Synthetic method of medical intermediate 7-nitro-3-(trifluoromethyl) quinoline

Abstract

The invention discloses a synthetic method of a medical intermediate 7-nitro-3-(trifluoromethyl) quinoline, which comprises the following steps: by taking 1, 2, 3, 4-tetrahydroquinoline as a raw material and glacial acetic acid as a solvent, carrying out nitration reaction under the action of nitric acid to obtain 7-nitrotetrahydroquinoline (1); the preparation method comprises the following steps: by taking toluene as a solvent, preparing 7-nitroquinoline (2) from 7-nitrotetrahydroquinoline (1) under the action of 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ); reacting the 7-nitroquinoline (2) with N-iodosuccinimide (NCI) by using acetic acid as a solvent to obtain 7-nitro-3-iodoquinoline (3); and reacting the 7-nitro-3-iodoquinoline (3) with potassium trifluoroacetate to obtain the 7-nitro-3-(trifluoromethyl) quinoline.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a synthesis method of a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl) quinoline. BACKGROUND

[0002] 7-nitro-3-(trifluoromethyl) quinoline heterocyclic compounds are important pharmaceutical intermediates. Patent WO2024260316A1 reports that compounds containing the 3-(trifluoromethyl) quinoline mother nucleus are inhibitors of TRADD protein, TRADD is a protein with a molecular weight of 34KDa, and inhibiting TRADD activity can regulate and treat diseases from various angles such as anti-inflammatory and anti-apoptosis, and has an important role in the treatment and prevention of diseases related to inflammation or cell death.

[0003] Patent EP2589592A1 reports that compounds containing 7-nitro-3-(trifluoromethyl) quinoline can be used as inhibitors of spleen tyrosine kinase (Syk), spleen tyrosine kinase (Syk) is a non-receptor type intracellular tyrosine kinase, which plays an important role in the activation of B cells and Fc receptor-mediated intracellular signaling system. By inhibiting Syk, various cellular responses are expected to be inhibited, and it can be used for treating representative diseases associated with type I allergy, such as bronchial asthma, allergic rhinitis, urticaria and atopic dermatitis.

[0004] A large number of compounds with Syk inhibitory activity have been reported, and compounds containing 3-(trifluoromethyl) quinoline have shown strong biological activity in clinical trials for rheumatoid arthritis and idiopathic thrombocytopenic purpura. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a synthesis method of a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl) quinoline, which can realize efficient synthesis of the target product by optimizing the reaction path and conditions.

[0006] The present application is realized by the following method: a synthesis method of a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl) quinoline, the method comprising the following steps:

[0007] Step S1, using 1,2,3,4-tetrahydroquinoline as a raw material, using glacial acetic acid as a solvent, and carrying out nitration under the action of nitric acid to obtain 7-nitrotetrahydroquinoline;

[0008] Step S2, 7-nitrotetrahydroquinoline (1) is used as a solvent, and 2,3-dichloro-5,6-dicyanoquinone (DDQ) is used to obtain 7-nitroquinoline;

[0009] Step S3, 7-nitroquinoline (2) reacts with N-iodosuccinimide (NCI) using acetic acid as a solvent to obtain 7-nitro-3-iodoquinoline;

[0010] Step S4: 7-nitro-3-iodoquinoline (3) reacts with potassium trifluoroacetate to obtain 7-nitro-3-(trifluoromethyl)quinoline.

[0011] Furthermore, in step S1, the solvent for reacting 1,2,3,4-tetrahydroquinoline as a raw material under the action of nitric acid to obtain 7-nitrotetrahydroquinoline is acetic acid.

[0012] Furthermore, in step S2, the oxidant used for the oxidation of 7-nitrotetrahydroquinoline is 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to obtain 7-nitroquinoline, and the solvent used is toluene or dichloromethane.

[0013] Furthermore, in step S3, 7-nitroquinoline reacts with N-iodosuccinimide (NCI) to obtain 7-nitro-3-iodoquinoline, and the reagent used is acetic acid.

