CN114262308B - 2-methylene-2, 3-dihydrothiazole compound and synthetic method and application thereof - Google Patents
2-methylene-2, 3-dihydrothiazole compound and synthetic method and application thereof Download PDFInfo
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- -1 2-methylene-2, 3-dihydrothiazole compound Chemical class 0.000 title claims abstract description 59
- 238000010189 synthetic method Methods 0.000 title claims description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003446 ligand Substances 0.000 claims abstract description 11
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052709 silver Inorganic materials 0.000 claims abstract description 9
- 239000004332 silver Substances 0.000 claims abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 239000011593 sulfur Substances 0.000 claims abstract description 7
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 5
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract 2
- 238000003786 synthesis reaction Methods 0.000 claims abstract 2
- 238000010992 reflux Methods 0.000 claims description 47
- 230000035484 reaction time Effects 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000004982 aromatic amines Chemical class 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000003441 thioacyl group Chemical group 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 101710134784 Agnoprotein Proteins 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000007259 addition reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 145
- 239000000047 product Substances 0.000 description 52
- 238000002474 experimental method Methods 0.000 description 37
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 33
- 239000007858 starting material Substances 0.000 description 27
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 description 9
- HAOOXLOWFGXQEQ-UHFFFAOYSA-N 2-methylidene-3h-1,3-thiazole Chemical class C=C1NC=CS1 HAOOXLOWFGXQEQ-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000000922 anti-bactericidal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- VJZNUICECYWOFV-UHFFFAOYSA-N o-phenyl carbamothioate Chemical compound NC(=S)OC1=CC=CC=C1 VJZNUICECYWOFV-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000007979 thiazole derivatives Chemical group 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a 2-methylene-2, 3-dihydrothiazole compound and a synthesis method thereof, wherein N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in a formula (1) and malonate shown in a formula (2) are used as raw materials, and in the presence of a silver catalyst, a phosphine ligand and inorganic base, in an organic solvent, the addition/isomerization reaction of a sulfur end with adjustable position and chemical selectivity to alkyne is carried out at the temperature of 40-85 ℃ to obtain the 2-methylene-2, 3-dihydrothiazole compound; the synthesis method of the 2-methylene-2, 3-dihydrothiazole compound has the advantages of simple operation, atom economy, step economy, green and high efficiency, wide substrate application range and the like through condition control. The invention also discloses the potential application value of the 2-methylene-2, 3-dihydrothiazole compound in the aspect of drug synthesis.
Description
Technical Field
The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to a 2-methylene-2, 3-dihydrothiazole compound, a synthetic method and application thereof.
Background
Thiazole is a very important nitrogen-containing/sulfur-containing five-membered heterocyclic compound, and is a basic unit structure in a plurality of drug molecules. In recent years, the biological activity of thiazole derivative structures such as 2-methylene-2, 3-dihydrothiazole compounds is widely studied, and the compounds can be used for anti-inflammatory, bactericidal and anticancer drugs and can also be used as constituent fragments and basic units of various complex drug molecules. Therefore, the development of a simple and efficient method for synthesizing the 2-methylene-2, 3-dihydrothiazole compounds has great research value.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, and provides a 2-methylene-2, 3-dihydrothiazole compound and a synthesis method thereof, wherein the synthesis method adopts a silver catalyst, a phosphine ligand and an inorganic base which are easy to prepare, and the 2-methylene-2, 3-dihydrothiazole compound is synthesized in moderate to good yield through the efficient generation position and the chemically selective controllable sulfur end addition/isomerization reaction of alkyne in an atomic and step economical way. The method has the advantages of simple operation, atom economy, step economy, green and high efficiency, wide substrate application range and the like.
The specific technical scheme for realizing the aim of the invention is as follows:
a class of 2-methylene-2, 3-dihydrothiazole compounds, which has the structure of the following formula (3):
wherein,
R 1 is alkyl or aryl;
R 2 is hydrogen or aryl;
R 3 is hydrogen, aryl or alkyl;
R 4 /R 5 methyl, benzyl, isopropyl or phosphate alone;
a synthetic method of 2-methylene-2, 3-dihydrothiazole compounds comprises the following steps: N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in a formula (1), malonate shown in a formula (2), a silver catalyst, a phosphine ligand and inorganic alkali are subjected to an addition and re-isomerization reaction of a sulfur end to alkyne, wherein the sulfur end is adjustable in high efficiency generation position and chemical selectivity, in an organic solvent under the condition of reflux temperature, so that the 2-methylene-2, 3-dihydrothiazole compound is obtained; the process is shown in a reaction formula (I):
wherein,
R 1 is alkyl or aryl;
R 2 is hydrogen or aryl;
R 3 is hydrogen, aryl or alkyl;
R 4 /R 5 methyl, benzyl, isopropyl or phosphate alone;
wherein the molar ratio of the N-propargyl-N-alkyl I aryl amine thioacyl fluoride shown in the formula (1) to the malonate shown in the formula (2) is 1:1-4.5; the mol ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the silver catalyst is 1:0.05-1; the molar ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the phosphine ligand is 1:0.05-1; the molar ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the inorganic base is 1:1-4.
Wherein the palladium catalyst is AgSbF 6 、Ag 2 O、AgOTf、AgOAc、Ag 2 CO 3 、AgCO 2 CF 3 、AgBF 4 、AgF、AgNO 3 Or AgNTf 2 。
Wherein the phosphine ligand is PCy 3 (tricyclohexylphosphine), PPh 3 (triphenylphosphine) or MeP (trimethylphosphorus)
Wherein the inorganic base is NaO t Bu、LiO t Bu、KOH、K 3 PO 4 、K 2 CO 3 、NaOH、K 2 HPO 4 、KH 2 PO 4 Or Cs 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably Cs 2 CO 3 。
Wherein the organic solvent is anhydrous acetonitrile, anhydrous toluene, anhydrous 1, 4-dioxane, anhydrous dimethyl sulfoxide, anhydrous N, N-dimethylformamide, anhydrous 1, 2-dichloroethane or anhydrous tetrahydrofuran; preferably anhydrous acetonitrile.
