Preparation method of beta-methylenepyridine-2-ethanol

Abstract

The invention relates to a preparation method of beta-methylenepyridine-2-ethyl alcohol. The preparation method comprises the following steps of: adding a catalyst, the preparation method of beta-methylenepyridine-2-ethanol takes 2-picoline as a first raw material, a formaldehyde aqueous solution or paraformaldehyde as a second raw material and urotropine as a catalyst, and comprises the following steps: (1) mixing the first raw material, the second raw material, the catalyst and water, putting the mixture into a high-pressure reaction kettle, heating to 140-160 DEG C, reacting for 18-20 hours, cooling to room temperature, filtering, washing, and drying to obtain beta-methylenepyridine-2-ethanol; a solution containing the beta-methylenepyridine-2-ethanol is obtained; and (2) rectifying the solution containing the beta-methylenepyridine-2-ethanol to obtain a product. According to the method, the urotropine is selected as the catalyst, the reaction selectivity is improved by utilizing the specific space structure and charge distribution of the urotropine, the solvent is friendly in the reaction process, the steps are simple, the beta-methylenepyridine-2-ethanol can be obtained through a one-pot method, and the method is suitable for industrialization.

Description

Technical Field

[0001] The invention belongs to the field of preparation of pharmaceutical intermediates, and specifically relates to a preparation method of 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 of palladium chloride to obtain a palladium catalyst with a ligand for 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 synthesis, and the bromine atom is removed, resulting in poor atom economy and serious waste. It is necessary to develop a new synthesis method of beta-methylenepyridine-2-ethanol with relatively high atom utilization rate in the art. Summary of the invention

[0004] In view of the steps of the prior art, one of the purposes of the present invention is to provide a method for preparing beta-methylenepyridine-2-ethanol, wherein 2-methylpyridine is used as a first raw material, formaldehyde aqueous solution or paraformaldehyde is used as a second raw material, and hexamethylenetetramine is used 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 to 160° C., and reacting the mixture for 18 to 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 urotropine as a catalyst and utilizes the unique spatial structure of urotropine. 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 material is high.

[0008] The preparation method provided in the present application is solvent-friendly and has simple steps. β-methylenepyridine-2-ethanol can be obtained 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 to the second raw material 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 as 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 a suitable 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 comprises the following steps: (1') distilling the solution containing beta-methylenepyridine-2-ethanol under reduced pressure before step (2) 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] The present application selects hexamethylenetetramine as a catalyst, and utilizes its unique spatial structure and charge distribution to improve the selectivity of the reaction. The reaction process is solvent-friendly and has simple steps. Beta-methylenepyridine-2-ethanol can be obtained in a one-pot method, which is suitable for industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 A 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 protection scope 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 urotropine (0.18 mol) and 40.00 g of water (2.2 mol) were mixed and placed in a high-pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 140-145° C., and reacted for 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0028] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 74.22 g of product with a purity of 99.56%. The molar yield was calculated to be 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, 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 urotropine (0.16 mol) and 40.01 g of water (2.2 mol) were mixed and placed in a high-pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 145-150° C., and reacted for 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0033] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 72.46 g of product with a purity of 99.43%. The molar yield was calculated to be 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 urotropine (0.20 mol) and 40.00 g of water (2.2 mol) were mixed and placed in a high-pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 150-155° C., and reacted for 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0037] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 72.85 g of product with a purity of 99.27%. The molar yield was calculated to be 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 a high-pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 140-145° C., and reacted for 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0041] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 73.36 g of product with a purity of 99.35%. The molar yield was calculated to be 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 urotropine (0.18 mol) and 40.02 g of water (2.2 mol) were mixed and placed in a high-pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 140-145° C., and reacted for 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0045] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 71.47 g of product with a purity of 99.21%. The molar yield was calculated to be 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 urotropine (0.18 mol) and 40.02 g of water (2.2 mol) were mixed and placed in a high-pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 140-145° C., and reacted for 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol;

[0049] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 68.52 g of product with a purity of 99.37%. The molar yield was calculated to be 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 a high pressure reactor, stirred at a speed of 500 rpm, and simultaneously heated to 140-145° C., reacted for 20 hours, and obtained a solution containing beta-methylenepyridine-2-ethanol;

[0053] (2) The solution containing beta-methylenepyridine-2-ethanol was distilled under reduced pressure at 1000-2000 Pa, and the distillate was distilled under reduced pressure at 100-200 Pa and 95-100° C. to obtain 30.97 g of product with a purity of 99.54%. The molar yield was calculated to be 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 aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned 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 urotropine as the catalyst, and the reaction is carried out according to the following steps: (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 to 160° C., and reacting the mixture for 18 to 20 hours to obtain a solution containing beta-methylenepyridine-2-ethanol; (2) The solution containing beta-methylenepyridine-2-ethanol is distilled to obtain the product.

2. The preparation method according to claim 1, characterized in that 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, preferably 2.5:1 to 3.0:

1.

3. The preparation method according to claim 1 or 2, characterized in that: Based on the molar amount of formaldehyde in the second raw material being 100%, the added molar amount of the catalyst is 6-8%.

4. The preparation method according to any one of claims 1 to 3, characterized in that: Calculated 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.

5. The preparation method according to any one of claims 1 to 4, characterized in that: During the reaction process of step (1), the reaction solution is stirred.

6. The preparation method according to claim 5, characterized in that: The stirring speed is 400-800 rpm.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The distillation in step (2) is vacuum distillation; The pressure of the vacuum distillation is 100-200 Pa; The temperature of the vacuum distillation is 95-100°C.

8. The preparation method according to claim 7, characterized in that: The preparation method comprises the following steps: performing step (1') of distilling the solution containing beta-methylenepyridine-2-ethanol under reduced pressure before step (2) to obtain a concentrated solution containing beta-methylenepyridine-2-ethanol.

9. The preparation method according to claim 8, characterized in that: The pressure of the reduced pressure distillation is 1000-2000Pa.

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