A method for synthesizing a key intermediate of a lenvatinib derivative

Abstract

The application provides a synthesis method of a key intermediate 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile of a lenvatinib derivative, and has the advantages of simple synthesis steps, short reaction time, mild reaction conditions, easy purification, high yield and low cost, and has a good industrial production prospect.

Description

Technical Field

[0001] This invention belongs to the field of synthetic technology, specifically relating to a method for synthesizing a key intermediate of lenvatinib derivatives. Background Technology

[0002] Lenvatinib is an oral, multi-target tyrosine kinase receptor inhibitor suitable for the clinical treatment of solid tumors such as thyroid cancer, kidney cancer, glioma, liver cancer, and ovarian cancer. However, hypertension is one of the main side effects of lenvatinib in cancer treatment. US Patent 10550086 discloses a derivative of lenvatinib with a nitrate ester group, which produces nitric oxide (NO) in vivo, thus potentially allowing for higher concentrations of lenvatinib to reach target molecules present on cancer cells and vascular endothelial cells, while also suppressing the side effect of hypertension. In the synthesis of this lenvatinib derivative, 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile is a key intermediate. The disclosed synthetic route is as follows: starting with 2-chloro-4-aminobenzonitrile, it is obtained through substitution, addition, and cyclization.

[0003]

[0004] In addition, patent CN101029022A discloses the specific reaction conditions and synthesis results of a method for synthesizing 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile, which is the same as the above-mentioned route.

[0005] In summary, the existing synthetic routes for 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile are cumbersome, require harsh conditions, necessitate cyclization under high temperature conditions, and have low yields, which are not conducive to industrial production.

[0006] Therefore, it is of great significance to provide a synthetic method for 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile that is simple in synthetic steps, short in reaction time, mild in reaction conditions, easy to purify, high in yield and low in cost, and suitable for industrial-scale production. Summary of the Invention

[0007] To address the problems encountered in the synthesis of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile, a key intermediate for lenvatinib derivatives, this invention provides a method for synthesizing 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile.

[0008] This invention provides a method for synthesizing a key intermediate of a lenvatinib derivative, characterized by comprising the following steps:

[0009] (1) The compound shown in Formula I is ammonolyzed under the action of an amination agent to obtain the compound shown in Formula II;

[0010] (2) The compound of formula II obtained in step (1) was dehydrated under the action of a dehydrating agent to obtain the key intermediate of lenvatinib derivative of formula III.

[0011] The reaction route is as follows:

[0012]

[0013] Where R is C 1～5 Alkyl group, preferably R is methyl group.

[0014] Furthermore, the amination agent is selected from liquid ammonia, ammonia water, urea, ammonium salts and organic amines, preferably ammonia water; the dehydrating agent is selected from phosphorus oxychloride, acetic anhydride, trifluoroacetic anhydride, thionyl chloride, cyanuric chloride, phosphorus pentoxide or triphosgene, preferably thionyl chloride.

[0015] Further, step (1) above is: the compound shown in Formula I and the amination agent are reacted in an aqueous solution at 60-80°C for 1.5-2.5 h to obtain a crude product solution, preferably, the crude product solution is obtained by reacting at 70°C for 2 h.

[0016] Furthermore, step (1) above also includes the following post-processing steps: cooling the crude product solution to room temperature, filtering, washing the filter cake, and drying.

[0017] Further, the reaction conditions for step (2) above are as follows: the compound shown in formula II and the dehydrating agent are dissolved in an organic solvent and reacted at 50-70°C for 2-6 hours to obtain a reaction solution, preferably, the reaction is carried out at 60°C for 3-5 hours to obtain a reaction solution.

[0018] Furthermore, the aforementioned organic solvent is selected from acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or toluene.

[0019] Furthermore, the molar ratio of the compound shown in Formula II to the dehydrating agent is 1:(1-5), preferably 1:(2-2.5); and / or the mass-volume ratio of the compound shown in Formula II to the organic solvent is 1:(5-15), preferably 1:(6-10), and more preferably 1:8.

