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

Abstract

The invention discloses a simple and convenient synthesis method of 3,3-dimethylpyrrolidin-2-one, relates to the technical field of pharmaceutical intermediate processing, and specifically comprises the following steps; Methyl-3-hydroxypropionate: Triethylamine: Methanesulfonyl chloride: Dichloromethane DCM = 1: 2.0-2.5: 1.3-1.5: 5-10; S2: Under ice-water bath, mix 2,2- Dissolve methyl dimethyl-3-hydroxypropionate in dichloromethane DCM, add triethylamine dropwise, then add methanesulfonyl chloride dropwise, keep warm at room temperature after the dropwise addition, then quench the reaction with 1N hydrochloric acid, separate, dry and concentrate Dichloromethane DCM was removed to give the sulfonate. S3: Dissolve the crude sulfonate obtained by the reaction of S2 in DMSO at room temperature, add sodium cyanide NaCN DMSO solution dropwise in batches, and after the addition, control the temperature at 100°C and stir. Methyl 3-mesylate-2,2-dimethylpropionate prepared by reaction of methyl 2,2-dimethyl-3-hydroxypropionate with triethylamine, methanesulfonyl chloride, sodium cyanide Adding cyano groups, followed by hydrogenation reduction ring closure to obtain the product, the cost of raw materials is low, the operation is simple, the safety is high, and it meets the requirements of green chemistry.

Description

A Simple Synthesis Method of 3,3-Dimethylpyrrolidin-2-one

technical field

The invention relates to the technical field of pharmaceutical intermediate processing, in particular to a convenient synthesis method of 3,3-dimethylpyrrolidin-2-one.

Background technique

3,3-Dimethylpyrrolidin-2-one (C6H11NO) is a common pharmaceutical intermediate. The commonly used method for preparing the compound starts from the nitrogen-protected pyrrolidone, reacts with methyl iodide under strong base such as sodium hydroxide or LDA conditions, and then deprotects to generate the product. The main by-product is monomethylated pyrrolidone, because and The physical and chemical properties such as polarity and boiling point of the product are very close, and purification and separation are quite difficult. The patented methods disclosed in WO2007016364, WO2011075699, US2019192668, etc. require the use of lithium diisopropylamide reagent, methyl iodide and strict anhydrous operation; Reddy, P.Amruta, etc. start with methyl isobutyrate and use Bromoacetonitrile treatment, and then use sodium borohydride and Lewis acid to reduce the cyano group and simultaneously close the ring to obtain the product; Reagent treatment followed by Raney nickel hydrogen reduction to 3,3-dimethylpyrrolidin-2-one.

Application numbers are WO2007016364, WO2011075699, US2019192668 and other disclosed patent methods with strict temperature control (ultra-low temperature) and high difficulty in operation; Reddy, P.Amruta requires ultra-low temperature conditions in the process of synthesis method, and uses sodium borohydride to release hydrogen, which is large The operation risk is very high during production, and the metal salt produced makes post-processing and purification very difficult; the raw materials of Milewska, MariaJ. and other synthetic methods are expensive, strong odor is produced during the reaction process, the yield is not high, and the operation is relatively complicated. In summary, the synthesis methods or reaction conditions reported in various literatures are harsh, or the operation is cumbersome or the raw materials are not easy to obtain, resulting in high cost. Therefore, we proposed a simple and convenient method for 3,3-dimethylpyrrolidin-2-one resolve resolution.

Contents of the invention

Aiming at the deficiencies in the prior art, the present invention provides a simple and convenient synthesis method of 3,3-dimethylpyrrolidin-2-one, which solves the current existing problem of synthesizing 3,3-dimethylpyrrolidin-2-one proposed in the above-mentioned background technology. The patented method of ylpyrrolidin-2-one has strict conditions, high production risk, and difficulty in industrialization; the synthesis method is cumbersome to operate and the production cost is high.

