Process for the preparation of 5H-benzo[c][1,6]naphthyridin-6-ones derivatives

Abstract

The application discloses a preparation method of 5H-benzo[c][1,6]naphthyridin-6-one derivatives, and belongs to the field of organic synthesis. Under the protection of inert gas, compound 1 or a salt thereof, compound 2, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), a base and a solvent are added into a reaction container, after the reaction is completed, post-treatment is carried out, and compound 3 is obtained, and the yield reaches 73 %.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives. Background Technology

[0002] 5H-benzo[c][1,6]naphthidine-6-one derivatives can serve as intermediates for protein kinase regulators. For example, Chinese patent CN 102036561A discloses that PIM protein kinase is involved in various biological processes. PIM-1 can participate in multiple signal transduction pathways highly related to tumorigenesis and also plays an important role in the proliferation of the hematopoietic system, and can be used to treat certain types of cancer. Methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthidine-8-carboxylic acid is an intermediate for synthesizing the aforementioned protein kinase regulator.

[0003] In the existing technology, the article "Novel CK2-Specific Pt(II)Compound Reverses Cisplatin-Induced Resistance by Inhibiting Cancer Cell Stemness and Suppressing DNA Damage Repair in Non-small Cell Lung Cancer Treatments" (Journal of Medicinal Chemistry, 2021, vol. 64, 7, 4163-4178) reports a method for preparing methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyl-8-carboxylate. 2-amino-4-methoxycarbonylphenylborate and ethyl 3-bromopyridine-4-carboxylate are reacted at 120°C for 12 h in a system of alkali (NaOAc or Cs2CO3), catalyst PdCl2 (dppf), and solvent (DMF or dioxane), but the reaction yield is only 56%.

[0004] Chinese patent CN 105492444A also discloses a method for preparing methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthidine-8-carboxylic acid, using 2-amino-4-methoxycarbonylphenylboronic acid as the substrate and reacting it with methyl 4-chloronicotinic acid. The catalyst used is a complex of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride and dichloromethane, the base is sodium acetate, the solvent is N,N-dimethylformamide, the reaction is purged with nitrogen, and heated in a microwave reactor at 150°C for 10 min. The reaction yield is 55%, which is relatively low. Summary of the Invention

[0005] The present invention was made to solve the above-mentioned problems, and the purpose is to provide a method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives in high yield.

[0006] A method for preparing a 5H-benzo[c][1,6]naphthidine-6-one derivative, the reaction formula of which is shown below:

[0007]

[0008] In the above formula, X is selected from halogens (F, Cl, Br, I), R1 and R2 are independently selected from C1-C5 alkyl groups, and R3 is a borate group or a borate ester group.

[0009] Includes the following steps:

[0010] Under an inert gas atmosphere, compound 1 or its salt, compound 2, palladium catalyst, base, and solvent were added to a reaction vessel. After the reaction was complete, post-processing was performed to obtain compound 3.

[0011] The palladium catalyst is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0012] In one embodiment of the present invention, the borate group is The borate ester group is

[0013] In one embodiment of the present invention, the molar ratio of compound 2 to compound 1 or its salt is (0.9-1.5):1.

[0014] In one embodiment of the present invention, the molar ratio of the palladium catalyst to the compound 1 or its salt is (0.01-0.1):1.

[0015] In one embodiment of the present invention, the solvent is a mixture of dioxane and water.

[0016] In one embodiment of the present invention, the volume ratio of dioxane to water in the solvent is (4-5):1.

[0017] In one embodiment of the present invention, the concentration of compound 1 or its salt relative to the solvent is 0.05-0.5 mmol / mL.

[0018] In one embodiment of the present invention, the alkali is potassium phosphate or sodium phosphate.

[0019] In one embodiment of the present invention, the molar ratio of the alkali to the compound 1 or its salt is (2-4):1.

[0020] In one embodiment of the present invention, the inert gas is nitrogen or argon.

[0021] In one embodiment of the present invention, the reaction temperature is 90-110°C, preferably 95-105°C.

[0022] In one embodiment of the present invention, the reaction time is 3-16 hours; preferably 3-12 hours; and more preferably 3-6 hours.

[0023] In one embodiment of the present invention, the salt of compound 1 may be a hydrochloride salt.

[0024] The role and effect of invention

[0025] According to the preparation method of 5H-benzo[c][1,6]naphthidine-6-one derivatives involved in this application, since the palladium catalyst used in the reaction is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), this application can obtain a higher reaction yield at a milder reaction temperature and a shorter reaction time. Detailed Implementation

[0026] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments.

