CN114349704A - Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof - Google Patents
Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof Download PDFInfo
- Publication number
- CN114349704A CN114349704A CN202210068950.2A CN202210068950A CN114349704A CN 114349704 A CN114349704 A CN 114349704A CN 202210068950 A CN202210068950 A CN 202210068950A CN 114349704 A CN114349704 A CN 114349704A
- Authority
- CN
- China
- Prior art keywords
- nmr
- trifluoromethyl
- conjugated
- pyrazole
- substituted
- 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.)
- Pending
Links
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 27
- -1 pyrazole spiro cyclopropane compound Chemical class 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 17
- ZQLAVYZSSPTFPN-UHFFFAOYSA-N C1CC11N=NC=C1 Chemical class C1CC11N=NC=C1 ZQLAVYZSSPTFPN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000654 additive Substances 0.000 claims abstract description 11
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 6
- XSGHLZBESSREDT-UHFFFAOYSA-N methylenecyclopropane Chemical class C=C1CC1 XSGHLZBESSREDT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001879 copper Chemical class 0.000 claims abstract description 5
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940125782 compound 2 Drugs 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000006267 biphenyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 115
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Images
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一类三氟甲基缀合的吡唑螺环丙烷化合物及其合成方法，属于有机合成技术领域。将取代亚甲基环丙烷1、1‑取代吡唑烷酮类化合物2、无机碱、铜盐或银盐添加剂和三氟乙醇3混合，升温反应制得三氟甲基缀合的吡唑螺环丙烷类化合物4；该合成方法通过取代亚甲基环丙烷、1‑取代吡唑烷酮和三氟乙醇之间的一锅串联反应高效完成，整个过程原子经济性高，反应条件温和，过程简单而高效；同时具有底物范围广和官能团耐受性好等优点。
The invention discloses a class of trifluoromethyl-conjugated pyrazole spirocyclopropane compounds and a synthesis method thereof, belonging to the technical field of organic synthesis. Mixing substituted methylene cyclopropane 1, 1-substituted pyrazolidinone compound 2, inorganic base, copper salt or silver salt additive and trifluoroethanol 3, heating reaction to prepare trifluoromethyl-conjugated pyrazole spiro Cyclopropane compound 4; the synthesis method is efficiently completed by a one-pot series reaction between substituted methylenecyclopropane, 1-substituted pyrazolidone and trifluoroethanol, the whole process has high atom economy, mild reaction conditions, and the process Simple and efficient; it also has the advantages of a wide substrate range and good functional group tolerance.
Description
技术领域technical field
本发明属于有机合成技术领域，具体涉及一种三氟甲基缀合的吡唑螺环丙烷类化合物的合成方法。The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing a trifluoromethyl-conjugated pyrazole spirocyclopropane compound.
背景技术Background technique
众所周知，螺环骨架广泛存在于天然产物、药物、有机配体和香料分子中，具有重要的研究价值。其中，吡唑螺环丙烷衍生物因具有较大的张力和显著的生物活性而引起了人们的广泛关注，是新药开发的优势结构之一。此外，吡吡螺环丙烷衍生物还具有活泼且多样的反应性能，已成为合成药物、农用化学品和有机光电材料的通用中间体。It is well known that spiro skeletons are widely found in natural products, drugs, organic ligands and fragrance molecules, and have important research value. Among them, pyrazole spiro cyclopropane derivatives have attracted extensive attention due to their large tension and significant biological activity, and are one of the advantageous structures for new drug development. In addition, pyripirocyclopropane derivatives have active and diverse reactivity, and have become general intermediates for the synthesis of pharmaceuticals, agrochemicals, and organic optoelectronic materials.
另一方面，三氟甲基结构片段由于氟原子的独特电子性能和空间尺寸，是多种药物分子必不可少的组成部分，目前30％上市药物分子都含有氟原子。On the other hand, due to the unique electronic properties and spatial size of fluorine atoms, trifluoromethyl structural fragments are indispensable components of many drug molecules, and currently 30% of marketed drug molecules contain fluorine atoms.
根据药效基团拼合原理，我们预计含有上述两种优势结构单元的三氟甲基缀合的吡唑螺环丙烷类化合物可能具有更为显著的生物活性及理化性能，具有潜在的应用开发价值。According to the principle of pharmacophore combination, we predict that the trifluoromethyl-conjugated pyrazolespirocyclopropane compounds containing the above two advantageous structural units may have more significant biological activity and physicochemical properties, and have potential application development value .
目前，尚未有关于三氟甲基缀合的吡唑螺环丙烷类化合物合成的报道。因此，研究并开发从简单易得的原料出发，通过简便的途径和过程合成三氟甲基缀合吡唑螺环丙烷类化合物的高效可持续方法，具有十分重要的理论意义和应用前景。Currently, there is no report on the synthesis of trifluoromethyl-conjugated pyrazole spiropropanes. Therefore, it is of great theoretical significance and application prospect to research and develop an efficient and sustainable method for synthesizing trifluoromethyl-conjugated pyrazolespirocyclopropanes from simple and readily available raw materials through a facile route and process.
发明内容SUMMARY OF THE INVENTION
本发明解决的技术问题是提供了一类三氟甲基缀合的吡唑螺环丙烷化合物及其合成方法，该合成方法通过取代亚甲基环丙烷、1-取代吡唑烷酮和三氟乙醇之间的一锅串联反应高效完成，具有底物范围广、反应条件温和、官能团耐受性好等优点。The technical problem solved by the present invention is to provide a class of trifluoromethyl-conjugated pyrazole spirocyclopropane compounds and a synthesis method thereof. The one-pot tandem reaction between ethanol is efficiently completed, and has the advantages of a wide substrate range, mild reaction conditions, and good functional group tolerance.
本发明所提供的三氟甲基缀合的吡唑螺环丙烷类化合物，其结构通式为：The trifluoromethyl-conjugated pyrazole spirocyclopropane compounds provided by the present invention have the general structural formula:
其中，R1为萘基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代C1-4烷基、C1-4烷氧基、卤素、苯基、三氟甲基、C1-4烷氧羰基或硝基，R2为苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代C1-4烷基、C1-4烷氧基、苄氧基、硝基或卤素。Wherein, R 1 is naphthyl, thienyl, phenyl or substituted phenyl, and the substituents on the substituted phenyl benzene ring are mono- or multi-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen, benzene base, trifluoromethyl, C 1-4 alkoxycarbonyl or nitro, R 2 is phenyl or substituted phenyl, and the substituent on the substituted phenyl benzene ring is a mono- or multi-substituted C 1-4 alkyl, C 1-4 alkoxy, benzyloxy, nitro or halogen.
本发明还提供了上述三氟甲基缀合的吡唑螺环丙烷类化合物的合成方法，采用的技术方案为：The present invention also provides a method for synthesizing the above-mentioned trifluoromethyl-conjugated pyrazole spirocyclopropane compounds, and the adopted technical scheme is:
三氟甲基缀合的吡唑螺环丙烷类化合物的合成方法，包括如下操作：将取代亚甲基环丙烷1、1-取代吡唑烷酮类化合物2、无机碱、铜盐或银盐添加剂和三氟乙醇3混合，升温反应制得三氟甲基缀合的吡唑螺环丙烷类化合物4，反应方程式为：The method for synthesizing trifluoromethyl-conjugated pyrazole spiro cyclopropanes includes the following operations: 1, 1-substituted pyrazolidinone compounds 2, inorganic bases, copper salts or silver salts The additive is mixed with trifluoroethanol 3, and the temperature rises reaction to obtain a trifluoromethyl-conjugated pyrazole spiropropane compound 4. The reaction equation is:
其中，R1为萘基、噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代C1-4烷基、C1-4烷氧基、卤素、苯基、三氟甲基、C1-4烷氧羰基或硝基，R2为苯基或取代苯基，取代苯基苯环上的取代基为一元或多元取代C1-4烷基、C1-4烷氧基、苄氧基、硝基或卤素。Wherein, R 1 is naphthyl, thienyl, phenyl or substituted phenyl, and the substituents on the substituted phenyl benzene ring are mono- or multi-substituted C 1-4 alkyl, C 1-4 alkoxy, halogen, benzene base, trifluoromethyl, C 1-4 alkoxycarbonyl or nitro, R 2 is phenyl or substituted phenyl, and the substituent on the substituted phenyl benzene ring is a mono- or multi-substituted C 1-4 alkyl, C 1-4 alkoxy, benzyloxy, nitro or halogen.
进一步地，在上述技术方案中，所述无机碱为碳酸钾、碳酸钠、碳酸铯、氢氧化钾或氢氧化钠。Further, in the above technical scheme, the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide.
进一步地，在上述技术方案中，所述铜盐添加剂为醋酸铜、氯化铜、氯化亚铜或碘化亚铜；银盐添加剂为六氟锑酸银或醋酸银。Further, in the above technical scheme, the copper salt additive is copper acetate, copper chloride, cuprous chloride or cuprous iodide; the silver salt additive is silver hexafluoroantimonate or silver acetate.
进一步地，在上述技术方案中，所述取代亚甲基环丙烷1、1-取代吡唑烷酮2、无机碱与添加剂摩尔比为1-2:1-1.2:1-2:0.5-1。Further, in the above technical scheme, the molar ratio of the substituted methylenecyclopropane 1, 1-substituted pyrazolidone 2, inorganic base and additive is 1-2:1-1.2:1-2:0.5-1 .
进一步地，在上述技术方案中，所述反应温度为40-60℃。Further, in the above technical solution, the reaction temperature is 40-60°C.
进一步地，在上述技术方案中，所述反应在空气或氧气氛围下进行。Further, in the above technical solution, the reaction is carried out in an atmosphere of air or oxygen.
发明有益效果：Invention Beneficial Effects:
本发明与现有技术相比具有以下优点：(1)三氟甲基缀合的吡唑螺环丙烷类化合物的合成是通过1-取代吡唑烷酮、取代亚甲基环丙烷和三氟乙醇之间的一锅串联反应完成的，整个过程原子经济性高，反应条件温和，过程简单而高效；(2)原料廉价易得、底物适用范围广、官能团耐受性好；(3)采用空气作为氧化剂，具有绿色、经济的特点。Compared with the prior art, the present invention has the following advantages: (1) The synthesis of trifluoromethyl-conjugated pyrazole spiro cyclopropanes is carried out through 1-substituted pyrazolidone, substituted methylene cyclopropane and trifluoro The one-pot series reaction between ethanol is completed, the whole process has high atom economy, mild reaction conditions, simple and efficient process; (2) The raw materials are cheap and easy to obtain, the substrate is suitable for a wide range, and the functional group tolerance is good; (3) Using air as the oxidant is green and economical.
说明书附图Instruction drawings
图1为实施例3中化合物4aj的X-射线单晶衍射图。FIG. 1 is an X-ray single crystal diffraction pattern of compound 4aj in Example 3. FIG.
具体实施方式Detailed ways
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。The above-mentioned content of the present invention is described in further detail below through the examples, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples, and all technologies realized based on the above-mentioned content of the present invention belong to the scope of the present invention.
实施例1Example 1
向15mL反应管中依次加入化合物2a、无机碱、添加剂和三氟乙醇(3)，然后加入化合物1a，在空气条件下将反应管密封，将其置于加热模块中升温搅拌反应。待反应结束后，冷却至室温，加入饱和氯化铵溶液淬灭反应，用硅藻土过滤，滤液用乙酸乙酯萃取，有机相干燥后，抽滤、旋干，过硅胶柱分离(石油醚/乙酸乙酯＝30/1)得到淡黄色油状产物4aa。Compound 2a, inorganic base, additives and trifluoroethanol (3) were added to a 15 mL reaction tube in sequence, and then compound 1a was added, the reaction tube was sealed under air conditions, and placed in a heating module to heat up and stir for reaction. After the reaction is completed, cool to room temperature, add saturated ammonium chloride solution to quench the reaction, filter with celite, extract the filtrate with ethyl acetate, dry the organic phase, filter with suction, spin dry, and separate through a silica gel column (petroleum ether). /ethyl acetate=30/1) to give the product 4aa as a light yellow oil.
通过改变反应的无机碱、添加剂、反应温度和物料比等反应条件，得到一系列的结果，见表1。By changing the reaction conditions such as inorganic base, additives, reaction temperature and material ratio of the reaction, a series of results were obtained, as shown in Table 1.
