CN111233841A - A kind of sunitinib related substance and preparation method and use thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a sunitinib related substance and a preparation method and application thereof. The related substance is compound A, and its preparation method includes the following steps: (1) compound II (chemical name: 2,4-dimethyl-5-aldehyde group-1H-pyrrole-3-carboxylic acid) and ethylenediamine Condensation reaction occurs to obtain intermediate III; (2) under the action of alkali, intermediate III and compound IV (chemical name: 5-fluoroindole-2-ketone) have an aldol condensation reaction to obtain sunitinib. Substance A. The compound A disclosed in the present invention can be used as a standard substance to conduct quality control research in the preparation process of sunitinib. The preparation method provided by the invention has the advantages of short reaction route, mild conditions, high yield and purity, and provides a reliable material basis for further safety assessment of compound A and subsequent quality control research in the preparation process of sunitinib.

Description

A kind of sunitinib related substance and preparation method and use thereof

technical field

The invention belongs to the technical field of medicine, and in particular relates to a sunitinib related substance and a preparation method and application thereof.

Background technique

Sunitinib (trade name Sutent) is a small molecule drug developed by Pfizer in the United States that can inhibit multiple receptor tyrosine kinases. Its molecular formula is C ₂₂ H ₂₇ FN ₄ O ₂ , and its chemical name is is N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene)methyl base]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the structural formula is shown in I. Based on the results of a large number of clinical trials, the drug has been recommended by medical guidelines in many countries and regions as a first-line treatment for patients with advanced renal cell carcinoma. The indications of the drug in mainland China include adult patients with gastrointestinal stromal tumor, inoperable advanced renal cell carcinoma and unresectable metastatic well-differentiated advanced pancreatic neuroendocrine tumor who have failed or cannot tolerate imatinib treatment. .

The type and content of related substances in drugs will directly affect their quality and safety. Therefore, it is of great significance to study related substances of listed drugs. The structures of sunitinib-related substances reported so far are shown in SNT-a-SNT-i:

After researching the synthesis of sunitinib, the inventor discovered a new related substance compound A, which has not been reported yet. Therefore, confirming the chemical structure and preparation method of compound A is of great significance for the subsequent safety assessment and quality control research during the preparation of sunitinib.

SUMMARY OF THE INVENTION

Aiming at the deficiencies in the prior art, the present invention provides a sunitinib related substance and a preparation method and application thereof.

For solving the above problems, the technical scheme of the present invention is as follows:

The present invention protects a sunitinib related substance, the substance is compound A, and the structural formula of the compound A is:

The present invention also protects a preparation method of the above-mentioned sunitinib related substances, comprising the following steps:

S1. Compound II (2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid) undergoes condensation reaction with ethylenediamine to obtain intermediate III;

S2. Under the action of alkali, intermediate III and compound IV (5-fluoroindol-2-one) undergo an aldol condensation reaction to obtain compound A.

Preferably, the step S1 specifically includes the following operations: in the first organic solvent, a condensation reaction occurs between compound II and ethylenediamine at 0 to 50°C, and the reaction is performed until compound II disappears; then water is added to the reaction solution to precipitate a solid , suction filtration, the filter cake is washed with water and isopropanol, and dried in vacuo to obtain the crude product of intermediate III; finally, the crude product of intermediate III is recrystallized with ethanol to obtain the pure product of intermediate III.

Preferably, the molar ratio of compound II, condensing agent and ethylenediamine in the step S1 is 2-5:2-5:1.

More preferably, the molar ratio of compound II, condensing agent and ethylenediamine is 2-3:2-3:1.

Preferably, 8-30 mL of the first organic solvent is added to each gram of compound II.

More preferably, 8-10 mL of the first organic solvent is added to each gram of 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 used condensing agent is one or more of DCC, EDCI, HATU and HBTU.

More preferably, the condensing agent used is EDCI.

Preferably, the temperature of the condensation reaction is 20-30°C.

Preferably, the step S2 specifically includes the following operations: dissolving the intermediate III in the second organic solvent, adding a base to the reaction solution at 0°C, and stirring for 10 min; then adding compound IV, and after the addition, the system The temperature was adjusted to 20-80°C, and the reaction was stirred until the intermediate III disappeared; then water was added to the reaction solution, followed by liquid separation extraction, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of compound A; finally , the crude compound A was recrystallized from acetonitrile to obtain the pure compound A.

