Method for efficiently preparing pyrmenol from 2-benzylpyridine

Abstract

The invention discloses a method for efficiently preparing pirmenol from 2-benzylpyridine, comprising four reaction steps, namely, Michael addition reaction of 2-benzylpyridine and amide compounds and functional group modification of intermediates. The molecular skeleton of the pirmenol drug is directly constructed by a one-step Michael addition reaction using cheap and readily available raw materials, and the reaction conditions are relatively mild, simple and efficient. The method reduces environmental pollution and has high atom economy.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and particularly relates to a method for efficiently preparing pymenol from 2-benzylpyridine. Background Art

[0002] The chemical name of pyrmenol is 2-[3-(2,6-dimethyl-1-piperidinyl)propyl]-2-phenyl-2-pyridinemethanol. It is a new broad-spectrum antiarrhythmic drug developed in recent years. It belongs to Class Ia antiarrhythmic drugs, and also has anticholinergic and mild negative inotropic effects. It is suitable for the treatment of ventricular premature beats and ventricular tachycardia caused by various reasons, and is effective for supraventricular arrhythmias. It is more effective than other antiarrhythmic drugs for arrhythmias caused by hypokalemia, and is not affected by blood potassium concentration. Most of the methods currently developed for the preparation of pyrmenol require strict and harsh reaction conditions, and are accompanied by the use of excessive metal salts, which are relatively harmful to the environment. Therefore, it is necessary to develop a convenient and efficient preparation method to synthesize pyrmenol. Summary of the invention

[0003] In view of the problems existing in the prior art, the present invention provides a method for preparing pimenol from 2-benzylpyridine, which directly constructs the carbon chain skeleton of the pimenol drug molecule through a one-step Michael addition reaction using cheap and readily available raw materials. The reaction conditions are relatively mild, simple and efficient.

[0004] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0005] A method for preparing pymenol from 2-benzylpyridine comprises the following steps:

[0006] (1) Acylation: In an air atmosphere, 2,6-dimethylpiperidine and acryloyl chloride are added to a reaction bottle containing tetrahydrofuran, and then triethylamine is added, and the temperature is raised to react; the temperature is lowered, and the layers are extracted and separated, and the organic layer is dried and concentrated, and chromatographic separation is performed to obtain the target product 2,6-dimethylpiperidine-vinyl ketone, referred to as compound 1. The reaction equation is as follows:

[0007]

[0008] (2) Michael addition: under an argon atmosphere, a tetrahydrofuran solution of compound 1 is added to 2-benzylpyridine and a bis(trimethylsilyl)amino metal compound, and the temperature is raised to react; the temperature is lowered, and the layers are extracted and separated, the organic layer is dried and concentrated, and the target product 2,6-dimethylpiperidin-4-phenyl-4-(pyridin-2-yl)-1-butanone is obtained by chromatography, referred to as compound 2. The reaction equation is as follows:

[0009]

[0010] (3) Oxidation: In an air atmosphere, a dimethyl sulfoxide solution of compound 2 is added to a dimethyl sulfoxide solution of a tert-butyl alcohol metal compound and the temperature is raised; after cooling, extraction and stratification are performed, the organic layer is dried and concentrated, and chromatographic separation is performed to obtain the target product 2,6-dimethylpiperidin-4-hydroxy-4-phenyl-4-(pyridin-2-yl)-1-butanone, referred to as compound 3. The reaction equation is as follows:

[0011]

[0012] (4) Reduction: Under an argon atmosphere, compound 3 and a reducing agent were added to a reaction bottle, tetrahydrofuran was added, and the temperature was raised; after cooling, ether, water, and sodium hydroxide were added in sequence to quench the reaction, and the layers were separated by extraction, the organic layer was dried and concentrated, and chromatographic separation was performed to obtain pyrimethylenetetramine. The reaction equation is as follows:

[0013]

[0014] Furthermore, the catalyst in step (2) is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or lithium bis(trimethylsilyl)amide.