表1不同条件下4aa的合成a Table 1 Synthesis of 4aa under different conditions a
实施例2Example 2
向15mL耐压管中依次加入2a(38mg,0.2mmol)、碘化亚铜(19.1mg,0.1mmol)、氢氧化钠(8.0mg,0.2mmol)、1a(52.1mg,0.4mmol)和三氟乙醇(3，2mL)，将反应管密封，并置于50℃油浴中反应12h。反应结束后，将反应体系冷却至室温，加入饱和氯化铵溶液淬灭反应，用硅藻土过滤，滤液用乙酸乙酯萃取，有机相干燥后，抽滤旋干，硅胶柱分离(石油醚/乙酸乙酯＝30/1)得到淡黄色油状产物4aa(56.6mg,68％)。1H NMR(600MHz,DMSO-d6):δ7.43(s,5H),7.27(t,J＝7.2Hz,2H),7.20(d,J＝8.4Hz,2H),6.82(t,J＝7.8Hz,1H),4.85(q,J＝9.0Hz,2H),4.63(s,1H),1.34-1.30(m,1H),1.25(s,3H),1.24(s,3H),1.18-1.11(m,2H),0.93-0.89(m,1H).13C NMR(100MHz,DMSO-d6):δ175.0,156.8,147.8,130.8,129.7,129.4,129.2,127.6,123.9(q,1JC-F＝276.1Hz),119.6,114.3,69.5,60.7(q,2JC-F＝35.1Hz),48.9,32.6,25.6,19.4,15.9,7.4.19F NMR(376MHz,DMSO-d6):δ-72.34(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H24F3N2O2 417.1784；Found 417.1779.2a (38 mg, 0.2 mmol), cuprous iodide (19.1 mg, 0.1 mmol), sodium hydroxide (8.0 mg, 0.2 mmol), 1a (52.1 mg, 0.4 mmol) and trifluoride were sequentially added to a 15 mL pressure-resistant tube Ethanol (3, 2 mL), the reaction tube was sealed, and placed in an oil bath at 50 °C for 12 h. After the reaction, the reaction system was cooled to room temperature, saturated ammonium chloride solution was added to quench the reaction, filtered with celite, and the filtrate was extracted with ethyl acetate. /ethyl acetate=30/1) to give the product 4aa (56.6 mg, 68%) as a pale yellow oil. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.43 (s, 5H), 7.27 (t, J=7.2 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 6.82 (t, J =7.8Hz,1H),4.85(q,J=9.0Hz,2H),4.63(s,1H),1.34-1.30(m,1H),1.25(s,3H),1.24(s,3H),1.18 -1.11(m, 2H), 0.93-0.89(m, 1H). 13 C NMR (100MHz, DMSO-d 6 ): δ175.0, 156.8, 147.8, 130.8, 129.7, 129.4, 129.2, 127.6, 123.9(q, 1 J CF = 276.1 Hz), 119.6, 114.3, 69.5, 60.7 (q, 2 J CF = 35.1 Hz), 48.9, 32.6, 25.6, 19.4, 15.9, 7.4. 19 F NMR (376 MHz, DMSO-d 6 ): δ -72.34(t, J=8.6Hz).HRMS(ESI)m/z: [M+H] + Calcd for C 23 H 24 F 3 N 2 O 2 417.1784; Found 417.1779.
实施例3Example 3
依照实施例2的方法和步骤a,b，通过改变反应物1和反应物2，可以合成出各种三氟甲基缀合的吡唑螺环丙烷化合物4，具体结果如下：According to the method and steps a, b of Example 2, by changing the reactants 1 and 2, various trifluoromethyl-conjugated pyrazole spirocyclopropane compounds 4 can be synthesized, and the specific results are as follows:
a反应条件：1(0.4mmol),2(0.2mmol),CuI(0.1mmol),NaOH(0.2mmol),三氟乙醇(3，2mL)，50℃，12h，空气氛围；b分离收率。 a Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), CuI (0.1 mmol), NaOH (0.2 mmol), trifluoroethanol (3, 2 mL), 50°C, 12 h, air atmosphere; b Isolated yield.
代表性产物表征数据如下：Representative product characterization data are as follows:
2,2,2-Trifluoroethyl 2-methyl-2-(7-phenyl-5-(p-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ab)2,2,2-Trifluoroethyl 2-methyl-2-(7-phenyl-5-(p-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ab)
1H NMR(400MHz,DMSO-d6):δ7.43-7.40(m,5H),7.10-7.05(m,4H),4.84(qd,J1＝8.8Hz,J2＝1.6Hz,2H),4.56(s,1H),2.23(s,3H),1.31-1.28(m,1H),1.23(s,3H),1.22(s,3H),1.15-1.10(m,2H),0.89-0.86(m,1H).13C NMR(100MHz,DMSO-d6):δ175.1,156.3,145.7,130.9,129.8,129.6,129.2,128.4,127.5,124.0(q,1JC-F＝273.0Hz),114.6,69.8,60.7(q,2JC-F＝34.4Hz),48.8,32.6,25.6,20.5,19.4,15.9,7.3.19F NMR(376MHz,DMSO-d6):δ-72.31(t,J＝9.4Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found431.1945. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.43-7.40 (m, 5H), 7.10-7.05 (m, 4H), 4.84 (qd, J 1 =8.8 Hz, J 2 =1.6 Hz, 2H) ,4.56(s,1H),2.23(s,3H),1.31-1.28(m,1H),1.23(s,3H),1.22(s,3H),1.15-1.10(m,2H),0.89-0.86 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ): δ 175.1, 156.3, 145.7, 130.9, 129.8, 129.6, 129.2, 128.4, 127.5, 124.0 (q, 1 J CF =273.0 Hz), 114.6, 69.8, 60.7 (q, 2 J CF = 34.4 Hz), 48.8, 32.6, 25.6, 20.5, 19.4, 15.9, 7.3. 19 F NMR (376 MHz, DMSO-d 6 ): δ-72.31 (t, J = 9.4 Hz ).HRMS(ESI) m/z: [M+H] + Calcd for C 24 H 26 F 3 N 2 O 2 431.1941; Found431.1945.
2,2,2-Trifluoroethyl 2-(5-(4-ethylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methylpropanoate(4ac)2,2,2-Trifluoroethyl 2-(5-(4-ethylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methylpropanoate(4ac)
1H NMR(400MHz,DMSO-d6):δ7.43-7.40(m,5H),7.10(s,4H),4.84(q,J＝9.2Hz,2H),4.56(s,1H),2.55-2.51(m,2H),1.32-1.29(m,1H),1.23(s,6H),1.17-1.09(m,5H),0.90-0.85(m,1H).13CNMR(100MHz,DMSO-d6):δ175.1,156.5,145.9,135.0,130.9,129.6,129.2,128.6,127.5,124.0(q,1JC-F＝275.6Hz),114.5,69.9,60.7(q,2JC-F＝32.4Hz),48.8,32.6,27.8,25.6,19.4,16.4,15.9,7.3.19F NMR(376MHz,DMSO-d6):δ-72.32(t,J＝9.4Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O2 445.2097；Found 445.2086. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.43-7.40 (m, 5H), 7.10 (s, 4H), 4.84 (q, J=9.2 Hz, 2H), 4.56 (s, 1H), 2.55 -2.51(m, 2H), 1.32-1.29(m, 1H), 1.23(s, 6H), 1.17-1.09(m, 5H), 0.90-0.85(m, 1H). 13 CNMR(100MHz, DMSO-d) 6 ): δ175.1, 156.5, 145.9, 135.0, 130.9, 129.6, 129.2, 128.6, 127.5, 124.0 (q, 1 J CF = 275.6Hz), 114.5, 69.9, 60.7 (q, 2 J CF = 32.4 Hz), 48.8 , 32.6, 27.8, 25.6, 19.4, 16.4, 15.9, 7.3. 19 F NMR (376MHz, DMSO-d 6 ): δ-72.32(t, J=9.4Hz).HRMS(ESI)m/z:[M+ H] + Calcd for C 25 H 28 F 3 N 2 O 2 445.2097; Found 445.2086.
2,2,2-Trifluoroethyl 2-(5-(4-isopropylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ad)2,2,2-Trifluoroethyl 2-(5-(4-isopropylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ad)
1H NMR(400MHz,DMSO-d6):δ7.44-7.40(m,5H),7.15-7.09(m,4H),4.84(q,J＝8.8Hz,2H),4.55(s,1H),2.84-2.77(m,1H),1.32-1.28(m,1H),1.23(s,6H),1.18(s,3H),1.17(s,3H),1.14-1.10(m,2H),0.90-0.84(m,1H).13C NMR(100MHz,DMSO-d6):δ175.1,156.6,146.0,139.7,130.8,129.6,129.2,127.5,127.1,124.0(q,1JC-F＝275.8Hz),114.4,69.9,60.7(q,2JC-F＝35.0Hz),48.8,33.0,32.6,25.6,24.6,24.5,19.4,15.9,7.3.19F NMR(376MHz,DMSO-d6):δ-72.32(t,J＝10.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C26H30F3N2O2459.2254；Found 459.2250. 1 H NMR (400MHz, DMSO-d 6 ): δ 7.44-7.40 (m, 5H), 7.15-7.09 (m, 4H), 4.84 (q, J=8.8Hz, 2H), 4.55 (s, 1H) ,2.84-2.77(m,1H),1.32-1.28(m,1H),1.23(s,6H),1.18(s,3H),1.17(s,3H),1.14-1.10(m,2H),0.90 -0.84 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ): δ 175.1, 156.6, 146.0, 139.7, 130.8, 129.6, 129.2, 127.5, 127.1, 124.0 (q, 1 J CF =275.8 Hz), 114.4, 69.9, 60.7 (q, 2 J CF = 35.0 Hz), 48.8, 33.0, 32.6, 25.6, 24.6, 24.5, 19.4, 15.9, 7.3. 19 F NMR (376 MHz, DMSO-d 6 ): δ-72.32 ( t,J=10.5Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 30 F 3 N 2 O 2 459.2254; Found 459.2250.
2,2,2-Trifluoroethyl 2-(5-(4-methoxyphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ae)2,2,2-Trifluoroethyl 2-(5-(4-methoxyphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ae)
1H NMR(600MHz,DMSO-d6):δ7.42-7.40(m,5H),7.14-7.12(m,2H),6.89-6.87(m,2H),4.83(qd,J1＝9.0H,J2＝4.2Hz,2H),4.50(s,1H),3.71(s,3H),1.29-1.27(m,1H),1.228(s,3H),1.225(s,3H),1.14-1.11(m,2H),0.87-0.84(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,156.3,153.6,142.1,130.9,129.5,129.2,127.5,124.0(q,1JC-F＝275.7Hz),116.3,114.8,70.5,60.6(q,2JC-F＝35.1Hz),55.7,48.7,32.5,25.6,19.3,15.9,7.3.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝7.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O3447.1890；Found 447.1884. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.42-7.40 (m, 5H), 7.14-7.12 (m, 2H), 6.89-6.87 (m, 2H), 4.83 (qd, J 1 =9.0H , J 2 =4.2Hz, 2H), 4.50(s, 1H), 3.71(s, 3H), 1.29-1.27(m, 1H), 1.228(s, 3H), 1.225(s, 3H), 1.14-1.11 (m, 2H), 0.87-0.84 (m, 1H). 13 C NMR (150 MHz, DMSO-d 6 ): δ 175.1, 156.3, 153.6, 142.1, 130.9, 129.5, 129.2, 127.5, 124.0(q, 1 J CF = 275.7 Hz), 116.3, 114.8, 70.5, 60.6 (q, 2 J CF =35.1 Hz), 55.7, 48.7, 32.5, 25.6, 19.3, 15.9, 7.3. 19 F NMR (565 MHz, DMSO-d 6 ): δ -72.29(t, J=7.9Hz).HRMS(ESI)m/z: [M+H] + Calcd for C 24 H 26 F 3 N 2 O 3 447.1890; Found 447.1884.
2,2,2-Trifluoroethyl 2-(5-(4-(benzyloxy)phenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4af)2,2,2-Trifluoroethyl 2-(5-(4-(benzyloxy)phenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4af )
1H NMR(400MHz,CDCl3):δ7.44-7.42(m,2H),7.40-7.34(m,7H),7.33-7.29(m,1H),7.21-7.17(m,2H),6.94-6.92(m,2H),5.03(s,2H),4.53(s,1H),4.52-4.46(m,2H),1.35(s,3H),1.33(s,3H),1.31-1.28(m,1H),1.12-1.05(m,2H),0.85-0.81(m,1H).13C NMR(100MHz,CDCl3):δ175.7,156.4,152.8,142.4,137.5,130.9,129.1,128.6,127.9,127.5,127.3,123.0(q,1JC-F＝276.0Hz),116.1,115.6,70.6,70.3,60.5(q,2JC-F＝36.9Hz),48.9,32.6,25.7,18.8,16.2,7.3.19F NMR(376MHz,CDCl3):δ-73.54(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C30H30F3N2O3 523.2203；Found 523.2196. 1 H NMR (400 MHz, CDCl 3 ): δ 7.44-7.42 (m, 2H), 7.40-7.34 (m, 7H), 7.33-7.29 (m, 1H), 7.21-7.17 (m, 2H), 6.94- 6.92(m, 2H), 5.03(s, 2H), 4.53(s, 1H), 4.52-4.46(m, 2H), 1.35(s, 3H), 1.33(s, 3H), 1.31-1.28(m, 1H), 1.12-1.05(m, 2H), 0.85-0.81(m, 1H). 13 C NMR (100MHz, CDCl 3 ): δ175.7, 156.4, 152.8, 142.4, 137.5, 130.9, 129.1, 128.6, 127.9, 127.5 19F NMR _ _ _ (376MHz, CDCl 3 ): δ-73.54 (t, J=8.3 Hz). HRMS(ESI) m/z: [M+H] + Calcd for C 30 H 30 F 3 N 2 O 3 523.2203; Found 523.2196.