Wherein the temperature of the reaction is 40-85 degrees, preferably reflux temperature.
Wherein the reaction time is 3-24 hours.
Wherein, the method of the invention also comprises the steps of post-treatment and column chromatography separation and purification; wherein, the separation and purification are carried out by column chromatography with the mixed solvent of ethyl acetate and petroleum ether as eluent, and the volume ratio of the mixed solvent of ethyl acetate and petroleum ether is 1:3-1:5.
In one embodiment, the method of the present invention comprises: the method comprises the steps of (1) putting N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in a formula (1), malonate shown in a formula (2), a silver catalyst, a phosphine ligand and inorganic alkali into an organic solvent, and monitoring by TLC under the condition of reflux temperature until the reaction of a raw material (1) is finished; filtering to remove precipitate in the reaction system, concentrating the filtrate under reduced pressure, and separating the residue by column chromatography with petroleum ether/ethyl acetate mixed solvent to obtain 2-methylene-2, 3-dihydrothiazole compound shown in formula (3).
The method for synthesizing the 2-methylene-2, 3-dihydrothiazole compound is characterized in that N-propargyl-N-alkyl/aryl amine thioacyl fluoride, malonate, a phosphine ligand and inorganic alkali are placed in an organic solvent, and the 2-methylene-2, 3-dihydrothiazole compound is obtained through an efficient intermolecular series experiment under the condition of reflux temperature; and (3) performing post-treatment and column chromatography separation and purification to obtain the purified 2-methylene-2, 3-dihydrothiazole compound.
The invention also provides application of the 2-methylene-2, 3-dihydrothiazole compound in the aspects of biological pharmacy and materials.
The invention adopts the silver catalyst, phosphine ligand and inorganic base which are easy to prepare and easily obtained, and the 2-methylene-2, 3-dihydrothiazole compound is obtained through the addition/isomerization reaction of the sulfur end to alkyne with high-efficiency generation position and controllable chemical selectivity. The method has the advantages of simple operation, green and high efficiency, economical atomic steps, wide substrate application range and the like. The 2-methylene-2, 3-dihydrothiazole synthesized by the invention is a new compound, is synthesized for the first time, and can be applied to biological pharmacy and special preparations.
Drawings
FIGS. 1 to 15 show nuclear magnetic resonance of 2-methylene-2, 3-dihydrothiazoles synthesized in examples 1 to 15 of the present invention 1 H NMR、 13 C NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, but the scope of the present invention is not limited to the following examples. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.
Example 1
AgOTf (5.1 mg,0.02 mmol), PPh were added to the dried reaction tube 3 (5.2 mg,0.02 mmol) and Cs 2 CO 3 (162.9 mg,0.5 mmol) and 4mL of anhydrous acetonitrile-dissolved phenyl (3-phenylprop-2-yn-1-yl) aminothiofluoro (53.8 mg,0.2 mmol) were added and dimethyl malonate (66.0 mg,0.5 mmol) was added using a microinjection syringe. The reaction was allowed to react for 3 hours at reflux temperature, TLC monitored the complete consumption of the starting N-propargyl-N-alkyl/aryl amine thioacyl fluoride, then the solvent was dried by spin-drying under vacuum reduced pressure, and the residue was purified by silica gel column chromatography to give pure product 71.6mg. The structure is shown as a formula (3-1). The yield was 94%.
(1. Under the same conditions, when trimethylphosphorus was used instead of triphenylphosphine, the yield was 66%;2. Under the same conditions, when tricyclohexylphosphorus was used instead of triphenylphosphine, the yield was 75%;3. Under the same conditions, when sodium carbonate was used instead of cesium carbonate, the yield was 26%;4. Under the same conditions, when sodium tert-butoxide was used instead of cesium carbonate, the yield was 19%;5. Under the same conditions, when lithium tert-butoxide was used instead of cesium carbonate, the yield was 19%;6. Under the same conditions, when potassium phosphate was used instead of cesium carbonate, the yield was 45%;7. Under the same conditions, when sodium hydroxide was used instead of cesium carbonate, the yield was 10%;8. Under the same conditions, when potassium hydroxide was used instead of cesium carbonate, the yield was 12%;8. Under the same conditions, the alkali was used instead of cesium carbonate)When dipotassium hydrogen phosphate replaces cesium carbonate, the yield is 28%;9. under the same conditions, when the alkali potassium dihydrogen phosphate replaces cesium carbonate, the yield is 25%;10. AgSbF under the same conditions