Preparation method of 2-methylpyridine derivative

Abstract

The invention relates to a preparation method of a 2-methylpyridine derivative as shown in a chemical structural formula I. Pyridine or substituted pyridine and polyhydric alcohol are subjected to alpha-methylation reaction under high temperature, high pressure and Raney nickel catalysis to prepare the 2-methylpyridine derivative as shown in the formula I. The preparation reaction is as follows: # imgabs0 #, wherein R is selected from H, 4-CH3, 5-CH3, 3, 5-(CH3) 2; the polyol is selected from the group consisting of ethylene glycol, 1, 3-propylene glycol, 1, 2-propylene glycol, glycerol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, 1, 2-pentanediol, 1, 3-pentanediol, 1, 4-pentanediol, 1, 5-pentanediol, 2, 3-pentanediol or 2, 4-pentanediol; the methylation reaction temperature is selected from 200 DEG C to 270 DEG C; the methylation reaction pressure is selected from 3.0 MPa to 6.0 MPa.

Description

Technical Field

[0001] The invention relates to a preparation method of a class of 2-methylpyridine derivatives, in particular to a preparation method of 2,3,5-trimethylpyridine, 2,5-dimethylpyridine, 2,4-dimethylpyridine and 2-methylpyridine. Background Art

[0002] Omeprazole, chemically known as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, is a proton pump inhibitor developed and marketed by AstraZeneca in the United Kingdom in 1988. It is now available in many countries and is mainly used to treat peptic ulcer and reflux gastritis [Fu Jianwei, Tao Xingfa, Fu Zhaojuan, et al. Synthesis of omeprazole. Chinese Journal of Pharmaceutical Industry, 2007, 38(2): 78-80]. 2,3,5-Trimethylpyridine is an important intermediate for the synthesis of omeprazole. Although it can be separated and purified from coal tar or shale oil, its natural content is very low and the separation cost is high. Therefore, 2,3,5-trimethylpyridine is prepared by synthesis in industry. There are four main synthesis methods: Chichibabin pyridine synthesis method, Hantzsch pyridine synthesis method, dealkylation method and alkylation method. The four methods are summarized as follows:

[0003] (1) The Qiqibabin pyridine synthesis method is mainly to generate 2,3,5-trimethylpyridine by two molecules of aldehyde and one molecule of ammonia under the action of alumina and other catalysts. First, two molecules of propionaldehyde are dehydrated to generate 2-methyl-2-pentenal, and one molecule of propionaldehyde and one molecule of ammonia generate propane-1-imine. Then, 2-methyl-2-pentenal and propane-1-imine are dehydrated and oxidized at 380°C under the action of Zn-Cr-Al catalyst to obtain 2,3,5-trimethylpyridine [Xiao Guomin, Wu Pingdong. Review of the Synthesis Route of 2,3,5-Trimethylpyridine. Zhejiang Chemical Industry, 1996, 27(02): 10-12]. This method has low raw material cost, but more by-products and low yield.

[0004]

[0005] In 1995, Nitto et al. [JP19950083488] used methacrolein and ammonia as raw materials, with a molar ratio of methacrolein to ammonia of 1:1, and synthesized 2,3,5-trimethylpyridine at 380°C and 2atm over a metal composite catalyst with a yield of 16.5%.

[0006]

[0007] In 2000, Itoh Naorou et al. [US06111113A] used methacrolein, methyl ethyl ketone, water and ammonia as raw materials, and synthesized 2,3,5-trimethylpyridine at 450°C with a yield of 45.0% using silica-alumina containing 5.5wt.% cadmium oxide as the catalytic agent.

[0008]

[0009] In 2001, Kulkarni et al. [US2002 / 0173660] used methyl ethyl ketone, formaldehyde and ammonia as raw materials, and synthesized 2,3,5-trimethylpyridine at 400°C under the catalysis of HZSM-5 with a yield of 39.4%. This method is simple to operate, has low raw material cost, and realizes the quantitative production of pyridine derivatives, but the yield is low.