2,2,2-Trifluoroethyl 2-(5-(4-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ag)2,2,2-Trifluoroethyl 2-(5-(4-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ag)
1H NMR(600MHz,CDCl3):δ7.39-7.35(m,5H),7.20-7.18(m,2H),6.99-6.96(m,2H),4.56(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.8Hz,2H),1.35(s,3H),1.33-1.30(m,4H),1.13-1.08(m,2H),0.88-0.85(m,1H).13C NMR(150MHz,CDCl3):δ175.6,157.01,157.00(d,1JC-F＝235.5Hz),144.3(d,4JC-F＝2.0Hz),130.7,129.2,128.6,127.4,123.0(q,1JC-F＝275.6Hz),115.5(d,3JC-F＝6.8Hz),115.4(d,2JC-F＝21.8Hz),70.1,60.6(q,2JC-F＝35.4Hz),49.0,32.7,25.7,18.8,16.2,7.4.19F NMR(565MHz,CDCl3):δ-73.56(t,J＝7.9Hz),-125.47–-125.52(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1685. 1 H NMR (600 MHz, CDCl 3 ): δ 7.39-7.35 (m, 5H), 7.20-7.18 (m, 2H), 6.99-6.96 (m, 2H), 4.56 (s, 1H), 4.51 (qd, 13 _ _ C NMR (150 MHz, CDCl 3 ): δ 175.6, 157.01, 157.00 (d, 1 J CF = 235.5 Hz), 144.3 (d, 4 J CF = 2.0 Hz), 130.7, 129.2, 128.6, 127.4, 123.0 (q, 1 J CF = 275.6 Hz), 115.5 (d, 3 J CF = 6.8 Hz), 115.4 (d, 2 J CF = 21.8 Hz), 70.1, 60.6 (q, 2 J CF = 35.4 Hz), 49.0, 32.7, 25.7 , 18.8, 16.2, 7.4. 19 F NMR(565MHz, CDCl 3 ): δ-73.56(t, J=7.9Hz),-125.47–-125.52(m).HRMS(ESI)m/z:[M+H ] + Calcd for C 23 H 23 F 4 N 2 O 2 435.1690; Found 435.1685.
2,2,2-Trifluoroethyl 2-(5-(4-chlorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ah)2,2,2-Trifluoroethyl 2-(5-(4-chlorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ah)
1H NMR(600MHz,DMSO-d6):δ7.45-7.41(m,5H),7.30-7.28(m,2H),7.19-7.17(m,2H),4.84(qd,J＝9.0Hz,J＝4.8Hz,2H),4.61(s,1H),1.34-1.30(m,1H),1.23(s,3H),1.22(s,3H),1.17-1.12(m,2H),0.96-0.93(m,1H).13C NMR(150MHz,DMSO-d6):δ174.9,157.5,146.5,130.5,129.9,129.23,129.16,127.6,125.8(q,1JC-F＝276.3Hz),123.0,115.8,69.6,60.7(q,2JC-F＝34.5Hz),48.9,32.8,25.5,19.5,15.8,7.5.19F NMR(565MHz,DMSO-d6):δ-72.24(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2 451.1395；Found 451.1390. 1 H NMR (600MHz, DMSO-d 6 ): δ 7.45-7.41 (m, 5H), 7.30-7.28 (m, 2H), 7.19-7.17 (m, 2H), 4.84 (qd, J=9.0Hz, J=4.8Hz, 2H), 4.61(s, 1H), 1.34-1.30(m, 1H), 1.23(s, 3H), 1.22(s, 3H), 1.17-1.12(m, 2H), 0.96-0.93 (m, 1H). 13 C NMR (150 MHz, DMSO-d 6 ): δ 174.9, 157.5, 146.5, 130.5, 129.9, 129.23, 129.16, 127.6, 125.8 (q, 1 J CF =276.3 Hz), 123.0, 115.8, 69.6, 60.7 (q, 2 J CF = 34.5 Hz), 48.9, 32.8, 25.5, 19.5, 15.8, 7.5. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.24 (t, J = 9.0 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 23 H 23 ClF 3 N 2 O 2 451.1395; Found 451.1390.
2,2,2-Trifluoroethyl 2-(5-(4-bromophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ai)2,2,2-Trifluoroethyl 2-(5-(4-bromophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ai)
1H NMR(400MHz,DMSO-d6):δ7.45-7.39(m,7H),7.16-7.12(m,2H),4.85(qd,J1＝8.8Hz,J2＝1.6Hz,2H),4.61(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.17-1.12(m,2H),0.98-0.92(s,1H).13C NMR(100MHz,DMSO-d6):δ174.9,157.5,146.9,132.0,130.5,129.9,129.2,127.6,123.9(q,1JC-F＝276.0Hz),116.3,110.7,69.5,60.7(q,2JC-F＝34.7Hz),48.9,32.8,25.5,19.5,15.8,7.5.19F NMR(376MHz,DMSO-d6):δ-72.26(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found 495.0875. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.45-7.39 (m, 7H), 7.16-7.12 (m, 2H), 4.85 (qd, J 1 =8.8 Hz, J 2 =1.6 Hz, 2H) ,4.61(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.17-1.12(m,2H),0.98-0.92(s,1H) .13 C NMR (100 MHz, DMSO-d 6 ): δ 174.9, 157.5, 146.9, 132.0, 130.5, 129.9, 129.2, 127.6, 123.9 (q, 1 J CF = 276.0 Hz), 116.3, 110.7, 69.5, 60.7 (q, 2 J CF = 34.7 Hz), 48.9, 32.8, 25.5, 19.5, 15.8, 7.5. 19 F NMR (376 MHz, DMSO-d 6 ): δ-72.26 (t, J=8.6 Hz).HRMS (ESI) m/z :[M+H] + Calcd for C 23 H 23 BrF 3 N 2 O 2 495.0890; Found 495.0875.
2,2,2-Trifluoroethyl 2-methyl-2-(5-(4-nitrophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4aj)2,2,2-Trifluoroethyl 2-methyl-2-(5-(4-nitrophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4aj)
1H NMR(600MHz,DMSO-d6):δ8.16(d,J＝9.6Hz,2H),7.50-7.45(m,5H),7.31(d,J＝9.6Hz,2H),4.90(s,1H),4.85(q,J＝9.0Hz,2H),1.42-1.39(m,1H),1.24-1.22(m,7H),1.15-1.12(m,2H).13C NMR(150MHz,DMSO-d6):δ174.5,160.9,151.8,138.7,130.5,129.8,129.4,127.8,126.1,123.9(q,1JC-F＝276.0Hz),113.4,69.1,60.9(q,2JC-F＝35.0Hz),49.0,33.1,25.4,20.0,15.6,7.9.19F NMR(565MHz,DMSO-d6):δ-72.18(t,J＝8.5 Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F3N3O4 462.1635；Found 462.1624. 1 H NMR (600 MHz, DMSO-d 6 ): δ 8.16 (d, J=9.6 Hz, 2H), 7.50-7.45 (m, 5H), 7.31 (d, J=9.6 Hz, 2H), 4.90 (s , 1H), 4.85(q, J=9.0Hz, 2H), 1.42-1.39(m, 1H), 1.24-1.22(m, 7H), 1.15-1.12(m, 2H). 13 C NMR(150MHz, DMSO) -d 6 ): δ174.5, 160.9, 151.8, 138.7, 130.5, 129.8, 129.4, 127.8, 126.1, 123.9 (q, 1 J CF = 276.0Hz), 113.4, 69.1, 60.9 (q, 2 J CF = 35.0Hz) , 49.0, 33.1, 25.4, 20.0, 15.6, 7.9. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.18 (t, J=8.5 Hz). HRMS(ESI) m/z: [M+H] + Calcd for C 23 H 23 F 3 N 3 O 4 462.1635; Found 462.1624.
2,2,2-Trifluoroethyl 2-(5-(2-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ak)2,2,2-Trifluoroethyl 2-(5-(2-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ak)
1H NMR(400MHz,DMSO-d6):δ7.59(td,J1＝8.4Hz,J2＝1.6Hz,1H),7.43-7.39(m,5H),7.23-7.13(m,2H),7.03-6.98(m,1H),4.78(s,1H),4.74(qd,J1＝8.8Hz,J2＝1.2Hz,2H),1.39-1.33(m,1H),1.22(s,3H),1.17-1.13(m,1H),1.09-1.04(m,4H),1.01-0.96(m,1H).13C NMR(100MHz,DMSO-d6):δ174.4,155.1,153.1(d,1JC-F＝241.8Hz),134.9(d,2JC-F＝8.7Hz),130.7,129.5,129.2,127.6,125.5(d,4JC-F＝2.7Hz),123.9(q,1JC-F＝275.4Hz),123.4(d,3JC-F＝7.8Hz),122.4(d,3JC-F＝3.2Hz),116.8(d,2JC-F＝20.4Hz),71.6(d,4JC-F＝6.5Hz),60.6(q,2JC-F＝34.3Hz),48.9,32.8,24.2,19.6,15.1,7.4.19F NMR(376MHz,DMSO-d6):δ-72.36(t,J＝9.4Hz),-122.68–-122.76(m).HRMS(ESI)m/z:[M+H]+Calcd forC23H23F4N2O2 435.1690；Found 435.1687. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.59 (td, J 1 =8.4 Hz, J 2 =1.6 Hz, 1H), 7.43-7.39 (m, 5H), 7.23-7.13 (m, 2H) ,7.03-6.98(m,1H),4.78(s,1H),4.74(qd,J 1 =8.8Hz,J 2 =1.2Hz,2H),1.39-1.33(m,1H),1.22(s,3H ), 1.17-1.13(m, 1H), 1.09-1.04(m, 4H), 1.01-0.96(m, 1H). 13 C NMR (100MHz, DMSO-d 6 ): δ174.4, 155.1, 153.1(d, 1 J CF = 241.8 Hz), 134.9 (d, 2 J CF = 8.7 Hz), 130.7, 129.5, 129.2, 127.6, 125.5 (d, 4 J CF = 2.7 Hz), 123.9 (q, 1 J CF = 275.4 Hz) , 123.4 (d, 3 J CF = 7.8 Hz), 122.4 (d, 3 J CF = 3.2 Hz), 116.8 (d, 2 J CF = 20.4 Hz), 71.6 (d, 4 J CF = 6.5 Hz), 60.6 (q, 2 J CF = 34.3 Hz), 48.9, 32.8, 24.2, 19.6, 15.1, 7.4. 19 F NMR (376 MHz, DMSO-d 6 ): δ-72.36 (t, J = 9.4 Hz), -122.68– -122.76(m).HRMS(ESI)m/z: [M+H] + Calcd for C 23 H 23 F 4 N 2 O 2 435.1690; Found 435.1687.
2,2,2-Trifluoroethyl 2-methyl-2-(7-phenyl-5-(m-tolyl)-5,6-diazaspiro[2.4]hept-6--4-yl)propanoate(4al)2,2,2-Trifluoroethyl 2-methyl-2-(7-phenyl-5-(m-tolyl)-5,6-diazaspiro[2.4]hept-6--4-yl)propanoate(4al)
1H NMR(600MHz,DMSO-d6):δ7.43-7.41(m,5H),7.14(t,J＝7.8Hz,1H),7.05(s,1H),6.93(dd,J1＝7.8Hz,J2＝1.8Hz,1H),6.64(d,J＝7.2Hz,1H),4.84(q,J＝8.4Hz,2H),4.60(s,1H),2.28(s,3H),1.32-1.29(m,1H),1.23(s,3H),1.22(s,3H),1.16-1.11(m,2H),0.92-0.89(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,156.6,147.7,138.6,130.8,129.7,129.24,129.20,127.5,124.0(q,1JC-F＝275.6Hz),120.4,115.0,111.5,69.5,60.7(q,2JC-F＝34.1Hz),48.8,32.6,25.6,21.9,19.5,15.9,7.4.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝8.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found 431.1945. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.43-7.41 (m, 5H), 7.14 (t, J=7.8 Hz, 1H), 7.05 (s, 1H), 6.93 (dd, J 1 =7.8 Hz, J 2 =1.8Hz,1H),6.64(d,J=7.2Hz,1H),4.84(q,J=8.4Hz,2H),4.60(s,1H),2.28(s,3H),1.32 -1.29(m, 1H), 1.23(s, 3H), 1.22(s, 3H), 1.16-1.11(m, 2H), 0.92-0.89(m, 1H). 13 C NMR (150MHz, DMSO-d 6 ): δ175.0, 156.6, 147.7, 138.6, 130.8, 129.7, 129.24, 129.20, 127.5, 124.0 (q, 1 J CF = 275.6Hz), 120.4, 115.0, 111.5, 69.5, 60.7 (q, 2 J CF = 34.1 Hz ), 48.8, 32.6, 25.6, 21.9, 19.5, 15.9, 7.4. 19 F NMR(565MHz, DMSO-d 6 ): δ-72.30(t, J=8.5Hz).HRMS(ESI)m/z:[M +H] + Calcd for C 24 H 26 F 3 N 2 O 2 431.1941; Found 431.1945.
