CN110981833A - Method for preparing immaric acid by one-pot method - Google Patents
Method for preparing immaric acid by one-pot method Download PDFInfo
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- CN110981833A CN110981833A CN201911120531.3A CN201911120531A CN110981833A CN 110981833 A CN110981833 A CN 110981833A CN 201911120531 A CN201911120531 A CN 201911120531A CN 110981833 A CN110981833 A CN 110981833A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
The invention discloses a method for preparing immaric acid by a one-pot method, which comprises the following steps: carrying out condensation reaction on N-methylpiperazine and p-cyanobenzyl chloride under the action of an alkali catalyst to obtain an intermediate; then the imma acid is obtained by hydrochloric acid hydrolysis. The method has the advantages of convenient operation, short reaction time, easy separation and purification of the final product, high yield, less three wastes and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a method for preparing immaric acid by a one-pot method.
Background
Imatic acid is a key intermediate of Imatinib mesylate (generic name Imatinib, trade name gleevec), a small molecule tyrosine kinase inhibitor developed by Novartis, switzerland. The traditional Chinese medicine composition is clinically used for treating chronic myelogenous leukemia and malignant gastrointestinal stromal tumors. Imatinib mesylate was approved by the U.S. Food and Drug Administration (FDA) in 5 months 2001.
Imatinib was the first small molecule target inhibitor. The medicine has high efficiency and low toxicity, becomes one of the most promising anti-tumor medicines, and provides some ideas for guiding the targeted treatment and research of other tumors.
The chemical name of the imatic acid is 4- (4-methylpiperazinomethyl) benzoic acid dihydrochloride, methyl p-methylbenzoate is used as a raw material, N-bromosuccinimide is used as a bromination reagent in the conventional synthesis process, the reaction is finished, the post-treatment is carried out, the crystallization, purification and drying are carried out, the methyl p-bromomethylbenzoate is prepared, the reaction is carried out with N-methylpiperazine to obtain an intermediate, and the intermediate is hydrolyzed after the purification to prepare the imatic acid. The intermediate methyl p-bromomethylbenzoate obtained by the prior art needs to be purified and dried, the product is dazzling, the reaction route is long, the reaction yield is low, the operation is complicated, and the industrial production is not facilitated.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a one-pot method for preparing the imaric acid, which has the advantages of convenient operation, short reaction time, easy separation and purification of the final product, high yield, less three wastes and low production cost, and is suitable for industrial production.
The invention provides a method for preparing immaric acid by a one-pot method, which comprises the following steps: carrying out condensation reaction on N-methylpiperazine and p-cyanobenzyl chloride under the action of an alkali catalyst to obtain an intermediate; then the imma acid is obtained by hydrochloric acid hydrolysis.
Preferably, the method comprises the following steps: uniformly mixing N-methylpiperazine, an alkali catalyst and an organic solvent, dropwise adding the organic solvent in which p-cyanobenzyl chloride is dissolved, carrying out condensation reaction, then carrying out suction filtration, and taking filtrate to remove the solvent to obtain an intermediate; and adding water and hydrochloric acid into the intermediate for hydrolysis, and then cooling and crystallizing to obtain the imatic acid.
Preferably, the base catalyst is an alkali metal carbonate.
Preferably, the base catalyst is at least one of potassium carbonate and sodium carbonate.
Preferably, when the base catalyst is potassium carbonate, the mass ratio of potassium carbonate to p-cyanobenzyl chloride is 1.12-1.42: 1.
preferably, when the alkali catalyst is sodium carbonate, the mass ratio of the sodium carbonate to the p-cyanobenzyl chloride is 1.05-1.28: 1.
preferably, the organic solvent is an aprotic organic solvent.
Preferably, the organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
Preferably, the mass ratio of the organic solvent to the paracyano-chlorobenzyl chloride is 2.0-3.0: 1.
preferably, the mass ratio of the N-methylpiperazine to the p-cyanobenzyl chloride is 0.75 to 0.95: 1.
preferably, the condensation reaction is carried out at a temperature of 60-100 ℃ for a reaction time of 12-18 h.