[0027] In the following examples, unless otherwise stated, all reactants are commercially available products.

[0028] In the following examples, XPhos Pd G2 is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), CAS No.: 1310584-14-5; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, CAS No.: 72287-26-4; Pd(PPh3)4 is tetra(triphenylphosphine)palladium, CAS No.: 14221-01-3.

[0029] <Example 1>

[0030] Preparation of compound 3a

[0031] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0032]

[0033] Includes the following steps:

[0034] 150 g of compound 1a (0.65 mol, 1.0 eq), 168 g of methyl 3-bromopyridine-4-carboxylic acid (0.78 mol, 1.2 eq), 15.3 g of XPhos Pd G2 (0.02 mol, 0.03 eq), and 413.9 g of K3PO4 (1.95 mol, 3 eq) were added to dioxane (3 L) and deionized water (600 mL). The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for 3 hours. After the reaction mixture was allowed to stand until it cooled to room temperature, it was filtered, and the solid was collected, washed with ice water and petroleum ether, and dried in a forced-air drying oven to obtain 120 g of grayish-brown solid product 3a, with a yield of 72.8%.

[0035] <Example 2>

[0036] Screening of palladium catalysts

[0037] In this embodiment, the palladium catalyst was screened using the following method, and the reaction formula is as follows:

[0038]

[0039] Includes the following steps:

[0040] 200 mg of compound 1a (0.86 mmol, 1.0 eq), 222.5 mg of methyl 3-bromopyridine-4-carboxylic acid (1.03 mmol, 1.2 eq), 547.6 mg of potassium phosphate (2.58 mmol, 3 eq), palladium catalyst (0.05 eq), dioxane (10 mL), and water (2 mL) were added to a reaction vessel. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for 3 h. After standing until the reaction system cooled to room temperature, it was filtered, rinsed with ice water and petroleum ether, and dried in a forced-air drying oven to obtain product 3a.

[0041] The preparation results of different palladium catalysts are shown in Table 1.

[0042] Table 1. Preparation results of different palladium catalysts

[0043] 1 XPhos Pd G2 73.5％ 2 <![CDATA[Pd(dppf)Cl2]]> 31.3％ 3 <![CDATA[Pd(PPh3)4]]> 2.1％

[0044] As shown in the table above, the product yield is high at 73.5% when the palladium catalyst is XPhos Pd G2, while the effect is poor when other palladium catalysts are used, especially when the palladium catalyst is Pd(PPh3)4, the product yield is only 2.1%.

[0045] <Example 3>

[0046] Screening of reaction solvents

[0047] In this embodiment, the reaction solvent was screened using the following method, and the reaction formula is as follows:

[0048]

[0049] Includes the following steps:

[0050] 200 mg of compound 1a (0.86 mmol, 1.0 eq), 225.1 mg of methyl 3-bromopyridine-4-carboxylic acid (1.03 mmol, 1.2 eq), 547.6 mg of potassium phosphate (2.58 mmol, 3 eq), 31.5 mg of XPhos Pd G2 (0.04 mmol, 0.05 eq), and solvent were added to a reaction vessel. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for a period of time. After the reaction system was allowed to cool to room temperature, it was filtered, washed with ice water and petroleum ether, and dried in a forced-air drying oven to obtain product 3a.

[0051] The preparation results under different solvent environments are shown in Table 2.

[0052] Table 2. Preparation results of different reaction solvents

[0053] 1 Dioxane (10 mL) and water (2 mL) 3h 73.5％ 2 Dioxane (10 mL) and water (2 mL) 12h 84.5％ 3 Dioxane (10mL) 12h 51.3％ 4 Water (10mL) 12h NR 5 DMF (10 mL) 3h 39.6％

[0054] As shown in the table above, the reaction effect is best when the reaction solvent is dioxane and water, and the reaction time is 3 hours, with a yield of 73.5%; when the reaction solvent is dioxane, the reaction effect deteriorates when the reaction time is 12 hours, with a yield of 51.3%.

[0055] <Example 4>

[0056] Screening of bases

[0057] In this embodiment, the following method was used to screen for bases, and the reaction formula is as follows:

[0058]

[0059] Includes the following steps:

[0060] 200 mg of compound 1a (0.86 mmol, 1.0 eq), 222.5 mg of methyl 3-bromopyridine-4-carboxylic acid (1.03 mmol, 1.2 eq), a base (3 eq), 31.5 mg of XPhos Pd G2 (0.04 mmol, 0.05 eq), dioxane (10 mL), and water (2 mL) were added to a reaction vessel. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for 3 h. After the reaction system was allowed to cool to room temperature, it was rinsed with ice water and petroleum ether, and then dried in a forced-air drying oven to obtain product 3a.