as above 6 When AgOTf is replaced, the yield is 57%;11. under the same conditions, ag 2 When O replaces AgOTf, the yield is 74%;12. under the same conditions, when AgOAc replaces AgOTf, the yield is 50%;13. under the same conditions, ag 2 CO 3 When AgOTf is replaced, the yield is 66%;14. AgCO under the same conditions as above 2 CF 3 When AgOTf is replaced, the yield is 60%;15. AgBF under the same conditions as above 4 When AgOTf is replaced, the yield is 60%;16. under the same conditions, when AgF replaces AgOTf, the yield is 15%;17. AgNO under the same conditions as above 3 When AgOTf is replaced, the yield is 60%;18. AgNTf under the same conditions as above 2 When AgOTf is replaced, the yield is 65%;19. under the same conditions, when anhydrous toluene is used for replacing anhydrous acetonitrile, the yield is 10%;20. under the same conditions, when anhydrous tetrahydrofuran is used for replacing anhydrous acetonitrile, the yield is 11%;21. under the same conditions, when anhydrous thionyl chloride is used for replacing anhydrous acetonitrile, the yield is 15%;22. under the same conditions, when anhydrous N, N-dimethylformamide replaces anhydrous acetonitrile, the yield is 20%;23. under the same conditions, when anhydrous 1, 2-dichloroethane is used instead of anhydrous acetonitrile, the yield is 15%;24. under the same conditions, the temperature is 80 ℃ instead of reflux, and the yield is 90%;25. under the same conditions, the temperature is 70 ℃ instead of reflux, and the yield is 75%;26. under the same conditions, the temperature is 60 ℃ instead of reflux, and the yield is 60%;27. under the same conditions, the temperature is 50 ℃ instead of reflux, and the yield is 40%;28. under the same conditions, the temperature is 40 ℃ instead of reflux, and the yield is 30%)
Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 1, the product: 1 H NMR(500MHz，CDCl 3 )δ7.44(t，J＝7.8Hz，2H)，7.35-7.24(m，8H)，6.63(s，1H)，3.90(s，2H)，3.34(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.1，140.7，137.4，129.7，128.8，128.6，128.1，127.5，127.4，127.1，124.2，86.5，51.0，33.1.HRMS(EI)calculated for C 21 H 19 NO 4 S[M] + 381.1035，found：381.1031。
example 2
The experimental procedure of this example was substantially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (p-tolyl) aminothiofluoro and dimethyl malonate were used as the raw materials, and the reaction time at reflux temperature was 4 hours, and the obtained product was represented by the structural formula (3-2). The yield was 95%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 2, the product: 1 H NMR(600MHz，CDCl 3 )δ7.35-7.29(m，2H)，7.28-7.20(m，5H)，7.16(d，J＝8.2Hz，2H)，6.61(s，1H)，3.89(s，2H)，3.34(s，6H)，2.36(s，3H). 13 C NMR(150MHz，CDCl 3 )δ166.6，166.0，138.1，138.1，137.4，130.1，128.7，128.5，127.7，127.2，127.1，123.9，86.1，51.0，33.0，20.9.HRMS(EI)calculated for C 22 H 21 NO 4 S[M] + 395.1191，found：395.1187。
example 3
The experimental procedure of this example was essentially the same as that of example 1, except that (4-fluorophenyl) (3-phenylprop-2-yn-1-yl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time at reflux temperature was 8 hours, and the obtained product was represented by the following structural formula (3-3). The yield was 64%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 3, the product: 1 H NMR(500MHz，CDCl 3 )δ7.37-7.23(m，7H)，7.12(t，J＝8.4Hz，2H)，6.58(s，1H)，3.89(s，2H)，3.39(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.1，162.5(d，J＝313.7Hz)，137.2，136.5(d，J＝3.3Hz)，128.8，128.6，127.4，127.3，127.1，126.3(d，J＝8.6Hz)，116.6(d，J＝22.7Hz)，86.4，51.2，33.0.HRMS(EI)calculated for C 21 H 18 FNO 4 S[M] + 399.0941，found：399.0944。
example 4
The experimental procedure of this example was essentially the same as that of example 1, except that (2-methoxyphenyl) (3-phenylprop-2-yn-1-yl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-4). The yield was 87%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 4, the product: 1 H NMR(600MHz，CDCl 3 )δ7.29-7.09(m，7H)，6.95(d，J＝8.1Hz，1H)，6.89(t，J＝7.3Hz，1H)，6.44(s，1H)，3.80(d，J＝4.9Hz，5H)，3.27(s，6H). 13 C NMR(150MHz，CDCl 3 )δ166.7，165.9，153.4，137.6，129.8，128.6，128.5，128.4，127.3，126.9，126.7，125.6，120.8，112.2，86.6，55.8，51.0，33.0.HRMS(EI)calculated for C 22 H 21 NO 5 S[M] + 411.1140，found：411.1144。
example 5
The experimental procedure of this example was essentially the same as that of example 1, except that (2-fluorophenyl) (3-phenylprop-2-yn-1-yl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time at reflux temperature was 4 hours, and the obtained product was represented by the structural formula (3-5). The yield was 89%. Nuclear magnetic resonance 1 H NMR、 13 CNMR profile as shown in fig. 5, product: 1 H NMR(500MHz，CDCl 3 )δ7.40-7.15(m，9H)，6.54(s，1H)，3.90(s，2H)，3.39(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.5，156.3(d，J＝253.3Hz)，137.2，130.1(d，J＝7.7Hz)，128.8，128.6，128.0(d，J＝12.3Hz)，127.1，127.0，126.8，126.4(d，J＝1.6Hz)，125.0(d，J＝3.8Hz)，117.1(d，J＝19.2Hz)，87.3，51.2，33.0.HRMS(EI)calculated for C 21 H 18 FNO 4 S[M] + 399.0941，found：399.0944。
