CN101012194A - Method for preparing 2,3,5-trimethylpyridine - Google Patents

Abstract

The preparation method of 2,3,5-collidine disclosed by the present invention comprises the following steps: 1) preparing a cobalt-aluminum phosphate composite catalyst containing an acidity regulator; 2) putting the composite catalyst into a fixed-bed reactor, and feeding Propionaldehyde and ammonia gas, catalyzed ring formation reaction to generate 2-ethyl-3,5-lutidine; 3) 2-ethyl-3,5-lutidine and sulfur powder for demethylation reaction , to obtain 2,3,5-collidine. The invention has the advantages of simple preparation process, low raw material cost and high yield, which can reach more than 50%. At the same time, the catalyst can be recycled, so that the production efficiency is high, and it has industrial significance.

Description

The preparation method of 2,3,5-collidine

technical field

The invention relates to a preparation method of 2,3,5-collidine.

Background technique

2,3,5-collidine is an intermediate for preparing H+/K+-ATPase inhibitors omeprazole and tetuprazole for treating peptic ulcer. Existing 2,3,5-collidine main preparation method has following several kinds: method one (Uzb.Khim.Zh.1990, (1), 29～31), with propionaldehyde and ammonia in Zn-Cr -In the presence of an Al catalyst, react at 380°C under normal pressure conditions, the resulting product contains 27.6% of 2,3,5-collidine and 31.1% of 2-ethyl-3,5-lutidine; method Two (Japanese Open Patent 87-72666), this method is to obtain 3-amino-2-methyl-2-butenoic acid ethyl ester by 2-methyl acetoacetate and liquefied ammonia reaction in autoclave, then 2 -Diethyl methylmalonate reacts with 3-amino-2-methyl-2-butenoic acid ethyl ester in the presence of sodium ethoxide to obtain 4-hydroxyl-3,5,6-trimethyl-2( 1H)-pyridone, then react with phosphorus oxychloride in an autoclave to obtain 2,4-dichloro-3,5,6-collidine, and finally use 10% Pd/C as catalyst, 2,4-dichloro -3,5,6-collidine reacts with concentrated ammonia water and rectifies to obtain 2,3,5-collidine; method three (US4658032), by reacting 3,5-lutidine with methyllithium Preparation, the yield is 67%; Method 4 (US5061805), 2-ethyl-3,5-lutidine is used as raw material to react with sulfur, and 2,3,5 - Collidine, the theoretical yield is between 60% and 70%.

Wherein, the first method has many by-products, the yield of 2,3,5-collidine is very low, and the separation is more difficult, which makes the cost higher; the basic raw material used in the second ring closure of the method is ethyl 2-methylacetoacetate and 2-methyldiethylmalonate, the raw materials are not easy to obtain, while the process route is longer, and the noble metal palladium is used as a catalyst, the total yield is 59.4%, and the cost is high; the shortcoming of method three is that methyllithium is very expensive , and it will decompose when encountering water or oxygen, the reaction conditions are harsh, and 3,5-lutidine is difficult to obtain, so it cannot be used in industrial production; the raw material 2-ethyl-3,5-dimethylpyridine used in method four Pyridine is more expensive, and the synthesis yield is relatively low, the highest being 30%.

Contents of the invention

The purpose of the present invention is to provide a method for preparing 2,3,5-collidine with high yield and low cost, which has industrial significance.

The preparation method of 2,3,5-Collidine of the present invention comprises the steps:

The first step is to dissolve (NH ₄ ) ₃ PO ₄ 3H ₂ O in distilled water, add an acid regulator, stir evenly, dissolve cobalt nitrate and aluminum nitrate in distilled water, and then slowly drop them into the above solution, and the resulting precipitate is pumped filter, wash the filter cake and dry it into shape, and then bake at 400-600°C for 8-12 hours to obtain a cobalt-aluminum phosphate composite catalyst, wherein the weight ratio of the acid regulator to (NH ₄ ) ₃ PO ₄ ·3H ₂ O is 0.25～0.5:1; the molar ratio of cobalt nitrate to (NH ₄ ) ₃ PO ₄ ·3H ₂ O is 3:4; the molar ratio of aluminum nitrate to (NH ₄ ) ₃ PO ₄ ·3H ₂ O is 1:2;

In the second step, put the composite catalyst into a fixed-bed reactor, feed propionaldehyde and ammonia gas into the fixed-bed reactor, and carry out continuous catalytic ring-forming reaction at 300-450°C to generate 2-ethyl-3,5- The feeding speed of lutidine and propionaldehyde is 1.82～2.9mL/min, and the feeding speed of ammonia is 200mL/min.