[0020] Furthermore, step (2) above also includes the following post-processing steps: (a) quenching the reaction solution to obtain a product solution; (b) purifying the product solution obtained in step (a). Specifically, the quenching method in step (a) is to slowly pour the reaction solution into ice water; the purification method in step (b) is to filter the product solution to obtain a filter cake, wash the filter cake, add a purification solvent to the filter cake, heat under reflux, cool to room temperature, filter, and dry the filter cake; furthermore, the purification solvent is selected from: methyl tert-butyl ether, isopropyl ether, diethyl ether, dichloromethane, n-heptane, n-hexane, preferably methyl tert-butyl ether; the reflux conditions are heating under reflux at 50–60°C for 0.5–1.5 h, preferably heating under reflux at 55°C for 1 h.

[0021] The synthetic method for preparing key intermediates of lenvatinib derivatives of the present invention has the advantages of simple synthetic steps, short reaction time, mild reaction conditions, easy purification, high yield and low cost, and is suitable for industrial scale-up production, and has good application prospects.

[0022] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0023] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0024] Figure 1 This is the 1H NMR spectrum of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide (compound II).

[0025] Figure 2 This is the 1H NMR spectrum of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile (compound of formula III). Detailed Implementation

[0026] Example 1: Synthesis of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide (Compound II)

[0027] Methyl 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1 kg, 4.29 mol), ammonia (10 L), and water (10 L) were added to a reaction flask and heated to 70 °C for 2 h. The mixture was then cooled to room temperature, filtered, and the filter cake was washed with water (10 L) and tetrahydrofuran (10 L), respectively, and dried to obtain 0.87 kg of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide, with a yield of 93% and a purity of 98.51%.

[0028] Experimental results: such as Figure 1 As shown, 1 H-NMR (400MHz, DMSO-d6): δ11.64(s,1H),8.52(s,1H),7.85(d,1H),7.66(s,1H),7.56(s,1H),7.01(s,1H),5.98(d,1H),3.92(s,3H).

[0029] Example 2: Synthesis of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile (Compound III)

[0030] The compound 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide (2 kg, 9.16 mol), phosphorus oxychloride (3.51 kg, 22.90 mol), and acetonitrile (16 L) prepared in Example 1 were added to a reaction flask, and the mixture was heated to 60 °C and stirred for 3 h. The reaction solution was slowly poured into 20 L of ice water, filtered, and the filter cake was washed with water (10 L) and dried under vacuum. Methyl tert-butyl ether (14 L) was added to the filter cake, and the mixture was heated to reflux (approximately 55 °C) and stirred for 1 h. The mixture was then cooled to room temperature, filtered, and the filter cake was collected and dried to obtain 1.58 kg of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile. The yield of this step was 86%, and the overall yield of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile was 80.0%. The purity was 99.21%.

[0031] Experimental results: such as Figure 2 As shown, 1 H-NMR (400MHz, DMSO-d6): δ11.85(s,1H),8.32(s,1H),7.91(d,1H),7.07(s,1H),6.04(d,1H),3.98(s,3H).

[0032] LCMS:m / z 201.2(M + H + ).

[0033] Example 3: Synthesis of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile (Compound III)

[0034] The compound 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide (1 kg, 4.58 mol), thionyl chloride (1.09 kg, 9.16 mol), and N,N-dimethylformamide (8 L) prepared in Example 1 were added to a reaction flask, and the mixture was heated to 60 °C and stirred for 5 h. The reaction solution was slowly poured into 10 L of ice water, filtered, and the filter cake was washed with water (5 L) and dried under vacuum. Methyl tert-butyl ether (7 L) was added to the filter cake, and the mixture was heated to reflux (approximately 55 °C) and stirred for 1 h. The mixture was then cooled to room temperature, filtered, and the filter cake was collected and dried to obtain 0.82 kg of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile. The yield of this step was 89%, and the overall yield of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile was 82.8%. The purity was 99.54%.

[0035] Experimental results: such as Figure 2 As shown, 1 H-NMR (400MHz, DMSO-d6): δ11.85(s,1H),8.32(s,1H),7.91(d,1H),7.07(s,1H),6.04(d,1H),3.98(s,3H).

[0036] LCMS:m / z 201.2(M + H + ).