Preferably, the hydrochloric acid is 28-32% of hydrochloric acid aqueous solution in mass fraction.
Preferably, the mass ratio of hydrochloric acid to p-cyanobenzyl chloride is 3.5-4.5: 1.
preferably, the hydrolysis temperature is 95-115 deg.C and the time is 5-10 h.
Preferably, after cooling and crystallization, the imma acid is obtained by washing and drying through methanol, wherein the mass ratio of the methanol to the p-cyanobenzyl chloride is 2.2-3.0: 1.
according to the invention, N-methylpiperazine is used as a raw material, under the action of an alkali catalyst, a solution in which p-cyanobenzyl chloride is dissolved is dripped, and condensation reaction is carried out to obtain an intermediate; the obtained intermediate is directly hydrolyzed in one pot under the condition of hydrochloric acid without refining and purification, and then cooled and crystallized to obtain a crude product of the immaric acid, and the crude product of the immaric acid is washed and refined by methanol and dried to obtain the immaric acid; the intermediate does not need to be refined, and the intermediate and other raw materials are added in a one-pot method, so the method has the advantages of convenient operation, short reaction time, easy separation and purification of the final product, high yield, less three wastes and low production cost, and is suitable for industrial production.
Drawings
FIG. 1 is a reaction scheme of the present invention.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
A method for preparing immaric acid by a one-pot method comprises the following steps: adding 120kg of N, N-dimethylformamide, 60kg of N-methylpiperazine and 96kg of anhydrous potassium carbonate into a 500L reaction kettle in sequence, starting stirring, starting jacket circulating water, dropwise adding 70kg of N, N-dimethylformamide dissolved with 75kg of p-cyanobenzyl chloride, controlling the dropwise adding temperature to be 30-40 ℃, heating to 80 ℃ after dropwise adding, carrying out heat preservation reaction for 15 hours, then carrying out suction filtration, carrying out reduced pressure distillation on filtrate to remove an organic solvent to obtain an intermediate, wherein the temperature of the reduced pressure distillation is less than or equal to 95 ℃; then cooling to 50 ℃, sequentially adding 50kg of water and 300kg of a hydrochloric acid aqueous solution with the mass fraction of 30%, heating to 106 ℃ and 110 ℃ to enable the mixture to flow back for 6 hours, cooling to 10 ℃, stirring and crystallizing for 2 hours, performing suction filtration to obtain a filter cake, and performing centrifugal drying to obtain a crude product of the imatic acid; adding 200kg of methanol into a 500L reaction kettle, adding the crude product of the imatic acid, stirring for 2h at room temperature, carrying out suction filtration to obtain a filter cake, centrifuging, drying to obtain the imatic acid, wherein the yield of the imatic acid is 85%, and the purity of the imatic acid is 99.2%.
Example 2
A method for preparing immaric acid by a one-pot method comprises the following steps: adding 100kg of N, N-dimethylformamide, 72kg of N-methylpiperazine and 96kg of anhydrous potassium carbonate into a 500L reaction kettle in sequence, starting stirring, starting jacket circulating water, dropwise adding 90kg of N, N-dimethylformamide dissolved with 75kg of p-cyanobenzyl chloride, controlling the dropwise adding temperature to be 30-40 ℃, heating to 80 ℃ after dropwise adding, carrying out heat preservation reaction for 15 hours, then carrying out suction filtration, carrying out reduced pressure distillation on filtrate to remove an organic solvent to obtain an intermediate, wherein the temperature of the reduced pressure distillation is less than or equal to 95 ℃; then cooling to 50 ℃, sequentially adding 50kg of water and 300kg of a hydrochloric acid aqueous solution with the mass fraction of 30%, heating to 106 ℃ and 110 ℃ to enable the mixture to flow back for 6 hours, cooling to 10 ℃, stirring and crystallizing for 2 hours, performing suction filtration to obtain a filter cake, and performing centrifugal drying to obtain a crude product of the imatic acid; adding 200kg of methanol into a 500L reaction kettle, adding the crude product of the imatic acid, stirring for 2h at room temperature, carrying out suction filtration to obtain a filter cake, centrifuging, drying to obtain the imatic acid, wherein the yield of the imatic acid is 86.2%, and the purity is 99.0%.