In order to achieve the above purpose, the present invention is achieved through the following technical solutions: a simple synthesis method of 3,3-dimethylpyrrolidin-2-one, comprising the following steps;

S1: First measure 2,2-dimethyl-3-hydroxypropionate methyl ester according to the molar ratio: triethylamine: methanesulfonyl chloride: dichloromethane DCM = 1: 2.0～2.5: 1.3～1.5: 5～10 ;

S2: Under an ice-water bath, dissolve methyl 2,2-dimethyl-3-hydroxypropionate in dichloromethane DCM, add triethylamine dropwise, then add methanesulfonyl chloride dropwise, keep warm at room temperature after the dropwise addition, Then quench the reaction with 1N hydrochloric acid, separate the layers, dry and concentrate to remove dichloromethane DCM to obtain sulfonate.

S3: Dissolve the crude sulfonate obtained by the reaction of S2 in DMSO at room temperature, add sodium cyanide NaCN DMSO solution dropwise in batches, after the addition is completed, stir at 100 degrees at the temperature, and stop when there is no intermediate sulfonate in the central control reaction.

S4: Then add water and ethyl acetate to separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, wash twice with saline, dry over anhydrous sodium sulfate, concentrate and dry the organic phases, distill under reduced pressure, the oil temperature is 90 degrees , Collect the 75-degree fraction to obtain a pure cyano compound intermediate.

S5: Dissolving the cyano compound intermediate in methanol, adding 10% palladium carbon catalyst under the protection of nitrogen at room temperature, hydrogenation reduction under 4 atmospheres of hydrogen pressure.

S6: recover palladium carbon by filtration, evaporate the filtrate to dryness, and recrystallize 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 commonly used organic solvents in organic laboratories.

Preferably, the purity of the 3,3-dimethylpyrrolidin-2-one is greater than 98%.

Preferably, diatomaceous earth is used for the recovery of palladium carbon by filtration.

The invention provides a simple and convenient synthesis method of 3,3-dimethylpyrrolidin-2-one, which has the following beneficial effects:

1. The simple and convenient synthetic method of this 3,3-dimethylpyrrolidin-2-one is prepared by using methyl 2,2-dimethyl-3-hydroxypropionate, triethylamine and methanesulfonyl chloride to react 3 - Methylsulfonate-2,2-dimethylpropionate, cyano group on sodium cyanide, and then hydrogenation reduction ring closure to obtain the product, the raw material cost is low, the operation is simple, the safety is high, and it meets the requirements of green chemistry, and The obtained 3,3-dimethylpyrrolidin-2-one has a high purity, and most of the reaction steps in the preparation method are carried out at room temperature, without the need for harsh anhydrous or ultra-low temperature operating conditions, and the reactants and solvents, etc. They are all commonly used raw materials, among which dichloromethane DCM, DMSO, and methanol are organic solvents commonly used in organic laboratories, triethylamine is a low-cost organic base, palladium carbon can be recycled, and the post-reaction treatment is relatively simple. The production cost is reduced, the utility model has stronger economic practicability and flexibility, less environmental pollution, and is suitable for industrialized production.

Description of drawings

Fig. 1 is the process structure schematic diagram prepared by the present invention;

Fig. 2 is the structural representation of product proton nuclear magnetic spectrogram of the present invention;

Fig. 3 is the structural representation of intermediate nuclear magnetic hydrogen spectrogram of the present invention;

Fig. 4 is the schematic diagram of the experimental report of the second embodiment of the present invention;

Fig. 5 is the schematic diagram of the experimental report of the third embodiment of the present invention;

Fig. 6 is a schematic diagram of an experiment report of Example 4 of the present invention.

Detailed ways

The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, not all, embodiments of the present invention.

Example 1, please refer to Figure 1 to Figure 3, the present invention provides a technical solution: a simple synthesis method of 3,3-dimethylpyrrolidin-2-one, including the following steps;

S1: First measure 2,2-dimethyl-3-hydroxypropionate methyl ester according to the molar ratio: triethylamine: methanesulfonyl chloride: dichloromethane DCM = 1: 2.0～2.5: 1.3～1.5: 5～10 ;

S2: Under an ice-water bath, dissolve methyl 2,2-dimethyl-3-hydroxypropionate in dichloromethane DCM, add triethylamine dropwise, then add methanesulfonyl chloride dropwise, keep warm at room temperature after the dropwise addition, Then quench the reaction with 1N hydrochloric acid, separate the layers, dry and concentrate to remove dichloromethane DCM to obtain sulfonate.