2,2,2-Trifluoroethyl 2-(5-(3-methoxyphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4am)2,2,2-Trifluoroethyl 2-(5-(3-methoxyphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4am)
1H NMR(400MHz,DMSO-d6):δ7.45-7.41(m,5H),7.16(t,J＝8.0Hz,1H),6.75-6.70(m,2H),6.42(dd,J1＝8.0Hz,J2＝2.0Hz,1H),4.84(q,J＝8.8Hz,2H),4.58(s,1H),3.73(s,3H),1.32-1.30(m,1H),1.23(s,6H),1.15-1.10(m,2H),0.93-0.90(m,1H).13C NMR(100MHz,DMSO-d6):δ175.0,160.5,157.0,149.0,130.7,130.2,129.8,129.2,127.6,124.0(q,1JC-F＝275.4Hz),106.9,105.1,100.4,69.6,60.7(q,2JC-F＝34.6Hz),55.4,48.8,32.6,25.7,19.5,15.8,7.4.19F NMR(376MHz,DMSO-d6):δ-72.30(t,J＝7.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O3447.1890；Found 447.1883. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.45-7.41 (m, 5H), 7.16 (t, J=8.0 Hz, 1H), 6.75-6.70 (m, 2H), 6.42 (dd, J 1 =8.0Hz,J 2 =2.0Hz,1H),4.84(q,J=8.8Hz,2H),4.58(s,1H),3.73(s,3H),1.32-1.30(m,1H),1.23( s, 6H), 1.15-1.10 (m, 2H), 0.93-0.90 (m, 1H). 13 C NMR (100MHz, DMSO-d 6 ): δ175.0, 160.5, 157.0, 149.0, 130.7, 130.2, 129.8, 129.2 , 127.6, 124.0 (q, 1 J CF = 275.4 Hz), 106.9, 105.1, 100.4, 69.6, 60.7 (q, 2 J CF = 34.6 Hz), 55.4, 48.8, 32.6, 25.7, 19.5, 15.8, 7.4. 19 F NMR (376 MHz, DMSO-d 6 ): δ-72.30 (t, J=7.5 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 24 H 26 F 3 N 2 O 3 447.1890 ;Found 447.1883.
2,2,2-Trifluoroethyl 2-(5-(3-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4an)2,2,2-Trifluoroethyl 2-(5-(3-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4an)
1H NMR(600MHz,DMSO-d6):δ7.46-7.43(m,5H),7.28(q,J＝7.8Hz,1H),6.99-6.94(m,2H),6.61(td,J1＝8.4Hz,J2＝1.8Hz,1H),4.84-4.82(q,J1＝9.0Hz,J2＝2.4Hz,2H),4.64(s,1H),1.35-1.31(m,1H),1.24(s,6H),1.19-1.15(m,1H),1.13-1.11(m,1H),1.00-0.96(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,163.4(d,1JC-F＝239.9Hz),157.9,149.4(d,3JC-F＝11.4Hz),131.0(d,3JC-F＝10.1Hz),130.4,129.9,129.2,127.7,123.9(q,1JC-F＝276.0Hz),110.0,105.7(d,2JC-F＝21.8Hz),101.2(d,2JC-F＝25.8Hz),69.6,60.7(q,2JC-F＝34.7Hz),48.9,32.8,25.5,19.6,15.8,7.5.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝8.5Hz),-112.40–-112.45(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1692. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.46-7.43 (m, 5H), 7.28 (q, J=7.8 Hz, 1 H), 6.99-6.94 (m, 2H), 6.61 (td, J 1 =8.4Hz,J 2 =1.8Hz,1H),4.84-4.82(q,J 1 =9.0Hz,J 2 =2.4Hz,2H),4.64(s,1H),1.35-1.31(m,1H), 1.24(s, 6H), 1.19-1.15(m, 1H), 1.13-1.11(m, 1H), 1.00-0.96(m, 1H). 13 C NMR (150MHz, DMSO-d 6 ): δ174.8, 163.4( d, 1 J CF = 239.9 Hz), 157.9, 149.4 (d, 3 J CF = 11.4 Hz), 131.0 (d, 3 J CF = 10.1 Hz), 130.4, 129.9, 129.2, 127.7, 123.9 (q, 1 J CF = 276.0 Hz), 110.0, 105.7 (d, 2 J CF = 21.8 Hz), 101.2 (d, 2 J CF = 25.8 Hz), 69.6, 60.7 (q, 2 J CF = 34.7 Hz), 48.9, 32.8, 25.5, 19.6, 15.8, 7.5. 19 F NMR (565MHz, DMSO-d 6 ): δ-72.30(t, J=8.5Hz), -112.40--112.45(m).HRMS(ESI)m/z:[ M+H] + Calcd for C 23 H 23 F 4 N 2 O 2 435.1690; Found 435.1692.
2,2,2-Trifluoroethyl 2-(5-(3-chlorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ao)2,2,2-Trifluoroethyl 2-(5-(3-chlorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ao)
1H NMR(600MHz,DMSO-d6):δ7.47-7.42(m,5H),7.28(t,J＝7.8Hz,1H),7.22-7.21(m,1H),7.07(dd,J1＝7.8Hz,J2＝1.8Hz,1H),6.84(dd,J1＝8.4Hz,J2＝1.8Hz,1H),4.86-4.81(m,2H),4.65(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.19-1.15(m,1H),1.13-1.10(m,1H),1.02-0.98(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,158.0,148.8,134.1,131.0,130.4,130.0,129.3,127.7,123.9(q,1JC-F＝275.0Hz),118.9,113.8,112.6,69.4,60.7(q,2JC-F＝34.5Hz),48.9,32.8,25.5,19.6,15.8,7.6.19F NMR(565MHz,DMSO-d6):δ-72.25(t,J＝9.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2 451.1395；Found 451.1386. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.47-7.42 (m, 5H), 7.28 (t, J=7.8 Hz, 1H), 7.22-7.21 (m, 1H), 7.07 (dd, J 1 =7.8Hz,J 2 =1.8Hz,1H),6.84(dd,J 1 =8.4Hz,J 2 =1.8Hz,1H),4.86-4.81(m,2H),4.65(s,1H),1.35- 1.31(m, 1H), 1.23(s, 3H), 1.22(s, 3H), 1.19-1.15(m, 1H), 1.13-1.10(m, 1H), 1.02-0.98(m, 1H). 13 C NMR (150MHz, DMSO-d 6 ): δ 174.8, 158.0, 148.8, 134.1, 131.0, 130.4, 130.0, 129.3, 127.7, 123.9 (q, 1 J CF = 275.0 Hz), 118.9, 113.8, 112.6, 69.4, 60.7 ( q, 2 J CF = 34.5 Hz), 48.9, 32.8, 25.5, 19.6, 15.8, 7.6. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.25 (t, J = 9.6 Hz).HRMS (ESI) m/z: [M+H] + Calcd for C 23 H 23 ClF 3 N 2 O 2 451.1395; Found 451.1386.
2,2,2-Trifluoroethyl 2-(5-(3-bromophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ap)2,2,2-Trifluoroethyl 2-(5-(3-bromophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ap)
1H NMR(600MHz,DMSO-d6):δ7.47-7.42(m,5H),7.373-7.366(m,1H),7.21(t,J＝8.4Hz,1H),7.11(dd,J1＝8.4Hz,J2＝1.8Hz,1H),6.97(d,J＝7.8Hz,1H),4.84(q,J＝9.0Hz,2H),4.65(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.18-1.15(m,1H),1.14-1.10(m,1H),1.02-0.98(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,158.0,148.9,131.3,130.4,130.0,129.3,127.7,123.9(q,1JC-F＝275.4Hz),122.8,121.8,116.6,112.9,69.4,60.7(q,2JC-F＝34.8Hz),48.9,32.8,25.5,19.6,15.8,7.6.19F NMR(565MHz,DMSO-d6):δ-72.27(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found495.0881. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.47-7.42 (m, 5H), 7.373-7.366 (m, 1H), 7.21 (t, J=8.4 Hz, 1H), 7.11 (dd, J 1 =8.4Hz,J 2 =1.8Hz,1H),6.97(d,J=7.8Hz,1H),4.84(q,J=9.0Hz,2H),4.65(s,1H),1.35-1.31(m, 1H), 1.23(s, 3H), 1.22(s, 3H), 1.18-1.15(m, 1H), 1.14-1.10(m, 1H), 1.02-0.98(m, 1H). 13 C NMR(150MHz, DMSO-d 6 ): δ174.8, 158.0, 148.9, 131.3, 130.4, 130.0, 129.3, 127.7, 123.9 (q, 1 J CF = 275.4 Hz), 122.8, 121.8, 116.6, 112.9, 69.4, 60.7 (q, 2 J CF = 34.8 Hz), 48.9, 32.8, 25.5, 19.6, 15.8, 7.6. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.27 (t, J = 9.0 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 23 H 23 BrF 3 N 2 O 2 495.0890; Found495.0881.
2,2,2-Trifluoroethyl 2-(5-(3,5-dimethylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4aq)2,2,2-Trifluoroethyl 2-(5-(3,5-dimethylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4aq)
1H NMR(400MHz,CDCl3):δ7.40-7.35(m,5H),6.89(s,2H),6.52(s,1H),4.62(s,1H),4.52(q,J＝8.4Hz,2H),2.30(s,6H),1.35(s,3H),1.33(s,3H),1.30-1.26(m,1H),1.12-1.04(m,2H),0.89-0.83(m,1H).13C NMR(100MHz,CDCl3):δ175.8,156.5,147.8,138.6,130.9,129.1,128.6,127.4,123.0(q,1JC-F＝275.4Hz),121.3,112.1,69.4,60.5(q,2JC-F＝36.2Hz),49.0,32.6,25.9,21.7,18.9,16.1,7.3.19F NMR(376MHz,CDCl3):δ-73.58(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O2 445.2097；Found 445.2090.. 1 H NMR (400MHz, CDCl 3 ): δ 7.40-7.35(m, 5H), 6.89(s, 2H), 6.52(s, 1H), 4.62(s, 1H), 4.52(q, J=8.4Hz ,2H),2.30(s,6H),1.35(s,3H),1.33(s,3H),1.30-1.26(m,1H),1.12-1.04(m,2H),0.89-0.83(m,1H) ). 13 C NMR (100MHz, CDCl 3 ): δ 175.8, 156.5, 147.8, 138.6, 130.9, 129.1, 128.6, 127.4, 123.0 (q, 1 J CF = 275.4 Hz), 121.3, 112.1, 69.4, 60.5 (q, 2 J CF = 36.2 Hz), 49.0, 32.6, 25.9, 21.7, 18.9, 16.1, 7.3. 19 F NMR (376 MHz, CDCl 3 ): δ-73.58 (t, J=8.3 Hz).HRMS(ESI)m/ z:[M+H] + Calcd for C 25 H 28 F 3 N 2 O 2 445.2097; Found 445.2090..
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(p-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ba)2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(p-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ba)
1H NMR(600MHz,CDCl3):δ7.30-7.23(m,6H),7.17(d,J＝7.8Hz,2H),6.86-6.83(m,1H),4.61(s,1H),4.50(qd,J1＝8.4Hz,J2＝0.6Hz,2H),2.35(s,3H),1.35(s,3H),1.34(s,3H),1.32-1.30(m,1H),1.10-1.05(m,2H),0.86-0.82(m,1H).13C NMR(150MHz,CDCl3):δ175.7,156.9,147.9,139.3,129.3,129.0,127.9,127.3,123.0(q,1JC-F＝275.7Hz),119.3,114.2,69.6,60.6(q,2JC-F＝36.5Hz),49.0,32.7,25.8,21.3.18.9,16.1,7.3.19F NMR(575MHz,CDCl3):δ-73.54(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2431.1941；Found 431.1936. 1 H NMR (600 MHz, CDCl 3 ): δ 7.30-7.23 (m, 6H), 7.17 (d, J=7.8 Hz, 2H), 6.86-6.83 (m, 1H), 4.61 (s, 1H), 4.50 (qd, J 1 =8.4Hz, J 2 =0.6Hz, 2H), 2.35(s, 3H), 1.35(s, 3H), 1.34(s, 3H), 1.32-1.30(m, 1H), 1.10- 1.05 (m, 2H), 0.86-0.82 (m, 1H). 13 C NMR (150 MHz, CDCl 3 ): δ 175.7, 156.9, 147.9, 139.3, 129.3, 129.0, 127.9, 127.3, 123.0 (q, 1 J CF = 275.7Hz), 119.3, 114.2, 69.6, 60.6 (q, 2 J CF =36.5 Hz), 49.0, 32.7, 25.8, 21.3.18.9, 16.1, 7.3. 19 F NMR (575 MHz, CDCl 3 ): δ-73.54 ( t, J=9.0Hz).HRMS(ESI)m/z: [M+H] + Calcd for C 24 H 26 F 3 N 2 O 2 431.1941; Found 431.1936.
