CN110054597B - Thiazolidine-4-ketone derivative synthesized under condition of no metal catalyst and preparation method thereof - Google Patents
Thiazolidine-4-ketone derivative synthesized under condition of no metal catalyst and preparation method thereof Download PDFInfo
- Publication number
- CN110054597B CN110054597B CN201910306156.5A CN201910306156A CN110054597B CN 110054597 B CN110054597 B CN 110054597B CN 201910306156 A CN201910306156 A CN 201910306156A CN 110054597 B CN110054597 B CN 110054597B
- Authority
- CN
- China
- Prior art keywords
- reaction
- thiazolidine
- metal catalyst
- solvent
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003054 catalyst Substances 0.000 title claims abstract description 17
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 16
- 239000002184 metal Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- 239000011593 sulfur Substances 0.000 claims abstract description 8
- 229910052979 sodium sulfide Inorganic materials 0.000 claims abstract description 7
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims abstract description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 5
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims abstract description 5
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 10
- NOLHRFLIXVQPSZ-UHFFFAOYSA-N 1,3-thiazolidin-4-one Chemical class O=C1CSCN1 NOLHRFLIXVQPSZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 13
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 3
- 239000000376 reactant Substances 0.000 abstract description 3
- 239000000706 filtrate Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 230000006872 improvement Effects 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 6
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 6
- 238000011161 development Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- XOHMYQLKPHUOQR-UHFFFAOYSA-N 2,3-diphenylpropanamide Chemical compound C=1C=CC=CC=1C(C(=O)N)CC1=CC=CC=C1 XOHMYQLKPHUOQR-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- OVWGAGKOPGNUGC-UHFFFAOYSA-N n,3-diphenylpropanamide Chemical compound C=1C=CC=CC=1NC(=O)CCC1=CC=CC=C1 OVWGAGKOPGNUGC-UHFFFAOYSA-N 0.000 description 1
- JDXWZGXJTQCYCS-UHFFFAOYSA-N n-(4-methoxyphenyl)-3-phenylpropanamide Chemical compound C1=CC(OC)=CC=C1NC(=O)CCC1=CC=CC=C1 JDXWZGXJTQCYCS-UHFFFAOYSA-N 0.000 description 1
- UZTVEZLZUTUCBJ-UHFFFAOYSA-N n-butyl-3-phenylpropanamide Chemical compound CCCCNC(=O)CCC1=CC=CC=C1 UZTVEZLZUTUCBJ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a thiazolidine-4-ketone derivative synthesized under the condition of no metal catalyst and a preparation method thereof, N-aryl (alkyl) -3-aryl propynamide is taken as a substrate, sodium sulfide or potassium sulfide is added into the substrate to be taken as a sulfur source, dichloromethane or dibromomethane is taken as a carbon source to react, a reaction solvent is tetrahydrofuran or acetonitrile or 1,4-dioxane solvent, the reaction temperature is 80 ℃, and the reaction time is 14-16 hours; the whole reaction is carried out under normal pressure, the reaction condition is mild and is easy to achieve, meanwhile, the reaction time is short, and the time cost is low; the reactant raw materials are easy to obtain, no metal catalyst is used, and the raw material cost is low. A series of thiazolidine-4-ketone derivatives are prepared, and the method has stronger substrate universality; provides powerful guarantee for developing the medicine containing thiazolidine-4-ketone derivatives.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to thiazolidine-4-ketone derivatives synthesized under the condition of no metal catalyst and a preparation method thereof.
Background
Thiazolidin-4-one scaffolds are important structures in bioactive compounds and drug molecules (eur.j.med.chem.2007, 42,948-954, bioor.med.chem.lett.2001,11, 1179-179), and their derivatives have biological activities of antibacterial, antiviral, anti-inflammatory, and anticancer, and have attracted widespread interest in academia (bioorg.med.chem.2006, 14,7476-7481 bioorg.med.chem.2008,16, 3714-3724.
