CN115650895A - Simple synthesis method of 3, 3-dimethylpyrrolidin-2-one - Google Patents

Simple synthesis method of 3, 3-dimethylpyrrolidin-2-one Download PDF

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CN115650895A
CN115650895A CN202211285317.5A CN202211285317A CN115650895A CN 115650895 A CN115650895 A CN 115650895A CN 202211285317 A CN202211285317 A CN 202211285317A CN 115650895 A CN115650895 A CN 115650895A
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dimethylpyrrolidin
dropwise adding
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薛嵩
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Shanghai Ruiheda Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a simple and convenient synthesis method of 3, 3-dimethylpyrrolidin-2-one, which relates to the technical field of medical intermediate processing and specifically comprises the following steps; s1: firstly, taking 2, 2-dimethyl-3-hydroxy methyl propionate according to a molar ratio: triethylamine: methanesulfonyl chloride: dichloromethane DCM =1: 2.0-2.5: 1.3-1.5: 5 to 10; s2: under the ice-water bath, dissolving 2, 2-dimethyl-3-hydroxy methyl propionate in dichloromethane DCM, dropwise adding triethylamine, dropwise adding methanesulfonyl chloride, keeping the temperature at room temperature after dropwise adding, then quenching reaction by 1N hydrochloric acid, separating liquid, drying and concentrating to remove dichloromethane DCM to obtain the sulfonic acid ester. S3: dissolving the sulfonic acid ester crude product obtained by the S2 reaction in DMSO at room temperature, dropwise adding a DMSO solution of sodium cyanide NaCN in batches, and then controlling the temperature to be 100 ℃ and stirring. The 3-methyl methanesulfonate-2, 2-dimethyl methyl propionate is prepared by reacting 2, 2-dimethyl-3-methyl hydroxypropionate with triethylamine and methanesulfonyl chloride, cyano is added to sodium cyanide, and then the product is obtained by hydrogenation reduction ring closure.

Description

Simple synthesis method of 3, 3-dimethylpyrrolidin-2-one
Technical Field
The invention relates to the technical field of medical intermediate processing, in particular to a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one.
Background
3, 3-dimethylpyrrolidin-2-one (C6H 11 NO) is a common pharmaceutical intermediate. The commonly used method for preparing the compound is to start from pyrrolidone protected on nitrogen, react with methyl iodide under the condition of strong base such as sodium hydroxide or LDA, and then remove protection to generate a product, wherein the main byproduct is monomethylation pyrrolidone, and the purification and separation are quite difficult because the product is very close to the physicochemical properties such as polarity, boiling point and the like. The processes of the patents disclosed in WO2007016364, WO2011075699, US2019192668, etc. require the use of a lithium diisopropylamide reagent, and methyl iodide, as well as a strictly anhydrous operation; starting from methyl isobutyrate, performing hydrogen extraction by LDA, treating with bromoacetonitrile, and reducing cyano by using sodium borohydride and Lewis acid while closing the ring to obtain a product, wherein Reddy, P.Amruta and the like are adopted; milewska, mariaJ et al used 3, 3-dimethylpyrrolidin-2, 5-dione as the starting material, treated with Lawson's reagent, and then reduced with Raney nickel hydrogen to produce 3, 3-dimethylpyrrolidin-2-one.
The temperature conditions of the methods disclosed in the patents with the application numbers of WO2007016364, WO2011075699, US2019192668 and the like are strictly controlled (ultralow temperature), and the operation difficulty is high; ultralow temperature conditions are required in the process of the Reddy and P.Amruta synthesis method, sodium borohydride is used to release hydrogen, the operation risk is high during large-scale production, and the generated metal salt greatly increases the difficulty in post-treatment and purification; the synthesis methods of Milewska, mariaJ, and the like have the disadvantages of expensive raw materials, strong odor generation in the reaction process, low yield and relatively complex operation. In summary, the synthesis methods or reaction conditions reported in the documents are harsh, or the operation is tedious or the raw materials are not easy to obtain, which results in higher cost, so we propose a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one, which solves the problems that the existing synthesis method of 3, 3-dimethylpyrrolidin-2-one in the background art has strict conditions, large production risk and difficult industrialization; the synthetic method has the problems of complex operation and high production cost.