2,2,2-Trifluoroethyl 2-(7-(4-(tert-butyl)phenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ca)2,2,2-Trifluoroethyl 2-(7-(4-(tert-butyl)phenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate (4ca)
1H NMR(600MHz,CDCl3):δ7.39-7.37(m,2H),7.35-7.33(m,2H),7.28-7.24(m,4H),6.86-6.83(m,1H),4.61(s,1H),4.51(q,J＝8.4Hz,2H),1.38-1.36(m,1H),1.35(s,3H),1.34(s,3H),1.32(s,9H),1.13-1.07(m,2H),0.87-0.84(m,1H).13C NMR(150MHz,CDCl3):δ175.7,156.8,152.4,147.9,128.9,127.9,127.0,125.6,123.0(d,1JC-F＝275.4Hz),119.2,114.2,69.6,60.6(q,2JC-F＝36.9Hz),49.0,34.7,32.7,31.2,25.8,18.9,16.2,7.3.19F NMR(575MHz,CDCl3):δ-73.56(t,J＝9.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C27H32F3N2O2473.2410；Found 473.2398. 1 H NMR (600 MHz, CDCl 3 ): δ 7.39-7.37 (m, 2H), 7.35-7.33 (m, 2H), 7.28-7.24 (m, 4H), 6.86-6.83 (m, 1H), 4.61 ( s, 1H), 4.51(q, J=8.4Hz, 2H), 1.38-1.36(m, 1H), 1.35(s, 3H), 1.34(s, 3H), 1.32(s, 9H), 1.13-1.07 (m, 2H), 0.87-0.84 (m, 1H). 13 C NMR (150 MHz, CDCl 3 ): δ 175.7, 156.8, 152.4, 147.9, 128.9, 127.9, 127.0, 125.6, 123.0 (d, 1 J CF =275.4 Hz), 119.2, 114.2, 69.6, 60.6 (q, 2 J CF =36.9 Hz), 49.0, 34.7, 32.7, 31.2, 25.8, 18.9, 16.2, 7.3. 19 F NMR (575 MHz, CDCl 3 ): δ-73.56 (t, J=9.6 Hz). HRMS(ESI) m/z: [M+H] + Calcd for C 27 H 32 F 3 N 2 O 2 473.2410; Found 473.2398.
2,2,2-Trifluoroethyl 2-(7-(4-methoxyphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4da)2,2,2-Trifluoroethyl 2-(7-(4-methoxyphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4da)
1H NMR(600MHz,DMSO-d6):δ7.37(d,J＝9.0Hz,2H),7.25(t,J＝7.8Hz,2H),7.16(d,J＝8.4Hz,2H),6.97(d,J＝8.4Hz,2H),6.8(t,J＝7.2Hz,1H),4.84(qd,J1＝9.0Hz,J2＝3.0Hz,2H),4.56(s,1H),3.78(s,3H),1.33-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.13-1.09(m,2H),0.89-0.86(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,160.5,156.7,148.0,129.4,129.0,124.0(q,1JC-F＝276.9Hz),123.0,119.4,114.7,114.2,69.7,60.7(q,JC-F＝35.3Hz),55.7,48.8,32.6,25.6,19.4,15.8,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝7.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O3 447.1890；Found 447.1897. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.37 (d, J=9.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.97(d, J=8.4Hz, 2H), 6.8(t, J=7.2Hz, 1H), 4.84(qd, J 1 =9.0Hz, J 2 =3.0Hz, 2H), 4.56(s, 1H), 13 C NMR (150MHz, DMSO-d 6 ): δ 175.1, 160.5, 156.7, 148.0, 129.4, 129.0, 124.0 (q, 1 J CF = 276.9 Hz), 123.0, 119.4, 114.7, 114.2, 69.7, 60.7 (q, J CF =35.3Hz), 55.7, 48.8, 32.6, 25.6, 19.4, 15.8, 7.4. 19 F NMR (565MHz, DMSO-d 6 ): δ-72.29(t, J=7.3Hz).HRMS(ESI)m/z :[M+H] + Calcd for C 24 H 26 F 3 N 2 O 3 447.1890; Found 447.1897.
2,2,2-Trifluoroethyl 2-(7-(4-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ea)2,2,2-Trifluoroethyl 2-(7-(4-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ea)
1H NMR(600MHz,DMSO-d6):δ7.50-7.46(m,2H),7.28-7.23(m,4H),7.18(d,J＝7.8Hz,2H),6.82(t,J＝7.2Hz,1H),4.87-4.82(m,2H),4.62(s,1H),1.33-1.29(m,1H),1.23(s,6H),1.17-1.11(m,2H),0.93-0.90(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,163.1(d,1JC-F＝245.3Hz),155.9,147.7,129.9(d,3JC-F＝7.35Hz),129.4,127.2(d,4JC-F＝3.6Hz),124.0(q,1JC-F＝277.2Hz),119.6,116.2(d,2JC-F＝22.8Hz),114.3,69.5,60.7(q,2JC-F＝35.0Hz),48.8,32.6,25.6,19.5,15.8,7.4.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝9.0Hz),-111.92–-111.95(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1679. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.50-7.46 (m, 2H), 7.28-7.23 (m, 4H), 7.18 (d, J=7.8 Hz, 2H), 6.82 (t, J= 7.2Hz, 1H), 4.87-4.82(m, 2H), 4.62(s, 1H), 1.33-1.29(m, 1H), 1.23(s, 6H), 1.17-1.11(m, 2H), 0.93-0.90 (m, 1H). 13 C NMR (150 MHz, DMSO-d 6 ): δ 175.0, 163.1 (d, 1 J CF = 245.3 Hz), 155.9, 147.7, 129.9 (d, 3 J CF = 7.35 Hz), 129.4, 127.2 (d, 4 J CF = 3.6 Hz), 124.0 (q, 1 J CF = 277.2 Hz), 119.6, 116.2 (d, 2 J CF = 22.8 Hz), 114.3, 69.5, 60.7 (q, 2 J CF = 35.0Hz), 48.8, 32.6, 25.6, 19.5, 15.8, 7.4. 19 F NMR (565MHz, DMSO-d 6 ): δ-72.30(t, J=9.0Hz), -111.92–-111.95(m).HRMS (ESI) m/z: [M+H] + Calcd for C 23 H 23 F 4 N 2 O 2 435.1690; Found 435.1679.
2,2,2-Trifluoroethyl 2-(7-(4-chlorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4fa)2,2,2-Trifluoroethyl 2-(7-(4-chlorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4fa)
1H NMR(600MHz,DMSO-d6):δ7.48-7.45(m,4H),7.27(t,J＝9.0Hz,2H),7.19(d,J＝7.8Hz,2H),6.83(t,J＝7.2Hz,1H),4.84(qd,J1＝9.0Hz,J2＝1.2Hz,2H),4.64(s,1H),1.37-1.35(m,1H),1.22(s,6H),1.18-1.14(m,2H),0.94-0.92(m,1H).13C NMR(150MHz,DMSO-d6):δ174.9,155.4,147.5,134.5,129.6,129.4,129.3,129.2,124.0(q,1JC-F＝276.3Hz),119.8,114.4,69.6,60.7(q,2JC-F＝34.7Hz),48.9,32.5,25.6,19.5,15.9,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝7.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2451.1395；Found 451.1393. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.48-7.45 (m, 4H), 7.27 (t, J=9.0 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 6.83 (t , J=7.2Hz, 1H), 4.84(qd, J 1 =9.0Hz, J 2 =1.2Hz, 2H), 4.64(s, 1H), 1.37-1.35(m, 1H), 1.22(s, 6H) , 1.18-1.14 (m, 2H), 0.94-0.92 (m, 1H). 13 C NMR (150MHz, DMSO-d 6 ): δ174.9, 155.4, 147.5, 134.5, 129.6, 129.4, 129.3, 129.2, 124.0 (q , 1 J CF = 276.3 Hz), 119.8, 114.4, 69.6, 60.7 (q, 2 J CF = 34.7 Hz), 48.9, 32.5, 25.6, 19.5, 15.9, 7.4. 19 F NMR (565 MHz, DMSO-d 6 ) : δ-72.29(t, J=7.9Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 23 ClF 3 N 2 O 2 451.1395; Found 451.1393.
2,2,2-Trifluoroethyl 2-(7-(4-bromophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ga)2,2,2-Trifluoroethyl 2-(7-(4-bromophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ga)
1H NMR(600MHz,CDCl3):δ7.50-7.48(m,2H),7.29-7.26(m,4H),7.25-7.23(m,2H),6.88-6.85(m,1H),4.65(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.8Hz,2H),1.34-1.30(m,7H),1.14-1.10(m,1H),1.09-1.05(m,1H),0.89-0.86(m,1H).13C NMR(150MHz,CDCl3):δ175.6,155.1,147.4,131.9,129.8,129.0,128.8,123.5,122.9(q,1JC-F＝275.6Hz),119.6,114.3,69.5,60.6(q,2JC-F＝36.8Hz),49.0,32.5,25.8,18.9,16.2,7.3.19F NMR(565MHz,CDCl3):δ-73.54(t,J＝7.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found495.0874. 1 H NMR (600MHz, CDCl 3 ): δ 7.50-7.48 (m, 2H), 7.29-7.26 (m, 4H), 7.25-7.23 (m, 2H), 6.88-6.85 (m, 1H), 4.65 ( s, 1H), 4.51(qd, J 1 =8.4Hz, J 2 =1.8Hz, 2H), 1.34-1.30(m, 7H), 1.14-1.10(m, 1H), 1.09-1.05(m, 1H) , 0.89-0.86 (m, 1H). 13 C NMR (150 MHz, CDCl 3 ): δ 175.6, 155.1, 147.4, 131.9, 129.8, 129.0, 128.8, 123.5, 122.9 (q, 1 J CF =275.6 Hz), 119.6, 114.3, 69.5, 60.6 (q, 2 J CF = 36.8 Hz), 49.0, 32.5, 25.8, 18.9, 16.2, 7.3. 19 F NMR (565 MHz, CDCl 3 ): δ-73.54 (t, J = 7.9 Hz). HRMS(ESI) m/z: [M+H] + Calcd for C 23 H 23 BrF 3 N 2 O 2 495.0890; Found495.0874.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(4-(trifluoromethyl)phenyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ha)2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(4-(trifluoromethyl)phenyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ha )
1H NMR(400MHz,DMSO-d6):δ7.76(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),7.31-7.22(m,4H),6.86(t,J＝6.8Hz,1H),4.84(q,J＝9.2Hz,2H),4.72(s,1H),1.45-1.42(m,1H),1.24-1.18(m,8H),1.01-0.97(m,1H).13C NMR(100MHz,DMSO-d6):δ174.9,154.6,147.1,134.8,129.6(q,2JC-F＝35.4Hz),129.4,128.1,126.1(q,3JC-F＝3.5Hz),124.5(q,1JC-F＝269.8Hz),123.9(q,1JC-F＝275.4Hz),120.0,114.6,69.6,60.7(q,2JC-F＝35.3Hz),48.9,32.4,25.6,19.5,16.0,7.4.19F NMR(376MHz,DMSO-d6):δ-61.39(s),-72.35(t,J＝10.2Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H23F6N2O2 485.1658；Found 485.1651. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.76 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.31-7.22 (m, 4H), 6.86 (t , J=6.8Hz, 1H), 4.84(q, J=9.2Hz, 2H), 4.72(s, 1H), 1.45-1.42(m, 1H), 1.24-1.18(m, 8H), 1.01-0.97( m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ): δ 174.9, 154.6, 147.1, 134.8, 129.6 (q, 2 J CF = 35.4 Hz), 129.4, 128.1, 126.1 (q, 3 J CF = 3.5 Hz), 124.5 (q, 1 J CF = 269.8 Hz), 123.9 (q, 1 J CF = 275.4 Hz), 120.0, 114.6, 69.6, 60.7 (q, 2 J CF = 35.3 Hz), 48.9, 32.4, 25.6 , 19.5, 16.0, 7.4. 19 F NMR(376MHz, DMSO-d 6 ): δ-61.39(s),-72.35(t, J=10.2Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 23 F 6 N 2 O 2 485.1658; Found 485.1651.
2,2,2-Trifluoroethyl 2-methyl-2-(7-(4-nitrophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ia)2,2,2-Trifluoroethyl 2-methyl-2-(7-(4-nitrophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ia)
1H NMR(400MHz,CDCl3):δ8.22-8.19(m,2H),7.61-7.58(m,2H),7.33-7.26(m,4H),6.93-6.89(m,1H),4.76(s,1H),4.52(q,J＝8.4Hz,2H),1.48-1.44(m,1H),1.32(s,3H),1.30(s,3H),1.23-1.18(m,2H),0.99-0.95(m,1H).13C NMR(100MHz,CDCl3):δ175.3,152.5,147.7,146.5,137.5,129.1,127.3,123.9,122.9(q,1JC-F＝275.7Hz),120.3,114.7,69.7,60.6(q,2JC-F＝36.5Hz),49.2,32.3,25.9,18.9,16.6,7.4.19F NMR(376MHz,CDCl3):δ-73.55(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F3N3O4 462.1635；Found462.1630. 1 H NMR (400MHz, CDCl 3 ): δ 8.22-8.19 (m, 2H), 7.61-7.58 (m, 2H), 7.33-7.26 (m, 4H), 6.93-6.89 (m, 1H), 4.76 ( s,1H),4.52(q,J＝8.4Hz,2H),1.48-1.44(m,1H),1.32(s,3H),1.30(s,3H),1.23-1.18(m,2H),0.99 -0.95 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 175.3, 152.5, 147.7, 146.5, 137.5, 129.1, 127.3, 123.9, 122.9 (q, 1 J CF =275.7 Hz), 120.3, 114.7, 69.7, 60.6 (q, 2 J CF = 36.5 Hz), 49.2, 32.3, 25.9, 18.9, 16.6, 7.4. 19 F NMR (376 MHz, CDCl 3 ): δ-73.55 (t, J = 8.3 Hz).HRMS( ESI) m/z: [M+H] + Calcd for C 23 H 23 F 3 N 3 O 4 462.1635; Found462.1630.
