | 2017-09-05 | 南京普氟生物检测技术有限公司 | A kind of Raltitrexed is condensed the preparation method of impurity |
| CN109280052A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | The related substance F of Raltitrexed and its preparation and application |
| CN109280044A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | Raltitrexed impurity C and its preparation and application |
| CN107400109A (en) * | 2017-09-11 | 2017-11-28 | 南京正大天晴制药有限公司 | The impurity A of Raltitrexed and its preparation and application |
| CN107400110A (en) * | 2017-09-11 | 2017-11-28 | 南京正大天晴制药有限公司 | The impurity B of Raltitrexed and its preparation and application |
| CN107721995A (en) * | 2017-09-11 | 2018-02-23 | 南京正大天晴制药有限公司 | The relevant material G of Raltitrexed and its preparation and application |
| CN115772165A (en) * | 2022-12-03 | 2023-03-10 | 山东百诺医药股份有限公司 | Key impurity of raltitrexed and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115772165A (en) * | 2022-12-03 | 2023-03-10 | 山东百诺医药股份有限公司 | Key impurity of raltitrexed and preparation method thereof |
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