In 1947, alexander R et al first reported that thiazolidinone is obtained by reacting Schiff base and mercaptoacetic acid (j.am.chem.soc.1947, 69 (11), 2911-2912.), and then with the development of research, the research method for synthesizing thiazolidinone by using aldehyde, amine and mercaptoacetic acid as starting materials and a three-component one-pot method is one of the main methods for synthesizing thiazolidinone at present, for example, in 2010, zhang Jinchao, a subject group synthesizes thiazolidine-4-one derivative (j.org.chem., 2010,30,611-616) with pharmaceutical activity by using diethyl tartrate, mercaptoacetic acid and aromatic amine through a multi-step method, but the method has complicated synthesis steps and low economic value; in order to reduce reaction steps and improve economic value; liu et al directly synthesized thiazolidin-4-one derivatives (Y.Liu, X.Chen, Y.Liu, RSC adv.2017,7,37839, X.Chen, C.Hu, J. -P.Wan, Y.Liu, tetrahedron Lett.2016,57,5116) in one step by taking dihaloalkane as a carbon source, but the cost is still too high because copper and noble metal Pd are used as catalysts to participate in the reaction; so that the applicability of these methods is greatly limited.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a thiazolidine-4-ketone derivative synthesized under the condition of no metal catalyst and a preparation method thereof, and the preparation method does not need a metal catalyst and directly synthesizes the thiazolidine-4-ketone derivative by a one-step method.
In order to achieve the purpose, the invention provides the following technical scheme: a thiazolidine-4-ketone derivative synthesized under the condition of no metal catalyst, the molecular structural formula of which is shown in the specification
wherein-R 1 Is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-methoxyphenyl and n-butyl; -R 2 Is any one of phenyl, 4-methylphenyl and 4-methoxyphenyl.
As a further improvement of the invention, the thiazolidine-4-ketone derivative is prepared by reacting N-aryl (alkyl) -3-aryl propynamide, a carbon source and a sulfur source;
the reaction formula is as follows:
as a further improvement of the invention, the sulfur source is sodium sulfide or potassium sulfide.
As a further improvement of the invention, the carbon source is dichloromethane or dibromomethane.
As a further improvement of the invention, the preparation method of thiazolidine-4-ketone derivatives synthesized under the condition of no metal catalyst comprises the steps of sequentially putting N-phenyl-3-phenyl propynamide, a sulfur source and a carbon source into a reaction vessel filled with a solvent, stirring and mixing to obtain a reaction solution; then raising the temperature for reaction; and after the reaction is finished, filtering and purifying the reaction solution to obtain the thiazolidine-4-ketone derivative.
As a further improvement of the invention, the solvent is tetrahydrofuran or acetonitrile or 1,4-dioxane.
As a further improvement of the invention, the reaction is carried out by raising the temperature, namely raising the temperature of the reaction solution to 80 ℃ and the reaction time to 14-16h.
As a further improvement of the invention, the filtration and purification treatment means that the reaction solution is filtered, rotary evaporated, separated by a column layer, eluted by liquid, and finally concentrated in vacuum to obtain the thiazolidine-4-ketone derivative.
As a further development of the invention, the eluent comprises the following composition of matter in parts by volume:
10 parts of petroleum ether;
and 1 part of ethyl acetate.
The invention has the beneficial effects that: n-aryl (alkyl) -3-aryl propiolamide is taken as a substrate, sodium sulfide or potassium sulfide is added into the substrate as a sulfur source, dichloromethane or dibromomethane is taken as a carbon source for reaction, a reaction solvent is tetrahydrofuran or acetonitrile or 1,4-dioxane solvent, the reaction temperature is 80 ℃, and the reaction time is 14-16 hours; the whole reaction is carried out under normal pressure, the reaction condition is mild and is easy to achieve, meanwhile, the reaction time is short, and the time cost is low; the raw materials of the reactants are easy to obtain, no metal catalyst is used, the reaction process is environment-friendly, the atom economy is high, the raw material cost is low, and the industrial value is high.
