阅读说明：本技术 一种制备4-异丙基吡啶的新方法 (Novel method for preparing 4-isopropyl pyridine ) 是由 吴细兵 刘斌 孙洪亮 于 2019-08-27 设计创作，主要内容包括：本发明公开了一种制备4-异丙基吡啶的新方法,4-异丙基吡啶的新方法由异烟酸甲酯为起始原料与氯甲烷格氏试剂反应制备得到4-异丙醇吡啶,4-异丙醇吡啶再与氯化亚砜反应得到4-(2-氯)异丙基吡啶,4-(2-氯)异丙基吡啶再与钯碳加氢还原得到4-异丙基吡啶；本发明的优势在于起始原料为大工业原料,氯甲烷格氏试剂比传统的碘甲烷格氏试剂或溴甲烷格氏试剂更加具有价格优势,且由于分子量远小于碘甲烷或溴甲烷,所以用量也大大减少；最后一步加氢还原同样也几乎无三废产生。此工艺操作简单,三废少,对环境友好,同时该工艺转化率高,几乎无副产物生成,成本低廉,市场竞争优势明显。(The invention discloses a new method for preparing 4-isopropyl pyridine, which is characterized in that 4-isopropyl pyridine is prepared by reacting methyl isonicotinate serving as a starting raw material with a chloromethane Grignard reagent, 4-isopropyl pyridine is reacted with thionyl chloride to obtain 4- (2-chloro) isopropyl pyridine, and the 4- (2-chloro) isopropyl pyridine is hydrogenated and reduced with palladium carbon to obtain 4-isopropyl pyridine; the invention has the advantages that the initial raw material is a large industrial raw material, the chloromethane Grignard reagent has more price advantage than the traditional iodomethane Grignard reagent or bromomethane Grignard reagent, and the dosage is greatly reduced because the molecular weight is far less than the iodomethane or bromomethane; the final hydrogenation reduction also hardly generates three wastes. The process has the advantages of simple operation, less three wastes, environmental friendliness, high conversion rate, almost no byproduct generation, low cost and obvious market competitive advantage.)

1. A new method for preparing 4-isopropyl pyridine, the new method of 4-isopropyl pyridine is to take methyl isonicotinate as the starting material to react with chloromethane Grignard reagent to prepare 4-isopropyl pyridine, the 4-isopropyl pyridine then reacts with thionyl chloride to obtain 4- (2-chloro) isopropyl pyridine, the 4- (2-chloro) isopropyl pyridine then reacts with palladium carbon to be hydrogenated and reduced to obtain 4-isopropyl pyridine; the method is characterized in that: the novel method of the 4-isopropyl pyridine specifically comprises the following steps:

step 1: dropping a quantitative chloromethane Grignard reagent into the methyl isonicotinate at the temperature controlled below 30 ℃ to react to prepare 4-isopropanol pyridine;

step 2: 4- (2-chloro) isopropyl pyridine is prepared from 4-isopropyl pyridine and thionyl chloride under the reflux condition; after the reaction is finished, evaporating excessive thionyl chloride, and then distilling under reduced pressure to obtain 4- (2-chloro) isopropylpyridine;

and step 3: 4- (2-chloro) isopropylpyridine is hydrogenated and reduced in 80 percent ethanol solution by palladium carbon to prepare 4-isopropylpyridine hydrochloride, and 4-isopropylpyridine is obtained after neutralization.

2. The process of claim 1, wherein the reaction mixture is prepared by the following steps: the specific steps of the step 1 are as follows: introducing chloromethane into a proper amount of THF (tetrahydrofuran/tetrahydrofuran) at the temperature of below 0 ℃ to prepare chloromethane/THF mixed solution, adding dried magnesium into a reaction kettle, controlling the temperature to be 5-15 ℃, dropwise adding the chloromethane/THF mixed solution, keeping the temperature to be 10-15 ℃ for reaction for 1 hour, slowly heating to 30 ℃ for reaction for 2 hours, adding a proper amount of tetrahydrofuran and a proper amount of methyl isonicotinate into another reaction kettle, controlling the temperature to be below 30 ℃, dropwise adding the prepared chloromethane Grignard reagent, keeping the temperature to be 25-30 ℃ for reaction for 12 hours after dropwise adding, recovering THF (tetrahydrofuran) at normal pressure till the temperature is basically not removed, reducing the temperature to be below 30 ℃, dropwise adding a hydrochloric acid aqueous solution till the pH of a system is 6-7, centrifuging to obtain 4-isopropanolpyridin, and drying to obtain the 4-isopropano.