In order to achieve the purpose, the invention is realized by the following technical scheme: a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one comprises the following steps;
s1: firstly, taking 2, 2-dimethyl-3-hydroxy methyl propionate according to a molar ratio: triethylamine: methanesulfonyl chloride: dichloromethane DCM =1: 2.0-2.5: 1.3-1.5: 5 to 10;
s2: under the ice-water bath, dissolving 2, 2-dimethyl-3-hydroxy methyl propionate in dichloromethane DCM, dropwise adding triethylamine, dropwise adding methanesulfonyl chloride, keeping the temperature at room temperature after dropwise adding, then quenching reaction by 1N hydrochloric acid, separating liquid, drying and concentrating to remove dichloromethane DCM to obtain the sulfonic acid ester.
S3: and (3) dissolving the sulfonic acid ester crude product obtained by the S2 reaction in DMSO at room temperature, dropwise adding a DMSO solution of sodium cyanide NaCN in batches, controlling the temperature at 100 ℃ and stirring after adding, and stopping the reaction after intermediate sulfonic acid ester does not exist in the central control.
S4: then adding water and ethyl acetate for separating liquid, extracting the water phase with ethyl acetate, combining organic phases, washing twice with salt solution, drying with anhydrous sodium sulfate, concentrating the dried organic phase, distilling under reduced pressure, heating the oil at 90 ℃, and collecting 75-degree fractions to obtain a pure cyano compound intermediate.
S5: dissolving the intermediate of the cyano compound in methanol, adding 10 percent palladium carbon for catalysis under the protection of nitrogen at room temperature, and carrying out hydrogenation reduction under the pressure of 4 atmospheres of hydrogen.
S6: filtering and recovering palladium carbon, evaporating filtrate to dryness, and recrystallizing the crude product with methyl tert-butyl ether and heptane to obtain the pure product 3, 3-dimethylpyrrolidin-2-one.
Preferably, the dichloromethane, DCM, DMSO and methanol are organic solvents commonly used in organic laboratories.
Preferably, the 3, 3-dimethylpyrrolidin-2-one is more than 98% pure.
Preferably, the palladium-carbon filtration recovery is carried out by using diatomite.
The invention provides a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one, which has the following beneficial effects:
1. according to the simple synthesis method of the 3, 3-dimethylpyrrolidin-2-one, the 2, 2-dimethyl-3-hydroxypropionic acid methyl ester reacts with triethylamine and methane sulfonyl chloride to prepare the 3-methanesulfonate-2, 2-dimethylpropionate methyl ester, the cyano group is formed on sodium cyanide, and then the product is obtained by hydrogenating, reducing and ring closing, the raw material cost is low, the operation is simple, the safety is high, the green chemical requirements are met, the purity of the obtained 3, 3-dimethylpyrrolidine-2-one is high, most of the reaction steps in the preparation method are carried out at room temperature, strict anhydrous or ultralow temperature operation conditions are not needed, reactants, solvents and the like are common raw materials, wherein dichloromethane DCM, DMSO and methanol are common organic solvents for organic laboratories, the triethylamine is a low-price organic base, the palladium carbon can be recycled and reused, the post-reaction treatment is relatively simple, the production cost is greatly reduced, the method has stronger economic practicability and flexibility, the environmental pollution is small, and the method is suitable for industrial production.
Drawings
FIG. 1 is a schematic view of the process structure of the present invention;
FIG. 2 is a schematic structural diagram of a nuclear magnetic hydrogen spectrum of the product of the present invention;
FIG. 3 is a schematic structural diagram of nuclear magnetic hydrogen spectrograms of the intermediate of the present invention;
FIG. 4 is a schematic illustration of an experimental report according to a second embodiment of the present invention;
FIG. 5 is a schematic illustration of a third experimental report according to an embodiment of the present invention;
FIG. 6 is a schematic diagram of a fourth experimental report according to an embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.
