A preparation method of beta-methylenepyridine-2-ethanol

Abstract

The present invention relates to a preparation method of beta-methylenepyridine-2-ethanol. The preparation method of beta-methylenepyridine-2-ethanol uses 2-picoline as a first raw material, formaldehyde solution or paraformaldehyde as a second raw material, and urotropine as a catalyst, and reacts according to the following steps: (1) the first raw material, the second raw material, the catalyst and water are mixed and placed in an autoclave, the temperature is raised to 140-160° C., and after reacting for 18-20 hours, a solution containing beta-methylenepyridine-2-ethanol is obtained; (2) the solution containing beta-methylenepyridine-2-ethanol is distilled to obtain a product. The present application uses urotropine as a catalyst, utilizes its unique spatial structure and charge distribution, improves the selectivity of the reaction, and the reaction process is solvent-friendly, the steps are simple, and beta-methylenepyridine-2-ethanol can be obtained by a one-pot method, which is suitable for industrialization.

Description

Technical Field

[0001] The invention belongs to the field of preparation of pharmaceutical intermediates, and particularly relates to a method for preparing beta-methylenepyridine-2-ethanol. Background Art

[0002] Beta-methylenepyridine-2-ethanol, also known as 2-(2-pyridyl)-2-propene-1-ol, CAS number is 58379-60-5, the structural formula is It can be used as a ligand for palladium chloride to obtain a palladium catalyst with a ligand, which can be used in organic synthesis, carbon-carbon bond coupling, or carbon-heteroatom coupling reaction.

[0003] In the synthesis method disclosed in the prior art, o-bromopyridine and allyl alcohol are used for the synthesis, and the bromine atom is removed, resulting in poor atom economy and serious waste. There is a need in the art to develop a new synthesis method for beta-methylenepyridine-2-ethanol with relatively high atom utilization. Summary of the Invention

[0004] In view of the steps in the prior art, one of the objectives of the present invention is to provide a method for preparing beta-methylenepyridine-2-ethanol, wherein the method uses 2-methylpyridine as a first raw material, formaldehyde solution or paraformaldehyde as a second raw material, and hexamethylenetetramine as a catalyst, and the reaction is carried out according to the following steps:

[0005] (1) mixing a first raw material, a second raw material, a catalyst, and water, placing the mixture in a high-pressure reactor, heating the mixture to 140-160° C., and reacting the mixture for 18-20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0006] (2) The solution containing beta-methylenepyridine-2-ethanol is distilled to obtain the product.

[0007] This application uses methenamine as a catalyst and utilizes the unique spatial structure of methenamine. The selectivity of 1,3-propylene glycol-2-yl on the pyridine group is improved, the probability of hydroxyethyl group is reduced, and as the reaction time increases, propylene glycol removes one hydroxyl group to obtain 2-en-1-ol-2-yl, thereby obtaining beta-methylenepyridine-2-ethanol, and the atomic utilization rate of the raw materials is high.

[0008] The preparation method provided in this application is solvent-friendly, has simple steps, can obtain beta-methylenepyridine-2-ethanol in a one-pot process, and is suitable for industrialization.

[0009] Preferably, based on the amount of 2-methylpyridine and formaldehyde, the molar ratio of the first raw material and the second raw material added in step (1) is 1.0:1 to 3.0:1, for example, 1.3:1, 1.5:1, 1.6:1, 1.9:1, 2.0:1, 2.3:1, 2.5:1, 2.6:1, 2.8:1, etc., preferably 2.5:1 to 3.0:1.

[0010] If there is too much second raw material (formaldehyde), the cold and hard pipelines of the reaction equipment are prone to scaling, and formaldehyde is easily brought out during the subsequent rectification or distillation process, affecting the purity of the product and polluting the environment. If there is too little second raw material (formaldehyde), it is easy to lead to a decrease in product yield.

[0011] Preferably, based on the molar amount of formaldehyde in the second raw material being 100%, the added molar amount of the catalyst is 6-8%, for example, 6.3%, 6.5%, 6.8%, 6.9%, 7.3%, 7.6%, 7.8%, etc.