3. The process of claim 1, wherein the reaction mixture is prepared by the following steps: the specific steps of the step 2 are as follows: pumping toluene into a reaction kettle, adding 4-isopropyl pyridine, dropwise adding thionyl chloride at the temperature controlled below 30 ℃, controlling the temperature to be 50-60 ℃ after dropwise adding, reacting for 5 hours, recovering thionyl chloride at normal pressure to the liquid temperature of 90 ℃, cooling to the temperature below 30 ℃, dropwise adding the thionyl chloride into a post-treatment kettle filled with water at the temperature controlled below 10 ℃, separating a water layer, washing an organic layer with water once, and carrying out reduced pressure distillation on the organic layer to collect a fraction (-0.095mpa) at the temperature of 110-140 ℃ so as to obtain the 4- (2-chloro) isopropyl pyridine.

4. The process of claim 1, wherein the reaction mixture is prepared by the following steps: the specific steps of the step 3 are as follows: adding 4- (2-chloro) isopropylpyridine into a hydrogenation kettle filled with 80% ethanol, adding palladium carbon (10%), controlling the temperature to be 55-60 ℃, carrying out 0.5-1mpa hydrogenation reaction until no pressure drop exists basically, filtering out reaction liquid, leaching filter cakes by using a small amount of water, recovering ethanol at normal pressure until the liquid temperature is 100 ℃ and the ethanol does not exist basically, adjusting the pH value to be more than 9 by using 30% sodium hydroxide aqueous solution, separating out a water layer, wherein the organic layer is 4-isopropylpyridine, and the content is more than or equal to 99%.

Technical Field

The invention belongs to the synthesis and application of a medical intermediate (3-hydroxy-4-amino-butyl-2-yl) -3- (2-thiazole-2-yl-pyrrolidinyl-1-carbonyl) benzamide and a derivative thereof (a beta-secretase inhibitor which is mainly used for treating Alzheimer's disease) and an important intermediate of a novel marine antifouling biocide diphenyl-methyl-4-isopropyl pyridyl boron (KM-2), and belongs to the technical field of medical manufacturing.

Background

Alzheimer's Disease (AD) is a progressive degenerative disease of the nervous system with occult onset. Clinically, the overall dementia such as dysmnesia, aphasia, disuse, agnosia, impairment of visual spatial skills, dysfunction in execution, and personality and behavior changes are characterized, and the etiology is unknown. Patients who are older than 65 years are called presenile dementia; the patient after 65 years old is called senile dementia. Beta-secretase inhibitors are currently the most commonly used drugs for treating this disease.

However, if the ship bottom, the fishing net, the seawater supply and drainage pipe, the underwater structure, etc. are exposed to water for a long time, animals such as oyster, mussel, barnacle, etc., plants such as sea sedge, etc., or various aquatic organisms such as bacteria, etc. may be attached to the surface of the ship bottom, the fishing net, the seawater supply and drainage pipe, the underwater structure, etc. and propagate on the surface of the ship bottom, the sea sedge, etc.. Particularly, if such aquatic organisms adhere to and propagate on the bottom of the ship, the surface roughness of the ship body increases, which may result in a decrease in the ship speed and an increase in fuel consumption. Furthermore, a lot of manpower and working time are required to remove these organisms from the bottom of the ship. In addition, if these aquatic organisms attach, breed and breed nets or other fixing nets, clogging of the net may occur, causing oxygen deficiency of the fisheries and hunting or breeding organisms, and thus death, resulting in loss. Further, if these organisms adhere to and propagate in seawater supply and drainage pipes of thermal power plants, nuclear power plants, etc., they may have a bad influence on the supply and circulation of cooling water. KM-2 is a new type of marine antifouling biocide which is effective in preventing the attachment and reproduction of marine organisms and is environmentally friendly.

Disclosure of Invention

The invention provides a new method for preparing 4-isopropyl pyridine, which comprises the steps of reacting methyl isonicotinate serving as a starting material with a chloromethane Grignard reagent to prepare 4-isopropyl pyridine, reacting with thionyl chloride to obtain 4- (2-chloro) isopropyl pyridine, and performing hydrogenation reduction with palladium carbon to obtain 4-isopropyl pyridine; the method has the advantages of easily obtained raw materials, overcoming the high pollution of the prior art, being environment-friendly and being suitable for large-scale industrial production.