In a first embodiment, please refer to fig. 1 to 3, the present invention provides a technical solution: a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one comprises the following steps;
s1: firstly, taking 2, 2-dimethyl-3-hydroxy methyl propionate according to a molar ratio: triethylamine: methanesulfonyl chloride: dichloromethane DCM =1: 2.0-2.5: 1.3-1.5: 5 to 10;
s2: under the ice-water bath, dissolving 2, 2-dimethyl-3-hydroxy methyl propionate in dichloromethane DCM, dropwise adding triethylamine, dropwise adding methanesulfonyl chloride, keeping the temperature at room temperature after dropwise adding, then quenching reaction by 1N hydrochloric acid, separating liquid, drying and concentrating to remove dichloromethane DCM to obtain the sulfonic acid ester.
S3: and (3) dissolving the sulfonic acid ester crude product obtained by the S2 reaction in DMSO at room temperature, dropwise adding a DMSO solution of sodium cyanide NaCN in batches, controlling the temperature at 100 ℃ and stirring after adding, and stopping the reaction after intermediate sulfonic acid ester does not exist in the central control.
S4: then adding water and ethyl acetate for separating liquid, extracting the water phase with ethyl acetate, combining organic phases, washing twice with salt solution, drying with anhydrous sodium sulfate, concentrating the dried organic phase, distilling under reduced pressure, heating the oil at 90 ℃, and collecting 75-degree fractions to obtain a pure cyano compound intermediate.
S5: dissolving the intermediate of the cyano compound in methanol, adding 10 percent palladium carbon for catalysis under the protection of nitrogen at room temperature, and carrying out hydrogenation reduction under the pressure of 4 atmospheres of hydrogen.
S6: filtering and recovering palladium carbon, evaporating filtrate to dryness, and recrystallizing the crude product with methyl tert-butyl ether and heptane to obtain the pure product 3, 3-dimethylpyrrolidin-2-one.
Wherein the dichloromethane DCM, DMSO and methanol are organic solvents commonly used in organic laboratories.
Wherein the purity of the 3, 3-dimethylpyrrolidin-2-one is more than 98%.
Wherein, the palladium-carbon filtration and recovery need to be carried out by adopting diatomite.
Example two:
referring to fig. 1-4, the present invention provides a technical solution: a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one comprises the following steps; at room temperature, 10g of methyl 2, 2-dimethyl-3-hydroxypropionate is dissolved in 50ml of dichloromethane DCM, 16g of triethylamine is added, 13g of methanesulfonyl chloride is dropwise added, after the reaction is carried out for 5 hours, 1N hydrochloric acid is used for quenching reaction, liquid separation is carried out, an organic phase is washed by brine, dried by anhydrous sodium sulfate, and a crude product of sulfonic acid ester obtained by concentration is used for standby. The crude sulfonic acid ester obtained in the above step was dissolved in 80ml of DMSO at room temperature, 10g of sodium cyanide was added, the reaction solution was heated to 100 ℃ and stirred for 12 hours. Cooling the reaction liquid to room temperature, adding water and ethyl acetate, separating liquid, extracting the water phase twice by using ethyl acetate, combining organic phases, washing twice by using saline solution, drying by using anhydrous sodium sulfate, concentrating the dried organic phase, distilling under reduced pressure by using a diaphragm pump, and collecting 75-degree fractions, namely the cyano compound intermediate. 5g of the intermediate cyano compound was dissolved in 25ml of methanol, and 250mg of 10% palladium on carbon was added under nitrogen protection at room temperature to displace hydrogen, followed by hydrogenation reduction under 4 atmospheres of hydrogen pressure for 15 hours. Filtering with diatomite, evaporating the filtrate to dryness, recrystallizing the crude product with methyl tert-butyl ether and heptane to obtain pure product 3, 3-dimethylpyrrolidin-2-one, wherein the purity of the obtained target product 3, 3-dimethylpyrrolidin-2-one is more than 98%.