Preferably, 10-50 mL of the second organic solvent is added per gram of intermediate III.

More preferably, 10-12 mL of the second organic solvent is added per gram of 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,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 1:2-5:2-5.

More preferably, the molar ratio of compound III, base and compound IV is 1:2-2.5:2-2.5.

Preferably, the temperature of the aldol condensation reaction is 60-65°C.

The present invention also protects the application of the above-mentioned sunitinib related substances in the quality control of sunitinib.

The beneficial effects of the present invention are: first, the present invention discovers for the first time that the existing sunitinib will produce a new related substance compound A during the synthesis process, which provides a basis for further improving the quality control of the existing sunitinib preparation process Secondly, the present invention provides a related substance compound A, and the structure of the substance is confirmed, and the related substance compound A can be used as a standard substance, which is expected to further improve and improve the quality standard of sunitinib; finally, the present invention also Provided is a preparation method of related substance compound A, which has the advantages of short route, mild conditions, high yield and high purity, and is used for subsequent safety evaluation of related substance A and quality control research in the preparation process of sunitinib provides an important material basis.

Detailed ways

The principles and features of the present invention are described below, and the examples are only used to explain the present invention, but not to limit the scope of the present invention.

The sunitinib related substance of the present invention is compound A, and its structural formula is:

The present invention provides the preparation method of the above-mentioned sunitinib related substance compound A, comprising the following steps:

S1. In the first organic solvent, compound II (chemical name: 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid) is condensed with ethylenediamine at 0～50°C The reaction was continued until compound II disappeared. An appropriate amount of water was added to the reaction solution, and the solid was precipitated, filtered with suction, and the filter cake was washed with water and isopropanol, and dried in vacuo. The crude product is recrystallized from ethanol to obtain the pure product of intermediate III;

S2. Dissolve the intermediate III in the second organic solvent, add a suitable base to the reaction solution at °C, and stir for 10 min. Subsequently, compound IV was added, and after the addition was completed, the temperature of the system was adjusted to 20-80° C., and the reaction was stirred until the intermediate III disappeared. Water was added to the reaction solution, followed by liquid separation extraction. After drying the organic layer over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The crude product was recrystallized from acetonitrile to obtain compound A.

In some preferred embodiments, the molar ratio of compound II, condensing agent and ethylenediamine is 2-5:2-5:1, more preferably, the molar ratio of compound II, condensing agent and ethylenediamine is 2-3 : 2 to 3: 1. Within this dosage ratio, the condensation reaction can be ensured to proceed more fully, the generation of by-products can be reduced, and the waste of raw materials can be avoided.

In some preferred embodiments, 8-30 mL of the first organic solvent is added per gram of compound II, more preferably, 8-10 mL of the first organic solvent is added to each gram of compound II, within this dosage ratio, the compound II can be completely dissolved In the first organic solvent, the compound II, the condensing agent and the ethylenediamine are fully contacted, and the waste of the solvent is avoided.

In some preferred embodiments, 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 N-dimethylformamide.

In some preferred embodiments, the condensing agent used in step S1 is one or more of DCC, EDCI, HATU and HBTU, more preferably, the condensing agent is EDCI.

In some preferred embodiments, the temperature of the condensation reaction in step S1 is 0-50°C, and more preferably, the reaction temperature is 20-30°C.

In some preferred embodiments, 10-50 mL of the second organic solvent is added per gram of intermediate III, more preferably, 10-12 mL of the second organic solvent is added per gram of intermediate III to ensure that compound III is fully dissolved and avoid solvent waste.

In some preferred embodiments, the second organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol and N,N-dimethylformamide, more preferably, the second organic solvent for chloroform.

In some preferred embodiments, the base used is one or more of triethylamine, N,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 compound III, base and compound IV is 1:2-2.5:2 ~2.5.

In some preferred embodiments, the aldol condensation reaction temperature in step S2 is 20-80°C, and more preferably, the reaction temperature is 60-65°C.

The progress of the above reaction can be monitored by conventional monitoring methods in the art (eg TLC, HPLC or NMR), and generally the end point of the reaction is the disappearance of compound II and intermediate III.

In order to make the objectives, technical solutions and advantages of the present invention clearer, the following specific embodiments will 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 only used to explain the present invention, but not to limit the present invention.