After the reaction is finished, cooling, filtering the reaction solution to obtain filtrate, then carrying out rotary evaporation on the filtrate, and removing the solvent to obtain a residue. Eluting the residue by a silica gel column with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10 to 1, collecting the effluent according to an actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent by rotating the combined effluent by a rotary evaporator, and finally drying in vacuum to obtain the target product. A series of thiazolidine-4-ketone derivative derivatives are prepared, and the method has stronger substrate universality. Therefore, the invention fills the blank of the method for preparing the thiazolidine-4-ketone derivative at the present stage, promotes the development of the polysubstituted thiazolidine-4-ketone derivative and provides a powerful guarantee for developing the medicine containing the thiazolidine-4-ketone derivative.
The invention does not need to separate intermediate products, can directly synthesize the target product by simple raw materials, simplifies the process, has less waste solution in the reaction process, does not discharge other polluted gas and liquid, and has the advantages of protecting the environment and ensuring the health of operators.
Drawings
FIG. 1 is a reaction mechanism diagram of the first embodiment of the present invention.
Detailed Description
The first embodiment is as follows: 44.2 mg (0.2 mmol) of N-phenyl-3-phenylpropionamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL of dichloromethane, added to 2mL of solvent THF. The reaction was stirred at 80 ℃ for 15 hours. Cooling after the reaction is finished, filtering the reaction solution to obtain a filtrate, carrying out rotary evaporation on the filtrate to remove the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, eluting the residue by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10, 1 H NMR(400MHz,CDCl 3 )δ7.70-7.64(m,4H),7.56-7.49(m,5H),7.42-7.39(m,1H),7.36-7.34(m,1H),5.23(s,2H).
the second embodiment is as follows: 47.0 mg (0.2 mmol) of N-phenyl-3- (p-tolyl) propynamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL methylene chlorideAdded to 2mL of THF as a solvent. The reaction was stirred at 80 ℃ for 16 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, carrying out rotary evaporation on the filtrate, removing the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10, collecting effluent liquid according to an actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a white solid, (Z) -5-benzyl-3- (p-tolyl) thiazolidin-4-one. 1 H NMR(400MHz,CDCl 3 )δ7.66-7.61(m,3H),7.51-7.47(m,4H),7.39-7.36(m,1H),7.31-7.29(m,2H),5.01(s,2H),2.42(s,3H). 13 C NMR(125MHz,CDCl 3 )δ165.3,136.7,136.3,135.2,129.9,129.4,128.7,128.3,126.4,125.7,122.9,47.8,21.0.
The third concrete example: 50.2 mg (0.2 mmol) of N-phenyl-3- (4-methoxyphenyl) propynamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL of dichloromethane, added to 2mL of THF, a solvent. The reaction was stirred at 80 ℃ for 14 hours. And cooling after the reaction is finished, filtering the reaction solution to obtain a filtrate, carrying out rotary evaporation on the filtrate, removing the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, eluting the residue by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10. 1 H NMR(400MHz,CDCl 3 )δ7.65-7.61(m,3H),7.51-7.47(m,4H),7.39-7.36(m,1H),7.03-7.01(m,2H),5.00(s,2H),3.88(s,3H). 13 C NMR(125MHz,CDCl 3 )δ164.3,157.3,134.2,130.6,128.4,127.7,127.3,125.3,124.7,123.8,113.6,54.4,47.0.
The fourth concrete example: 50.2 mg (0.2 mmol) of N-phenyl-3- (2-methoxyphenyl) propynamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL of dichloromethane, added to 2mL of solvent THF. The reaction was stirred at 80 ℃ for 15 hours. And cooling after the reaction is finished, filtering the reaction solution to obtain filtrate, carrying out rotary evaporation on the filtrate, removing the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, leaching the residue by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10Collecting effluent, detecting by TLC, combining the effluent containing the product, distilling by a rotary evaporator to remove the solvent, and drying in vacuum to obtain white solid (Z) -5-benzyl-3- (2-methoxyphenyl) thiazolidin-4-one. 1 H NMR(400MHz,CDCl 3 )δ7.64-7.63(m,3H),7.52-7.48(m,2H),7.45-7.36(m,3H),7.12-7.06(m,2H),4.92(s,2H),3.90(s,3H). 13 C NMR(125MHz,CDCl 3 )δ166.2,155.2,135.3,129.9,129.4,129.3,128.7,128.1,126.5,126.1,125.5,121.2,112.3,55.8,47.3.
