CN111233841A - Sunitinib related substance and preparation method and application thereof - Google Patents
Sunitinib related substance and preparation method and application thereof Download PDFInfo
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- CN111233841A CN111233841A CN202010185798.7A CN202010185798A CN111233841A CN 111233841 A CN111233841 A CN 111233841A CN 202010185798 A CN202010185798 A CN 202010185798A CN 111233841 A CN111233841 A CN 111233841A
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The invention belongs to the field of pharmaceutical chemistry, and discloses sunitinib related substances, and a preparation method and application thereof. The related substance is a compound A, and the preparation method comprises the following steps: (1) carrying out condensation reaction on a compound II (with the chemical name of 2, 4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid) and ethylenediamine to obtain an intermediate III; (2) under the action of alkali, the intermediate III and a compound IV (chemical name: 5-fluoroindole-2-ketone) undergo an aldol condensation reaction to obtain a sunitinib related substance A. The compound A disclosed by the invention can be used as a standard substance for controlling and researching the quality of sunitinib in the preparation process. The preparation method provided by the invention has the advantages of short reaction route, mild condition and high yield and purity, and provides a reliable material basis for further safety evaluation of the compound A and subsequent quality control research in the sunitinib preparation process.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to sunitinib related substances as well as a preparation method and application thereof.
Background
Sunitinib (trade name is Sutent) is a small molecule drug developed by sponish corporation in the united states capable of inhibiting multiple receptor tyrosine kinases, and the molecular formula is C22H27FN4O2The chemical name of which is N- [2- (diethylamino) ethyl]-5- [ (Z) - (5-fluoro-1, 2-bis)hydro-2-oxo-3H-indol-3-ylidene) methyl]-2, 4-dimethyl-1H-pyrrole-3-carboxamide, the structural formula is shown as I. Based on the results of a number of clinical trials, this drug has been recommended by medical guidelines in various countries and regions as a first-line treatment for patients with advanced renal cell carcinoma. The indications of the medicine in continental China include adult patients who have failed imatinib treatment or have intolerant gastrointestinal stromal tumors, inoperable advanced renal cell carcinoma and unresectable metastatic well-differentiated advanced pancreatic neuroendocrine tumors.
The quality and safety of the medicine can be directly influenced by the type and content of related substances in the medicine, so that the research on related substances of marketed medicines is of great significance. The structure of sunitinib related substances reported at present is shown as SNT-a-SNT-i:
after the research on the synthesis of sunitinib, the inventor finds a new related substance compound A, and has no report. Therefore, the chemical structure and the preparation method of the compound A are confirmed to have important significance for subsequent safety evaluation and quality control research in the sunitinib preparation process.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a sunitinib related substance, a preparation method and application thereof.
In order to solve the problems, the technical scheme of the invention is as follows:
the invention provides a sunitinib related substance, which is a compound A, wherein the structural formula of the compound A is shown in the specification
The invention also provides a preparation method of the sunitinib related substance, which comprises the following steps:
s1, carrying out condensation reaction on a compound II (2, 4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid) and ethylenediamine to obtain an intermediate III;
s2, under the action of alkali, carrying out aldol condensation reaction on the intermediate III and the compound IV (5-fluoroindole-2-ketone) to obtain a compound A.
Preferably, the step S1 specifically includes the following operations: in a first organic solvent, carrying out condensation reaction on a compound II and ethylenediamine at 0-50 ℃ until the compound II disappears; adding water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and isopropanol, and performing vacuum drying to obtain a crude product of the intermediate III; and finally, recrystallizing the crude product of the intermediate III by using ethanol to obtain a pure product of the intermediate III.
Preferably, the molar ratio of the compound II, the condensing agent and the ethylenediamine in the step S1 is 2 to 5: 2-5: 1.
more preferably, the molar ratio of the compound II, the condensing agent and the ethylenediamine is 2-3: 2-3: 1.
preferably, 8-30 mL of the first organic solvent is added to each gram of the compound II.
More preferably, 8-10 mL of the first organic solvent is added to each gram of the compound II.
Preferably, the first organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile and N, N-dimethylformamide.
More preferably, the first organic solvent is N, N-dimethylformamide.
Preferably, the condensing agent used is one or more of DCC, EDCI, HATU and HBTU.
More preferably, the condensing agent used is EDCI.
Preferably, the condensation reaction temperature is 20-30 ℃.