Example 3
A method for preparing immaric acid by a one-pot method comprises the following steps: adding 120kg of N, N-dimethylformamide, 57kg of N-methylpiperazine and 105kg of anhydrous potassium carbonate into a 500L reaction kettle in sequence, starting stirring, starting jacket circulating water, dropwise adding 70kg of N, N-dimethylformamide dissolved with 75kg of p-cyanobenzyl chloride, controlling the dropwise adding temperature to be 30-40 ℃, heating to 80 ℃ after dropwise adding, carrying out heat preservation reaction for 15 hours, then carrying out suction filtration, carrying out reduced pressure distillation on filtrate to remove an organic solvent to obtain an intermediate, wherein the temperature of the reduced pressure distillation is less than or equal to 95 ℃; then cooling to 50 ℃, sequentially adding 50kg of water and 300kg of a hydrochloric acid aqueous solution with the mass fraction of 30%, heating to 106 ℃ and 110 ℃ to enable the mixture to flow back for 6 hours, cooling to 10 ℃, stirring and crystallizing for 2 hours, performing suction filtration to obtain a filter cake, and performing centrifugal drying to obtain a crude product of the imatic acid; adding 200kg of methanol into a 500L reaction kettle, adding the crude product of the imatic acid, stirring for 2h at room temperature, carrying out suction filtration to obtain a filter cake, centrifuging, drying to obtain the imatic acid, wherein the yield of the imatic acid is 84.5%, and the purity is 99.1%.
Example 4
A method for preparing immaric acid by a one-pot method comprises the following steps: adding 225kg of N, N-dimethylacetamide, 56.25kg of N-methylpiperazine and 78.75kg of anhydrous sodium carbonate into a 500L reaction kettle in sequence, starting stirring, starting jacket circulating water, dropwise adding 70kg of N, N-dimethylacetamide in which 75kg of p-cyanobenzyl chloride is dissolved, controlling the dropwise adding temperature to be 30-40 ℃, heating to 60 ℃ after dropwise adding, carrying out heat preservation reaction for 18 hours, carrying out suction filtration, carrying out reduced pressure distillation on filtrate to remove an organic solvent to obtain an intermediate, wherein the temperature of the reduced pressure distillation is less than or equal to 95 ℃; then cooling to 50 ℃, sequentially adding 50kg of water and 262.5kg of a 28% hydrochloric acid aqueous solution by mass fraction, heating to 95-115 ℃ to reflux for 10h, cooling to 10 ℃, stirring for crystallization for 2h, carrying out suction filtration to obtain a filter cake, and carrying out centrifugal drying to obtain a crude product of the imaric acid; adding 165kg of methanol into a 500L reaction kettle, adding the crude product of the imatic acid, stirring for 2h at room temperature, carrying out suction filtration to obtain a filter cake, centrifuging, drying to obtain the imatic acid, wherein the yield of the imatic acid is 85.1%, and the purity is 99.0%.
