CN115650895A - Simple synthesis method of 3, 3-dimethylpyrrolidin-2-one - Google Patents
Simple synthesis method of 3, 3-dimethylpyrrolidin-2-one Download PDFInfo
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- IYZVTTRRGCJXGK-UHFFFAOYSA-N 3,3-dimethylpyrrolidin-2-one Chemical compound CC1(C)CCNC1=O IYZVTTRRGCJXGK-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title claims abstract description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000047 product Substances 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 14
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 229940017219 methyl propionate Drugs 0.000 claims abstract description 11
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 8
- 238000010791 quenching Methods 0.000 claims abstract description 6
- 230000000171 quenching effect Effects 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 239000005457 ice water Substances 0.000 claims abstract description 4
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000012074 organic phase Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- -1 cyano compound Chemical class 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 150000003459 sulfonic acid esters Chemical class 0.000 abstract description 12
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 4
- KJRFTNVYOAGTHK-UHFFFAOYSA-N methyl 3-hydroxy-2,2-dimethylpropanoate Chemical compound COC(=O)C(C)(C)CO KJRFTNVYOAGTHK-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- JVQHRYVXOWBSNS-UHFFFAOYSA-N 3,3-dimethylpyrrolidine-2,5-dione Chemical compound CC1(C)CC(=O)NC1=O JVQHRYVXOWBSNS-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- PYZLRNMGUBDIHK-UHFFFAOYSA-N molecular hydrogen;nickel Chemical compound [Ni].[H][H] PYZLRNMGUBDIHK-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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
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.
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| CN114957078A (en) * | 2022-01-19 | 2022-08-30 | 广州谷森制药有限公司 | Preparation method of deuterated pharmaceutical intermediate |
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