example 6
The experimental procedure of this example was essentially the same as that of example 1, except that (3-chlorophenyl) (3-phenylprop-2-yn-1-yl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-6). The yield was 90%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 6, the product: 1 H NMR(600MHz，CDCl 3 )δ7.31(td，J＝31.0，8.0Hz，8H)，7.19(d，J＝7.9Hz，1H)，6.60(s，1H)，3.89(s，2H)，3.40(s，6H). 13 C NMR(150MHz，CDCl 3 )δ166.4，165.6，141.4，137.2，135.2，130.7，128.8，128.5，128.2，127.5，127.1，126.8，124.7，122.4，87.0，51.1，33.0.HRMS(EI)calculated for C 21 H 18 ClNO 4 S[M] + 415.0645，found：415.0649。
example 7
The experimental method of this example is basically the same as that of example 1, the raw materials adopted in this example are benzyl (3-phenylprop-2-yn-1-yl) aminothiofluoro and dimethyl malonate, and the reaction time is 8 hours at reflux temperature, and the obtained product is shown as structural formula (3-7). The yield was 70%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 7, the product: 1 H NMR(600MHz，CDCl 3 )δ7.38-7.33(m，3H)，7.29-7.26(m，2H)，7.23(t，J＝7.2Hz，1H)，7.12(dd，J＝13.3，7.5Hz，4H)，6.43(s，1H)，4.86(s，2H)，3.83(s，2H)，3.71(s，6H). 13 C NMR(150MHz，CDCl 3 )δ169.3，167.4，137.5，134.7，129.1，128.9，128.8，128.6，128.4，128.1，127.1，126.7，83.7，56.5，51.4，33.2.HRMS(EI)calculated for C 22 H 21 NO 4 S[M] + 395.1191，found：395.1195。
example 8
The experimental procedure of this example was essentially the same as that of example 1, and the starting materials used in this example were phenyl (prop-2-yn-1-yl) aminothiofluoro and dimethyl malonate, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-8). The yield was 68%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 8, the product: 1 H NMR(500MHz，CDCl 3 )δ7.47(t，J＝7.8Hz，2H)，7.39-7.30(m，3H)，6.72(s，1H)，3.37(s，6H)，2.29(s，3H). 13 C NMR(125MHz，CDCl 3 )δ166.7，166.2，140.8，129.7，128.0，127.5，124.2，122.7，86.1，51.0，11.7.HRMS(EI)calculated for C 15 H 15 NO 4 S[M] + 305.0722，found：305.0726。
example 9
The experimental procedure of this example was essentially the same as that of example 1, except that the starting materials used in this example were fluorine (3- (4-methoxyphenyl) prop-2-yn-1-yl) (phenyl) thiocarbamate and dimethyl malonate, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-9). The yield was 88%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 9, the product: 1 H NMR(500MHz，CDCl 3 )δ7.43(t，J＝7.8Hz，2H)，7.37-7.25(m，3H)，7.17(d，J＝8.5Hz，2H)，6.86(t，J＝5.7Hz，2H)，6.61(s，1H)，3.84(s，2H)，3.79(s，3H)，3.33(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.1，158.6，140.7，129.7，129.6，129.4，128.0，127.3，124.2，114.2，86.3，55.2，51.0，32.2.HRMS(EI)calculated for C 22 H 21 NO 5 S[M]+411.1140，found：411.1142。
example 10
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (2-fluorophenyl) prop-2-yn-1-yl) (phenyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-10). The yield thereof was found to be 61%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 10, the product: 1 H NMR(500MHz，CDCl 3 )δ7.44(t，J＝7.8Hz，2H)，7.37-7.23(m，5H)，7.08(dt，J＝18.0，8.1Hz，2H)，6.69(s，1H)，3.93(s，2H)，3.34(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.0，160.7(d，J＝246.8Hz)，140.6，130.7(d，J＝3.9Hz)，129.7，129.1(d，J＝8.1Hz)，128.1，127.8，125.7，124.6(d，J＝15.5Hz)，124.4(d，J＝3.4Hz)，124.2，115.6(d，J＝21.6Hz)，86.6，51.1，26.2(d，J＝3.8Hz).HRMS(EI)calculated for C 21 H 18 FNO 4 S[M] + 399.0941，found：399.0938。
example 11
The experimental procedure of this example is essentially the same as that of example 1, wherein the starting materials used in this example are fluorine (3- (3-cyanophenyl) propan-2-yl-1-yl) (phenyl) thiocarbamate and dimethyl malonate, and the reaction time is 4 hours at reflux temperature, and the resulting product is represented by the formula (3-11)Shown. The yield was 677%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 11, the product: 1 H NMR(500MHz，CDCl 3 )δ7.56-7.36(m，6H)，7.33-7.18(m，3H)，6.62(d，J＝0.8Hz，1H)，3.87(s，2H)，3.27(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.5，165.6，140.4，139.0，133.1，132.0，130.9，129.8，129.7，128.3，128.1，125.1，124.3，118.4，113.0，87.2，51.1，32.6.HRMS(EI)calculated for C 22 H 18 N 2 O 4 S[M] + 406.0987，found：406.0992。
example 12
The experimental method of this example is basically the same as that of example 1, the raw materials adopted in this example are phenyl (4-phenylbutan-3-yn-2-yl) aminothiofluoro and dimethyl malonate, and the reaction time is 8 hours at reflux temperature, and the obtained product is shown as structural formula (3-12). The yield was 71%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 12, the product: 1 H NMR(500MHz，CDCl 3 )δ7.49(t，J＝7.5Hz，2H)，7.44(t，J＝7.3Hz，1H)，7.36-7.32(m，2H)，7.27(dd，J＝12.2，5.0Hz，5H)，3.92(s，2H)，3.39(s，6H)，1.87(s，3H). 13 C NMR(125MHz，CDCl 3 )δ166.9，165.2，138.6，138.2，132.5，129.3，129.0，128.8，128.5，128.3，126.9，118.9，87.1，51.2，32.6，13.0.HRMS(EI)calculated for C 22 H 21 NO 4 S[M] + 395.1191，found：395.1192。