In the third step, 2-ethyl-3,5-lutidine and sulfur powder are stirred and mixed, and the temperature is raised to 150-200°C for demethylation reaction to obtain 2,3,5-collidine. The weight ratio of 2-ethyl-3,5-lutidine to sulfur powder is 1-2:1.

In order to further reduce the cost and improve the service life of the catalyst, the present invention further proposes a catalyst activation and regeneration method, the process is to raise the bed temperature of the fixed bed reactor to 500°C, and at the same time feed air and a catalyst with a volume concentration of 5-10%. The aqueous solution of methanol or ethanol is at least 3.5hr, the air or oxygen intake rate is 100-200mL/min, the methanol or ethanol aqueous solution is introduced at a rate of 0.1-0.5mL/min, and then stop feeding air or oxygen and methanol or ethanol For the aqueous solution, change to nitrogen gas for at least 3 hours, the rate of nitrogen gas introduction is 100mL-200mL/min, and finally ammonia gas is introduced for activation, and the rate of ammonia gas is 100mL-200mL/min.

In the present invention, the acid regulator used in the first step can be basic aluminum oxide or basic silicon oxide.

The invention has the beneficial effects of simple preparation process, low cost of raw materials, high yield up to over 50%, and the catalyst can be regenerated, so that the production efficiency is high, and it has industrial significance.

Detailed ways

Below in conjunction with embodiment further illustrate the present invention.

Example 1

The first step prepares the cobalt-aluminum phosphate catalyst that contains acid regulator

Dissolve 81.2g (NH ₄ ) ₃ PO ₄ 3H ₂ O crystals in 250mL of distilled water, weigh 20.3g of basic aluminum oxide and pour it into a 1000mL flask, add about 250mL of deionized water and stir, mix 54.9g of cobalt nitrate and 42.6g of nitric acid Dissolve aluminum in 250mL of distilled water, slowly drop it into the prepared flask containing (NH ₄ ) ₃ PO ₄ solution under stirring, stir for 30min, filter the formed precipitate with suction, and wash the filter cake with 4×200mL of distilled water. It can be molded after proper drying, and then baked at 400°C for 12 hours before use.

In the second step, propionaldehyde and ammonia are used as raw materials for ring-forming reaction

Add a certain amount of catalyst into the fixed-bed reactor, raise the temperature to 450°C, control the injection speed of ammonia gas at about 200mL/min, turn on the injection pump, and adjust the injection speed of propionaldehyde to 1.82mL/min. min, gas phase analysis of the distillate, until the content of 2-ethyl-3,5-lutidine was significantly reduced, the sampling pump and the ammonia gas valve were turned off, and the catalyst was left to be activated.

The distillate containing crude 2-ethyl-3,5-lutidine is rectified to obtain a product with a content of more than 98%, and the molar yield is 60% in terms of propionaldehyde.

In the third step, 400g 2-ethyl-3,5-lutidine and 800g sulfur powder were stirred, mixed, heated to 150°C, and reacted for 28 hours, until the raw material 2-ethyl-3,5-lutidine Until the content of the compound is substantially constant, distill under reduced pressure, then rectify to obtain 230g of 2,3,5-collidine with a content of more than 99.5%, and reclaim 95.5g of 2-ethyl-3,5-collidine, Based on the consumed 2-ethyl-3,5-lutidine, the molar yield is 84.3%.

The fourth step is catalyst activation and regeneration

Raise the bed temperature of the fixed-bed reactor to 500°C, and at the same time, feed oxygen and methanol aqueous solution with a volume concentration of 5% for at least 3.5 hours. min, then stop feeding oxygen and methanol aqueous solution, and switch to nitrogen for at least 3 hours at a rate of 100mL/min, and finally activate with ammonia gas at a rate of 100mL/min. After the activation is completed, the reaction can continue, which is basically equivalent to the activity of the new catalyst, and the activation can be repeated several times.