Example three:
referring to fig. 1-3 and fig. 5, the present invention provides a technical solution: a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one comprises the following steps; at room temperature, 15g of methyl 2, 2-dimethyl-3-hydroxypropionate is dissolved in 42ml of dichloromethane DCM, 28.7g of triethylamine is added, 16.8g of methanesulfonyl chloride is added dropwise, after the reaction is carried out for 5 hours, 1N hydrochloric acid is used for quenching the reaction, liquid separation is carried out, the organic phase is washed by brine, dried by anhydrous sodium sulfate, and the crude sulfonic acid ester obtained by concentration is used for standby. The crude sulfonate obtained in the above step was dissolved in 80ml of DMSO at room temperature, 8g of sodium cyanide was added, the reaction solution was heated to 100 ℃ and stirred for 12 hours. Cooling the reaction liquid to room temperature, adding water and ethyl acetate, separating liquid, extracting the water phase twice by using ethyl acetate, combining organic phases, washing twice by using saline solution, drying by using anhydrous sodium sulfate, concentrating the dried organic phase, distilling under reduced pressure by using a diaphragm pump, and collecting 75-degree fractions, namely the cyano compound intermediate. 5g of the intermediate cyano compound was dissolved in 25ml of methanol, and 250mg of 10% palladium on carbon was added under nitrogen protection at room temperature to displace hydrogen, followed by hydrogenation reduction under 4 atmospheres of hydrogen pressure for 15 hours. Filtering with diatomite, evaporating the filtrate to dryness, recrystallizing the crude product with methyl tert-butyl ether and heptane to obtain pure product 3, 3-dimethylpyrrolidin-2-one, wherein the purity of the obtained target product 3, 3-dimethylpyrrolidin-2-one is more than 98%.
Example four:
referring to fig. 1-3 and fig. 6, the present invention provides a technical solution: a simple synthesis method of 3, 3-dimethylpyrrolidin-2-one comprises the following steps; at room temperature, 2.0kg of 2, 2-dimethyl-3-hydroxypropionic acid methyl ester is dissolved in 8L of dichloromethane DCM, 3.2kg of triethylamine is added, 2.6kg of methanesulfonyl chloride is added dropwise, after 5 hours of reaction, 2L of 1N hydrochloric acid is quenched for reaction, liquid separation is carried out, an organic phase is washed by 2L of brine, 1kg of anhydrous sodium sulfate is dried, and crude sulfonic acid ester obtained by concentration is used for standby. Dissolving the crude sulfonic ester obtained in the previous step in 15LDMSO at room temperature, adding 2.0kg of sodium cyanide, heating the reaction solution to 100 ℃, and stirring for 15 hours. Cooling the reaction liquid to room temperature, adding 2L of water and 5L of ethyl acetate, separating liquid, extracting the water phase twice by using ethyl acetate (2L), combining organic phases, washing twice by using 2L of saline solution, drying by using 2kg of anhydrous sodium sulfate, concentrating the dried organic phase, distilling under reduced pressure by using a diaphragm pump, heating to 90 ℃, and collecting 75-degree fractions to obtain a cyano compound intermediate. 1.0kg of the intermediate cyano compound was dissolved in 4L of methanol, and 20g of 10% palladium on carbon was added at room temperature under nitrogen protection to displace hydrogen, followed by hydrogenation reduction under 4 atmospheres of hydrogen pressure for 15 hours. And filtering the solution by using kieselguhr to recover the palladium-carbon. After the filtrate is evaporated to dryness, the crude product is recrystallized by using 3L methyl tert-butyl ether and heptane to obtain the target product 3, 3-dimethylpyrrolidin-2-one with the purity of more than 99 percent.
The 3-methanesulfonate-2, 2-dimethyl methyl propionate is prepared by reacting 2, 2-dimethyl-3-hydroxy methyl propionate with triethylamine and methane sulfonyl chloride, a cyano group is formed on sodium cyanide, and then the product is obtained by hydrogenation reduction ring closure, so that the raw material cost is low, the operation is simple, the safety is high, the green chemical requirements are met, and the purity of the obtained 3, 3-dimethylpyrrolidin-2-one is high.