Preferably, the step S2 specifically includes the following operations: dissolving the intermediate III in a second organic solvent, adding alkali into the reaction liquid at 0 ℃, and stirring for 10 min; then adding a compound IV, adjusting the temperature of the system to 20-80 ℃ after the addition is finished, and stirring for reaction until the intermediate III disappears; adding water into the reaction solution, separating and extracting, drying an organic layer by anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a crude product of the compound A; and finally, recrystallizing the crude product of the compound A by acetonitrile to obtain a pure product of the compound A.
Preferably, 10-50 mL of the second organic solvent is added per gram of the intermediate III.
More preferably, 10-12 mL of the second organic solvent is added per gram of the intermediate III.
Preferably, the second organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol and N, N-dimethylformamide.
More preferably, the second organic solvent is chloroform.
Preferably, the base used is one or more of triethylamine, N' -diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate.
More preferably, the base used is triethylamine.
Preferably, the molar ratio of the compound III, the base and the compound IV is 1: 2-5: 2 to 5.
More preferably, the molar ratio of compound III, base and compound IV is 1: 2-2.5: 2 to 2.5.
Preferably, the aldol condensation reaction temperature is 60-65 ℃.
The invention also protects the application of the sunitinib related substance in sunitinib quality control.
The invention has the beneficial effects that: firstly, the invention discovers that the existing sunitinib can generate a new related substance compound A in the synthesis process for the first time, and provides a foundation for further improving the quality control of the existing sunitinib preparation process; secondly, the invention provides a related substance compound A, and the structure of the substance is confirmed, the related substance compound A can be used as a standard substance, and the quality standard of sunitinib is expected to be further improved; finally, the invention also provides a preparation method of the related substance compound A, which has the advantages of short route, mild condition, higher yield and high purity, and provides an important material basis for the subsequent safety evaluation of the related substance A and the quality control research in the sunitinib preparation process.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The sunitinib related substance is a compound A, and the structural formula of the sunitinib related substance is as follows:
the invention provides a preparation method of the sunitinib related substance compound A, which comprises the following steps:
s1, in a first organic solvent, carrying out condensation reaction on a compound II (the chemical name is 2, 4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid) and ethylenediamine at 0-50 ℃ until the compound II disappears. Adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and isopropanol, and performing vacuum drying. Recrystallizing the crude product by using ethanol to obtain a pure product of the intermediate III;
s2, dissolving the intermediate III in a second organic solvent, adding a proper alkali into the reaction liquid at the temperature, and stirring for 10 min. And then adding a compound IV, adjusting the temperature of the system to 20-80 ℃ after the addition is finished, and stirring for reaction until the intermediate III disappears. Water was added to the reaction solution, followed by liquid separation and extraction, and the organic layer was dried over anhydrous sodium sulfate, followed by removal of the solvent under reduced pressure. And recrystallizing the crude product by acetonitrile to obtain the compound A.
In some preferred embodiments, the molar ratio of compound II, condensing agent and ethylenediamine is 2 to 5: 2-5: 1, more preferably, the molar ratio of the compound II, the condensing agent and the ethylenediamine is 2-3: 2-3: 1. within the dosage ratio, the condensation reaction can be ensured to be carried out more fully, the generation of byproducts is reduced, and the waste of raw materials is avoided.
In some preferred embodiments, 8 to 30mL of the first organic solvent is added per gram of the compound II, and more preferably, 8 to 10mL of the first organic solvent is added per gram of the compound II, and in the amount ratio, the compound II can be completely dissolved in the first organic solvent, the compound II, the condensing agent and the ethylenediamine can be fully contacted, and the waste of the solvent can be avoided.
In some preferred embodiments, the first organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile, and N, N-dimethylformamide, and more preferably, the first organic solvent is N, N-dimethylformamide.
In some preferred embodiments, the condensing agent used in step S1 is one or more of DCC, EDCI, HATU, and HBTU, and more preferably, the condensing agent is EDCI.
In some preferred embodiments, the condensation reaction temperature in step S1 is 0 to 50 ℃, and more preferably, the reaction temperature is 20 to 30 ℃.
In some preferred embodiments, 10 to 50mL of the second organic solvent is added per gram of the intermediate III, and more preferably, 10 to 12mL of the second organic solvent is added per gram of the intermediate III, so as to ensure that the compound III is sufficiently dissolved and avoid waste of the solvent.