[0037] Example 4: Synthesis of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile (Compound III)

[0038] The compound 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide (5 kg, 22.91 mol), acetic anhydride (4.68 kg, 45.83 mol), and tetrahydrofuran (40 L) prepared in Example 1 were added to a reaction flask, and the mixture was heated to 60 °C and stirred for 5 h. The reaction solution was slowly poured into 50 L of ice water, filtered, and the filter cake was washed with water (25 L) and dried under vacuum. Methyl tert-butyl ether (35 L) was added to the filter cake, and the mixture was heated to reflux (around 55 °C) and stirred for 1 h. The mixture was then cooled to room temperature, filtered, and the filter cake was collected and dried to obtain 3.81 kg of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile. The yield of this step was 83%, and the overall yield of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile was 77.2%, with a purity of 99.10%.

[0039] Experimental results: such as Figure 2 As shown, 1H-NMR (400MHz, DMSO-d6): δ11.85(s,1H),8.32(s,1H),7.91(d,1H),7.07(s,1H),6.04(d,1H),3.98(s,3H).

[0040] LCMS:m / z 201.2(M + H + ).

[0041] In summary, this invention provides a method for synthesizing 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxynitrile, a key intermediate of lenvatinib derivatives. The synthesis steps are simple, the reaction time is short, the reaction conditions are mild, it is easy to purify, the overall yield is as high as 77.2% or more, and the cost is low, showing good prospects for industrial production.

Claims

1. A method for synthesizing a key intermediate of a lenvatinib derivative, characterized in that, The steps are as follows: (1) The compound shown in Formula I was subjected to ammonolysis at 60-80℃ for 1.5-2.5h under the action of ammonia water to obtain a crude product solution. The solution was cooled to room temperature, filtered, the filter cake was washed and dried to obtain the compound shown in Formula II. (2) Dissolve the compound of formula II obtained in step (1) and thionyl chloride in an organic solvent and react at 50-70°C for 2-6 hours to obtain a reaction solution. Quench the reaction solution to obtain a product solution. Purify the product solution to obtain the key intermediate of lenvatinib derivative of formula III. The reaction route is as follows: Where R is C 1～5 alkyl.

2. The synthesis method according to claim 1, characterized in that, R stands for methyl.

3. The synthesis method as described in claim 1, characterized in that, The reaction conditions for step (1) are: react at 70°C for 2 hours to obtain a crude product solution.

4. The synthesis method according to claim 1, characterized in that, The reaction conditions for step (2) are: react at 60°C for 3 to 5 hours to obtain the reaction solution.

5. The synthesis method according to claim 1, characterized in that, The organic solvent used in step (2) is selected from acetonitrile, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or toluene.

6. The synthesis method according to claim 1, characterized in that, In step (2), the molar ratio of the compound of formula II to thionyl chloride is 1:(1-5); and / or, the mass-volume ratio of the compound of formula II to the organic solvent is 1:(5-15).

7. The synthesis method according to claim 6, characterized in that, The molar ratio of the compound shown in Formula II to thionyl chloride is 1:(2 to 2.5), and / or the mass-volume ratio of the compound shown in Formula II to the organic solvent is 1:(6 to 10).

8. The synthesis method according to claim 7, characterized in that, The mass-to-volume ratio of the compound shown in Formula II to the organic solvent is 1:

8.

9. The synthesis method according to claim 1, characterized in that, The method for quenching the reaction in step (2) is to slowly pour the reaction solution into ice water.

10. The synthesis method according to claim 1, characterized in that, The purification process described in step (2) involves filtering the product solution to obtain a filter cake, washing the filter cake, adding a purification solvent to the filter cake, heating under reflux, cooling to room temperature, filtering, and drying the filter cake. The purification solvent is selected from: methyl tert-butyl ether, isopropyl ether, diethyl ether, dichloromethane, n-heptane, and n-hexane. The reflux conditions are heating under reflux at 50–60°C for 0.5–1.5 h.

11. The synthesis method according to claim 10, characterized in that, The purification solvent is methyl tert-butyl ether, and the reflux conditions are reflux at 55°C for 1 hour.

Images