[0010]

[0011] (2) Hans Yunek's pyridine synthesis method refers to the use of two molecules of β-carbonyl ester, one molecule of aldehyde and one molecule of ammonia as raw materials, which undergo condensation under specific conditions to produce 2,3,5-trimethylpyridine. In 1987, Hans Yunek et al. [JPH0780851B2] synthesized 2,3,5-trimethylpyridine using 3-amino-2-methyl-2-butenoic acid ethyl ester and 2-methylmalonic acid diethyl ester as raw materials. However, this method has complex raw materials, a long route, and a high cost of palladium-carbon catalyst.

[0012]

[0013] (3) Dealkylation method: 2-ethyl-3,5-dimethylpyridine is used as the raw material, and one methyl group is removed by elemental sulfur to generate 2,3,5-trimethylpyridine. In 1991, Goe [US5061805] reported that at 200°C, one methyl group of 2-ethyl-3,5-dimethylpyridine was removed by elemental sulfur to generate 2,3,5-trimethylpyridine, with a yield of 67.0%.

[0014]

[0015] In 1997, Xiao Guomin et al. [Study on the synthesis of 2,3,5-trimethylpyridine. Chemical World, 1997(08): 417-419] optimized the reaction conditions based on U.S. Patent [US5061805], lowered the temperature to 180°C, reacted for 10 hours, and prepared 2,3,5-trimethylpyridine with a yield of 73.0%.

[0016] In 2007, Chen Yingqi et al. [CN101012194] extended the process route based on the US patent [US5061805], using propionaldehyde and ammonia as raw materials to first generate 2-ethyl-3,5-dimethylpyridine, and then demethylating it with elemental sulfur under the catalysis of cobalt aluminum phosphate to obtain 2,3,5-trimethylpyridine, with a total yield of more than 50.0%. This method has a simple process and a high yield, and is currently a commonly used process route in industry. However, this route uses sulfur as a demethylating agent, and hydrogen sulfide gas is produced during the production process, which seriously pollutes the environment.

[0017]

[0018] (4) The alkylation method uses 3,5-dimethylpyridine as the raw material and alcohol as the methylation agent to catalyze the reaction to obtain 2,3,5-trimethylpyridine. In 1987, Yamaji et al. [US4658032] used 3,5-dimethylpyridine and methanol as raw materials, the molar ratio of methanol to 3,5-dimethylpyridine was 6:1, 240°C, 4.4-5.9 MPa hydrogen, and Raney cobalt catalysis for 7 hours to obtain 2,3,5-trimethylpyridine with a yield of 86.0%.

[0019]

[0020] In 2007, Organosys et al. [IN2002DE00817] used 3,5-dimethylpyridine and methanol as raw materials, Raney nickel as catalyst, and the molar ratio of methanol to 3,5-dimethylpyridine was 2.7:1. The reaction was carried out at 260°C and 5.5-5.7 MPa nitrogen. 2,3,5-trimethylpyridine was obtained by distillation separation with a yield of 86.0% and a purity of 99.5%.

[0021]

[0022] In 2014, Shimazu et al. [JP2014148488] used 3,5-dimethylpyridine and methanol as raw materials, nickel-loaded HY zeolite as catalyst, and a fixed bed reactor to synthesize 2,3,5-trimethylpyridine in the gas phase at 425°C with an average yield of less than 20%.

[0023]

[0024] In 2008, Broring et al. [Convenient Procedure for the alpha-Methylation of Simple Pyridines. Synthetic Communications, 2008, 38: 3672-3682] used n-octanol and n-decanol as methylating agents to study the α-methylation reaction of various substituted pyridines. Among them, n-decanol was used as the methylating agent, 3,5-dimethylpyridine was used as the substrate, and 10% Raney nickel was used as the catalysis. The reflux reaction was carried out for 68 hours to obtain 2,3,5-trimethylpyridine with a yield of 60.0%.

[0025]

[0026] In 2015, Manansala et al. [Flow Synthesis of 2-Methylpyridines via α-Methylation. Molecules, 2015, 20: 15797-15806] used a fixed bed reactor and 1-propanol as a methylating agent to perform gas-phase α-methylation reactions on a variety of substituted pyridines. 5.5 g of Raney Ni was loaded into a 150×4.6 mm stainless steel tube, and 5 mL of a 0.05 M substituted pyridine 1-propanol solution was passed through a 180°C reaction tube at a flow rate of 0.1 to 0.3 mL / min, with a residence time of 30 min and a pressure of 6.9 MPa. The yield of 2,3,5-trimethylpyridine was 90.0%.