Example 2

The first step prepares the cobalt-aluminum phosphate catalyst that contains acid regulator

Dissolve 81.2g (NH ₄ ) ₃ PO ₄ ·3H ₂ O crystals in 250mL of distilled water, weigh 32.5g of basic alumina and pour it into a 1000mL flask, add about 250mL of deionized water and stir, mix 54.9g of cobalt nitrate and 42.6g of nitric acid Dissolve aluminum in 250mL of distilled water, slowly drop it into the prepared flask containing (NH ₄ ) ₃ PO ₄ solution under stirring, stir for 30min, filter the formed precipitate with suction, and wash the filter cake with 4×200mL of distilled water. It can be molded after proper drying, and then baked at 400°C for 12 hours before use.

In the second step, propionaldehyde and ammonia are used as raw materials for ring-forming reaction

Add a certain amount of catalyst into the fixed-bed reactor, raise the temperature to 380°C, control the injection speed of ammonia gas at about 200mL/min, turn on the injection pump, and adjust the injection speed of propionaldehyde to 2.32mL/min min, gas phase analysis of the distillate, until the content of 2-ethyl-3,5-lutidine was significantly reduced, the sampling pump and the ammonia gas valve were turned off, and the catalyst was left to be activated.

The distillate containing crude 2-ethyl-3,5-lutidine is rectified to obtain a product with a content of more than 98%, and the molar yield is 61.2% in terms of propionaldehyde.

In the third step, 400g 2-ethyl-3,5-lutidine and 600g sulfur powder were stirred, mixed, heated to 175°C, and reacted for 24 hours until the raw material 2-ethyl-3,5-lutidine Till the content of 2-collidine is substantially constant, distill under reduced pressure, then rectify to obtain 226g of 2,3,5-collidine with a content of more than 99.5%, and reclaim 100g 2-ethyl-3,5-collidine to Based on the consumed 2-ethyl-3,5-lutidine, the molar yield is 84.1%.

The fourth step is catalyst activation and regeneration

Raise the bed temperature of the fixed-bed reactor to 300°C, and at the same time, feed oxygen and 10% aqueous methanol solution for at least 3.5 hours. min, then stop feeding oxygen and methanol aqueous solution, change to nitrogen for at least 3 hours, nitrogen gas feeding rate is 150mL/min, and finally pass ammonia gas to activate, ammonia gas speed is 150mL/min. After the activation is completed, the reaction can continue, which is basically equivalent to the activity of the new catalyst, and the activation can be repeated several times.

Example 3

The first step prepares the cobalt-aluminum phosphate catalyst that contains acid regulator

Dissolve 81.2g (NH ₄ ) ₃ PO ₄ ·3H ₂ O crystals in 250mL of distilled water, weigh 40.6g of basic silicon oxide and pour it into a 1000mL flask, add about 250mL of deionized water and stir, mix 54.9g of cobalt nitrate and 42.6g of nitric acid Dissolve aluminum in 250mL of distilled water, slowly drop it into the prepared flask containing (NH ₄ ) ₃ PO ₄ solution under stirring, stir for 30min, filter the formed precipitate with suction, and wash the filter cake with 4×200mL of distilled water. It can be molded after proper drying, and then baked at 400°C for 12 hours before use.

In the second step, propionaldehyde and ammonia are used as raw materials for ring-forming reaction

Add a certain amount of catalyst into the fixed-bed reactor, raise the temperature to 300°C, control the injection speed of ammonia gas at about 200mL/min, turn on the injection pump, and adjust the injection speed of propionaldehyde to 2.9mL/min min, gas phase analysis of the distillate, until the content of 2-ethyl-3,5-lutidine was significantly reduced, the sampling pump and the ammonia gas valve were turned off, and the catalyst was left to be activated.

The distillate containing crude 2-ethyl-3,5-lutidine is rectified to obtain a product with a content of more than 98%, and the molar yield is 60.5% in terms of propionaldehyde.

In the third step, 400g 2-ethyl-3,5-lutidine and 400g sulfur powder were stirred, mixed, heated to 200°C, and reacted for 21 hours until the raw material 2-ethyl-3,5-lutidine Until the content of the compound is substantially constant, distill under reduced pressure, then rectify to obtain 220g of 2,3,5-collidine with a content of more than 99.5%, and reclaim 106.5g 2-ethyl-3,5-collidine, Based on the consumed 2-ethyl-3,5-lutidine, the molar yield is 83.6%.