[0012] The addition of an appropriate amount of catalyst can shorten the reaction time and increase the yield of the product.

[0013] Preferably, based on the amount of water and formaldehyde, the molar ratio of water to the second raw material in step (1) is 0.8:1 to 1:1, for example, 0.82:1, 0.86:1, 0.89:1, 0.95:1, 0.97:1, etc.

[0014] Preferably, during the reaction process of step (1), the reaction solution is stirred.

[0015] Preferably, the stirring speed is 400-800 rpm, for example, 420 rpm, 460 rpm, 540 rpm, 590 rpm, 630 rpm, 680 rpm, 750 rpm, 790 rpm, etc.

[0016] Preferably, the distillation in step (2) is vacuum distillation; the pressure of the vacuum distillation is 100-200 Pa (for example, 110 Pa, 130 Pa, 170 Pa, 190 Pa, etc.); the temperature of the vacuum distillation is 95-100° C. (for example, 96° C., 97° C., 98° C., 99° C., etc.).

[0017] Preferably, the preparation method carries out step (1') before step (2) to subject the solution containing beta-methylenepyridine-2-ethanol to reduced pressure distillation to obtain a concentrated solution containing beta-methylenepyridine-2-ethanol.

[0018] Preferably, the pressure of the pressurized distillation is 1000-2000 Pa, for example, 1100 Pa, 1200 Pa, 1300 Pa, 1400 Pa, 1500 Pa, 1600 Pa, 1700 Pa, 1800 Pa, 1900 Pa, etc.

[0019] Compared with the prior art, this application has the following beneficial effects:

[0020] This application uses hexamethylenetetramine as a catalyst, utilizing its unique spatial structure and charge distribution to improve the selectivity of the reaction. The reaction process is solvent-friendly and has simple steps. β-methylenepyridine-2-ethanol can be obtained in a one-pot method, which is suitable for industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The gas chromatogram of the product of step (2) is given;

[0022] Figure 2 is the mass spectrum of beta-methylenepyridine-2-ethanol, from Figure 2 It can be seen that ESI-API m / z: 134.0[M-1] - . DETAILED DESCRIPTION

[0023] The technical solution of the present invention is further explained below in conjunction with specific implementation methods. However, it should be noted that the specific implementation methods are only a specific implementation and explanation of the essence of the technical solution of the present invention and should not be understood as a limitation on the scope of protection of the present invention.

[0024] The reagents and instruments used in the examples can all be purchased from commercial products, and the detection methods are conventional methods well known in the art.

[0025] Example 1

[0026] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0027] (1) 659.22 g of 2-methylpyridine (7.09 mol), 75.20 g of paraformaldehyde (2.5 mol as formaldehyde), 25.37 g of hexamethylenetetramine (0.18 mol), and 40.00 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 140-145° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0028] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 74.22 g of product with a purity of 99.56%. The calculated molar yield was 22%.

[0029] Figure 1 The gas chromatogram of the product of step (2) is given. The peak at 0-5 minutes is the solvent peak, and the peak at 14-15 minutes is the peak of beta-methylenepyridine-2-ethanol. Figure 1 After normalization, the purity of the product was 99.56%. Figure 2 is the mass spectrum of beta-methylenepyridine-2-ethanol, from Figure 2 It can be seen that ESI-API m / z: 134.0[M-1] - .

[0030] Example 2

[0031] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0032] (1) 659.15 g of 2-methylpyridine (7.09 mol), 75.11 g of paraformaldehyde (2.5 mol as formaldehyde), 21.86 g of hexamethylenetetramine (0.16 mol), and 40.01 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 145-150° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0033] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 72.46 g of product with a purity of 99.43%. The calculated molar yield was 21%.

[0034] Example 3

[0035] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0036] (1) 659.17 g of 2-methylpyridine (7.09 mol), 75.26 g of paraformaldehyde (2.5 mol as formaldehyde), 28.34 g of hexamethylenetetramine (0.20 mol), and 40.00 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 150-155° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0037] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 72.85 g of product with a purity of 99.27%. The calculated molar yield was 21%.

