CN112441964A - Novel method for preparing 4-isopropyl pyridine - Google Patents
Novel method for preparing 4-isopropyl pyridine Download PDFInfo
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- CN112441964A CN112441964A CN201910795582.XA CN201910795582A CN112441964A CN 112441964 A CN112441964 A CN 112441964A CN 201910795582 A CN201910795582 A CN 201910795582A CN 112441964 A CN112441964 A CN 112441964A
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- FRGXNJWEDDQLFH-UHFFFAOYSA-N 4-propan-2-ylpyridine Chemical compound CC(C)C1=CC=NC=C1 FRGXNJWEDDQLFH-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 48
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- -1 chloromethane Grignard reagent Chemical class 0.000 claims abstract description 23
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 21
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 12
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000010410 layer Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002386 leaching Methods 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- BHFRNWSEICUVPB-UHFFFAOYSA-N Cl.C(C)(C)C1=CC=NC=C1 Chemical compound Cl.C(C)(C)C1=CC=NC=C1 BHFRNWSEICUVPB-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 9
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 abstract description 6
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 3
- 230000002860 competitive effect Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 8
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 229940050176 methyl chloride Drugs 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- 239000013535 sea water Substances 0.000 description 3
- PFYPDUUXDADWKC-UHFFFAOYSA-N 2-propan-2-ylpyridine Chemical compound CC(C)C1=CC=CC=N1 PFYPDUUXDADWKC-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 241000541656 Carex marina Species 0.000 description 2
- 230000003373 anti-fouling effect Effects 0.000 description 2
- 239000002439 beta secretase inhibitor Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003139 biocide Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- 229960003750 ethyl chloride Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- IHELYFQSNOJLTC-UHFFFAOYSA-N 4-propan-2-yloxypyridine Chemical compound CC(C)OC1=CC=NC=C1 IHELYFQSNOJLTC-UHFFFAOYSA-N 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
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.
Description
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.
Claims (4)
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%.
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| MICHAEL VAN DER PUY: ""Trifluoroethylation of olefins with trichlorotrifluoroethane"", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
| TAKASHI OYAMA ET AL: ""Heterogeneously Palladium-catalyzed Acceptorless dehydrogenative Aromatization of Cyclic Amines"", 《CHEMISTRY LETTERS》 * |
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