example 13
The experimental procedure of this example is essentially the same as that of example 1, using (1, 3-diphenylprop-2-yn-1-yl) (phenyl) thio as starting materialFluorine carbamate and dimethyl malonate, and the reaction time is 7 hours at the reflux temperature, and the obtained product is shown as a structural formula (3-13). The yield was 88%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 13, the product: 1 H NMR(500MHz，CDCl 3 )δ7.32-7.11(m，11H)，7.03-6.93(m，4H)，3.74(s，2H)，3.35(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.9，165.1，138.7，138.2，137.7，130.9，129.7，128.9，128.7，128.7，128.4，128.4，128.2，128.2，126.8，122.7，87.1，51.2，32.9.HRMS(EI)calculated for C 27 H 23 NO 4 S[M] + 457.1348，found：457.1353。
example 14
The experimental procedure of this example was essentially the same as that of example 1, and the starting materials used in this example were phenyl (3-phenylprop-2-yn-1-yl) aminothiofluoro and ethyl acetoacetate, and the reaction time was 24 hours at reflux temperature, and the resulting product was represented by the structural formula (3-14). The yield was 31%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 14, the product: 1 H NMR(500MHz，CDCl 3 )δ7.38(t，J＝7.8Hz，2H)，7.30-7.17(m，8H)，6.65(s，1H)，3.87(s，2H)，3.24(q，J＝7.1Hz，2H)，2.25(s，3H)，0.92(t，J＝7.1Hz，3H). 13 C NMR(125MHz，CDCl 3 )δ189.1，167.2，164.6，141.1，137.5，129.7，128.8，128.7，128.6，128.2，127.3，127.1，124.0，99.3，59.6，33.0，27.1，14.1.HRMS(EI)calculated for C 22 H 21 NO 3 S[M] + 379.1242，found：379.1246。
example 15
The experimental method of the embodiment is basically and practicallyExample 1 the starting materials employed in this example were phenyl (3-phenylprop-2-yn-1-yl) aminothiofluoro and methyl 2- (dimethoxyphosphoryl) acetate, and the reaction time was 24 hours at reflux temperature, and the resulting product was represented by the structural formula (3-15). The yield was 44%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 15, the product: 1 H NMR(500MHz，CDCl 3 )δ7.46(t，J＝7.7Hz，2H)，7.41-7.22(m，8H)，6.71(d，J＝0.5Hz，1H)，3.92(s，2H)，3.51(s，3H)，3.49(s，6H). 13 C NMR(125MHz，CDCl 3 )δ167.6，167.5，142.0，137.1，129.4，129.1，128.9，128.7，128.6，127.8，127.2，124.6，52.1，52.0，51.1，33.2.HRMS(EI)calculated for C 21 H 22 NO 5 PS[M] + 431.0956，found：431.0961。
example 16
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (p-methoxyphenyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time at reflux temperature was 4 hours, and the obtained product was represented by the structural formula (3-16). The yield was 76%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(600MHz，CDCl 3 )δ7.36-7.30(m，2H)，7.28-7.24(m，3H)，7.20(d，J＝8.9Hz，2H)，6.92(d，J＝8.9Hz，2H)，6.57(s，1H)，3.88(s，2H)，3.81(s，3H)，3.38(s，6H). 13 C NMR(150MHz，CDCl 3 )δ166.7，166.1，159.0，137.4，133.3，128.7，128.5，127.8，127.0，127.0，125.7，114.6，86.0，55.5，51.1，33.0.HRMS(EI)m/z：[M] + calculated for C 22 H 21 NO 5 S 411.1140，found 411.1144.Mp：140-141℃。
example 17
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (p-bromophenyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-17). The yield was 76%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(600MHz，CDCl 3 )δ7.56(d，J＝8.7Hz，2H)，7.33(t，J＝7.4Hz，2H)，7.29-7.23(m，3H)，7.17(d，J＝8.7Hz，2H)，6.58(s，1H)，3.89(s，2H)，3.39(s，6H). 13 C NMR(150MHz，CDCl 3 )δ166.5，165.9，139.6，137.2，132.8，128.8，128.5，127.7，127.1，126.9，125.9，121.6，86.7，51.1，33.0.HRMS(EI)m/z：[M] + calculated for C 21 H 18 BrNO 4 S 459.0140，found 459.0138。
example 18
The experimental procedure of this example was substantially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (o-methylphenyl) aminothiofluoro and dimethyl malonate were used as the raw materials, and the reaction time at reflux temperature was 4 hours, and the obtained product was represented by the structural formula (3-18). The yield was 76%. 1 H NMR(600MHz，CDCl 3 )δ7.35-7.22(m，8H)，7.18(d，J＝7.7Hz，1H)，6.40(s，1H)，3.89(s，2H)，3.34(s，6H)，2.19(s，3H). 13 C NMR(150MHz，CDCl 3 )δ166.6，164.7，138.4，137.5，134.9，131.4，129.0，128.8，128.5，127.0，127.0，126.8，126.7，126.1，86.9，51.2，33.0，17.8.HRMS(EI)m/z：[M] + calculated for C 22 H 21 NO 4 S395.1191.found 395.1187。
Example 19
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (m-methoxyphenyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time at reflux temperature was 4 hours, and the obtained product was represented by the structural formula (3-19). The yield was 84%. 1 H NMR(500MHz，CDCl 3 )δ7.33(t，J＝7.8Hz，3H)，7.28-7.24(m，3H)，6.87(dd，J＝8.1，2.2Hz，2H)，6.80(t，J＝2.1Hz，1H)，6.65(s，1H)，3.89(s，2H)，3.80(s，3H)，3.37(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.7，165.5，160.4，141.6，137.4，130.4，128.8，128.6，127.5，127.1，127.0，116.2，114.2，109.4，86.8，55.5，51.0，33.0.HRMS(EI)m/z：[M] + calculated for C 22 H 21 NO 5 S 411.1140，found 411.1144。
