Heterocyclic compound for anti-inflammatory drugs and preparation method thereof

Abstract

The invention relates to the field of drug synthesis, in particular to a heterocyclic compound for anti-inflammatory drugs and a preparation method of the heterocyclic compound. The heterocyclic compound is a 1-(2-chloropyridine-3-yl) piperidine-4-ketone compound, and the chemical formula of the compound is # imgabs0 # (I). The invention provides a preparation process of the 1-(2-chloropyridine-3-yl) piperidine-4-ketone compound, which is simple and convenient, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and more particularly to a heterocyclic compound used as an anti-inflammatory drug and a preparation method thereof. Background Art

[0002] 1-(2-chloropyridin-3-yl)piperidin-4-one compounds contain a chloropyridine group and a piperidone structure. Similar to chloropyridine intermediates (such as 2-chloro-5-chloromethylpyridine), they can serve as synthetic intermediates for novel insecticides (such as the neonicotinoid imidacloprid) or herbicides (such as diquat). Chloropyridine compounds also play a key role in the development of fifth-generation insecticides (such as chlorantraniliprole). Piperidone derivatives are often used as core backbones in drug synthesis. For example, donepezil, a drug for the treatment of Alzheimer's disease, contains a piperidone structure. This compound may contribute to the development of drugs for neurodegenerative diseases through structural modification or serve as a precursor for the synthesis of complex nitrogen-containing heterocycles (such as 2,4-piperidinedione). The active sites of the chlorine atom and pyridine ring in its structure make it suitable for coupling reactions or nucleophilic substitution reactions, enabling the preparation of functional materials or fine chemicals with unique activities.

[0003] In summary, 1-(2-chloropyridin-3-yl)piperidin-4-one compounds have shown potential application value in the fields of pesticides, medicines and fine chemicals, and have broad market prospects. Summary of the Invention

[0004] The present invention aims to develop a simple and convenient preparation process for 1-(2-chloropyridin-3-yl)piperidin-4-one compound suitable for industrial production.

[0005] In a first aspect, the present invention provides a heterocyclic compound for use as an anti-inflammatory drug, wherein the heterocyclic compound is a 1-(2-chloropyridin-3-yl)piperidin-4-one compound, and the chemical formula of the compound is: (I).

[0006] Preferably, the synthetic route of the compound is: .

[0007] In a second aspect, the present invention provides a process for preparing a heterocyclic compound for use as an anti-inflammatory drug, comprising the following steps: 8-(Pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane was added as the starting material to solvent 1, and N-bromosuccinimide was added dropwise under reflux to obtain ‌8-(6-bromopyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane compound II; Compound II was added to solvent 1, and N-chlorosuccinimide was added dropwise under reflux to react to obtain 3-(1,4-dioxaspiro[4.5]decane-8-yl)-2-chloro-6-bromopyridine compound III; Compound III was added to solvent 2, and an organic lithium reagent solution was added dropwise under a nitrogen atmosphere at low temperature, and the mixture was slowly quenched with water to obtain compound 3-(1,4-dioxaspiro[4.5]decane-8-yl)-2-chloropyridine IV; Compound IV was added to the acid solution and stirred for 30-40 min to obtain ‌1-(2-chloropyridin-3-yl)piperidin-4-one compound.

[0008] Preferably, in step 1), the solvent 1 is selected from one of acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform and carbon tetrachloride.

[0009] Preferably, in step 3), the solvent 2 is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-hexane, methyl tert-butyl ether and diethyl ether; The organic lithium reagent is selected from one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, isopropyl lithium and phenyl lithium.

[0010] Preferably, in step 4), the acid solution is selected from one or two of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid.

[0011] Preferably, in step 1), the reaction temperature is 40 to 100°C; in step 2), the reaction temperature is 40 to 100°C; in step 3), the reaction temperature is -80 to -50°C.

[0012] Preferably, the molar ratio of N-bromosuccinimide to 8-(pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane is 1:0.8-1.5.

[0013] Preferably, in step 3), the molar ratio of the organolithium reagent to compound III is 1:0.8-1.5.

[0014] In a third aspect, the present invention provides a heterocyclic compound for use in a drug for treating inflammation.

[0015] In summary, the present invention has the following beneficial effects: The raw materials and reagents used in the reaction of the heterocyclic compound prepared by the present invention are all conventional synthetic reagents, which are inexpensive and readily available. The reaction conditions in each step are mild, the post-processing operation is simple, the reaction selectivity is good, the yield is high, and the product purity is high. The overall preparation process is convenient to operate, the product cost is low, and it meets the requirements of industrial production.

[0016] 2. The raw materials acetophenone, thiophene-2-carboxaldehyde, and reaction reagents used in the preparation process of the present invention are all conventional synthetic reagents, which are cheap and easily available.

[0017] 3. The reaction conditions of each step of the preparation method of the present invention are mild, the post-processing operation is simple, the reaction yield is high, and the product purity is high.

[0018] It should be understood that the above general description and the following detailed description are merely exemplary and explanatory and are not intended to limit the scope of protection of the present invention. DETAILED DESCRIPTION

[0019] The present invention is further described in detail below with reference to the examples. It is particularly noted that if no specific conditions are specified in the following examples, the reactions were carried out according to conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can be obtained from common commercial sources.

[0020] Example Example 1 The preparation method of compound II comprises the following steps: 8-(Pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (300.0 g, 1362 mmol) was dissolved in acetonitrile (300 mL). The temperature was raised and NBS (290.90 g, 1630 mmol) was slowly added portionwise at reflux. After the addition was complete, reflux was continued for 1 hour. TLC monitoring (CH2Cl2:MeOH = 10:1) indicated complete reaction. The solvent was evaporated under reduced pressure, and 400 mL of water was added. The mixture was extracted with 200 x 3 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 378.9 g of a pale yellow solid (Compound II) in a 93% yield.