In some preferred embodiments, the second organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, and N, N-dimethylformamide, and more preferably, the second organic solvent is chloroform.
In some preferred embodiments, the base used is one or more of triethylamine, N' -diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate, more preferably, the base used is triethylamine.
In some preferred embodiments, the molar ratio of compound III, base and compound IV is 1: 2-5: 2-5, more preferably, the molar ratio of the compound III, the base and the compound IV is 1: 2-2.5: 2 to 2.5.
In some preferred embodiments, the aldol condensation reaction temperature in step S2 is 20 to 80 ℃, and more preferably, the reaction temperature is 60 to 65 ℃.
The progress of the above reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), typically ending when compound II and intermediate III have disappeared.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The liquid phase conditions in the following examples were: agilent1260 hplc, G1322A degasser, G1312 binary high pressure pump, G1329A autosampler, G1316A column oven, G4212B diode array detector. The column was Xbridge C18(250 mm. times.4.6 mm, 5 μm), mobile phase A was deionized water and mobile phase B was acetonitrile containing 0.1% trifluoroacetic acid, and the gradient elution was performed as follows:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 5 | 90 | 10 |
| 17 | 70 | 30 |
| 25 | 10 | 90 |
| 30 | 10 | 90 |
| 30.01 | 90 | 10 |
| 35 | 90 | 10 |
The flow rate was 1.0ml/min, the column temperature was 35 ℃ and the detection wavelength was 254 nm.
Example 1:
embodiment 1 of the present invention provides a preparation method of an intermediate III, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
compound II (5.0g, 29.9mmol) and N, N-dimethylformamide (40mL) were added to the reaction flask and stirred until compound II was completely dissolved. Ethylenediamine (0.9g, 15.0mmol) and EDCI (6.3g,32.9mmol) were dissolved in N, N-dimethylformamide (10mL) and slowly added dropwise to Compound II at 0 ℃. After the addition, the temperature of the reaction system was raised to 25 ℃, the reaction was stirred for 6 hours, and the disappearance of compound II was detected by TLC. Water (50mL) was added to the reaction mixture to precipitate a solid, which was then stirred for 20min, filtered, the filter cake was washed with water and isopropanol, and dried in vacuo. And recrystallizing the crude product by using ethanol to obtain a pure product of the intermediate III.
The preparation method is adopted to obtain 4.8g of light yellow solid with the yield of 90%.
The identification of intermediate III prepared in this example gave the following results:
ESI-MS(m/z):359.2；
1HNMR(500MHz,DMSO-d6):δ9.54(s,2H),8.68(s,2H),6.91(s,2H),3.36–3.38(m,4),2.41(s,6H),2.23(s,6H)；13CNMR(126MHz,DMSO-d6)：δ174.0,169.6,134.8,123.4,118.8,117.1,40.1,16.7,14.2。
example 2:
embodiment 2 of the present invention provides a preparation method of an intermediate III, which specifically adopts the following method:
compound II (4.5g, 26.9mmol) and N, N-dimethylformamide (36mL) were added to the reaction flask and stirred until compound II was completely dissolved. Ethylenediamine (0.8g, 15.0mmol) and DCC (6.1g, 29.6mmol) were dissolved in N, N-dimethylformamide (9mL) and slowly added dropwise to Compound II at 0 ℃. After the addition, the temperature of the reaction system was raised to 2 ℃, the reaction was stirred for 10 hours, and the disappearance of compound II was detected by TLC. Water (45mL) was added to the reaction mixture to precipitate a solid, which was then stirred for 20min, filtered, the filter cake was washed with water and isopropanol, and dried in vacuo. And recrystallizing the crude product by using ethanol to obtain a pure product of the intermediate III.
The pale yellow solid obtained by this method was 3.9g, yield 81%.
Example 3:
embodiment 3 of the present invention provides a preparation method of an intermediate III, which specifically adopts the following method:
compound II (5.0g, 29.9mmol) and N, N-dimethylformamide (40mL) were added to the reaction flask and stirred until compound II was completely dissolved. Ethylenediamine (0.9g, 15.0mmol) and HBTU (12.5g, 32.9mmol) were dissolved in N, N-dimethylformamide (10mL) and slowly added dropwise to compound II at 0 ℃. After the addition, the temperature of the reaction system was raised to 25 ℃, the reaction was stirred for 3 hours, and the disappearance of compound II was detected by TLC. Water (50mL) was added to the reaction mixture to precipitate a solid, which was then stirred for 20min, filtered, the filter cake was washed with water and isopropanol, and dried in vacuo. And recrystallizing the crude product by using ethanol to obtain a pure product of the intermediate III.