[0027]

[0028] In 2021, Liu Min et al. [Research on the Synthesis Process of 2-Methylpyridine. Anhui Chemical Industry, 47(4): 66-68] used Fe-Mn / ZSM-5 molecular sieve as catalyst and fixed bed as reactor, and used pyridine and methanol to synthesize 2-methylpyridine. The suitable reaction conditions were screened out as Fe content of 1.2%, Mn content of 0.8%, reaction temperature of 350°C, catalyst dosage of 5%, pyridine: methanol = 1:1.3, and 2-methylpyridine with a yield of more than 93%. Summary of the invention

[0029] The object of the present invention is to provide a method for preparing a 2-methylpyridine derivative, characterized in that pyridine or substituted pyridine and a polyol undergo an α-methylation reaction under high temperature, high pressure and Raney nickel catalysis to prepare a 2-methylpyridine derivative (I), and the preparation reaction is as follows:

[0030]

[0031] in:

[0032] R is selected from: H, 4-CH3, 5-CH3, 3,5-(CH3)2;

[0033] The polyol is selected from the group consisting of ethylene glycol, 1,3-propylene glycol, 1,2-propylene glycol, glycerol, 1,2-butylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol, and 2,4-pentanediol;

[0034] The methylation reaction temperature is selected from: 200°C to 270°C;

[0035] The methylation reaction pressure is selected from: 3.0MPa to 6.0MPa;

[0036] The methylation reaction time is selected from: 15h to 30h;

[0037] The dosage of the raw materials is selected as follows: pyridine derivative: polyol = 1:2-5 molar ratio;

[0038] Selection of polyol feed rate: The feed rate per hour is 0.05-0.1 times the amount of polyol;

[0039] The amount of Raney nickel catalyst is selected as follows: pyridine derivative: Raney nickel = 1: 0.05-0.20 by mass ratio.

[0040] The specific operation of the methylation reaction is as follows: add pyridine derivatives and Raney nickel into a high-pressure reactor, protect with nitrogen, add polyols in batches at 200°C to 270°C, control the pressure at 3.0MPa to 6.0MPa, react for 15h to 30h, and after the reaction is completed, filter and recover the catalyst. Add sodium hydroxide to the filtrate to separate the layers, dry the oil layer with anhydrous sodium sulfate, and separate by distillation to obtain 2-methylpyridine derivatives.

[0041] Compared with the prior art, the present invention has the following advantages:

[0042] Pyridine derivatives and polyols undergo α-methylation reaction under Raney nickel catalysis at a certain temperature and pressure to prepare 2-methylpyridine derivatives. The process has cheap and readily available raw materials, simple operation, high product yield and purity, no environmental pollution, and has industrial application value. DETAILED DESCRIPTION

[0043] The following examples are intended to illustrate the present invention rather than to further limit the present invention.

[0044] Example 1

[0045] Preparation of 2,3,5-trimethylpyridine

[0046] 45g 3,5-dimethylpyridine and 4.5g Raney nickel were added to a high-pressure reactor, and the temperature was raised to 250°C under nitrogen protection. 67.5g ethylene glycol was added to the reactor in batches by a pump, and the feed rate was 4.5g / h. The reaction was carried out for 20h, and the pressure was controlled at 5.0-5.5MPa. After the reaction was completed, the catalyst was recovered by suction filtration, and NaOH was added to the filtrate, and the layers were allowed to stand for separation. The oil phase was dried with anhydrous sodium sulfate and filtered to obtain 50.9g of light brown crude product, and the yield of 2,3,5-trimethylpyridine was 81.4% (peak area normalization method).

[0047] Example 2

[0048] Preparation of 2,3,5-trimethylpyridine

[0049] 30g 3,5-dimethylpyridine and 3.6g Raney nickel were added to a high-pressure reactor, and the temperature was raised to 260°C under nitrogen protection. 35g ethylene glycol was added to the reactor in batches by a pump, and the feed rate was 3.0g / h. The reaction was carried out for 18h, and the pressure was controlled at 5.0-5.5MPa. After the reaction was completed, the catalyst was recovered by suction filtration, and NaOH was added to the filtrate, and the layers were separated. The oil phase was dried with anhydrous sodium sulfate and filtered to obtain 33.8g of light brown crude product, and the yield of 2,3,5-trimethylpyridine was 82.4% (peak area normalization method).