The fifth concrete example: 43.80 mg (0.2 mmol) of N-butyl-3-phenylpropionamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL of dichloromethane, added to 2mL of solvent THF. The reaction was stirred at 80 ℃ for 15 hours. And (2) cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, carrying out rotary evaporation on the filtrate to remove the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, eluting the residue by using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10, collecting effluent liquid according to an actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a white solid (Z) -5-benzyl-3-butylthiazolidine-4-ketone. 1 HNMR(400MHz,CDCl 3 )δ7.59-7.54(m,3H),7.48-7.44(m,2H),7.36-7.32(m,1H),4.62(s,2H),3.61(t,J＝9Hz,2H),1.70-1.63(m,2H),1.47-1.38(m,2H),1.01(t,J＝9.5Hz,2H) 13 C NMR(125MHz,CDCl 3 )δ166.2,135.3,129.2,128.7,128.0,126.0,125.3,46.6,44.9,29.4,20.0,13.7.
The sixth specific embodiment: 50.2 mg (0.2 mmol) of N- (4-methoxyphenyl) -3-phenylpropionamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL of dichloromethane, added to 2mL of solvent THF. The mixture was stirred at 80 ℃ for 15 hours. And (2) cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, carrying out rotary evaporation on the filtrate to remove the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, eluting the residue by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10, collecting effluent liquid according to an actual gradient, carrying out TLC (thin-layer chromatography) detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a white solid (Z) -5- (4-methoxybenzyl) -3-phenylthiazolidine-4-ketone. 1 H NMR(400MHz,CDCl 3 )δ7.63-7.57(m,5H),7.52-7.48(m,2H),7.35-7.31(m,1H),7.04-7.01(m,2H),5.04(s,2H).3.90(s,3H). 13 C NMR(125MHz,CDCl 3 )δ165.6,159.7,139.0,131.0,129.3,127.9,126.5,122.8,122.7,114.3,55.4,47.6.
The seventh specific embodiment: 47.0 mg (0.2 mmol) of N- (4-methyl) phenyl-3-phenylpropionamide, 31.2 mg (0.4 mmol) of Na 2 S,1mL of dichloromethane, added to 2mL of solvent THF. The reaction was stirred at 80 ℃ for 15 hours. And cooling after the reaction is finished, filtering the reaction solution to obtain a filtrate, carrying out rotary evaporation on the filtrate, removing the solvent to obtain a residue, carrying out silica gel column chromatography on the residue, eluting the residue by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 10. 1 H NMR(400MHz,CDCl 3 )δ7.66-7.61(m,3H),7.54-7.48(m,4H),7.35-7.29(m,3H),5.04(s,2H),2.44(s,3H). 13 C NMR(125MHz,CDCl 3 )δ165.8,139.3,138.9,132.6,129.8,129.7,129.6,127.0,126.8,124.7,123.0,47.9,21.7.
In the embodiment of the invention, N-aryl (alkyl) -3-aryl propiolamide is used as a substrate to react with 2.0-2.5 equivalents of sodium sulfide and 1mL of dichloromethane, and the solvent is based on tetrahydrofuran. Wherein examples one to five are R in N-aryl (alkyl) -3-arylpropynylamides 1 Substituted with different substituents as variables. It is noted that alkyl groups are also very good for use in the process of the invention; examples six to seven with R in N-aryl (alkyl) -3-arylpropynylamides 2 Substituted with different substituents as variables.
The general reaction formula of the invention is:
the reaction mechanism of the present invention: referring to fig. 1, the following description is made by taking the first embodiment as an example: n-phenyl-3-phenyl propynamide is used as a substrate; firstly, carrying out electrophilic addition reaction on sodium sulfide and a substrate to obtain a thiolene negative ion intermediate A, carrying out once [1,4] hydrogen migration on active nitrogen hydrogen in A to obtain an intermediate B, and carrying out nucleophilic substitution on B and dichloromethane to obtain a target product (Z) -5-benzyl-3-phenylthiazolidine-4-ketone.