The yellowish solid obtained by the method is 4.0g, and the yield is 75%.
Example 4:
embodiment 3 of the present invention provides a preparation method of an intermediate III, which specifically adopts the following method:
compound II (4.0g, 23.9mmol) and tetrahydrofuran (45mL) were added to the reaction flask and stirred until compound II was completely dissolved. Ethylenediamine (0.7g, 12.0mmol) and EDCI (5.1g, 26.3mmol) were dissolved in THF (15mL) and slowly added dropwise to compound II at 0 ℃. After the addition, the temperature of the reaction system was raised to 25 ℃, the reaction was stirred for 10 hours, and the disappearance of compound II was detected by TLC. The tetrahydrofuran was removed under reduced pressure, water (40mL) was added to the reaction mixture to precipitate a solid, stirring was continued for 30min, suction filtration was performed, the filter cake was washed with water and isopropanol, and vacuum drying was performed. And recrystallizing the crude product by using ethanol to obtain a pure product of the intermediate III.
The yield of the light yellow solid obtained by the method is 65 percent and is 2.8 g.
Example 5:
example 5 of the present invention provides a preparation method of compound a, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
compound III (3.0g, 8.4mmol) and chloroform (30mL) were added to a reaction flask, triethylamine (2.3mL, 16.7mmol) was added at 0 deg.C, and the mixture was stirred for 10 min. Then, a chloroform solution (6mL) of compound IV (2.5g, 16.7mmol) was added thereto, and after the addition was completed, the reaction solution was raised to 65 ℃ for reaction for 8 hours, and disappearance of the reaction compound III was detected by TLC. Water (40mL) was added to the reaction system, followed by liquid separation and extraction, and the organic layer was dried over anhydrous sodium sulfate and then chloroform was removed under reduced pressure. And recrystallizing the crude product by acetonitrile to obtain A.
The white solid obtained by the method is 4.8g, the yield is 92 percent, and the purity is 99.3 percent.
The compound a prepared in this example was identified with the following results:
ESI-MS(m/z):625.2；
1HNMR(500MHz,DMSO-d6)：δ 8.82(s,1H)7.48-7.60(m,2H), 6.69-7.10(m,4H),6.67(s,2H),6.38(s,2H),3.41-3.50(m,4H),2.41(s,6H),2.28(s, 6H); 13CNMR (126MHz, DMSO-d 6): δ 169.1,168.8,160.2(d, J ═ 253.8Hz),135.6(d, J ═ 3.8Hz),134.6,125.5,124.5(d, J ═ 7.7Hz),124.1,119.2,115.3(d, J ═ 20.2Hz),114.5(d, J ═ 7.7Hz),114.0(d, J ═ 20.2Hz),113.1(d, J ═ 3.8Hz),40.4,16.4, 14.1. The fonts of brackets and punctuation are unified, using TimesNewRoman
Example 6:
embodiment 5 of the present invention provides a preparation method of a compound a, which specifically adopts the following method:
compound III (3.5g, 9.8mmol) and chloroform (35mL) were added to a reaction flask, triethylamine (2.7mL, 19.5mmol) was added at 0 deg.C, and the mixture was stirred for 10 min. Then, a chloroform solution (8mL) of compound IV (3.0g, 19.5mmol) was added thereto, and after the addition was completed, the reaction solution was raised to 50 ℃ to react for 12 hours, and disappearance of the reaction compound III was detected by TLC. Water (40mL) was added to the reaction system, followed by liquid separation and extraction, and the organic layer was dried over anhydrous sodium sulfate and then chloroform was removed under reduced pressure. And recrystallizing the crude product by acetonitrile to obtain the compound A.
The white solid obtained by the method is 5.1g, the yield is 84 percent, and the purity is 98.2 percent.