[0038] Example 4

[0039] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0040] (1) 582.15 g of 2-methylpyridine (6.26 mol), 75.04 g of paraformaldehyde (2.5 mol as formaldehyde), 25.21 g of urotropine (0.18 mol), and 40.02 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 140-145° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0041] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 73.36 g of product with a purity of 99.35%. The calculated molar yield was 22%.

[0042] Example 5

[0043] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0044] (1) 695.78 g of 2-methylpyridine (7.48 mol), 75.04 g of paraformaldehyde (2.5 mol as formaldehyde), 25.30 g of hexamethylenetetramine (0.18 mol), and 40.02 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 140-145° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0045] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 71.47 g of product with a purity of 99.21%. The calculated molar yield was 21%.

[0046] Example 6

[0047] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0048] (1) 234.54 g of 2-methylpyridine (2.52 mol), 75.04 g of paraformaldehyde (2.5 mol as formaldehyde), 25.27 g of hexamethylenetetramine (0.18 mol), and 40.02 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 140-145° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0049] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 68.52 g of product with a purity of 99.37%. The calculated molar yield was 20%.

[0050] Comparative Example 1

[0051] A method for preparing beta-methylenepyridine-2-ethanol comprises the following steps:

[0052] (1) 659.22 g of 2-methylpyridine (7.09 mol), 75.20 g of paraformaldehyde (2.5 mol as formaldehyde), 18.55 g of triethylamine (0.18 mol), and 40.00 g of water (2.2 mol) were mixed and placed in an autoclave. The mixture was stirred at a speed of 500 rpm and the temperature was simultaneously raised to 140-145° C. After reacting for 20 hours, a solution containing beta-methylenepyridine-2-ethanol was obtained.

[0053] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was subjected to vacuum rectification at 100-200 Pa and 95-100° C. to obtain 30.97 g of product with a purity of 99.54%. The calculated molar yield was 9%.

[0054] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing beta-methylenepyridine-2-ethanol, characterized in that: The preparation method uses 2-methylpyridine as the first raw material, formaldehyde solution or paraformaldehyde as the second raw material, and hexamethylenetetramine as the catalyst, and the reaction is carried out according to the following steps: (1) The first raw material, the second raw material, the catalyst and water are mixed and placed in a high-pressure reactor, the temperature is raised to 140-160° C., and the reaction is carried out for 18-20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol; (2) distilling the solution containing beta-methylenepyridine-2-ethanol to obtain a product; According to the amount of 2-methylpyridine and formaldehyde, the molar ratio of the first raw material to the second raw material in step (1) is 1.0:1 to 3.0:1; Based on the molar amount of formaldehyde in the second raw material being 100%, the added molar amount of the catalyst is 6-8%.

2. The preparation method according to claim 1, wherein According to the amount of 2-methylpyridine and formaldehyde, the molar ratio of the first raw material to the second raw material in step (1) is 2.5:1 to 3.0:

1.

3. The preparation method according to claim 1, wherein According to the amount of water and formaldehyde, the molar ratio of water to the second raw material in step (1) is 0.8:1~1:

1.

4. The preparation method according to claim 1, wherein During the reaction process of step (1), the reaction solution is stirred.

5. The preparation method according to claim 4, wherein The stirring speed is 400-800 rpm.

6. The preparation method according to claim 1, wherein The distillation in step (2) is vacuum distillation; The pressure of the vacuum distillation is 100~200Pa; The temperature of the vacuum distillation is 95-100°C.

7. The preparation method according to claim 6, wherein The preparation method comprises the following steps: performing step (1') before step (2) to subject the solution containing beta-methylenepyridine-2-ethanol to reduced pressure distillation to obtain a concentrated solution containing beta-methylenepyridine-2-ethanol.

8. The preparation method according to claim 7, wherein The pressure of the reduced pressure distillation is 1000~2000Pa.

Images