[0014] Furthermore, in step S4, 7-nitro-3-iodoquinoline reacts with potassium trifluoroacetate to obtain 7-nitro-3-(trifluoromethyl)quinoline, and the solvent used is N-methylpyrrolidone.

[0015] Furthermore, in step S1, the molar ratio of nitric acid to tetrahydroquinoline is 1.04:1, the reaction solvent is glacial acetic acid, and the reaction temperature is -5 to 0°C; in step S2, the molar ratio of DDQ to 7-nitrotetrahydroquinoline is 2.3:1, and the oxidation reaction temperature is 20-25°C.

[0016] Furthermore, in step S3, the molar ratio of NIS to 7-nitroquinoline is 2:1, and the reaction temperature is 70-80° C.; in step S4, the molar ratio of potassium trifluoroacetate to 7-nitro-3-iodoquinoline is 4:1, and the catalyst is cuprous iodide.

[0017] Furthermore, after step S4, the method further comprises adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, filtering with diatomaceous earth, concentrating the organic phase under reduced pressure, and then recrystallizing with methanol.

[0018] The beneficial effects of the present invention are as follows: the present invention provides a method for synthesizing 7-nitro-3-(trifluoromethyl)quinoline, the synthetic route is concise, the process selection is reasonable, the raw materials are simple and easily available, and the operation and post-processing are convenient; by optimizing the reaction path and conditions, the efficient synthesis of the target product is achieved, the method has the advantages of simple operation, low cost and high yield, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Schematic diagram of the method of the present invention. DETAILED DESCRIPTION

[0020] The present invention will be further described below with reference to the accompanying drawings.

[0021] See also Figure 1 As shown, the present invention provides: 7-nitro-3-(trifluoromethyl)quinoline, the chemical structure of which is as follows:

[0022]

[0023] The invention discloses a method for synthesizing 7-nitro-3-(trifluoromethyl)quinoline. The method comprises the following steps: using 1,2,3,4-tetrahydroquinoline as a raw material and glacial acetic acid as a solvent, and subjecting the raw material to a nitration reaction under the action of nitric acid to obtain 7-nitro-tetrahydroquinoline (1); using toluene as a solvent, reacting the 7-nitro-tetrahydroquinoline (1) with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to obtain 7-nitro-quinoline (2); using acetic acid as a solvent, reacting the 7-nitro-quinoline (2) with N-iodosuccinimide (NCI) to obtain 7-nitro-3-iodoquinoline (3); and reacting the 7-nitro-3-iodoquinoline (3) with potassium trifluoroacetate to obtain 7-nitro-3-(trifluoromethyl)quinoline.

[0024] The synthetic route is as follows

[0025]

[0026] Step 1: Synthesis of 7-nitrotetrahydroquinoline (1)

[0027] Add 3 kg of glacial acetic acid to the reaction flask, control the internal temperature at 20-30°C, add tetrahydroquinoline (0.95 kg, 7.13 mol, 1 eq) dropwise, and stir for 30 min after the addition. Control the internal temperature at 20-30°C, add a mixture of fuming nitric acid (475 g, 7.39 mol, 1.04 eq) and concentrated sulfuric acid (2000 g) dropwise, and react at -5 to 0°C for 1 h. Control the starting material content by LC to stop the reaction.

[0028] The reaction solution was poured into ice water (6 kg) for quenching, cooled to -5°C and filtered, and a small amount of water was added to the filter cake; the filter cake was purified by adding ethanol (500 g) and n-hexane (1 kg) to obtain compound 1 (415 g, y = 32.7%).

[0029] Step 2: Synthesis of 7-nitroquinoline (2)

[0030] Compound 1 (400 g, 2.24 mol, 1 eq) and toluene (15 kg) were added to a reaction flask, cooled to 10-15°C, and then maintained at 10-15°C. DDQ (1170.7 g, 5.15 mol, 2.3 eq) was added portionwise. After addition, the reaction was stirred at 20-25°C for 1 h. LC control indicated that the starting material concentration was <0.5%, and the reaction was terminated. The reaction solution was maintained at 10-30°C, and 10% NaOH was added dropwise to control the pH to 8-9. The reaction mixture was allowed to stand for stratification, and the organic phase was separated and washed with saturated sodium sulfite solution. The organic phase was separated and washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain crude compound 2 (312.7 g, y = 80%).