Methyl 4-(7-(2-methyl-1-oxo-1-(2,2,2-trifluoroethoxy)propan-2-yl)-6-phenyl-5,6-diazaspiro[2.4]hept-4-en-4-yl)benzoate(4ja)Methyl 4-(7-(2-methyl-1-oxo-1-(2,2,2-trifluoroethoxy)propan-2-yl)-6-phenyl-5,6-diazaspiro[2.4]hept-4-en -4-yl)benzoate(4ja)
1H NMR(400MHz,CDCl3):δ8.02(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,2H),7.31-7.25(m,4H),6.90-6.86(m,1H),4.69(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.2Hz,2H),3.92(s,3H),1.42-1.38(m,1H),1.34(s,3H),1.32(s,3H),1.78-1.14(m,2H),0.93-0.89(m,1H).13CNMR(100MHz,CDCl3):δ175.5,166.6,154.7,147.2,135.3,130.4,129.8,129.0,126.9,122.9(q,1JC-F＝275.4Hz),119.8,114.4,69.6,60.6(q,2JC-F＝36.4Hz),52.3,49.1,32.5,25.8,18.9,16.4,7.4.19F NMR(376MHz,CDCl3):δ-73.46(t,J＝9.8Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H26F3N2O4 475.1839；Found 475.1821. 1 H NMR (400 MHz, CDCl 3 ): δ 8.02 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.31-7.25 (m, 4H), 6.90-6.86 (m ,1H),4.69(s,1H),4.51(qd,J 1 =8.4Hz,J 2 =1.2Hz,2H),3.92(s,3H),1.42-1.38(m,1H),1.34(s, 3H), 1.32(s, 3H), 1.78-1.14(m, 2H), 0.93-0.89(m, 1H). 13 CNMR (100MHz, CDCl 3 ): δ175.5, 166.6, 154.7, 147.2, 135.3, 130.4, 129.8 , 129.0, 126.9, 122.9 (q, 1 J CF = 275.4Hz), 119.8, 114.4, 69.6, 60.6 (q, 2 J CF = 36.4 Hz), 52.3, 49.1, 32.5, 25.8, 18.9, 16.4, 7.4. 19 F NMR (376 MHz, CDCl 3 ): δ-73.46 (t, J=9.8 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 25 H 26 F 3 N 2 O 4 475.1839; Found 475.1821.
2,2,2-Trifluoroethyl 2-(7-([1,1'-biphenyl]-4-yl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ka)2,2,2-Trifluoroethyl 2-(7-([1,1'-biphenyl]-4-yl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)- 2-methyl propanoate (4ka)
1H NMR(400MHz,CDCl3):δ7.60-7.58(m,4H),7.50-7.43(m,4H),7.38-7.34(m,1H),7.31-7.24(m,4H),6.88-6.84(m,1H),4.65(s,1H),4.52(q,J＝8.4Hz,2H),1.44-1.41(m,1H),1.37(s,3H),1.35(s,3H),1.19-1.10(m,2H),0.92-0.88(m,1H).13C NMR(100MHz,CDCl3):δ175.7,156.1,147.7,142.0,140.4,129.7,129.0,128.9,127.70,127.66,127.3,127.1,123.0(q,1JC-F＝275.4Hz),119.4,114.2,69.6,60.6(q,2JC-F＝37.3Hz),49.1,32.7,25.8,18.9,16.3,7.4.19F NMR(376MHz,CDCl3):δ-73.53(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C29H28F3N2O2 493.2097；Found 493.2088. 1 H NMR (400 MHz, CDCl 3 ): δ 7.60-7.58 (m, 4H), 7.50-7.43 (m, 4H), 7.38-7.34 (m, 1H), 7.31-7.24 (m, 4H), 6.88- 6.84(m, 1H), 4.65(s, 1H), 4.52(q, J=8.4Hz, 2H), 1.44-1.41(m, 1H), 1.37(s, 3H), 1.35(s, 3H), 1.19 -1.10(m, 2H), 0.92-0.88(m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ175.7, 156.1, 147.7, 142.0, 140.4, 129.7, 129.0, 128.9, 127.70, 127.66, 127.3, 127.1 , 123.0 (q, 1 J CF = 275.4 Hz), 119.4, 114.2, 69.6, 60.6 (q, 2 J CF = 37.3 Hz), 49.1, 32.7, 25.8, 18.9, 16.3, 7.4. 19 F NMR (376 MHz, CDCl 3 ): δ-73.53(t, J=8.6Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 29 H 28 F 3 N 2 O 2 493.2097; Found 493.2088.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(o-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4la)2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(o-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4la)
1H NMR(600MHz,DMSO-d6):δ7.34-7.30(m,2H),7.28-7.24(m,3H),7.18(d,J＝7.8Hz,2H),7.14(d,J＝7.8Hz,1H),6.83(t,J＝7.2Hz,1H),4.86(qd,J1＝9.0Hz,J2＝5.4Hz,2H),4.62(s,1H),2.30(s,3H),1.37(s,3H),1.27(s,3H),1.12-1.09(m,1H),0.89-0.85(m,1H),0.83-0.79(m,1H),0.70-0.67(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,157.7,148.7,137.6,131.0,129.5,129.4,129.2,126.0,124.0(q,1JC-F＝276.6Hz),119.6,114.4,68.1,60.7(q,2JC-F＝35.0Hz),48.8,33.9,26.0,20.1,19.4,14.5,7.4.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found 431.1937. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.34-7.30 (m, 2H), 7.28-7.24 (m, 3H), 7.18 (d, J=7.8 Hz, 2H), 7.14 (d, J= 7.8Hz, 1H), 6.83(t, J=7.2Hz, 1H), 4.86(qd, J 1 =9.0Hz, J 2 =5.4Hz, 2H), 4.62(s, 1H), 2.30(s, 3H) ,1.37(s,3H),1.27(s,3H),1.12-1.09(m,1H),0.89-0.85(m,1H),0.83-0.79(m,1H),0.70-0.67(m,1H) . 13 C NMR (150 MHz, DMSO-d 6 ): δ 175.1, 157.7, 148.7, 137.6, 131.0, 129.5, 129.4, 129.2, 126.0, 124.0 (q, 1 J CF = 276.6 Hz), 119.6, 114.4, 68.1, 60.7 (q, 2 J CF = 35.0 Hz), 48.8, 33.9, 26.0, 20.1, 19.4, 14.5, 7.4. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.30 (t, J=9.0 Hz).HRMS (ESI) m/z: [M+H] + Calcd for C 24 H 26 F 3 N 2 O 2 431.1941; Found 431.1937.
2,2,2-Trifluoroethyl 2-(7-(2-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ma)2,2,2-Trifluoroethyl 2-(7-(2-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ma)
1H NMR(600MHz,DMSO-d6):δ7.54-7.50(m,1H),7.36(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.32(t,J＝9.0Hz,1H),7.29-7.25(m,3H),7.18(d,J＝8.4Hz,2H),6.84(t,J＝7.8Hz,1H),4.85(q,J＝9.0Hz,2H),4.69(s,1H),1.33(s,3H),1.24(s,3H),1.16-1.12(m,1H),0.90-0.81(m,3H).13C NMR(150MHz,DMSO-d6):δ175.0,160.3(d,1JC-F＝245.1Hz),154.3,147.9,132.2(d,3JC-F＝8.1Hz),132.0(d,4JC-F＝2.0Hz),129.4,125.2(d,3JC-F＝2.7Hz),124.0(q,1JC-F＝276.0Hz),119.9,118.0(d,2JC-F＝16.2Hz),116.5(d,2JC-F＝21.5Hz),114.6,68.4,60.7(q,2JC-F＝34.8Hz),48.9,33.6,25.8,19.1,15.2,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝9.6Hz),-113.04–-113.08(m).HRMS(ESI)m/z:[M+H]+Calcd forC23H23F4N2O2 435.1690；Found 435.1689. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.54-7.50 (m, 1H), 7.36 (td, J 1 =7.2 Hz, J 2 =1.2 Hz, 1H), 7.32 (t, J = 9.0 Hz) ,1H),7.29-7.25(m,3H),7.18(d,J=8.4Hz,2H),6.84(t,J=7.8Hz,1H),4.85(q,J=9.0Hz,2H),4.69 (s,1H), 1.33(s,3H), 1.24(s,3H), 1.16-1.12(m,1H), 0.90-0.81(m,3H). 13 C NMR (150MHz, DMSO-d 6 ): δ175.0, 160.3 (d, 1 J CF = 245.1 Hz), 154.3, 147.9, 132.2 (d, 3 J CF = 8.1 Hz), 132.0 (d, 4 J CF = 2.0 Hz), 129.4, 125.2 (d, 3 J CF = 2.7 Hz), 124.0 (q, 1 J CF = 276.0 Hz), 119.9, 118.0 (d, 2 J CF = 16.2 Hz), 116.5 (d, 2 J CF = 21.5 Hz), 114.6, 68.4, 60.7 ( q, 2 J CF = 34.8 Hz), 48.9, 33.6, 25.8, 19.1, 15.2, 7.4. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.29 (t, J = 9.6 Hz), -113.04-- 113.08(m).HRMS(ESI)m/z: [M+H] + Calcd for C 23 H 23 F 4 N 2 O 2 435.1690; Found 435.1689.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(m-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4na)2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(m-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4na)
1H NMR(400MHz,DMSO-d6):δ7.32-7.24(m,5H),7.19-7.17(m,3H),6.81(t,J＝7.2Hz,1H),4.88-4.81(m,2H),4.60(s,1H),2.34(s,3H),1.34-1.27(m,1H),1.243(s,3H),1.235(s,3H),1.17-1.07(m,2H),0.91-0.87(m,1H).13C NMR(100MHz,DMSO-d6):δ175.0,157.0,147.8,138.5,130.7,130.4,129.4,129.0,128.1,124.6,124.0(q,1JC-F＝276.2Hz),119.5,114.3,69.5,60.7(q,2JC-F＝34.6Hz),48.8,32.6,25.6,21.4,19.5,15.9,7.4.19FNMR(376MHz,DMSO-d6):δ-72.32(t,J＝9.4Hz).HRMS(ESI)m/z:[M+H]+Calcd forC24H26F3N2O2 431.1941；Found 431.1943. 1 H NMR (400MHz, DMSO-d 6 ): δ 7.32-7.24 (m, 5H), 7.19-7.17 (m, 3H), 6.81 (t, J=7.2Hz, 1H), 4.88-4.81 (m, 2H), 4.60(s, 1H), 2.34(s, 3H), 1.34-1.27(m, 1H), 1.243(s, 3H), 1.235(s, 3H), 1.17-1.07(m, 2H), 0.91 -0.87 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ): δ 175.0, 157.0, 147.8, 138.5, 130.7, 130.4, 129.4, 129.0, 128.1, 124.6, 124.0 (q, 1 J CF = 276.2 Hz ), 119.5, 114.3, 69.5, 60.7 (q, 2 J CF =34.6 Hz), 48.8, 32.6, 25.6, 21.4, 19.5, 15.9, 7.4. 19 FNMR (376 MHz, DMSO-d 6 ): δ-72.32 (t , J=9.4Hz).HRMS(ESI)m/z:[M+H] + Calcd forC 24 H 26 F 3 N 2 O 2 431.1941; Found 431.1943.