In order to solve the technical problems, the invention provides the following technical scheme: a new method for preparing 4-isopropyl pyridine, the new method of 4-isopropyl pyridine is that methyl isonicotinate is used as the starting material to react with chloromethane Grignard reagent to prepare 4-isopropyl pyridine, 4-isopropyl pyridine reacts with thionyl chloride to obtain 4- (2-chlorine) isopropyl pyridine, 4- (2-chlorine) isopropyl pyridine reacts with palladium carbon to be hydrogenated and reduced to obtain 4-isopropyl pyridine; the novel method of 4-isopropyl pyridine specifically comprises the following steps:

step 1: dropping a quantitative chloromethane Grignard reagent into the methyl isonicotinate at the temperature controlled below 30 ℃ to react to prepare 4-isopropanol pyridine;

step 2: 4- (2-chloro) isopropyl pyridine is prepared from 4-isopropyl pyridine and thionyl chloride under the reflux condition; after the reaction is finished, evaporating excessive thionyl chloride, and then distilling under reduced pressure to obtain 4- (2-chloro) isopropylpyridine;

and step 3: 4- (2-chloro) isopropylpyridine is hydrogenated and reduced in 80 percent ethanol solution by palladium carbon to prepare 4-isopropylpyridine hydrochloride, and 4-isopropylpyridine is obtained after neutralization.

As a preferred technical scheme of the invention, the specific steps of the step 1 are as follows: introducing chloromethane into a proper amount of THF (tetrahydrofuran/tetrahydrofuran) at the temperature of below 0 ℃ to prepare chloromethane/THF mixed solution, adding dried magnesium into a reaction kettle, controlling the temperature to be 5-15 ℃, dropwise adding the chloromethane/THF mixed solution, keeping the temperature to be 10-15 ℃ for reaction for 1 hour, slowly heating to 30 ℃ for reaction for 2 hours, adding a proper amount of tetrahydrofuran and a proper amount of methyl isonicotinate into another reaction kettle, controlling the temperature to be below 30 ℃, dropwise adding the prepared chloromethane Grignard reagent, keeping the temperature to be 25-30 ℃ for reaction for 12 hours after dropwise adding, recovering THF (tetrahydrofuran) at normal pressure till the temperature is basically not removed, reducing the temperature to be below 30 ℃, dropwise adding a hydrochloric acid aqueous solution till the pH of a system is 6-7, centrifuging to obtain 4-isopropanolpyridin, and drying to obtain the 4-isopropano.

As a preferred technical scheme of the present invention, the specific steps of step 2 are: pumping toluene into a reaction kettle, adding 4-isopropyl pyridine, dropwise adding thionyl chloride at the temperature controlled below 30 ℃, controlling the temperature to be 50-60 ℃ after dropwise adding, reacting for 5 hours, recovering thionyl chloride at normal pressure to the liquid temperature of 90 ℃, cooling to the temperature below 30 ℃, dropwise adding the thionyl chloride into a post-treatment kettle filled with water at the temperature controlled below 10 ℃, separating a water layer, washing an organic layer with water once, and carrying out reduced pressure distillation on the organic layer to collect a fraction (-0.095mpa) at the temperature of 110-140 ℃ so as to obtain the 4- (2-chloro) isopropyl pyridine.

As a preferred technical scheme of the present invention, the specific steps of step 3 are: adding 4- (2-chloro) isopropylpyridine into a hydrogenation kettle filled with 80% ethanol, adding palladium carbon (10%), controlling the temperature to be 55-60 ℃, carrying out 0.5-1mpa hydrogenation reaction until no pressure drop exists basically, filtering out reaction liquid, leaching filter cakes by using a small amount of water, recovering ethanol at normal pressure until the liquid temperature is 100 ℃ and the ethanol does not exist basically, adjusting the pH value to be more than 9 by using 30% sodium hydroxide aqueous solution, separating out a water layer, wherein the organic layer is 4-isopropylpyridine, and the content is more than or equal to 99%.