Most of the reaction steps in the preparation method are carried out at room temperature, strict anhydrous or ultralow temperature operation conditions are not needed, reactants, solvents and the like are common raw materials, dichloromethane DCM, DMSO and methanol are common organic solvents in an organic laboratory, triethylamine is low-price organic base, palladium carbon can be recycled, the treatment after the reaction is relatively simple, the production cost is greatly reduced, the preparation method has stronger economical practicability and flexibility, and the preparation method also meets the requirement of green chemistry,
the method has the advantages of low cost, less environmental pollution and simple production operation, and the obtained 3, 3-dimethylpyrrolidin-2-one has high purity and is suitable for industrial production.
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 as the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.

Claims (4)

1. A simple synthesis method of 3, 3-dimethylpyrrolidin-2-one is characterized in that: comprises the following steps;
s1: firstly, taking 2, 2-dimethyl-3-hydroxy methyl propionate according to a molar ratio: triethylamine: methanesulfonyl chloride: dichloromethane DCM =1: 2.0-2.5: 1.3-1.5: 5 to 10;
s2: under an ice water bath, dissolving 2, 2-dimethyl-3-hydroxy methyl propionate in dichloromethane DCM, dropwise adding triethylamine, dropwise adding methanesulfonyl chloride, keeping the temperature at room temperature after dropwise adding, then quenching reaction by 1N hydrochloric acid, separating liquid, drying and concentrating to remove dichloromethane DCM to obtain sulfonic ester;
s3: dissolving a sulfonic ester crude product obtained by the S2 reaction in DMSO at room temperature, dropwise adding a DMSO solution of sodium cyanide NaCN in batches, controlling the temperature at 100 ℃ and stirring after the addition is finished, and stopping the reaction after intermediate sulfonic ester does not exist in central control;
s4: then adding water and ethyl acetate for separating liquid, extracting a water phase with ethyl acetate, combining organic phases, washing twice with salt solution, drying with anhydrous sodium sulfate, concentrating a dry organic phase, distilling under reduced pressure, heating the oil at 90 ℃, and collecting 75-degree fractions to obtain a pure cyano compound intermediate;
s5: dissolving the intermediate of the cyano compound in methanol, adding 10 percent palladium carbon for catalysis under the protection of nitrogen at room temperature, and carrying out hydrogenation reduction under the pressure of 4 atmospheres of hydrogen;
s6: filtering and recovering palladium carbon, evaporating filtrate to dryness, and recrystallizing the crude product with methyl tert-butyl ether and heptane to obtain the pure product 3, 3-dimethylpyrrolidin-2-one.
2. The simple synthesis method of 3, 3-dimethylpyrrolidin-2-one according to claim 1, wherein: the dichloromethane DCM, DMSO and methanol are organic solvents commonly used in organic laboratories.
3. The simple synthesis method of 3, 3-dimethylpyrrolidin-2-one according to claim 1, wherein: the purity of the 3, 3-dimethylpyrrolidin-2-one is more than 98%.
4. The simple synthesis method of 3, 3-dimethylpyrrolidin-2-one according to claim 1, wherein: the palladium-carbon filtration and recovery needs to be carried out by adopting diatomite.
CN202211285317.5A 2022-10-20 2022-10-20 Simple synthesis method of 3, 3-dimethylpyrrolidin-2-one Pending CN115650895A (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN113173924A (en) * 2020-05-12 2021-07-27 苏州阿尔脉生物科技有限公司 Pyridine acetamide derivative as CDK inhibitor, and preparation method and application thereof
CN114957078A (en) * 2022-01-19 2022-08-30 广州谷森制药有限公司 Preparation method of deuterated pharmaceutical intermediate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113173924A (en) * 2020-05-12 2021-07-27 苏州阿尔脉生物科技有限公司 Pyridine acetamide derivative as CDK inhibitor, and preparation method and application thereof
CN114957078A (en) * 2022-01-19 2022-08-30 广州谷森制药有限公司 Preparation method of deuterated pharmaceutical intermediate

Non-Patent Citations (2)

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Title
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