Example 20
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (m-ethylphenyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-20). The yield was 75%. 1 H NMR(600MHz，CDCl 3 )δ8.02(d，J＝7.4Hz，1H)，7.96(s，1H)，7.54-7.45(m，2H)，7.37-7.31(m，2H)，7.27(d，J＝7.6Hz，3H)，6.65(s，1H)，4.40(q，J＝7.1Hz，2H)，3.90(s，2H)，3.35(s，6H)，1.40(t，J＝7.1Hz，3H). 13 C NMR(150MHz，CDCl 3 )δ166.5，165.9，165.0，140.7，137.3，132.3，129.8，129.0，128.8，128.6，128.5，127.5，127.1，127.0，125.7，86.9，61.5，51.1，33.0，14.2.HRMS(EI)m/z：[M] + calculated for C 24 H 23 NO 6 S453.1246，found 453.1252。
Example 21
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (1-naphthylphenyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-21). The yield was 80%. 1 H NMR(600MHz，CDCl 3 )δ7.90(dd，J＝27.7，8.0Hz，2H)，7.74(d，J＝8.1Hz，1H)，7.63-7.53(m，2H)，7.48(t，J＝7.8Hz，1H)，7.39(d，J＝7.3Hz，1H)，7.35-7.21(m，5H)，6.59(s，1H)，3.93(s，2H)，3.00(s，6H). 13 C NMR(150MHz，CDCl 3 )δ166.5，166.4，137.5，136.3，134.4，129.2，128.8，128.8，128.5，128.4，127.6，127.4，127.1，126.8，126.3，125.4，124.0，122.6，87.3，50.7，33.1.HRMS(EI)m/z：[M] + calculated for C 25 H 21 NO 4 S431.1191，found 431.1184。
Example 22
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (cyclohexyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-21). The yield was 60%. 1 H NMR(500MHz，CDCl 3 )δ7.33(t，J＝7.3Hz，2H)，7.28(s，1H)，7.22(d，J＝7.5Hz，2H)，6.77(s，1H)，3.93(s，2H)，3.75(m，1H)，3.74(s，6H)，2.05(d，J＝11.2Hz，2H)，1.86(d，J＝13.3Hz，2H)，1.43(dd，J＝17.2，7.2Hz，2H)，1.30(m，3H)，1.15(d，J＝12.9Hz，1H). 13 C NMR(125MHz，CDCl 3 )δ169.8，167.5，137.4，130.7，128.9，128.5，127.2，123.3，99.9，62.6，51.2，33.4，32.8，25.7，25.0.HRMS(EI)m/z：[M] + calculated for C 21 H 25 NO 4 S 387.1504，found 387.1510。
Example 23
The experimental procedure of this example was essentially the same as that of example 1, except that the starting materials used in this example were (3-phenylprop-2-yn-1-yl) (n-hexyl) aminothiofluoro and dimethyl malonate, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-22). The yield was 65%. 1 H NMR(600MHz，CDCl 3 )δ7.32(t，J＝7.2Hz，2H)，7.26(s，1H)，7.22(d，J＝7.3Hz，2H)，6.60(s，1H)，3.90(s，2H)，3.76(s，6H)，3.72(t，J＝7.4Hz，2H)，1.70-1.64(m，2H)，1.25(d，J＝5.1Hz，6H)，0.86(t，J＝6.6Hz，3H). 13 C NMR(150MHz，CDCl 3 )δ168.5，167.4，137.5，129.0，128.8，128.5，127.1，126.5，83.0，52.7，51.3，33.2，31.1，28.4，26.1，22.3，13.8.HRMS(EI)m/z：[M] + calculated for C 21 H 27 NO 4 S 389.1661，found 389.1657。
Example 24
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (3, 4-dimethoxyphenethyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the following structural formula (3-22). The yield thereof was found to be 63%. 1 H NMR(500MHz，CDCl 3 )δ7.25-7.15(m，3H)，7.01(d，J＝7.4Hz，2H)，6.68(d，J＝8.1Hz，1H)，6.53(dd，J＝8.1，1.5Hz，1H)，6.45(d，J＝1.6Hz，1H)，6.20(s，1H)，3.94(t，J＝7.2Hz，2H)，3.79(s，3H)，3.71(d，J＝4.9Hz，11H)，2.83(t，J＝7.1Hz，2H). 13 C NMR(125MHz，CDCl 3 )δ167.5，167.5，149.0，147.9，137.3，129.5，128.7，128.5，127.9，127.7，127.1，120.5，111.6，111.3，83.7，55.9，55.8，53.8，51.5，33.1，32.9.HRMS(EI)m/z：[M] + calculated for C 25 H 27 NO 6 S 469.1559，found 469.1551。
Example 24
The experimental procedure of this example was essentially the same as that of example 1, except that (3-phenylprop-2-yn-1-yl) (2-thiophenoethyl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-22). The yield was 36%. 1 H NMR(500MHz，CDCl 3 )δ7.28-7.15(m，5H)，7.11-7.02(m，3H)，6.31(s，1H)，3.97(t，J＝7.2Hz，2H)，3.74(s，2H)，3.71(s，6H)，3.16-3.08(m，2H). 13 C NMR(125MHz，CDCl 3 )δ167.6，167.5，138.8，137.4，128.8，128.6，128.1，127.3，127.1，127.1，126.0，124.5，84.0，53.7，51.6，32.9，27.9.HRMS(EI)m/z：[M] + calculated for C 21 H 21 NO 4 S 2 415.0912，found 415.0917。
Example 25
The experimental method of this example is basically the same as that of example 1, wherein p-methoxyphenyl (prop-2-yn-1-yl) aminothiofluoro and dimethyl malonate are used as raw materials, and the reaction time is 4 hours at the reflux temperature, and the obtained product is shown as a structural formula (3-25). The yield was 68%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.23(d，J＝8.8Hz，2H)，6.95(d，J＝8.9Hz，2H)，6.64(s，1H)，3.84(s，3H)，3.41(s，6H)，2.27(s，3H). 13 C NMR(125MHz，CDCl 3 )δ166.8，166.2，159.0，133.5，127.8，125.7，122.3，114.7，85.7，55.5，51.1，11.7.HRMS(EI)m/z：[M] + calculated for C 16 H 17 NO 5 S 335.0827，found 335.0830。
example 26
The experimental procedure of this example was essentially the same as that of example 1, wherein p-bromophenyl (prop-2-yn-1-yl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-25). The yield was 65%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.62-7.57(m，2H)，7.20(d，J＝8.7Hz，2H)，6.66(d，J＝1.4Hz，1H)，3.43(s，6H)，2.28(d，J＝1.3Hz，3H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.0，139.7，132.9，126.9，125.9，123.0，121.6，86.5，51.2，11.8.HRMS(EI)m/z：[M] + calculated for C 15 H 14 BrNO 4 S 382.9827，found 382.9833。
example 27