Example 5
A method for preparing immaric acid by a one-pot method comprises the following steps: sequentially adding 150kg of N-methyl pyrrolidone, 71.25kg of N-methyl piperazine and 106.5kg of anhydrous potassium carbonate into a 500L reaction kettle, starting stirring, starting jacket circulating water, dropwise adding 70kg of N-methyl pyrrolidone dissolved with 75kg of p-cyanobenzyl chloride, controlling the dropwise adding temperature to be 30-40 ℃, heating to 100 ℃ after dropwise adding, carrying out heat preservation reaction for 12 hours, carrying out suction filtration, carrying out reduced pressure distillation on filtrate to remove an organic solvent to obtain an intermediate, wherein the temperature of the reduced pressure distillation is less than or equal to 95 ℃; then cooling to 50 ℃, sequentially adding 50kg of water and 337.5kg of aqueous solution of hydrochloric acid with the mass fraction of 32%, heating to 95-115 ℃ to enable the mixture to flow back for 5 hours, cooling to 10 ℃, stirring for crystallization for 2 hours, carrying out suction filtration to obtain a filter cake, and carrying out centrifugal drying to obtain a crude product of the imaric acid; adding 225kg of methanol into a 500L reaction kettle, adding the crude product of the imatic acid, stirring for 2h at room temperature, carrying out suction filtration to obtain a filter cake, centrifuging, drying to obtain the imatic acid, wherein the yield of the imatic acid is 85.2%, and the purity of the imatic acid is 99.1%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A method for preparing immaric acid by a one-pot method is characterized by comprising the following steps: carrying out condensation reaction on N-methylpiperazine and p-cyanobenzyl chloride under the action of an alkali catalyst to obtain an intermediate; then the imma acid is obtained by hydrochloric acid hydrolysis.
2. The one-pot process for the preparation of immamic acid as claimed in claim 1, comprising the steps of: uniformly mixing N-methylpiperazine, an alkali catalyst and an organic solvent, dropwise adding the organic solvent in which p-cyanobenzyl chloride is dissolved, carrying out condensation reaction, then carrying out suction filtration, and taking filtrate to remove the solvent to obtain an intermediate; and adding water and hydrochloric acid into the intermediate for hydrolysis, and then cooling and crystallizing to obtain the imatic acid.
3. The one-pot process for preparing ima acid according to claim 1 or 2, wherein the base catalyst is an alkali metal carbonate; preferably, the alkali catalyst is at least one of potassium carbonate and sodium carbonate; preferably, when the base catalyst is potassium carbonate, the mass ratio of potassium carbonate to p-cyanobenzyl chloride is 1.12-1.42: 1; preferably, when the alkali catalyst is sodium carbonate, the mass ratio of the sodium carbonate to the p-cyanobenzyl chloride is 1.05-1.28: 1.
4. the one-pot process for preparing imaric acid according to any one of claims 1 to 3, wherein the organic solvent is an aprotic organic solvent; preferably, the organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; preferably, the mass ratio of the organic solvent to the paracyano-chlorobenzyl chloride is 2.0-3.0: 1.
5. the one-pot process for preparing immamic acid as claimed in any one of claims 1 to 4 wherein the mass ratio of N-methylpiperazine to p-cyanobenzyl chloride is from 0.75 to 0.95: 1.
6. the one-pot process for preparing imma acid according to any one of claims 1 to 5, wherein the condensation reaction is carried out at a temperature of 60 to 100 ℃ and for a reaction time of 12 to 18 hours.
7. The one-pot method for preparing imaric acid according to any one of claims 1 to 6, wherein the hydrochloric acid is 28 to 32 mass% aqueous hydrochloric acid.
8. The one-pot process for the preparation of immamic acid as claimed in any one of claims 1 to 7 wherein the mass ratio of hydrochloric acid to p-cyanobenzyl chloride is between 3.5 and 4.5: 1.
9. the one-pot process for the preparation of immaric acid according to any one of claims 1 to 8, characterized in that the hydrolysis temperature is comprised between 95 and 115 ℃ and the time is comprised between 5 and 10 h.
10. The one-pot method for preparing the immaric acid according to any one of claims 1-9, characterized in that the immaric acid is obtained by cooling, crystallization, washing with methanol and drying, wherein the mass ratio of methanol to p-cyanobenzyl chloride is 2.2-3.0: 1.
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