2,2,2-Trifluoroethyl 2-(7-(3-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4oa)2,2,2-Trifluoroethyl 2-(7-(3-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4oa)
1H NMR(400MHz,DMSO-d6):δ7.50-7.44(m,1H),7.30-7.20(m,7H),6.84(t,J＝7.2Hz,1H),4.84(qd,J1＝8.8Hz,J2＝1.2Hz,2H),4.67(s,1H),1.40-1.36(m,1H),1.23(s,3H),1.22(s,3H),1.19-1.14(m,2H),0.96-0.92(m,1H).13C NMR(100MHz,DMSO-d6):δ174.9,162.6(d,1JC-F＝242.9Hz),155.1(d,4JC-F＝2.5Hz),147.4,133.0(d,3JC-F＝7.8Hz),131.3(d,3JC-F＝8.3Hz),129.4,124.0(q,1JC-F＝276.0Hz),123.5(d,4JC-F＝3.4Hz),119.8,116.5(d,2JC-F＝21.0Hz),114.5,114.2(d,2JC-F＝22.2Hz),69.6,60.7(q,2JC-F＝34.9Hz),48.9,32.5,25.6,19.5,16.0,7.5.19FNMR(376MHz,DMSO-d6):δ-72.31(t,J＝9.0Hz),-112.21–-112.28(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1677. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.50-7.44 (m, 1H), 7.30-7.20 (m, 7H), 6.84 (t, J=7.2 Hz, 1H), 4.84 (qd, J 1 =8.8Hz, J 2 =1.2Hz, 2H), 4.67(s, 1H), 1.40-1.36(m, 1H), 1.23(s, 3H), 1.22(s, 3H), 1.19-1.14(m, 2H) ), 0.96-0.92 (m, 1H). 13 C NMR (100 MHz, DMSO-d 6 ): δ 174.9, 162.6 (d, 1 J CF = 242.9 Hz), 155.1 (d, 4 J CF = 2.5 Hz), 147.4 , 133.0 (d, 3 J CF = 7.8 Hz), 131.3 (d, 3 J CF = 8.3 Hz), 129.4, 124.0 (q, 1 J CF = 276.0 Hz), 123.5 (d, 4 J CF = 3.4 Hz) , 119.8, 116.5 (d, 2 J CF = 21.0 Hz), 114.5, 114.2 (d, 2 J CF = 22.2 Hz), 69.6, 60.7 (q, 2 J CF = 34.9 Hz), 48.9, 32.5, 25.6, 19.5 , 16.0, 7.5. 19 FNMR (376MHz, DMSO-d 6 ): δ-72.31(t, J=9.0Hz),-112.21–-112.28(m).HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 23 F 4 N 2 O 2 435.1690; Found 435.1677.
2,2,2-Trifluoroethyl 2-(7-(3-chlorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4pa)2,2,2-Trifluoroethyl 2-(7-(3-chlorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4pa)
1H NMR(400MHz,DMSO-d6):δ7.51-7.43(m,3H),7.36-7.33(m,1H),7.29-7.25(m,2H),7.22-7.20(m,2H),6.84(t,J＝7.2Hz,1H),4.87-4.80(m,2H),4.67(s,1H),1.37-1.34(m,1H),1.23(s,3H),1.22(s,3H),1.19-1.17(m,2H),0.96-0.93(m,1H).13C NMR(100MHz,DMSO-d6):δ174.9,154.9,147.3,134.0,132.8,131.1,129.5,129.4,127.1,125.8,124.1(q,1JC-F＝276.1Hz),119.9,114.5,69.6,60.7(q,2JC-F＝34.8Hz),48.9,32.5,25.6,19.5,16.0,7.5.19F NMR(376MHz,DMSO-d6):δ-72.31(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcdfor C23H23ClF3N2O2 451.1395；Found 451.1394. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.51-7.43 (m, 3H), 7.36-7.33 (m, 1H), 7.29-7.25 (m, 2H), 7.22-7.20 (m, 2H), 6.84(t, J＝7.2Hz, 1H), 4.87-4.80(m, 2H), 4.67(s, 1H), 1.37-1.34(m, 1H), 1.23(s, 3H), 1.22(s, 3H) , 1.19-1.17(m, 2H), 0.96-0.93(m, 1H). 13 C NMR (100MHz, DMSO-d 6 ): δ174.9, 154.9, 147.3, 134.0, 132.8, 131.1, 129.5, 129.4, 127.1, 125.8 , 124.1 (q, 1 J CF = 276.1 Hz), 119.9, 114.5, 69.6, 60.7 (q, 2 J CF = 34.8 Hz), 48.9, 32.5, 25.6, 19.5, 16.0, 7.5. 19 F NMR (376 MHz, DMSO -d 6 ): δ-72.31 (t, J=8.3 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 23 H 23 ClF 3 N 2 O 2 451.1395; Found 451.1394.
2,2,2-Trifluoroethyl 2-(7-(3-bromophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4qa)2,2,2-Trifluoroethyl 2-(7-(3-bromophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4qa)
1H NMR(600MHz,DMSO-d6):δ7.64-7.62(m,2H),7.384-7.375(m,2H),7.27(t,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),6.84(t,J＝7.8Hz,1H),4.86-4.81(m,2H),4.67(s,1H),1.37-1.34(m,1H),1.23(s,3H),1.21(s,3H),1.19-1.16(m,2H),0.95-0.92(m,1H).13C NMR(150MHz,DMSO-d6):δ174.9,154.8,147.3,133.1,132.4,131.4,129.9,129.4,126.2,123.9(q,1JC-F＝275.6Hz),122.5,119.9,114.5,69.6,60.7(q,2JC-F＝35.1Hz),48.9,32.4,25.6,19.5,16.0,7.5.19F NMR(565MHz,DMSO-d6):δ-72.28(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found 495.0878. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.64-7.62 (m, 2H), 7.384-7.375 (m, 2H), 7.27 (t, J=8.4 Hz, 2H), 7.20 (d, J= 8.4Hz, 2H), 6.84(t, J=7.8Hz, 1H), 4.86-4.81(m, 2H), 4.67(s, 1H), 1.37-1.34(m, 1H), 1.23(s, 3H), 1.21(s, 3H), 1.19-1.16(m, 2H), 0.95-0.92(m, 1H). 13 C NMR (150MHz, DMSO-d 6 ): δ174.9, 154.8, 147.3, 133.1, 132.4, 131.4, 129.9 , 129.4, 126.2, 123.9 (q, 1 J CF = 275.6 Hz), 122.5, 119.9, 114.5, 69.6, 60.7 (q, 2 J CF = 35.1 Hz), 48.9, 32.4, 25.6, 19.5, 16.0, 7.5. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.28 (t, J=9.0 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 23 H 23 BrF 3 N 2 O 2 495.0890 ;Found 495.0878.
2,2,2-Trifluoroethyl 2-(7-(3,4-dimethylphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ra)2,2,2-Trifluoroethyl 2-(7-(3,4-dimethylphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ra)
1H NMR(600MHz,DMSO-d6):δ7.25(t,J＝7.8Hz,2H),7.22(s,1H),7.18-7.16(m,3H),7.10(d,J＝7.8Hz,1H)6.81(t,J＝7.2Hz,1H),4.87-4.82(m,2H),4.58(s,1H),2.25(s,3H),2.23(s,3H),1.33-1.29(m,1H),1.23(s,6H),1.13-1.08(m,2H),0.88-0.86(m,1H).13CNMR(150MHz,DMSO-d6):δ175.1,157.1,147.9,138.1,137.2,130.2,129.4,128.6,128.2,124.9,124.0(q,1JC-F＝279.2Hz),119.4,114.2,69.6,60.7(q,2JC-F＝34.8Hz),48.8,32.7,25.6,19.8,19.7,19.5,15.8,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29–-72.33(m).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O2 445.2097；Found 445.2094. 1 H NMR (600MHz, DMSO-d 6 ): δ 7.25 (t, J=7.8Hz, 2H), 7.22 (s, 1H), 7.18-7.16 (m, 3H), 7.10 (d, J=7.8Hz) ,1H)6.81(t,J＝7.2Hz,1H),4.87-4.82(m,2H),4.58(s,1H),2.25(s,3H),2.23(s,3H),1.33-1.29(m , 1H), 1.23(s, 6H), 1.13-1.08(m, 2H), 0.88-0.86(m, 1H). 13 CNMR (150MHz, DMSO-d 6 ): δ175.1, 157.1, 147.9, 138.1, 137.2, 130.2, 129.4, 128.6, 128.2, 124.9, 124.0 (q, 1 J CF = 279.2 Hz), 119.4, 114.2, 69.6, 60.7 (q, 2 J CF = 34.8 Hz), 48.8, 32.7, 25.6, 19.8, 19.7, 19.5, 15.8, 7.4. 19 F NMR (565MHz, DMSO-d 6 ): δ-72.29–-72.33 (m).HRMS (ESI) m/z: [M+H] + Calcd for C 25 H 28 F 3 N 2 O 2 445.2097; Found 445.2094.
2,2,2-Trifluoroethyl 2-(7-(3,4-dimethoxyphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4sa)2,2,2-Trifluoroethyl 2-(7-(3,4-dimethoxyphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4sa)
1H NMR(400MHz,CDCl3):δ7.30-7.24(m,4H),7.07(d,J＝1.2Hz,1H),6.87-6.81(m,3H),4.61(s,1H),4.52(qd,J1＝8.4Hz,J2＝1.2Hz,2H),3.91(s,3H),3.89(s,3H),1.42-1.39(m,1H),1.36(s,3H),1.34(s,3H),1.12-1.07(m,2H),0.87-0.84(m,1H).13C NMR(100MHz,CDCl3):δ175.7,156.5,150.1,149.1,147.9,129.0,123.4,123.0(q,1JC-F＝276.4Hz),119.5,119.3,114.2,110.9,69.7,60.6(q,2JC-F＝36.6Hz),56.02,56.00,49.0,32.6,25.8,19.0,16.3,7.5.19F NMR(376MHz,CDCl3):δ-73.55(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O4 477.1996；Found 477.1979. 1 H NMR (400 MHz, CDCl 3 ): δ 7.30-7.24 (m, 4H), 7.07 (d, J=1.2 Hz, 1H), 6.87-6.81 (m, 3H), 4.61 (s, 1H), 4.52 (qd, J 1 =8.4Hz, J 2 =1.2Hz, 2H), 3.91(s, 3H), 3.89(s, 3H), 1.42-1.39(m, 1H), 1.36(s, 3H), 1.34( s, 3H), 1.12-1.07(m, 2H), 0.87-0.84(m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 175.7, 156.5, 150.1, 149.1, 147.9, 129.0, 123.4, 123.0 (q , 1 J CF = 276.4 Hz), 119.5, 119.3, 114.2, 110.9, 69.7, 60.6 (q, 2 J CF = 36.6 Hz), 56.02, 56.00, 49.0, 32.6, 25.8, 19.0, 16.3, 7.5. 19 F NMR (376MHz, CDCl 3 ): δ-73.55 (t, J=8.3 Hz). HRMS(ESI) m/z: [M+H] + Calcd for C 25 H 28 F 3 N 2 O 4 477.1996; Found 477.1979.
2,2,2-Trifluoroethyl 2-methyl-2-(7-(naphthalen-2-yl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ta)2,2,2-Trifluoroethyl 2-methyl-2-(7-(naphthalen-2-yl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ta)
1H NMR(600MHz,DMSO-d6):δ8.04-8.03(m,1H),7.96-7.93(m,3H),7.68(d,J＝8.4Hz,1H),7.57-7.54(m,2H),7.29(t,J＝8.4Hz,2H),7.24(d,J＝7.8Hz,2H),6.84(t,J＝7.2Hz,1H),4.89-4.84(m,2H),4.68(s,1H),1.59-1.55(m,1H),1.29(s,3H),1.27-1.25(m,4H),1.22-1.19(m,1H),0.99-0.96(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,156.2,147.6,133.4,133.2,129.5,129.0,128.7,128.3,128.0,127.3,127.1,126.2,125.5,124.0(q,1JC-F＝275.6Hz),119.7,114.4,69.7,60.7(q,2JC-F＝35.0Hz),49.0,32.8,25.7,19.6,16.1,7.7.19F NMR(565MHz,DMSO-d6):δ-72.24(t,J＝9.6Hz).HRMS(ESI)m/z:[M+H]+Calcdfor C27H26F3N2O2 467.1941；Found 467.1921. 1 H NMR (600MHz, DMSO-d 6 ): δ 8.04-8.03 (m, 1H), 7.96-7.93 (m, 3H), 7.68 (d, J=8.4Hz, 1H), 7.57-7.54 (m, 2H), 7.29(t, J＝8.4Hz, 2H), 7.24(d, J＝7.8Hz, 2H), 6.84(t, J＝7.2Hz, 1H), 4.89-4.84(m, 2H), 4.68( s, 1H), 1.59-1.55(m, 1H), 1.29(s, 3H), 1.27-1.25(m, 4H), 1.22-1.19(m, 1H), 0.99-0.96(m, 1H). 13 C NMR (150MHz, DMSO-d 6 ): δ175.0, 156.2, 147.6, 133.4, 133.2, 129.5, 129.0, 128.7, 128.3, 128.0, 127.3, 127.1, 126.2, 125.5, 124.0 (q, 1 J CF =275.6 Hz), 119.7, 114.4, 69.7, 60.7 (q, 2 J CF = 35.0 Hz), 49.0, 32.8, 25.7, 19.6, 16.1, 7.7. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.24 (t, J = 9.6Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 27 H 26 F 3 N 2 O 2 467.1941; Found 467.1921.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(thiophen-2-yl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ua)2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(thiophen-2-yl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ua)
1H NMR(600MHz,DMSO-d6):δ7.60(d,J＝4.8Hz,1H),7.27(t,J＝9.0Hz,2H),7.16(d,J＝8.4Hz,2H),7.13(d,J＝3.0Hz,1H),7.09-7.08(m,1H),6.83(t,J＝7.8Hz,1H),4.88-4.82(m,2H),4.65(s,1H),1.69-1.65(m,1H),1.29-1.25(m,1H),1.20(s,3H),1.19(s,3H),1.17-1.14(m,1H),0.98-0.94(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,151.5,147.5,132.7,129.5,128.7,128.1,125.7,124.0(q,1JC-F＝275.4Hz),119.8,114.4,69.6,60.7(q,2JC-F＝37.3Hz),48.9,32.6,25.7,19.3,16.3,8.0.19F NMR(565MHz,DMSO-d6):δ-72.25(t,J＝11.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C21H22F3N2O2S 423.1349；Found 423.1330. 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.60 (d, J=4.8 Hz, 1H), 7.27 (t, J=9.0 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.13(d,J=3.0Hz,1H),7.09-7.08(m,1H),6.83(t,J=7.8Hz,1H),4.88-4.82(m,2H),4.65(s,1H),1.69 -1.65(m,1H),1.29-1.25(m,1H),1.20(s,3H),1.19(s,3H),1.17-1.14(m,1H),0.98-0.94(m,1H) .13 C NMR (150MHz, DMSO-d 6 ): δ 175.0, 151.5, 147.5, 132.7, 129.5, 128.7, 128.1, 125.7, 124.0 (q, 1 J CF = 275.4 Hz), 119.8, 114.4, 69.6, 60.7 (q, 2 J CF = 37.3 Hz), 48.9, 32.6, 25.7, 19.3, 16.3, 8.0. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.25 (t, J = 11.3 Hz).HRMS (ESI) m/z :[M+H] + Calcd for C 21 H 22 F 3 N 2 O 2 S 423.1349; Found 423.1330.