Compared with the prior art, the invention can achieve the following beneficial effects: the invention has the advantages that the initial raw material is a large industrial raw material, the chloromethane Grignard reagent has more price advantage than the traditional iodomethane Grignard reagent or bromomethane Grignard reagent, and the dosage is greatly reduced because the molecular weight is far less than the iodomethane or bromomethane; thionyl chloride is selected for halogenation, no other three wastes are generated except a certain amount of hydrogen chloride and sulfur dioxide gas generated in the reaction, and the generated hydrogen chloride and sulfur dioxide can be used for preparing ethyl chloride and sodium sulfite after treatment and purification, and can be used for synthesizing other chemical products. The final hydrogenation reduction also hardly generates three wastes. The process has the advantages of simple operation, less three wastes, environmental friendliness, high conversion rate, almost no byproduct generation, low cost and obvious market competitive advantage.

Drawings

FIG. 1 is a chemical reaction scheme of 4-isopropylpyridine according to the present invention.

Detailed Description

The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it will be understood that they are described herein for the purpose of illustration and explanation and not limitation.

The invention discloses a new method for preparing 4-isopropyl pyridine, which is characterized in that 4-isopropyl pyridine is prepared by reacting methyl isonicotinate serving as a starting raw material with a chloromethane Grignard reagent, 4-isopropyl pyridine is reacted with thionyl chloride to obtain 4- (2-chloro) isopropyl pyridine, and the 4- (2-chloro) isopropyl pyridine is hydrogenated and reduced with palladium carbon to obtain 4-isopropyl pyridine; the novel method of 4-isopropyl pyridine specifically comprises the following steps:

step 1: dropping a quantitative chloromethane Grignard reagent into the methyl isonicotinate at the temperature controlled below 30 ℃ to react to prepare 4-isopropanol pyridine;

step 2: 4- (2-chloro) isopropyl pyridine is prepared from 4-isopropyl pyridine and thionyl chloride under the reflux condition; after the reaction is finished, evaporating excessive thionyl chloride, and then distilling under reduced pressure to obtain 4- (2-chloro) isopropylpyridine;

and step 3: 4- (2-chloro) isopropylpyridine is hydrogenated and reduced in 80 percent ethanol solution by palladium carbon to prepare 4-isopropylpyridine hydrochloride, and 4-isopropylpyridine is obtained after neutralization.

The specific steps of the step 1 are as follows: introducing chloromethane into a proper amount of THF (tetrahydrofuran/tetrahydrofuran) at the temperature of below 0 ℃ to prepare chloromethane/THF mixed solution, adding dried magnesium into a reaction kettle, controlling the temperature to be 5-15 ℃, dropwise adding the chloromethane/THF mixed solution, keeping the temperature to be 10-15 ℃ for reaction for 1 hour, slowly heating to 30 ℃ for reaction for 2 hours, adding a proper amount of tetrahydrofuran and a proper amount of methyl isonicotinate into another reaction kettle, controlling the temperature to be below 30 ℃, dropwise adding the prepared chloromethane Grignard reagent, keeping the temperature to be 25-30 ℃ for reaction for 12 hours after dropwise adding, recovering THF (tetrahydrofuran) at normal pressure till the temperature is basically not removed, reducing the temperature to be below 30 ℃, dropwise adding a hydrochloric acid aqueous solution till the pH of a system is 6-7, centrifuging to obtain 4-isopropanolpyridin, and drying to obtain the 4-isopropano.

The specific steps of the step 2 are as follows: pumping toluene into a reaction kettle, adding 4-isopropyl pyridine, dropwise adding thionyl chloride at the temperature controlled below 30 ℃, controlling the temperature to be 50-60 ℃ after dropwise adding, reacting for 5 hours, recovering thionyl chloride at normal pressure to the liquid temperature of 90 ℃, cooling to the temperature below 30 ℃, dropwise adding the thionyl chloride into a post-treatment kettle filled with water at the temperature controlled below 10 ℃, separating a water layer, washing an organic layer with water once, and carrying out reduced pressure distillation on the organic layer to collect a fraction (-0.095mpa) at the temperature of 110-140 ℃ so as to obtain the 4- (2-chloro) isopropyl pyridine.