The experimental procedure of this example was essentially the same as that of example 1, wherein p-bromophenyl (prop-2-yn-1-yl) aminothiofluoro and dimethyl malonate were used as the starting materials, and the reaction time was 4 hours at reflux temperature, and the obtained product was represented by the structural formula (3-25). The yield was 56%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.41-7.35(m，3H)，7.18-7.13(m，2H)，6.45(d，J＝1.0Hz，1H)，4.88(s，2H)，3.75(s，6H)，2.22(d，J＝0.8Hz，3H). 13 C NMR(125MHz，CDCl 3 )δ169.5，167.4，134.7，129.1，128.6，128.3，126.4，124.8，82.6，56.4，51.3，12.0.HRMS(EI)m/z：[M] + calculated for C 16 H 17 NO 4 S 319.0878.found 319.0882。
example 28
The experimental procedure of this example was essentially the same as that of example 1, except that the starting materials used in this example were fluorine (3- (4-methylphenyl) prop-2-yn-1-yl) (phenyl) thiocarbamate and dimethyl malonate, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-28). The yield was 91%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.36(dd，J＝10.8，4.9Hz，2H)，7.29-7.17(m，3H)，7.13-7.02(m，4H)，6.54(s，1H)，3.77(s，2H)，3.26(s，6H)，2.25(s，3H). 13 C NMR(125MHz，CDCl 3 )δ166.6，166.1，140.7，136.7，134.3，129.7，129.4，128.5，128.0，127.8，127.3，124.2，86.3，51.0，32.6，20.9.HRMS(EI)m/z：[M] + calculated for C 22 H 21 NO 4 S395.1191，found 395.1193。
example 29
The experimental procedure of this example was essentially the same as that of example 1, except that the starting materials used in this example were fluorine (3- (4-fluorophenyl) prop-2-yn-1-yl) (phenyl) thiocarbamate and dimethyl malonate, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-29). The yield was 76%. 1 H NMR(500MHz，CDCl 3 )δ7.44(t，J＝7.8Hz，2H)，7.34(t，J＝7.4Hz，1H)，7.31-7.27(m，2H)，7.23(dd，J＝8.4，5.4Hz，2H)，7.01(t，J＝8.6Hz，2H)，6.63(s，1H)，3.87(s，2H)，3.34(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，165.9，161.9(d，J＝246.2Hz)，140.6，133.1(d，J＝3.3Hz)，130.1(d，J＝8.2Hz)，129.7，128.1，127.5，127.0，124.2，115.6(d，J＝21.6Hz)，86.6，51.0，32.2.HRMS(EI)m/z：[M] + calculated for C 21 H 18 FNO 4 S 399.0941，found 399.0946。
Example 30
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-trifluoromethylphenyl) prop-2-yn-1-yl) (phenyl) thiocarbamic acid fluorine and dimethyl malonate were used as raw materials, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-30). The yield was 71%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.59(d，J＝8.1Hz，2H)，7.45(t，J＝7.8Hz，2H)，7.42-7.33(m，3H)，7.31-7.28(m，2H)，6.66(s，1H)，3.96(s，2H)，3.34(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，165.8，141.4，141.4，140.5，129.8，129.5(q，J＝32.6Hz)，129.0，128.2，127.9，125.8(q，J＝3.8Hz)，125.0，124.3，122.9，87.0，51.1，32.8.HRMS(EI)m/z：[M] + calculated for C 22 H 18 F 3 NO 4 S449.0909，found 449.0913。
example 31
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-methoxyphenyl) prop-2-yn-1-yl) (phenyl) thiocarbamic acid fluorine and dimethyl malonate were used as the raw materials, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-31). The yield was 63%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ8.05-7.96(m，2H)，7.43(dt，J＝10.2，2.0Hz，2H)，7.37-7.31(m，3H)，7.28(dd，J＝5.3，3.3Hz，2H)，6.62(s，1H)，3.94(s，2H)，3.90(s，3H)，3.33(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.7，166.6，165.9，142.6，140.6，130.1，129.8，129.1，128.7，128.2，127.9，126.0，124.2，86.9，52.1，51.1，33.0.HRMS(EI)m/z：[M] + calculated for C 23 H 21 NO 6 S 439.1090，found 439.1097。
example 32
The experimental procedure of this example was essentially the same as that of example 1, except that the starting materials used in this example were fluorine (3- (4-phenylphenyl) prop-2-yn-1-yl) (phenyl) thiocarbamate and dimethyl malonate, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-32). The yield was 93%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.48(t，J＝8.1Hz，4H)，7.36(td，J＝7.8，2.9Hz，4H)，7.24(tt，J＝24.7，12.3Hz，6H)，6.59(s，1H)，3.85(s，2H)，3.26(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.7，166.2，140.7，140.6，140.2，136.5，129.8，129.1，128.8，128.2，127.7，127.6，127.3.127.3，127.0，124.3，86.6，51.1，32.8.HRMS(EI)m/z：[M] + calculated for C 27 H 23 NO 4 S457.1348，found 457.1351。
example 33
The experimental procedure of this example is essentially the same as that of example 1, the starting material used in this example being (3- (3-fluoro) prop-2-yn-1-Fluoro (phenyl) thiocarbamate and dimethyl malonate are reacted for 3 hours at reflux temperature to obtain the product shown in the structural formula (3-33). The yield was 93%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.46(t，J＝7.7Hz，2H)，7.39-7.28(m，4H)，7.06(d，J＝7.6Hz，1H)，6.97(t，J＝7.6Hz，2H)，6.68(s，1H)，3.91(s，2H)，3.36(s，6H). 13 C NMR(125MHz，CDCl 3 )δ166.6，165.9，162.9(d，J＝246.9Hz)，140.6，139.8(d，J＝7.2Hz)，130.3(d，J＝8.3Hz)，129.7，128.1，127.8，126.3，124.3，124.2，115.6(d，J＝21.6Hz)，114.1(d，J＝21.4Hz)，86.8，51.1，32.7(d，J＝1.6Hz).HRMS(EI)m/z：[M] + calculated for C 21 H 18 FNO 4 S 399.0941，found 399.0945。
example 34