The fourth step is catalyst activation and regeneration

Raise the bed temperature of the fixed-bed reactor to 500°C, and at the same time feed air and 5% ethanol aqueous solution for at least 3.5 hours, the air inlet velocity is 200mL/min, and the methanol aqueous solution inlet velocity is 0.5mL/min. min, then stop feeding air and methanol aqueous solution, change to nitrogen for at least 3 hours, nitrogen feeding rate is 200mL/min, and finally pass ammonia gas to activate, ammonia gas speed is 200mL/min. After the activation is completed, the reaction can continue, which is basically equivalent to the activity of the new catalyst, and the activation can be repeated several times.

Example 4

Catalytic Cyclization with Regenerated Catalysts

A certain amount of cobalt-aluminum phosphate catalyst containing an acid regulator was regenerated and placed in a fixed-bed reactor, the temperature was raised to 400°C, the ammonia gas injection speed was controlled at about 180mL/min, the injection pump was turned on, and the acrylic acid The injection speed of the aldehyde was adjusted to 2.22mL/min, and the distillate was analyzed by gas phase. When the content of 2-ethyl-3,5-lutidine was significantly reduced, the injection pump and the ammonia gas valve were turned off.

The distillate containing crude 2-ethyl-3,5-lutidine is rectified to obtain a product with a content of more than 98%, and the molar yield is 60.5% in terms of propionaldehyde.

In the third step, 400g 2-ethyl-3,5-lutidine and 600g sulfur powder were stirred, mixed, heated to 180°C, and reacted for 22 hours until the raw material 2-ethyl-3,5-lutidine Until the content of the compound is substantially constant, distill under reduced pressure, then rectify to obtain 232.5g of 2,3,5-collidine with a content of more than 99.5%, and reclaim 90g of 2-ethyl-3,5-collidine, Based on the consumed 2-ethyl-3,5-lutidine, the molar yield is 83.7%.

Claims (3)

1.2,3, the preparation method of 5-trimethylpyridine in turn includes the following steps:

The first step dissolved in distilled water (NH ₄) ₃PO ₄3H ₂O, add acid regulator, evenly stir, Xiao Suangu and aluminum nitrate are dissolved in the distilled water, slowly splash into then in the above-mentioned solution, the precipitation suction filtration that generates, washing leaching cake and drying forming again 400～600 ℃ of roastings 8～12 hours, obtain cobaltous phosphate aluminium composite catalyst, wherein, acid regulator and (NH ₄) ₃PO ₄3H ₂The weight ratio of O is 0.25～0.5: 1; Xiao Suangu and (NH ₄) ₃PO ₄3H ₂The mol ratio of O is 3: 4; Aluminum nitrate and (NH ₄) ₃PO ₄3H ₂The mol ratio of O is 1: 2;

Second step was put into fixed-bed reactor with composite catalyst, feed propionic aldehyde and ammonia to fixed-bed reactor, under 300～450 ℃, carry out the continuous catalysis annulation, generate 2-ethyl-3, the 5-lutidine, the input speed of propionic aldehyde is 1.82～2.9mL/min, and the input speed of ammonia is for being 200mL/min;

5-lutidine and SULPHUR POWDER stirred, mixed, are warming up to 150～200 ℃ with 2-ethyl-3 the 3rd step, and carry out demethylation reaction and make 2,3, the 5-trimethylpyridine, 2-ethyl-3, the weight ratio of 5-lutidine and SULPHUR POWDER is 1～2: 1.

2. by claim 1 described 2,3, the preparation method of 5-trimethylpyridine, it is characterized in that also comprising catalyst activation regeneration, process is for to rise to 500 ℃ with the fixed-bed reactor bed temperature, simultaneously bubbling air and volumetric concentration are 5～10% methyl alcohol or alcoholic acid aqueous solution 3.5hr at least, the intake velocity of air or oxygen is 100～200mL/min, the feeding speed of methyl alcohol or aqueous ethanolic solution is 0.1～0.5mL/min, stop bubbling air or oxygen and methyl alcohol or the alcoholic acid aqueous solution then, change logical nitrogen at least 3 hours, nitrogen feeding speed is 100mL～200mL/min, feed ammonia activation at last, ammonia speed is 100mL～200mL/min.

3. by claim 1 or 2 described 2,3, the preparation method of 5-trimethylpyridine is characterized in that the used acid regulator of the first step is alkali alumina or alkaline oxygenated silicon.