[0050] Example 3

[0051] Purification of 2,3,5-trimethylpyridine

[0052] 195 g of the crude product was separated by vacuum distillation using a 1.5-m distillation column to obtain 23.4 g (55-57°C / 18 mmHg) of 3,5-dimethylpyridine with a purity of >94% which can be recycled, and 130.6 g (60°C / 18 mmHg) of 2,3,5-trimethylpyridine with a purity of >99.5%.

[0053] Example 4

[0054] Preparation of 2,3,5-trimethylpyridine

[0055] 30g 3,5-dimethylpyridine and 3.6g Raney nickel were added to a high-pressure reactor, and the temperature was raised to 240°C under nitrogen protection. 55g 1,3-propylene glycol was added to the reactor in batches by a pump, and the feed rate was 4.0g / h. The reaction was carried out for 22h, and the pressure was controlled at 5.0-5.5MPa. After the reaction was completed, the catalyst was recovered by suction filtration, NaOH was added to the filtrate, and the layers were allowed to stand for separation. The oil phase was dried with anhydrous sodium sulfate and filtered to obtain 33.8g of light brown crude product. The yield of 2,3,5-trimethylpyridine was 70.2% (peak area normalization method).

[0056] Example 5

[0057] Preparation of 2,3,5-trimethylpyridine

[0058] 30g 3,5-dimethylpyridine and 3.6g Raney nickel were added to a high-pressure reactor, and the temperature was raised to 255°C under nitrogen protection. 65g 1,4-butanediol was added to the reactor in batches by a pump, and the feed rate was 5.4g / h. The reaction was carried out for 20h, and the pressure was controlled at 5.0-5.5MPa. After the reaction was completed, the catalyst was recovered by suction filtration, NaOH was added to the filtrate, and the layers were allowed to stand for separation. The oil phase was dried with anhydrous sodium sulfate and filtered to obtain 31.2g of light brown crude product. The yield of 2,3,5-trimethylpyridine was 59.1% (peak area normalization method).

Claims

1. A method for preparing a 2-methylpyridine derivative represented by chemical formula I: Pyridine or substituted pyridine and polyol undergo α-methylation reaction under high temperature, high pressure and Raney nickel catalysis to prepare 2-methylpyridine derivatives shown in formula I. The preparation reaction is as follows: Wherein: R is selected from: H, 4-CH3, 5-CH3, 3,5-(CH3)2; the polyol is selected from: ethylene glycol, 1,3-propylene glycol, 1,2-propylene glycol, propylene glycol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol or 2,4-pentanediol; the methylation reaction temperature is selected from: 200°C to 270°C; the methylation reaction pressure is selected from: 3.0MPa to 6.0MPa; the methylation reaction time is selected from: 15h to 30h.

2. The method for preparing a 2-methylpyridine derivative according to claim 1, characterized in that The dosage of the raw materials is selected as follows: pyridine derivative: polyol = 1:2-5 molar ratio.

3. The method for preparing a 2-methylpyridine derivative according to claim 1, characterized in that Selection of polyol feed rate: The feed rate per hour is 0.05 to 0.1 times the amount of polyol.

4. The method for preparing a 2-methylpyridine derivative according to claim 1, characterized in that The amount of catalyst is selected as follows: pyridine derivative: Raney nickel = 1: 0.05-0.20 by mass ratio.

5. The method for preparing a 2-methylpyridine derivative according to claim 1, wherein the methylation reaction is specifically performed as follows: adding a pyridine derivative and Raney nickel into a high-pressure reactor, protecting with nitrogen, adding polyols in batches at 200° C. to 270° C., controlling the pressure at 3.0 MPa to 6.0 MPa, reacting for 15 h to 30 h, and after the reaction is completed, filtering with suction, recovering the catalyst, adding sodium hydroxide to the filtrate to separate the layers, drying the oil layer with anhydrous sodium sulfate, and separating by rectification to obtain the 2-methylpyridine derivative.

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