[0021] 1HNMR(300MHz,DMSO-d6)δ(ppm):8.15(d,J=4.8Hz,2H),7.93(d,J=15Hz,1H),7.79(d,J=4.8Hz,1H) ,7.52-7.71(m,5H),7.20(t,J=3.9Hz,1H).LC-MS:[M+1]=215.1;HPLC(214nm / 254nm)=95.8% / 91.6%. Example 2 The preparation method of compound III comprises the following steps: Compound II (100.0 g, 1362 mmol) was dissolved in acetonitrile (300 mL). The temperature was raised, and NCS (290.90 g, 1630 mmol) was slowly added portionwise under reflux. After the addition was complete, reflux was continued for 1 h. TLC monitoring (CH2Cl2:MeOH = 10:1) indicated complete reaction. After evaporation of the solvent under reduced pressure, 400 mL of water was added and the mixture was extracted with 200 x 3 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to yield 378.9 g of a light yellow solid (Compound II), a 93% yield. 1HNMR(300MHz,DMSO-d6)δ(ppm):8.15(d,J=4.8Hz,2H),7.93(d,J=15Hz,1H),7.79(d,J=4.8Hz,1H ),7.527.71(m,5H),7.20(t,J=3.9Hz,1H).LCMS:[M+1]=215.1;HPLC(214nm / 254nm)=95.8% / 91.6%. Example 3 The preparation method of compound IV comprises the following steps: To a 250 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere, 3-bromothiophene (44.0 g, 19.87 mmol, 10.00 equiv) and 30 mL of tetrahydrofuran were added. Subsequently, 8 mL of a 2.5 M solution of n-butyllithium in tetrahydrofuran (19.87 mmol) was slowly added dropwise at -78°C with stirring. The mixture was stirred in a liquid nitrogen bath at -78°C for approximately 30 minutes. The reaction progress was monitored by thin-layer chromatography (developing solvent ratio: ethyl acetate:petroleum ether = 1:1). Subsequently, a solution of ammonium chloride in tetrahydrofuran (4.004 g, 21.75 mmol, 11.00 equiv, dissolved in 30 mL of tetrahydrofuran) was slowly added dropwise over 15 minutes, maintaining the system at approximately -78°C with continuous stirring. 200 mL of deionized water was added, and the organic solvent was removed by concentration under reduced pressure. The mixture was extracted with 100 mL*3 of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 1.72 g of compound II (yield 85.2%) as a light yellow powder.

[0022] 1HNMR(300MHz,DMSO-d6)δ(ppm):8.22(m,8.21-8.23,2H),7.97(d,J=4.8Hz,1H),7.91(s,1H),7.79(d,J=7.2Hz,2H ),7.52-7.62(m,7H),7.35(t,J=4.8Hz,1H),7.27(br,2H).LC-MS:[M+1]=413.0.HPLC(214nm / 254nm)=96.5% / 99.1%. HPLC assay conditions: Chromatography column: Agela Venusil MP C-18 (5μm, 4.6×150mm); Mobile phase: gradient elution, 70% CH3CN (0.05% TFA), 30% H20 (0.05% TFA), 100% CH3CN (0.05% TFA).

[0023] Flow rate: 1.0 mL / min Detection wavelength: 214nm / 254nm.

[0024] The above description is merely an exemplary embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A heterocyclic compound for use as an anti-inflammatory drug, characterized in that: The heterocyclic compound is a 1-(2-chloropyridin-3-yl)piperidin-4-one compound, and the chemical formula of the compound is: （I）。 2. The heterocyclic compound for anti-inflammatory drugs according to claim 1, characterized in that The synthetic route of the compound is: 。 3. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to any one of claims 1 to 2, characterized in that: The following steps are involved: 1) 8-(pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane was added as the starting material to solvent 1, and N-bromosuccinimide was added dropwise under reflux to obtain ‌8-(6-bromopyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane compound II; 2) Compound II was added to solvent 1, and N-chlorosuccinimide was added dropwise under reflux to obtain 3-(1,4-dioxaspiro[4.5]decane-8-yl)-2-chloro-6-bromopyridine compound III; 3) Compound III was added to solvent 2, and an organolithium reagent solution was added dropwise under a nitrogen atmosphere at low temperature. The reaction was slowly quenched with water to obtain compound 3-(1,4-dioxaspiro[4.5]decane-8-yl)-2-chloropyridine IV; 4) Compound IV was added to the acid solution and stirred for 30-40 min to obtain ‌1-(2-chloropyridin-3-yl)piperidin-4-one compound.

4. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to claim 3, wherein: In step 1), the solvent 1 is selected from one of acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform and carbon tetrachloride.

5. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to claim 3, wherein: In step 3), the solvent 2 is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, n-hexane, methyl tert-butyl ether and diethyl ether; The organic lithium reagent is selected from one of n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, isopropyl lithium and phenyl lithium.

6. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to claim 3, wherein: In step 4), the acid solution is selected from one or two of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid.

7. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to claim 3, wherein: In step 1), the reaction temperature is 40 to 100°C; in step 2), the reaction temperature is 40 to 100°C; in step 3), the reaction temperature is -80 to -50°C.

8. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to claim 3, wherein: The molar ratio of the N-bromosuccinimide to 8-(pyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane is 1:0.8-1.

5.

9. The process for preparing a heterocyclic compound for use as an anti-inflammatory drug according to claim 3, wherein: In step 3), the molar ratio of the organolithium reagent to compound III is 1:0.8-1.

5.

10. Use of the heterocyclic compound according to any one of claims 1 to 2 in a drug for treating inflammation.

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