Example 7:
embodiment 7 of the present invention provides a preparation method of a compound a, which specifically adopts the following method:
compound III (2g, 5.6mmol) and methanol (20mL) were added to a reaction flask, triethylamine (1.6mL, 11.2mmol) was added at 0 deg.C, and the mixture was stirred for 10 min. Then, a methanol solution (4mL) of Compound IV (1.7g, 11.2mmol) was added thereto, and after the addition was completed, the reaction solution was raised to 50 ℃ for reaction for 15 hours, and disappearance of Compound III was detected by TLC. Methanol was removed under reduced pressure, water (20mL) and methylene chloride (20mL) were added to the reaction system, followed by liquid separation and extraction, and the organic layer was dried over anhydrous sodium sulfate, followed by removal of methylene chloride under reduced pressure. And recrystallizing the crude product by acetonitrile to obtain the compound A.
The white solid obtained by the method is 2.5g, the yield is 72 percent, and the purity is 98.4 percent.
Example 8:
embodiment 8 of the present invention provides a method for preparing a compound a, which specifically comprises the following steps:
compound III (3.0g, 8.4mmol) and chloroform (30mL) were added to a reaction flask, triethylamine (3.5mL, 25.1mmol) was added at 0 deg.C, and the mixture was stirred for 10 min. Then, a chloroform solution (8mL) of compound IV (3.8g, 25.1mmol) was added thereto, and after the addition was completed, the reaction solution was raised to 65 ℃ for reaction for 7 hours, and disappearance of the reaction compound III was detected by TLC. Water (40mL) was added to the reaction system, followed by liquid separation and extraction, and the organic layer was dried over anhydrous sodium sulfate and then chloroform was removed under reduced pressure. And recrystallizing the crude product by acetonitrile to obtain the compound A.
The white solid obtained by the method is 4.2g, the yield is 80 percent, and the purity is 98.8 percent.
According to the relevant regulations of national drug administration, strict quality control is required to be performed in the production of medicines, and the research on the relevant safety and the quality control in the production are required for new medicine impurities found in the production regardless of the content ratio. Therefore, the invention also protects the application of the sunitinib related substance in quality control of sunitinib.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. Sunitinib-related substance, characterized in that: the substance is a compound A, and the structural formula of the compound A is shown in the specification
2. A process for the preparation of sunitinib-related substances according to claim 1, comprising the steps of:
s1, carrying out condensation reaction on a compound II (2, 4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid) and ethylenediamine to obtain an intermediate III;
s2, under the action of alkali, carrying out aldol condensation reaction on the intermediate III and the compound IV (5-fluoroindole-2-ketone) to obtain a compound A.
3. The method for preparing sunitinib-related substance according to claim 2, wherein the step S1 specifically comprises the following operations: in a first organic solvent, carrying out condensation reaction on a compound II and ethylenediamine at 0-50 ℃ until the compound II disappears; adding water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and isopropanol, and performing vacuum drying to obtain a crude product of the intermediate III; and finally, recrystallizing the crude product of the intermediate III by using ethanol to obtain a pure product of the intermediate III.
4. The method for preparing sunitinib-related substance according to claim 3, wherein the molar ratio of the compound II, the condensing agent and the ethylenediamine in step S1 is 2-5: 2-5: 1.
5. the method for preparing sunitinib-related substance according to claim 3, wherein the first organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile and N, N-dimethylformamide; the condensing agent is one or more of DCC, EDCI, HATU and HBTU.
6. The method for preparing sunitinib-related substance according to claim 2, wherein the step S2 specifically comprises the following operations: dissolving the intermediate III in a second organic solvent, adding alkali into the reaction liquid at 0 ℃, and stirring for 10 min; then adding a compound IV, adjusting the temperature of the system to 20-80 ℃ after the addition is finished, and stirring for reaction until the intermediate III disappears; adding water into the reaction solution, separating and extracting, drying an organic layer by anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a crude product of the compound A; and finally, recrystallizing the crude product of the compound A by acetonitrile to obtain a pure product of the compound A.
7. The method for preparing sunitinib-related substance according to claim 6, wherein the second organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol and N, N-dimethylformamide.
8. The method of claim 6, wherein the base is one or more of triethylamine, N' -diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
9. The process for preparing sunitinib-related substance according to claim 6, wherein the molar ratio of compound III, base and compound IV is 1: 2-5: 2 to 5.
10. Use of a sunitinib-related substance according to claim 1 for quality control of sunitinib.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| 未公开: "舒尼替尼Sunitinb杂质", 《百度文库》 * |
| 苑冬雪: "L-苹果酸舒尼替尼的合成工艺研究", 《中国优秀硕士学位论文全文数据库工程科技I辑》 * |
| 钟瑞建: "《药物分析 第2版》", 31 December 2018 * |
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