S3: Dissolve the crude sulfonate obtained by the reaction of S2 in DMSO at room temperature, add sodium cyanide NaCN DMSO solution dropwise in batches, after the addition is completed, stir at 100 degrees at the temperature, and stop when there is no intermediate sulfonate in the central control reaction.

S4: Then add water and ethyl acetate to separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, wash twice with saline, dry over anhydrous sodium sulfate, concentrate and dry the organic phases, distill under reduced pressure, the oil temperature is 90 degrees , Collect the 75-degree fraction to obtain a pure cyano compound intermediate.

S5: Dissolving the cyano compound intermediate in methanol, adding 10% palladium carbon catalyst under the protection of nitrogen at room temperature, hydrogenation reduction under 4 atmospheres of hydrogen pressure.

S6: recover palladium carbon by filtration, evaporate the filtrate to dryness, and recrystallize 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 greater than 98%.

Wherein, the filtration recovery of palladium carbon needs to be operated with diatomaceous earth.

Embodiment two:

Please refer to Fig. 1-4, the present invention provides a kind of technical scheme: a kind of convenient synthetic method of 3,3-dimethylpyrrolidin-2-one, comprises the following steps; At room temperature, 10g2,2-dimethyl Dissolve methyl-3-hydroxypropionate in 50ml of dichloromethane DCM, add 16g of triethylamine, dropwise add 13g of methanesulfonyl chloride, react for 5 hours, quench the reaction with 1N hydrochloric acid, separate the layers, and wash the organic phase with brine , dried over anhydrous sodium sulfate, and concentrated the obtained crude sulfonate for use. Dissolve the crude sulfonate obtained in the previous step in 80ml of DMSO at room temperature, add 10g of sodium cyanide, and after the addition is complete, the reaction solution is heated to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, added water and ethyl acetate, separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline, dried over anhydrous sodium sulfate, concentrated to dry organic phase, and reduced by a diaphragm pump. Pressure distillation, the oil temperature is 90 degrees, and the fraction at 75 degrees is collected, which is the intermediate of the cyano compound. 5g of the cyano compound intermediate was dissolved in 25ml of methanol. At room temperature, 250mg of 10% palladium carbon was added under the protection of nitrogen. After the hydrogen was replaced, hydrogenation and reduction were carried out under 4 atmospheres of hydrogen pressure for 15 hours. After diatomaceous earth filtration, after the filtrate is evaporated to dryness, the crude product is recrystallized with methyl tert-butyl ether and heptane to obtain the pure product 3,3-dimethylpyrrolidin-2-one, and the target product 3,3-dimethyl The purity of ylpyrrolidin-2-one is greater than 98%.

Embodiment three:

Please refer to Fig. 1-3, Fig. 5, the present invention provides a kind of technical scheme: a kind of convenient synthetic method of 3,3-dimethylpyrrolidin-2-one, comprises the following steps; At room temperature, 15g2,2 - Methyl dimethyl-3-hydroxypropionate was dissolved in 42ml of dichloromethane DCM, 28.7g of triethylamine was added, 16.8g of methanesulfonyl chloride was added dropwise, after 5 hours of reaction, the reaction was quenched with 1N hydrochloric acid, and the liquids were separated , the organic phase was washed with brine, dried over anhydrous sodium sulfate, and the crude sulfonate was concentrated for use. Dissolve the crude sulfonate obtained in the previous step in 80ml of DMSO at room temperature, add 8g of sodium cyanide, and after the addition is complete, the reaction solution is heated to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, added water and ethyl acetate, separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saline, dried over anhydrous sodium sulfate, concentrated to dry organic phase, and reduced by a diaphragm pump. Pressure distillation, the oil temperature is 90 degrees, and the fraction at 75 degrees is collected, which is the intermediate of the cyano compound. 5g of the cyano compound intermediate was dissolved in 25ml of methanol. At room temperature, 250mg of 10% palladium carbon was added under the protection of nitrogen. After the hydrogen was replaced, hydrogenation and reduction were carried out under 4 atmospheres of hydrogen pressure for 15 hours. After diatomaceous earth filtration, after the filtrate is evaporated to dryness, the crude product is recrystallized with methyl tert-butyl ether and heptane to obtain the pure product 3,3-dimethylpyrrolidin-2-one, and the target product 3,3-dimethyl The purity of ylpyrrolidin-2-one is greater than 98%.

Embodiment four:

Please refer to Fig. 1-3, Fig. 6, the present invention provides a kind of technical scheme: a kind of convenient synthetic method of 3,3-dimethylpyrrolidin-2-one, comprises the following steps; At room temperature, 2.0kg2, Dissolve methyl 2-dimethyl-3-hydroxypropionate in 8L dichloromethane DCM, add 3.2kg triethylamine, dropwise add 2.6kg methanesulfonyl chloride, react for 5 hours, quench the reaction with 2L1N hydrochloric acid, divide liquid, the organic phase was washed with 2L of brine, dried over 1kg of anhydrous sodium sulfate, and the crude sulfonate was concentrated for use. Dissolve the crude sulfonate obtained in the previous step in 15 LDMSO at room temperature, add 2.0 kg of sodium cyanide, and after the addition is complete, heat the reaction solution to 100°C and stir for 15 hours. Cool the reaction solution to room temperature, add 2L of water and 5L of ethyl acetate, separate the layers, extract the aqueous phase twice with ethyl acetate (2L), combine the organic phases, wash twice with 2L of brine, dry with 2kg of anhydrous sodium sulfate, and concentrate Dry the organic phase, and distill it under reduced pressure with a diaphragm pump, the oil temperature is 90°C, and collect the fraction at 75°C to obtain the cyano compound intermediate. 1.0kg of the cyano compound intermediate was dissolved in 4L of methanol, at room temperature, 20g of 10% palladium carbon was added under the protection of nitrogen, after the hydrogen was replaced, hydrogenation and reduction was carried out under 4 atmospheres of hydrogen pressure for 15 hours. Diatomaceous earth filtration recovers palladium carbon. After the filtrate was evaporated to dryness, the crude product was recrystallized with 3L of methyl tert-butyl ether and heptane to obtain the target product 3,3-dimethylpyrrolidin-2-one with a purity greater than 99%.

Preparation of methyl 3-mesylate-2,2-dimethylpropionate by reaction of methyl 2,2-dimethyl-3-hydroxypropionate with triethylamine, methanesulfonyl chloride, sodium cyanide Adding a cyano group, followed by hydrogenation reduction ring closure to obtain a product, the raw material cost is low, the operation is simple, the safety is high, it meets the requirements of green chemistry, and the obtained 3,3-dimethylpyrrolidin-2-one has high purity.

Moreover, most of the reaction steps in this preparation method are carried out at room temperature, without the need for harsh anhydrous or ultra-low temperature operating conditions, and the reactants and solvents are commonly used raw materials, among which dichloromethane, DCM, DMSO, and methanol are the most commonly used materials in organic experiments. The organic solvent commonly used in laboratories, triethylamine is a cheap organic base, palladium carbon can be recycled and used mechanically, and the post-reaction treatment is relatively simple, which greatly reduces the production cost, has stronger economical practicability and flexibility, and is also in line with requirements of green chemistry,

The invention has low cost, less environmental pollution, simple production operation, and high purity of the obtained 3,3-dimethylpyrrolidin-2-one, which is suitable for industrial production.

The above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, any person familiar with the technical field within the technical scope disclosed in the present invention, according to the technical solution of the present invention Any equivalent replacement or change of the inventive concepts thereof shall fall within the protection 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.

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