The invention discloses (Z) -5-benzyl-3-aryl (alkyl) thiazole-alkane 4-ketone synthesized under the condition of no metal catalyst and a method thereof, N-aryl (alkyl) -3-aryl propynamide is taken as a substrate, sodium sulfide or potassium sulfide is added into the substrate as a sulfur source, methylene dichloride or dibromomethane is taken as a carbon source for reaction, a reaction solvent is tetrahydrofuran or acetonitrile or 1,4-dioxane solvent, the reaction temperature is 80 ℃, and the reaction time is 14-16 hours; the whole reaction is carried out under normal pressure, the reaction temperature is less than 100 ℃, the reaction condition is mild and easy to achieve, and meanwhile, the reaction time is short and the time cost is low; the reactant raw materials are easy to obtain, no metal catalyst is used, and the raw material cost is low.
After the reaction is finished, cooling, filtering the reaction solution to obtain filtrate, then carrying out rotary evaporation on the filtrate, and removing the solvent to obtain a residue. Eluting the residue by a silica gel column with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10 to 1, collecting the effluent according to an actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent by rotating the combined effluent by a rotary evaporator, and finally drying in vacuum to obtain the target product. A series of thiazolidine-4-ketone derivative derivatives are prepared, and the method has stronger substrate universality. Therefore, the invention fills the blank of the method for preparing the thiazolidine-4-ketone derivative at the present stage, promotes the development of the polysubstituted thiazolidine-4-ketone derivative and provides a powerful guarantee for developing the medicine containing the thiazolidine-4-ketone derivative.
According to the invention, the intermediate product does not need to be separated, the target product can be directly synthesized by simple raw materials, the process is simplified, the waste solution in the reaction process is less, other polluted gases and liquid are not discharged, and the method has the advantages of protecting the environment and guaranteeing the health of operators; in the above examples, a series of thiazolidine-4-ketone derivative derivatives can be prepared by selecting N-aryl (alkyl) -3-aryl propiolamide containing different substituents to participate in the reaction, and the method has certain substrate universality and operation simplicity.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and adaptations to those skilled in the art without departing from the principles of the present invention should also be considered as within the scope of the present invention.
Claims (4)
1. A method for preparing thiazolidine-4-ketone derivatives synthesized under the condition of no metal catalyst is characterized in that: the reaction formula is as follows
Wherein R1 is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-methoxyphenyl and n-butyl;
-R2 is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl;
the sulfur source is sodium sulfide or potassium sulfide; the carbon source is dichloromethane or dibromomethane;
the reaction steps are as follows: will be provided with
Sequentially putting the sulfur source and the carbon source into a reaction container filled with a solvent, and stirring and mixing to obtain a reaction solution; then raising the temperature for reaction; after the reaction is finished, filtering and purifying the reaction solution to obtain thiazolidine-4-ketone derivatives;
the reaction is carried out by raising the temperature, namely raising the temperature of the reaction solution to 80 ℃ and the reaction time to 14-16h.
2. The process according to claim 1, wherein the synthesis of thiazolidin-4-one derivatives is carried out in the absence of a metal catalyst, wherein: the solvent is tetrahydrofuran or acetonitrile or 1,4-dioxane.
3. The method according to claim 2, wherein the thiazolidin-4-one derivative is synthesized in the absence of a metal catalyst, and the method comprises the steps of: the filtration and purification treatment refers to that the reaction solution is filtered, rotary evaporated, separated by column layers, eluted liquid is leached, and finally the thiazolidine-4-ketone derivative is obtained by vacuum concentration.