[0031] Step 3: Synthesis of 7-nitro-3-iodoquinoline (3)

[0032] Compound 2 (300 g, 1.72 mol, 1 eq), AcOH (3.9 kg), and NIS (774 kg, 3.44 mol, 2 eq) were added to a reaction flask under nitrogen protection. The temperature was raised to 70-80°C and stirred for 16 h. The reaction was stopped by LC control when the starting material content was less than 5%. The temperature was lowered to 20-30°C, 3 kg of water was added, and stirring was performed to precipitate a solid. The solid was filtered and purified with 2 kg of ethanol and dried to obtain compound 3 (387.6 g, y = 75%).

[0033] Step 4: Synthesis of 7-nitro-3-(trifluoromethyl)quinoline (4)

[0034] Compound 3 (350 g, 1.17 mol, 1 eq), NMP (4 kg), potassium trifluoroacetate (711.9 g, 4.68 mol, 4 eq) and cuprous iodide (891.3 g, 4.68 mol, 4 eq) were added to the reaction flask, the temperature was raised to 150 ° C. and the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to room temperature, saturated ammonium chloride solution and 8 kg of ethyl acetate were added, and the mixture was filtered through diatomaceous earth. The filtrate was separated into an organic phase, which was washed with water, and the separated organic phase was evaporated to dryness under reduced pressure and then purified with methanol (600 g) to obtain product 4 (129.2 g, y = 45.6%).

[0035] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline, characterized in that: The method comprises the following steps: Step S1: using 1,2,3,4-tetrahydroquinoline as a raw material and glacial acetic acid as a solvent, nitrating under the action of nitric acid to obtain 7-nitrotetrahydroquinoline; Step S2, 7-nitrotetrahydroquinoline (1) is treated with toluene as solvent under the action of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to obtain 7-nitroquinoline; Step S3, 7-nitroquinoline (2) reacts with N-iodosuccinimide (NCI) using acetic acid as a solvent to obtain 7-nitro-3-iodoquinoline; Step S4: 7-nitro-3-iodoquinoline (3) reacts with potassium trifluoroacetate to obtain 7-nitro-3-(trifluoromethyl)quinoline.

2. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: In the step S1, 1,2,3,4-tetrahydroquinoline is used as a raw material to react under the action of nitric acid to obtain 7-nitrotetrahydroquinoline, and the solvent is acetic acid.

3. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: In step S2, the oxidant used for the oxidation of 7-nitrotetrahydroquinoline is 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to obtain 7-nitroquinoline, and the solvent used is toluene or dichloromethane.

4. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: In step S3, 7-nitroquinoline reacts with N-iodosuccinimide (NCI) to obtain 7-nitro-3-iodoquinoline, and the reagent used is acetic acid.

5. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: In step S4, 7-nitro-3-iodoquinoline reacts with potassium trifluoroacetate to obtain 7-nitro-3-(trifluoromethyl)quinoline, and the solvent used is N-methylpyrrolidone.

6. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: In step S1, the molar ratio of nitric acid to tetrahydroquinoline is 1.04:1, the reaction solvent is glacial acetic acid, and the reaction temperature is -5 to 0°C; in step S2, the molar ratio of DDQ to 7-nitrotetrahydroquinoline is 2.3:1, and the oxidation reaction temperature is 20-25°C.

7. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: In step S3, the molar ratio of NIS to 7-nitroquinoline is 2:1, and the reaction temperature is 70-80° C.; in step S4, the molar ratio of potassium trifluoroacetate to 7-nitro-3-iodoquinoline is 4:1, and the catalyst is cuprous iodide.

8. A method for synthesizing a pharmaceutical intermediate 7-nitro-3-(trifluoromethyl)quinoline according to claim 1, characterized in that: After step S4, the reaction is quenched by adding a saturated ammonium chloride solution, extracted with ethyl acetate, filtered with celite, and the organic phase is concentrated under reduced pressure and then recrystallized with methanol.

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