The liquid phase conditions in the following examples are: Agilent1260 high performance liquid chromatograph, G1322A degasser, G1312 binary high pressure pump, G1329A autosampler, G1316A column oven, G4212B diode array detector. The chromatographic column is XbridgeC18 (250mm×4.6mm, 5μm), deionized water is used as mobile phase A, and acetonitrile containing 0.1% trifluoroacetic acid is used as mobile phase B, and gradient elution is performed according to the following table:

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 1.0 ml/min, the column temperature was 35°C, and the detection wavelength was 254 nm.

Example 1:

Embodiment 1 of the present invention provides a kind of preparation method of intermediate III, and its synthetic route is as follows:

Specifically prepared by the following method:

Compound II (5.0 g, 29.9 mmol) and N,N-dimethylformamide (40 mL) were added to the reaction flask, and stirred until compound II was completely dissolved. Ethylenediamine (0.9 g, 15.0 mmol) and EDCI (6.3 g, 32.9 mmol) were dissolved in N,N-dimethylformamide (10 mL) and slowly added dropwise to compound II at 0°C. After the addition was completed, the temperature of the reaction system was raised to 25° C., and the reaction was stirred for 6 hours, and the disappearance of compound II was detected by TLC. Water (50 mL) was added to the reaction solution, and after the solid was precipitated, stirring was continued for 20 min, suction filtration, and the filter cake was washed with water and isopropanol, and dried in vacuo. The crude product was recrystallized from ethanol to give pure intermediate III.

This method was used to prepare 4.8 g of light yellow solid with a yield of 90%.

The intermediate III prepared in the present embodiment is identified, and the following results are obtained:

ESI-MS (m/z): 359.2;

¹ HNMR (500MHz, DMSO-d ₆ ): 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); 13C NMR (126 MHz, DMSO-d6): δ 174.0, 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 kind of preparation method of intermediate III, specifically adopts the following method to prepare:

Compound II (4.5 g, 26.9 mmol) and N,N-dimethylformamide (36 mL) were added to the reaction flask and stirred until compound II was completely dissolved. Ethylenediamine (0.8 g, 15.0 mmol) and DCC (6.1 g, 29.6 mmol) were dissolved in N,N-dimethylformamide (9 mL) and slowly added dropwise to compound II at 0°C. After the addition was completed, the temperature of the reaction system was raised to 2° C., and the reaction was stirred for 10 hours, and the disappearance of compound II was detected by TLC. Water (45 mL) was added to the reaction solution, and after a solid was precipitated, stirring was continued for 20 min, suction filtration, and the filter cake was washed with water and isopropanol, and dried in vacuo. The crude product was recrystallized from ethanol to obtain pure intermediate III.

The light yellow solid obtained by this method was 3.9 g, and the yield was 81%.

Example 3:

Embodiment 3 of the present invention provides a kind of preparation method of intermediate III, specifically adopts the following method to prepare:

Compound II (5.0 g, 29.9 mmol) and N,N-dimethylformamide (40 mL) were added to the reaction flask, and stirred until compound II was completely dissolved. Ethylenediamine (0.9 g, 15.0 mmol) and HBTU (12.5 g, 32.9 mmol) were dissolved in N,N-dimethylformamide (10 mL) and slowly added dropwise to compound II at 0°C. After the addition was completed, the temperature of the reaction system was raised to 25° C., and the reaction was stirred for 3 hours, and the disappearance of compound II was detected by TLC. Water (50 mL) was added to the reaction solution, and after the solid was precipitated, stirring was continued for 20 min, suction filtration, and the filter cake was washed with water and isopropanol, and dried in vacuo. The crude product was recrystallized from ethanol to give pure intermediate III.

The light yellow solid obtained by this method is 4.0 g, and the yield is 75%.

Example 4:

Embodiment 3 of the present invention provides a kind of preparation method of intermediate III, specifically adopts the following method to prepare:

Compound II (4.0 g, 23.9 mmol) and tetrahydrofuran (45 mL) were added to the reaction flask and stirred until compound II was completely dissolved. Ethylenediamine (0.7 g, 12.0 mmol) and EDCI (5.1 g, 26.3 mmol) were dissolved in THF (15 mL) and slowly added dropwise to compound II at 0°C. After the addition was completed, the temperature of the reaction system was raised to 25° C., and 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 (40 mL) was added to the reaction solution, a solid was precipitated, stirring was continued for 30 min, suction filtration, and the filter cake was washed with water and isopropanol, and dried in vacuo. The crude product was recrystallized from ethanol to give pure intermediate III.