[0061] The preparation results of different bases are shown in Table 3.

[0062] Table 3. Preparation results of different bases

[0063] 1 potassium phosphate 73.5％ 2 cesium carbonate 30.3％ 3 Potassium carbonate 2.4％

[0064] As shown in the table above, the product yield is higher when potassium phosphate is used as the alkali, at 73.5%, while the effect is worse when other alkalis are used, especially when potassium carbonate is used, the product yield is only 2.4%.

[0065] <Comparative Example 1>

[0066] A method for preparing compound 3a

[0067] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0068]

[0069] Includes the following steps:

[0070] 200 mg of compound 1a (0.86 mmol, 1.0 eq), 192.9 mg of methyl 3-bromopyridine-4-carboxylic acid (0.95 mmol, 1.1 eq), 560.4 mg of cesium carbonate (1.72 mmol, 2 eq), 29.3 mg of Pd(dppf)Cl2 (0.04 mmol, 0.05 eq), and 10 mL of DMF were added to a reaction vessel. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for 3 h. After the reaction system was allowed to cool to room temperature, it was washed with ice water and petroleum ether, and then dried in a forced-air drying oven to obtain product 3a, with a yield of 20.4%.

[0071] <Comparative Example 2>

[0072] A method for preparing compound 3a

[0073] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0074]

[0075] Includes the following steps:

[0076] Compound 1b (0.86 mmol, 1.0 eq), 192.9 mg methyl 3-bromopyridine-4-carboxylic acid (0.95 mmol, 1.1 eq), 560.4 mg cesium carbonate (1.72 mmol, 2 eq), 29.3 mg Pd(dppf)Cl2 (0.04 mmol, 0.05 eq), and DMF (10 mL) were added to a reaction vessel. The mixture was purged with nitrogen three times, and the temperature was raised to 100 °C for 3 h. After the reaction system was allowed to cool to room temperature, it was washed with ice water and petroleum ether, and then dried in a forced-air drying oven to obtain product 3a, with a yield of 28.9%.

[0077] The role and effect of the embodiments

[0078] According to the preparation method of 5H-benzo[c][1,6]naphthidine-6-one derivatives involved in the above embodiments, since XPhos Pd G2 is selected as palladium catalyst, a high reaction yield can be achieved in a relatively short reaction time of 3h.

[0079] Because the above embodiments selected dioxane and water as reaction solvents, compared with other solvents, dioxane and water can achieve a yield of 73.5% in 3 hours and 84.5% in 12 hours. Therefore, the above solvents are the optimal solvents for this application.

[0080] Because potassium phosphate was chosen as the base in the above examples, the reaction yielded a high rate.

[0081] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A method for preparing a 5H-benzo[c][1,6]naphthidine-6-one derivative, characterized in that: In the above formula, X is selected from halogens, R1 and R2 are independently selected from C1-C5 alkyl groups, and R3 is a borate group. Includes the following steps: Under an inert atmosphere, compound 1 or its salt, compound 2, palladium catalyst, base, and solvent were added to a reaction vessel. After the reaction was complete, post-processing was performed to obtain compound 3. in, The palladium catalyst is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); The solvent is dioxane and water; The alkali is potassium phosphate or sodium phosphate.

2. The method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives according to claim 1, characterized in that: in, The volume ratio of dioxane to water is (4-5):

1.

3. The method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives according to claim 1, characterized in that: in, The molar ratio of the base to compound 1 or its salt is (2-4):

1.

4. The method for preparing the 5H-benzo[c][1,6]naphthidine-6-one derivative according to claim 1, characterized in that: in, The inert atmosphere is nitrogen or argon.

5. The method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives according to claim 1, characterized in that: in, The molar ratio of compound 2 to compound 1 is (0.9-1.5):

1.

6. The method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives according to claim 1, characterized in that: in, The molar ratio of the palladium catalyst to compound 1 or its salt is (0.01-0.1):

1.

7. The method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives according to claim 1, characterized in that: in, The concentration of compound 1 or its salt relative to the solvent is 0.05-0.5 mmol / mL.

8. The method for preparing 5H-benzo[c][1,6]naphthidine-6-one derivatives according to any one of claims 1-7, characterized in that: wherein, The borate group is .

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