The specific steps of the step 3 are as follows: adding 4- (2-chloro) isopropylpyridine into a hydrogenation kettle filled with 80% ethanol, adding palladium carbon (10%), controlling the temperature to be 55-60 ℃, carrying out 0.5-1mpa hydrogenation reaction until no pressure drop exists basically, filtering out reaction liquid, leaching filter cakes by using a small amount of water, recovering ethanol at normal pressure until the liquid temperature is 100 ℃ and the ethanol does not exist basically, adjusting the pH value to be more than 9 by using 30% sodium hydroxide aqueous solution, separating out a water layer, wherein the organic layer is 4-isopropylpyridine, and the content is more than or equal to 99%.

Steps 1, 2 and 3 will now be described by way of example;

the first embodiment is as follows:

preparation of 4-Isopropoxypyridine:

introducing 8.7kg of methyl chloride into 30kg of THF at the temperature of below 0 ℃ to prepare a methyl chloride/THF mixed solution, adding 3.6kg of dried magnesium into a 50L reaction kettle, controlling the temperature to be 5-15 ℃, dropwise adding the methyl chloride/THF mixed solution, keeping the temperature to be 10-15 ℃ for reaction for 1 hour after dropwise adding, slowly heating to 30 ℃ for reaction for 2 hours, adding 30kg of tetrahydrofuran and 6.85kg of methyl isonicotinate into another 100L reaction kettle, controlling the temperature to be below 30 ℃, dropwise adding the prepared methyl chloride Grignard reagent, keeping the temperature to be 25-30 ℃ for reaction for 12 hours after dropwise adding, recovering THF at normal pressure until the temperature is not increased basically when the THF is 90 ℃, cooling to be below 30 ℃, dropwise adding a hydrochloric acid aqueous solution until the system pH is 6-7, centrifuging to obtain 4-isoproponal pyridine, and drying to obtain 5.4kg of 4-isoproponal pyridine with the content of not less than.

Preparation of 4- (2-chloro) isopropylpyridine:

100kg of toluene is pumped into a 500L reaction kettle, 50kg of 4-isopropyl pyridine is added, 65kg of thionyl chloride is dripped at the temperature controlled below 30 ℃, the temperature controlled 50-60 ℃ is controlled for reaction for 5 hours after the dripping, the thionyl chloride is recovered under normal pressure to the liquid temperature of 90 ℃, the temperature is reduced to below 30 ℃, the temperature controlled below 10 ℃ is dripped into an after-treatment kettle filled with 100kg of water, a water layer is separated, an organic layer is washed once by 100kg of water, and the organic layer is subjected to reduced pressure distillation to collect 110-140 ℃ fraction (-0.095mpa), so 55kg of 4- (2-chloro) isopropyl pyridine can be obtained.

Preparation of 4-isopropylpyridine:

adding 50kg of 4- (2-chloro) isopropylpyridine into a 500L hydrogenation kettle filled with 200kg of 80% ethanol, adding 5kg of palladium carbon (10%), controlling the temperature to be 55-60 ℃, carrying out 0.5-1mpa hydrogenation reaction until pressure drop does not exist basically, filtering reaction liquid, leaching filter cakes by using a small amount of water, recovering ethanol at normal pressure until the liquid temperature is 100 ℃, and basically not discharging, adjusting the pH value to be more than 9 by using 30% sodium hydroxide aqueous solution, separating out a water layer, wherein the organic layer is 4-isopropylpyridine, and the content of about 38kg. is more than or equal to 99%.

The invention has the advantages that the initial raw material is a large industrial raw material, the chloromethane Grignard reagent has more price advantage than the traditional iodomethane Grignard reagent or bromomethane Grignard reagent, and the dosage is greatly reduced because the molecular weight is far less than the iodomethane or bromomethane; thionyl chloride is selected for halogenation, no other three wastes are generated except a certain amount of hydrogen chloride and sulfur dioxide gas generated in the reaction, and the generated hydrogen chloride and sulfur dioxide can be used for preparing ethyl chloride and sodium sulfite after treatment and purification, and can be used for synthesizing other chemical products. The final hydrogenation reduction also hardly generates three wastes. The process has the advantages of simple operation, less three wastes, environmental friendliness, high conversion rate, almost no byproduct generation, low cost and obvious market competitive advantage.

The embodiments of the present invention are not limited thereto, and according to the above-described embodiments of the present invention, other embodiments obtained by modifying, replacing or combining the above-described preferred embodiments in various other forms without departing from the basic technical idea of the present invention by using the conventional technical knowledge and the conventional means in the field can fall within the scope of the present invention.