The light yellow solid obtained by this method was 2.8 g, and the yield was 65%.

Example 5:

Embodiment 5 of the present invention provides a kind of preparation method of compound A, and its synthetic route is as follows:

Specifically prepared by the following method:

Compound III (3.0 g, 8.4 mmol) and chloroform (30 mL) were added to the reaction flask, triethylamine (2.3 mL, 16.7 mmol) was added at 0° C., and the mixture was stirred for 10 min. Subsequently, a chloroform solution (6 mL) of compound IV (2.5 g, 16.7 mmol) was added. After the addition, the reaction solution was raised to 65° C. for 8 hours, and the disappearance of reaction compound III was detected by TLC. Water (40 mL) was added to the reaction system, followed by liquid separation extraction. After drying the organic layer over anhydrous sodium sulfate, chloroform was removed under reduced pressure. The crude product was recrystallized from acetonitrile to give A.

The white solid obtained by this method is 4.8 g, the yield is 92%, and the purity is 99.3%.

The compound A prepared in this example was identified, and the following results were obtained:

ESI-MS(m/z): 625.2;

¹ HNMR (500MHz, DMSO-d ₆ ): δ8.82(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-d6): δ169.1, 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 = 20.2 Hz), 113.1 (d, J = 3.8 Hz), 40.4, 16.4, 14.1. The font of brackets and punctuation should be unified, use TimesNewRoman

Example 6:

Embodiment 5 of the present invention provides a kind of preparation method of compound A, specifically adopts the following method to prepare:

Compound III (3.5 g, 9.8 mmol) and chloroform (35 mL) were added to the reaction flask, triethylamine (2.7 mL, 19.5 mmol) was added at 0° C., and the mixture was stirred for 10 min. Subsequently, a chloroform solution (8 mL) of compound IV (3.0 g, 19.5 mmol) was added. After the addition, the reaction solution was raised to 50° C. for 12 hours. TLC detected the disappearance of reaction compound III. Water (40 mL) was added to the reaction system, followed by liquid separation extraction. After drying the organic layer over anhydrous sodium sulfate, chloroform was removed under reduced pressure. The crude product was recrystallized from acetonitrile to obtain compound A.

The white solid obtained by this method is 5.1 g, the yield is 84%, and the purity is 98.2%.

Example 7:

Embodiment 7 of the present invention provides a kind of preparation method of compound A, specifically adopts the following method to prepare:

Compound III (2 g, 5.6 mmol) and methanol (20 mL) were added to the reaction flask, triethylamine (1.6 mL, 11.2 mmol) was added at 0° C., and the mixture was stirred for 10 min. Subsequently, a methanol solution (4 mL) of compound IV (1.7 g, 11.2 mmol) was added. After the addition, the reaction solution was raised to 50° C. for 15 hours, and the disappearance of reaction compound III was detected by TLC. Methanol was removed under reduced pressure, and water (20 mL) and dichloromethane (20 mL) were added to the reaction system, followed by liquid separation extraction. After drying the organic layer over anhydrous sodium sulfate, dichloromethane was removed under reduced pressure. The crude product was recrystallized from acetonitrile to obtain compound A.

The white solid obtained by this method is 2.5 g, the yield is 72%, and the purity is 98.4%.

Example 8:

Embodiment 8 of the present invention provides a kind of preparation method of compound A, specifically adopts the following method to prepare:

Compound III (3.0 g, 8.4 mmol) and chloroform (30 mL) were added to the reaction flask, triethylamine (3.5 mL, 25.1 mmol) was added at 0° C., and the mixture was stirred for 10 min. Subsequently, a chloroform solution (8 mL) of compound IV (3.8 g, 25.1 mmol) was added. After the addition, the reaction solution was raised to 65° C. for 7 hours, and TLC detected the disappearance of reaction compound III. Water (40 mL) was added to the reaction system, followed by liquid separation extraction. After drying the organic layer over anhydrous sodium sulfate, chloroform was removed under reduced pressure. The crude product was recrystallized from acetonitrile to obtain compound A.

The white solid obtained by this method is 4.2 g, the yield is 80%, and the purity is 98.8%.

According to the relevant regulations of the national drug administration, the production of drugs needs to implement strict quality control. For new drug impurities found in production, regardless of the proportion of the content, it is necessary to carry out relevant safety research and quality control during production. control. Therefore, the present invention also protects the application of the above-mentioned sunitinib related substances in the quality control of sunitinib.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

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.