The experimental procedure of this example was essentially the same as that of example 1, and the starting materials used in this example were phenyl (prop-2-yn-1-yl) aminothiofluoro and dimethyl malonate, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-34). The yield was 93%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.32-7.11(m，6H)，6.98(dd，J＝7.8，1.6Hz，2H)，6.94-6.85(m，2H)，3.36(s，6H)，2.10(s，3H). 13 C NMR(125MHz，CDCl 3 )δ167.0，164.9，138.8，137.3，130.7，129.9，128.7，128.3，128.1，128.1，118.4，86.5，51.2，12.0.HRMS(EI)m/z：[M] + calculated for C 21 H 19 NO 4 S381.1035，found 381.1037。
example 35
The experimental method of this example is basically the same as that of example 1, and the raw materials adopted in this example are phenyl (3-phenylprop-2-yn-1-yl) aminothiofluoro and diisopropyl malonate, and the reaction time is 3 hours at reflux temperature, and the obtained product is shown in the structural formula (3-35). The yield was 93%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.34(t，J＝7.7Hz，2H)，7.27-7.15(m，8H)，6.44(s，1H)，4.66-4.56(m，2H)，3.79(s，2H)，1.04(d，J＝6.2Hz，12H). 13 C NMR(125MHz，CDCl 3 )δ166.3，164.5，140.6，137.6，129.6，128.7，128.6，128.1，127.3，127.0，125.9，125.3，88.8，67.4，33.1，21.8.HRMS(EI)m/z：[M] + calculated for C 25 H 27 NO 4 S 437.1661，found 437.1667。
example 36
The experimental procedure of this example was essentially the same as that of example 1, and the starting materials used in this example were phenyl (3-phenylprop-2-yn-1-yl) aminothiofluoro and diisopropyl malonate, and the reaction time was 3 hours at reflux temperature, and the obtained product was represented by the structural formula (3-36). The yield was 93%. Nuclear magnetic resonance 1 H NMR、 13 C NMR was: 1 H NMR(500MHz，CDCl 3 )δ7.44-7.17(m，20H)，6.59(s，1H)，4.77(s，4H)，3.89(s，2H). 13 C NMR(125MHz，CDCl 3 )δ166.2，137.4，136.5，129.6，128.8，128.6，128.2，128.2，127.7，127.5，127.2，127.0，124.8，87.1，65.7，33.1.HRMS(EI)m/z：[M] + calculated for C 33 H 27 NO 4 S 533.1661，found 533.1669。
Claims (2)
1. a method for synthesizing a 2-methylene-2, 3-dihydrothiazole compound, which is characterized in that the compound has the structure of the following formula (3):
wherein,
R 1 is alkyl or aryl;
R 2 is hydrogen or aryl;
R 3 is hydrogen, aryl or alkyl;
R 4 methyl, benzyl, isopropyl or phosphate;
R 5 methyl, benzyl, isopropyl or phosphate;
the synthesis process comprises the following steps: N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in a formula (1), a compound shown in a formula (2), a silver catalyst, a phosphine ligand and inorganic alkali are subjected to addition and re-isomerization reaction of alkyne at a sulfur end with adjustable position and chemical selectivity in an organic solvent under the condition of reflux temperature, the reaction time is 3-24 hours, and the 2-methylene-2, 3-dihydrothiazole compound is obtained through post-treatment and column chromatography separation and purification; the process is shown in a reaction formula (I):
the molar ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the compound shown in the formula (2) is 1:1-4.5; the mol ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the silver catalyst is 1:0.05-1; the molar ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the phosphine ligand is 1:0.05-1;
the mol ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the inorganic base is 1:1-4;
the silver catalyst is AgSbF 6 、Ag 2 O、AgOTf、AgOAc、Ag 2 CO 3 、AgCO 2 CF 3 、AgBF 4 、AgF、AgNO 3 Or AgNTf 2 ；
The phosphine ligand isPCy 3 (tricyclohexylphosphine), PPh 3 (triphenylphosphine) or Me 3 P (trimethylphosphorus);
the inorganic base is NaO t Bu、LiO t Bu、KOH、K 3 PO 4 、K 2 CO 3 、NaOH、K 2 HPO 4 、KH 2 PO 4 Or Cs 2 CO 3 ；
The organic solvent is anhydrous acetonitrile, anhydrous toluene, anhydrous N, N-dimethylformamide, anhydrous 1, 2-dichloroethane or anhydrous tetrahydrofuran.
2. The synthetic method of claim 1 wherein the post-treatment and column chromatography separation and purification comprises: filtering to remove precipitate in the reaction system, concentrating the filtrate under reduced pressure, and separating and purifying the residue by column chromatography by adopting a petroleum ether/ethyl acetate mixed solvent, wherein the volume ratio of the ethyl acetate to the petroleum ether mixed solvent is 1:3-5.
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| CN106317044A (en) * | 2015-06-30 | 2017-01-11 | 刘玫君 | Method for manufacturing isavuconazole or ravuconazole |
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| Ag-Catalyzed or Ag/PPh3-Catalyzed Chemoselective Switchable Cascade Reactions of N-Propargyl Thiocarbamoyl Fluorides and Malonate Esters;Zhongliang Cai et al.;《Org. Lett.》;第24卷;第293-298页 * |
| Synthesis and functionalization of 2-alkylidene-5-(bromomethyl)-2,3-dihydro-1,3-thiazole derivatives;Mariia B. Litvinchuk et al.;《Chemistry of Heterocyclic Compounds》;第54卷(第5期);第559-567页 * |
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