4. The process according to claim 3, wherein the synthesis of the thiazolidin-4-one derivative is carried out in the absence of a metal catalyst, and wherein: the eluent comprises the following substances in parts by volume: 10 parts of petroleum ether; and 1 part of ethyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910306156.5A CN110054597B (en) | 2019-04-17 | 2019-04-17 | Thiazolidine-4-ketone derivative synthesized under condition of no metal catalyst and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910306156.5A CN110054597B (en) | 2019-04-17 | 2019-04-17 | Thiazolidine-4-ketone derivative synthesized under condition of no metal catalyst and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110054597A CN110054597A (en) | 2019-07-26 |
| CN110054597B true CN110054597B (en) | 2022-11-08 |
Family
ID=67317749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910306156.5A Expired - Fee Related CN110054597B (en) | 2019-04-17 | 2019-04-17 | Thiazolidine-4-ketone derivative synthesized under condition of no metal catalyst and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110054597B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329002A (en) * | 1996-09-30 | 2002-01-02 | 辉瑞大药厂 | Intermediate product for preparing aralkyl and aryl alkylene heterocyclic lactam and imide |
-
2019
- 2019-04-17 CN CN201910306156.5A patent/CN110054597B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329002A (en) * | 1996-09-30 | 2002-01-02 | 辉瑞大药厂 | Intermediate product for preparing aralkyl and aryl alkylene heterocyclic lactam and imide |
Non-Patent Citations (1)
| Title |
|---|
| "Transition-metal and base-free thioannulation of propynamides with sodium sulfide and dichloromethane for the selective synthesis of 1,3- thiazin-4-ones and thiazolidine-4-ones";Sui-Qian Wang et al.;《Tetrahedron》;20200207;第76卷;第131021-131029页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110054597A (en) | 2019-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tan et al. | Concise synthesis of chiral 2 (5H)-furanone derivatives possessing 1, 2, 3-triazole moiety via one-pot approach | |
| CN108314658B (en) | A kind of preparation method of polysubstituted oxazole derivatives | |
| CN108794357B (en) | N-difluoromethyl hydrazone compound and synthesis method thereof | |
| CN112812084B (en) | Synthetic method of benzofuran compound | |
| CN110054597B (en) | Thiazolidine-4-ketone derivative synthesized under condition of no metal catalyst and preparation method thereof | |
| CN104744390A (en) | Preparation method of ezetimibe internmediate ketone | |
| CN115108937B (en) | Synthesis method of alpha-azido ketone containing three-level stereo center | |
| CN105753733A (en) | AHU377 crystal form and preparation method and uses thereof | |
| CN111793017B (en) | Preparation method of lactam compound | |
| Ma et al. | A concise and practical stereoselective synthesis of ipragliflozin L-proline | |
| CN108610306B (en) | Synthetic method of 2H-1, 4-thiazine-3 (4H) -ketone derivative | |
| CN109053631B (en) | Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol | |
| CN108191737B (en) | Process for producing N- (2-methylthiophenyl) isoindole-1, 3-dione compound | |
| Stachel et al. | Synthesis of (±)-thioascorbic acid | |
| CN109384753B (en) | Synthetic method of 2-phenyl-3-methylbenzofuran compound | |
| CN115521268B (en) | Method for synthesizing iodo-alkenyl oxazolidone derivative | |
| JP2008543742A5 (en) | ||
| JPS58172344A (en) | Manufacture of phenylalkanoic acid | |
| CN109970703A (en) | The preparation method and application of 1,3- heterocyclic substituted aromatic ketone | |
| JP2008543742A (en) | Process for the preparation of biarylureas and their analogs | |
| CN109879832B (en) | 4-alkoxy-2-aryl mercaptomorpholine-3, 5-dione compound and preparation method thereof | |
| CN111943891B (en) | Rosuvastatin calcium impurity and rosuvastatin calcium quality control method | |
| CN107382899A (en) | A kind of polysubstituted benzo-oxazine derivative of 2 hydroxyl 1,4 | |
| CN112341444B (en) | 3- (2, 3-dihydropyrrole) indole compound and preparation method thereof | |
| CN107033056A (en) | A kind of preparation method of the pyrrolin of 2 methyl, 4 phenyl 1 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20221108 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |