A process for the preparation of the antiarrhythmic drug butoprozole

Abstract

The application discloses a preparation method of an antiarrhythmic drug molecule butoprozole, and comprises the following steps: (1) synthesizing compound II by using pyridine, alpha-brominated p-methoxyacetophenone and methyl pentenoate; (2) performing a deesterification reaction on the compound II to obtain compound III; (3) performing a demethylation reaction on the compound III to obtain compound IV; (4) performing a nucleophilic substitution reaction on the compound IV and N (3-chloropropyl) dibutylamine under alkaline conditions to obtain compound I butoprozole. The preparation method of butoprozole provided by the application is easy to operate, has few side reactions, high yield and strong practicability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a synthetic method of butoprozine. BACKGROUND

[0002] Butoprozine is a drug molecule for treating arrhythmia, and its core skeleton structure is indolizine. The existing method for synthesizing the drug molecule needs to go through the steps of nitrene salt formation, condensation ring closure, benzoylation reaction, desulfonyl, propane and amination (US patent 4103012A). The present application utilizes a three-component reaction to obtain the acyl indolizine skeleton structure, and obtains butoprozine molecules through delipidyl reaction, demethylation and nucleophilic substitution reaction. The present application has the advantages of easy operation, less side reaction, high yield and strong practicability for the preparation method of butoprozine.

[0003] SUMMARY

[0004] The present application provides a preparation method of butoprozine, comprising: (1) reacting pyridine, alpha-bromoparaoxyethyl phenone and methyl pentenoate to obtain compound II; (2) performing delipidyl reaction on the compound II to obtain compound III; (3) performing demethylation reaction on the compound III to obtain compound IV; and (4) reacting the compound IV with N-(3-chloropropyl) dibutylamine to obtain butoprozine compound I.

[0005] The butoprozine is shown as formula (I):

[0006]

[0007] The structure of the compound II is shown as formula (II):

[0008]

[0009] The structure of the compound III is shown as formula (III):

[0010]

[0011] The structure of the compound IV is shown as formula (IV):

[0012]

[0013] Synthesis of compound II. Pyridine (0.4 mmol), a-bromo-p-methoxyacetophenone (0.4 mmol), methyl pentenoate (0.2 mmol), anhydrous copper acetate (0.6 mmol), potassium phosphate (0.8 mmol) were dissolved in 1 mL of N,N-dimethylformamide solvent and reacted at 100 °C for 12 hours. After the completion of the reaction, saturated sodium chloride solution was added and then extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether: ethyl acetate 20: 1) to obtain compound II as a yellow liquid with a yield of 75%. 1 H NMR (400 MHz, Chloroform-d) δ 9.06 (d, J = 7.0 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.85 (t, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 2.79 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H). 13 CNMR (151 MHz, CDC13) δ 187.30, 165.34, 163.24, 142.72, 139.39, 133.20, 131.50, 127.71, 126.27, 122.52, 119.69, 113.93, 113.90, 103.58, 55.62, 51.01, 20.06, 16.09. LRMS (ESI) m / z (%) 360 (80) [M+Na] + , 697 (100) [2M+Na] + .

[0014] Synthesis of compound III. Compound II (0.3 mmol), anhydrous copper acetate (0.3 mol), 1,10 phenanthroline (0.3 mmol), quinoline (0.3 mmol), NMP (0.9 mmol) were added to a sealed reaction tube and reacted at 180 °C for 15 hours. After the completion of the reaction, dilute hydrochloric acid solution was added and then extracted with ethyl acetate 2-3 times, the combined organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether: ethyl acetate 20: 1) to obtain compound III as a yellow liquid with a yield of 56%. 1H NMR (600 MHz, Chloroform-d) δ 9.47 (d, J = 7.1 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.05 (ddd, J = 8.8, 6.7, 1.1 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.74 (t, J = 6.3 Hz, 1H), 6.40 (s, 1H), 3.88 (s, 3H), 2.36 (q, J = 7.5 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 186.02, 162.26, 141.08, 134.45, 130.90, 129.73, 128.21, 123.52, 117.92, 115.47, 113.70, 112.60, 102.54, 55.54, 22.01, 15.02. LRMS (ESI) m / z (%) 302 (35) [M+Na] + , 581 (100) [2M+Na] + .

[0015] Synthesis of compound IV. Compound III (0.2 mmol) was dissolved in dichloromethane (0.3 mmol) and boron tribromide (0.9 mmol) was added dropwise at 0 °C. The temperature was slowly raised to room temperature and after completion of the reaction, the reaction was quenched with ice water and saturated sodium chloride solution was added. It was extracted with ethyl acetate 2-3 times and the organic layer was combined and dried over anhydrous sodium sulfate and separated by column chromatography (petroleum ether: ethyl acetate 5: 1) to get compound IV as a yellow solid in 95% yield. 1 H NMR (600 MHz, Methanol-d4) δ 9.36 (d, J = 7.0 Hz, 1H), 7.53 - 7.49 (m, 3H), 7.13 (ddd, J = 8.8, 6.7, 1.1 Hz, 1H), 6.90 - 6.87 (m, 2H), 6.82 (td, J = 6.9, 1.4 Hz, 1H), 6.48 (s, 1H), 2.38 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, MeOD4) δ 187.91, 162.31, 142.85, 139.86, 134.00, 132.02, 128.90, 124.97, 122.18, 119.17, 116.19, 113.80, 104.03, 22.86, 15.36. LRMS (ESI) m / z (%) 288 (36) [M+Na] + , 553 (100) [2M+Na]+ .

[0016] Synthesis of Compound I Butoprozine. Compound IV (0.1 mmol), potassium carbonate (0.1 mmol) and N,N-dimethylformamide were added to a sealed reaction tube. The reaction was stirred at room temperature for half an hour, then potassium iodide (0.02 mmol) and N-(3-chloropropyl) dibutylamine (0.15 mmol) were added and reacted at 150 °C. After the reaction was completed, saturated sodium bicarbonate was added, and after extraction with diethyl ether, the organic layers were combined and dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain Compound I Butoprozine as a yellow liquid with a yield of 65%. 1 H NMR (600 MHz, Chloroform-d) δ 9.44 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.73 (t, J = 6.3 Hz, 1H), 6.39 (s, 1H), 4.09 (t, J = 6.3 Hz, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.46 - 2.43 (m, 4H), 2.37 (t, J = 7.5 Hz, 2H), 1.95 (p, J = 6.5 Hz, 2H), 1.46 - 1.40 (m, 4H), 1.32 - 1.28 (m, 4H), 1.08 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.3 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 186.05, 161.85, 140.87, 137.94, 134.26, 130.91, 128.14, 123.35, 121.27, 117.91, 114.17, 112.50, 102.40, 66.50, 54.05, 50.51, 29.29, 27.09, 21.99, 20.85, 15.03, 14.22. LRMS (ESI) m / z (%) 435 (100) [M+H] + .

Claims

1. A process for the preparation of the antiarrhythmic drug molecule, butoprozide, characterized by, The application relates to a synthesis method of butopiprine. The method comprises the following steps: (1) synthesizing compound II by taking pyridine, alpha-brominated p-methoxyacetophenone and methyl pentenoate as raw materials; (2) performing a deesterification reaction on the compound II to obtain compound III; (3) performing a demethylation reaction on the compound III to obtain compound IV; (4) performing a nucleophilic substitution reaction on the compound IV and N-(3-chloropropyl) dibutylamine under alkaline conditions to obtain butopiprine; The butopiprine is shown as formula (I): The structure of the compound II is shown as formula (II):

2. The process for the preparation of butoprozine according to claim 1, characterized in that, The structure of the compound III is shown as formula (III):

3. The process for the preparation of butoprozine according to claim 1, characterized in that, The structure of the compound IV is shown as formula (IV):

4. The process for the preparation of butoprozine according to claim 1, characterized in that, The compound II is synthesized by taking pyridine, alpha-brominated p-methoxyacetophenone and methyl pentenoate as raw materials, and taking N,N-dimethylformamide as a solvent and the temperature being 100 DEG C.

5. The process for the preparation of butoprozine according to claim 1, characterized in that, The compound II is synthesized by taking N-methyl pyrrolidone as a solvent and the temperature being 180 DEG C. The compound III is reacted with boron tribromide by taking dichloromethane as a solvent and the temperature being 0 DEG C to obtain the compound IV. The compound IV is synthesized by taking N,N-dimethylformamide as a solvent, the temperature being 150 DEG C, and the presence of potassium carbonate and potassium iodide to obtain butopiprine.

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