[0015] Furthermore, the tert-butoxide metal compound used in step (3) is lithium tert-butoxide, sodium tert-butoxide or potassium tert-butoxide.

[0016] Furthermore, in step (1), the molar ratio of 2,6-dimethylpiperidine to acryloyl chloride is 1:1 to 1.5, preferably 1:1.2.

[0017] Furthermore, in the step (2), the molar ratio of potassium bis(trimethylsilyl)amide to compound 1 is 1:5-10.

[0018] Furthermore, in the step (2), the molar ratio of compound 1 to 2-benzylpyridine is 1:(1.5-5).

[0019] Furthermore, the reaction temperature in step (2) is -20°C to 110°C, and the reaction time is 9h to 15h.

[0020] Furthermore, the reaction concentration of compound 2 in step (3) is 0.1 to 1.0 mol / L.

[0021] Furthermore, in step (3), the reaction temperature is 0°C to 110°C, and the reaction time is 4h to 24h.

[0022] Furthermore, the reducing agent in step (4) is sodium borohydride, lithium aluminum hydride, or phenylsilane.

[0023] Furthermore, in the step (4), the molar ratio of compound 3 to the reducing agent is 1:(2.5-5).

[0024] Furthermore, in step (4), the reaction temperature is -20°C to 160°C, and the reaction time is 1h to 48h.

[0025] Beneficial effects of the present invention: The present invention provides a novel synthesis method for preparing pirmenol stably and efficiently. The carbon chain skeleton of the pirmenol drug molecule is directly constructed by a one-step Michael addition reaction through cheap and readily available raw materials, and the reaction conditions are relatively mild, simple and efficient. It not only reduces environmental pollution, but also has high atom economy. DETAILED DESCRIPTION

[0026] The present invention will be further described below in conjunction with specific embodiments.

[0027] Example 1

[0028] The synthetic method of compound 1 of the present embodiment is as follows:

[0029] 2,6-dimethylpiperidine (3.35mL, 25mmol) and triethylamine (10.50mL, 75mmol) were added to a 250mL round-bottom flask containing 70mL tetrahydrofuran, and then 2-benzylpyridine (2.50mL, 30mmol) was slowly added to the above system and stirred at room temperature for 17h. After the reaction was completed, deionized water was added to the system, and the liquid was extracted and separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtered under reduced pressure, concentrated by rotary evaporation, and the mixture was separated by column chromatography to obtain 3.38g of light yellow liquid as compound 1, with a yield of 81%. 1 H NMR (600 MHz, CDCl 3 ), δ (ppm): 6.58 (dd, J=16.8, 10.6Hz, 1H), 6.24 (dd, J=16.7, 2.1Hz, 1H), 5.60 (dd, J=10.6, 2.1Hz, 1H) ,4.38(brs,2H),1.83–1.74(m,1H),1.60(m,4H),1.48(dt,J=13.4,3.7Hz,1H),1.23(d,J=7.2Hz,6H). 13 C{ 1 H}NMR (151 MHz, CDCl 3 ), δ(ppm):166.23,128.85,126.79,46.35,30.18,21.25,14.07.

[0030] Example 2

[0031] This embodiment is a method for synthesizing compound 2, which is as follows:

[0032] Use a glove box filled with argon to ensure anhydrous and oxygen-free conditions. Potassium bis(trimethylsilyl)amide (0.4g, 2mmol) and 2-benzylpyridine (3.38g, 20mmol) were added to a dry 100mL Schlenk bottle and cooled to -20°C, then 20mL of tetrahydrofuran was added and stirred for 15min. Keeping the reaction temperature at -20°C, 5mL of a tetrahydrofuran solution of compound 1 (1.67g, 10mmol) was added thereto and reacted for 12h. After the reaction was completed, deionized water was added to the system, and the mixed solution was extracted with ethyl acetate (10mL x 3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated by rotary evaporation. The mixture was separated by column chromatography to obtain 2.73g of an orange-yellow solid as compound 2 with a yield of 82%. mp85-86°C. 1 H NMR (600 MHz, CDCl 3 ), δ (ppm): 8.54 (dd, J = 5.4, 1.7Hz, 1H), 7.52 (td, J = 7.7Hz, 1.9Hz, 1H), 7.33 (d, J =7.6Hz,2H),7.26(t,J=7.6Hz,2H),7.19–7.14(m,2H),7.09–7.03(m,1H),4.75(s ,1H),4.17(t,J=7.8Hz,1H),3.88(d,J=53.0Hz,1H),2.57(dd,J=14.3,7.2Hz,1H ),2.46–2.16(m,3H),1.72(td,J=9.2,4.1Hz,1H),1.52(s,4H),1.42(d,J=13.4Hz 1H), 1.12 (d, J=38.2 Hz, 6H). 13 C{ 1 H}NMR (151 MHz, CDCl 3 ), δ (ppm): 171.85, 163.62, 149.19, 143.59, 136.46, 128.53, 128.14, 126.50, 123.02, 121. 36,52.90,47.22,43.52,31.56,30.81,30.55,29.97,21.53,20.57,13.93.HRMS(positive ESI):[M+H] + Calculate for C 22 H 29 N 2 O + ,337.2274;found,337.2289.

[0033] Example 3

[0034] The synthetic method of compound 3 of the present embodiment is as follows:

[0035] Under air atmosphere, keep the reaction temperature at 30℃, add lithium tert-butoxide (673mg, 6mmol) to a 50mL round-bottom flask containing 8mL dimethyl sulfoxide and stir for 3min. Dissolve compound 2 (673mg, 2mmol) in 4mL dimethyl sulfoxide under heating conditions, then add dropwise into the reaction system and react at 60℃ for 6h. After the reaction, add 10mL deionized water to the system and extract with ethyl acetate (15mL x 4). Wash the organic layer with saturated brine, dry with anhydrous sodium sulfate, filter under reduced pressure, concentrate by rotary evaporation, and separate the mixture by column chromatography to obtain 1.27g yellow-green solid as compound 3, with a yield of 90%. mp 100-101℃. 1 H NMR (600 MHz, CDCl 3 ), δ(ppm):8.49(d,J=5.4Hz,1H),7.65–7.56(m,3H),7.51(d,J=8.0Hz,1H), 7.29(t,J=7.8Hz,2H),7.18(t,J=7.3Hz,1H),7.14–7.09(m,1H),6.38(s,1H ),4.73(s,1H),3.97(s,1H),2.83–2.61(m,2H),2.55–2.21(m,2H),1.79–1. 68(m,1H),1.52(s,4H),1.42(dt,J=13.5,3.7Hz,1H),1.13(d,J=7.8Hz,6H). 13 C{ 1 H}NMR (151 MHz, CDCl 3 ), δ(ppm):172.87,164.24,147.30,146.27,136.99,128.16,126.75,125.98,121.88,1 21.04,47.35,43.77,36.34,30.43,29.85,28.40,21.46,20.44,13.81.HRMS(positive ESI):[M+H] + Calculate for C 22 H 29 N 2 O 2 + ,353.2224;found,353.2244.

[0036] Example 4

[0037] The synthetic method of the present embodiment Pirmenol is as follows:

[0038] Use a glove box filled with argon to ensure anhydrous and oxygen-free conditions. Add compound 3 (352 mg, 1 mmol) and sodium borohydride (113 mg, 3 mmol) to a 100 mL Schlenk bottle containing 30 mL tetrahydrofuran and react at 75 ° C for 6 hours. After the reaction is completed, add 15 mL of ether and cool to 0 ° C. Slowly add 0.2 mL of water, 0.2 mL of 15% sodium hydroxide solution, 0.6 mL of water and an appropriate amount of anhydrous magnesium sulfate to the system in sequence. Warm to room temperature and stir for another 15 minutes, filter to remove solids, and concentrate under reduced pressure to obtain a yellow oil. The mixture is separated by column chromatography to obtain 183 mg of yellow oil as pyrimidine, with a yield of 54%. 1 H NMR (600 MHz, CDCl 3 ), δ (ppm): 8.51 (d, J = 4.8Hz, 1H), 7.62 (td, J = 7.7, 1.8Hz, 1H), 7.57 (d, J = 7.0Hz, 2H), 7.4 6(d,J=8.0Hz,1H),7.29(t,J=7.8Hz,2H),7.18(t,J=7.3Hz,1H),7.13(ddd,J=7.4,4.9,1 .1Hz,1H),6.81(s,1H),2.77–2.65(m,2H),2.39(s,2H),2.27(t,J=7.3Hz,2H),1.63(s,1 H),1.56–1.47(m,3H),1.42–1.35(m,1H),1.32–1.25(m,3H),1.04(dd,J=6.4,2.3Hz,6H). 13 C{ 1 H}NMR (151 MHz, CDCl 3 ), δ(ppm):164.88,147.52,147.10,136.90,128.12,126.74,126.09,12 1.83,120.78,56.21,56.05,48.45,39.61,34.62,24.55,21.07,19.10.

[0039] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. 2-Benzylpyridine efficient preparation of pyrimethylenetetramine method, characterized in that The steps include: (1) Acylation: In an air atmosphere, 2,6-dimethylpiperidine and acryloyl chloride are added to a reaction bottle containing tetrahydrofuran, and then a catalyst, triethylamine, is added and the temperature is raised to react to obtain the target product, 2,6-dimethylpiperidine-vinyl ketone, referred to as compound 1; (2) Michael addition: under argon atmosphere, a tetrahydrofuran solution of compound 1 is added to 2-benzylpyridine and a bis(trimethylsilyl)amino metal compound, and the temperature is raised to react to obtain the target product 2,6-dimethylpiperidin-4-phenyl-4-(pyridin-2-yl)-1-butanone, referred to as compound 2; (3) Oxidation: under air atmosphere, a dimethyl sulfoxide solution of compound 2 is added to a dimethyl sulfoxide solution of a tert-butyl alcohol metal compound, and the temperature is raised to react to obtain the target product 2,6-dimethylpiperidin-4-hydroxy-4-phenyl-4-(pyridin-2-yl)-1-butanone, referred to as compound 3; (4) Reduction: Under an argon atmosphere, compound 3 and a reducing agent are added to a reaction bottle, tetrahydrofuran is added, and the temperature is raised to react to obtain pyrimethylenetetramine; The reaction route is as follows:

2. The method for preparing pyrimidine from 2-benzylpyridine according to claim 1, wherein: In the step (1), the molar ratio of 2,6-dimethylpiperidine to acryloyl chloride is 1:1-1.5; the molar ratio of 2,6-dimethylpiperidine to triethylamine is 1:

3. The reaction temperature in the step (1) is room temperature, and the reaction time is 15-20 hours.

3. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that: The bis(trimethylsilyl)amide metal compound in step (2) is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide.

4. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that: In the step (2), the molar ratio of bis(trimethylsilyl)amino metal to compound 1 is 1:(5-10); the molar ratio of compound 1 to 2-benzylpyridine is 1:(1.5-5).

5. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that: The reaction temperature in step (2) is -20°C to 110°C, and the reaction time is 9h to 15h.

6. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that: The tert-butoxide metal compound used in step (3) is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; the molar ratio of compound 2 to the tert-butoxide metal compound is 1:3, and the reaction concentration of compound 2 is 0.1-1.0 mol / L.

7. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that In step (3), the reaction temperature is 0°C to 110°C, and the reaction time is 4h to 24h.

8. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that The reducing agent in step (4) is sodium borohydride, lithium aluminum hydride, or phenylsilane.

9. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that The molar ratio of compound 3 to the reducing agent in step (4) is 1:(2.5-5).

10. The method for preparing pyrimethylenetetramine from 2-benzylpyridine according to claim 1, characterized in that In step (4), the reaction temperature is -20°C to 160°C, and the reaction time is 1h to 48h.

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