实施例4Example 4
本发明所合成的产物三氟甲基缀合的吡唑螺环丙烷类化合物4进行一系列反应，从而合成进一步的衍生物。例如：The trifluoromethyl-conjugated pyrazole spiropropane compound 4 synthesized in the present invention undergoes a series of reactions to synthesize further derivatives. E.g:
在25mL圆底烧瓶中，将4aa(200mg,0.48mmol)溶于超干二氯甲烷(10mL)中，随后将体系抽真空充氩气，然后将体系置于冰水浴中，向上述体系缓慢滴加二异丁基氢化铝(1.5Min toluene,1.6mL,2.4mmol)，之后将反应体系在0℃反应3h，反应结束后，缓慢加入饱和氯化铵溶液淬灭反应。有机相用乙醚萃取、水洗、干燥、过滤，将有机相浓缩过硅胶柱分离(石油醚/乙酸乙酯＝10/1)得淡黄色固体产物5(135.9mg,88％)。1H NMR(400MHz,CDCl3):δ7.47-7.44(m,2H),7.38-7.35(m,3H),7.27-7.23(m,4H),6.83-6.79(m,1H),3.98(s,1H),3.50(s,2H),1.92(br s,1H),1.74-1.68(m,1H),1.56-1.50(m,1H),1.04(s,3H),1.03(s,3H),0.84-0.78(m,1H),0.72-0.67(m,1H).13C NMR(100MHz,CDCl3):δ158.0,147.9,131.0,129.1,128.9,128.6,127.6,118.8,113.9,71.4,70.1,42.7,31.0,22.9,22.7,15.0,8.0.HRMS(ESI)m/z:[M+H]+Calcd for C21H25N2O 321.1961；Found 321.1954.In a 25 mL round-bottomed flask, 4aa (200 mg, 0.48 mmol) was dissolved in ultra-dry dichloromethane (10 mL), then the system was evacuated and filled with argon, then the system was placed in an ice-water bath, and slowly dripped into the above system Diisobutylaluminum hydride (1.5Min toluene, 1.6mL, 2.4mmol) was added, and then the reaction system was reacted at 0°C for 3h. After the reaction, saturated ammonium chloride solution was slowly added to quench the reaction. The organic phase was extracted with ether, washed with water, dried and filtered. The organic phase was concentrated and separated by silica gel column (petroleum ether/ethyl acetate=10/1) to obtain 5 (135.9 mg, 88%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.47-7.44 (m, 2H), 7.38-7.35 (m, 3H), 7.27-7.23 (m, 4H), 6.83-6.79 (m, 1H), 3.98 ( s,1H),3.50(s,2H),1.92(br s,1H),1.74-1.68(m,1H),1.56-1.50(m,1H),1.04(s,3H),1.03(s,3H) ), 0.84-0.78(m, 1H), 0.72-0.67(m, 1H). 13 C NMR (100MHz, CDCl 3 ): δ158.0, 147.9, 131.0, 129.1, 128.9, 128.6, 127.6, 118.8, 113.9, 71.4, 70.1, 42.7, 31.0, 22.9, 22.7, 15.0, 8.0. HRMS(ESI) m/z: [M+H] + Calcd for C 21 H 25 N 2 O 321.1961; Found 321.1954.
在50mL圆底烧瓶中将4aa(700mg,1.68mmol)溶于1,4-二氧六环(5mL)中，随后加入氢氧化钠溶液(0.6mL,6M)，将体系置于60℃油浴中反应5h。反应结束后冷却至室温，缓慢加入稀盐酸(2M)将体系的pH值调至pH＝1，有机相用乙酸乙酯萃取、水洗、干燥、过滤，将有机相浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝3/1)得到淡黄色固体产物6(527.5mg,94％)。1HNMR(400MHz,DMSO-d6):δ12.76(br s,1H),7.42(s,5H),7.24(t,J＝8.8Hz,2H),7.19(d,J＝7.6Hz,2H),6.79(t,J＝6.8Hz,1H),4.60(s,1H),1.36-1.27(m,2H),1.18(s,3H),1.16(s,3H),1.11-1.06(m,1H),0.92-0.87(m,1H).13C NMR(100MHz,DMSO-d6):δ178.5,156.8,148.1,131.0,129.6,129.3,129.2,127.5,119.2,114.2,69.8,48.4,32.7,26.1,19.5,15.9,7.4.HRMS(ESI)m/z:[M+H]+Calcd for C21H23N2O2 335.1754；Found 335.1742.In a 50 mL round-bottomed flask, 4aa (700 mg, 1.68 mmol) was dissolved in 1,4-dioxane (5 mL), followed by sodium hydroxide solution (0.6 mL, 6 M), and the system was placed in a 60°C oil bath The reaction was carried out for 5h. After the reaction was completed, it was cooled to room temperature, and diluted hydrochloric acid (2M) was slowly added to adjust the pH value of the system to pH=1. The organic phase was extracted with ethyl acetate, washed with water, dried and filtered. The organic phase was concentrated and separated through a silica gel column (petroleum ether/ethyl acetate = 3/1) to give the product 6 as a pale yellow solid (527.5 mg, 94%). 1 HNMR (400MHz, DMSO-d 6 ): δ 12.76 (br s, 1H), 7.42 (s, 5H), 7.24 (t, J=8.8Hz, 2H), 7.19 (d, J=7.6Hz, 2H) ), 6.79(t, J＝6.8Hz, 1H), 4.60(s, 1H), 1.36-1.27(m, 2H), 1.18(s, 3H), 1.16(s, 3H), 1.11-1.06(m, 1H), 0.92-0.87(m, 1H). 13 C NMR (100MHz, DMSO-d 6 ): δ178.5, 156.8, 148.1, 131.0, 129.6, 129.3, 129.2, 127.5, 119.2, 114.2, 69.8, 48.4, 32.7, 26.1, 19.5, 15.9, 7.4. HRMS(ESI) m/z: [M+H] + Calcd for C 21 H 23 N 2 O 2 335.1754; Found 335.1742.
在25mL两颈瓶中，将6(150mg,0.45mmol)溶于超干二氯甲烷(3mL)中，加入一滴N,N-二甲基甲酰胺，随后抽真空充氩气。将反应瓶置于冰水浴中，缓慢滴加草酰氯(86.3mg,0.68mmol),滴加完毕后于0℃反应1.5小时。旋走未反应完的草酰氯，将得到的粗产物溶于超干二氯甲烷(3mL)中，加入三氯化铝(90.7mg,0.68mmol)，于氩气氛围下继续在0℃反应1.5小时。反应结束后，加水淬灭反应，用二氯甲烷萃取。有机相水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝20/1)得到黄色固体产物7(50.5mg,35％)。1H NMR(400MHz,CDCl3):δ7.90(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.57(d,J＝8.0Hz,1H),7.49-7.47(m,2H),7.45-7.41(m,1H),7.39-7.37(m,3H),6.85-6.81(m,1H),4.17(s,1H),1.68-1.64(m,1H),1.52-1.46(m,1H),1.27-1.23(m,1H),1.19(s,6H),0.88-0.83(m,1H).13C NMR(100MHz,CDCl3):δ197.2,156.4,146.3,135.1,130.7,129.3,128.7,128.6,127.4,118.9,115.3,113.6,69.1,45.0,31.8,17.9,17.6,11.9,11.2.HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O317.1648；Found 317.1629.In a 25 mL two-neck flask, 6 (150 mg, 0.45 mmol) was dissolved in ultra-dry dichloromethane (3 mL), a drop of N,N-dimethylformamide was added, followed by vacuum and argon. The reaction flask was placed in an ice-water bath, oxalyl chloride (86.3 mg, 0.68 mmol) was slowly added dropwise, and the reaction was performed at 0° C. for 1.5 hours after the dropwise addition. The unreacted oxalyl chloride was spun away, the obtained crude product was dissolved in ultra-dry dichloromethane (3 mL), aluminum trichloride (90.7 mg, 0.68 mmol) was added, and the reaction was continued at 0 °C for 1.5 under argon atmosphere. Hour. After the reaction was completed, the reaction was quenched by adding water, and extracted with dichloromethane. The organic phase was washed with water, dried, filtered, concentrated, and separated by silica gel column (petroleum ether/ethyl acetate=20/1) to obtain yellow solid product 7 (50.5 mg, 35%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (dd, J 1 =8.0 Hz, J 2 =1.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1 H), 7.49-7.47 (m, 2H) ),7.45-7.41(m,1H),7.39-7.37(m,3H),6.85-6.81(m,1H),4.17(s,1H),1.68-1.64(m,1H),1.52-1.46(m , 1H), 1.27-1.23(m, 1H), 1.19(s, 6H), 0.88-0.83(m, 1H). 13 C NMR (100MHz, CDCl 3 ): δ197.2, 156.4, 146.3, 135.1, 130.7, 129.3 ,128.7,128.6,127.4,118.9,115.3,113.6,69.1,45.0,31.8,17.9,17.6,11.9,11.2.HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 21 N 2 O317 .1648;Found 317.1629.
在15mL反应管中依次加入4ai(69.3mg,0.14mmol)、苯乙炔(23μL,0.21mmol)、三苯基膦(7.3mg,0.028mmol)、磷酸钾(36.1mg,0.17mmol)、醋酸钯(1.6mg,0.007mmol)和二甲基亚砜(2mL)，置于80℃油浴中于氩气氛围下反应24h。反应结束后冷却至室温，缓慢加入碳酸氢钠溶液淬灭反应。用乙酸乙酯萃取，有机相水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝30/1)得到黄色固体8(25.5mg,35％)。1H NMR(600MHz,DMSO-d6):δ7.51(d,J＝8.4Hz,2H),7.46-7.36(m,10H),7.21(d,J＝7.8Hz,2H),4.85(qd,J1＝8.4Hz,J2＝2.4Hz,2H),4.71(s,1H),1.38-1.34(m,1H),1.24(s,6H),1.19-1.13(m,2H),1.02-0.98(m,1H).13CNMR(150MHz,DMSO-d6):δ174.8,157.8,147.4,132.9,131.5,130.4,129.9,129.3,129.2,128.7,127.6,124.0(q,1JC-F＝276.2Hz),123.5,114.2,112.4,90.7,88.3,69.2,60.8(q,2JC-F＝34.8Hz),49.0,32.8,25.6,19.6,15.8,7.6.19F NMR(565MHz,DMSO-d6):δ-72.20(t,J＝8.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C31H28F3N2O2 517.2097；Found 517.2087.4ai (69.3 mg, 0.14 mmol), phenylacetylene (23 μL, 0.21 mmol), triphenylphosphine (7.3 mg, 0.028 mmol), potassium phosphate (36.1 mg, 0.17 mmol), palladium acetate ( 1.6 mg, 0.007 mmol) and dimethyl sulfoxide (2 mL) were placed in an oil bath at 80°C and reacted under an argon atmosphere for 24 h. After the reaction was completed, it was cooled to room temperature, and sodium bicarbonate solution was slowly added to quench the reaction. Extracted with ethyl acetate, the organic phase was washed with water, dried, filtered, concentrated, and separated by silica gel column (petroleum ether/ethyl acetate=30/1) to obtain yellow solid 8 (25.5 mg, 35%). 1 H NMR (600 MHz, DMSO-d 6 ): δ 7.51 (d, J=8.4 Hz, 2H), 7.46-7.36 (m, 10H), 7.21 (d, J=7.8 Hz, 2H), 4.85 (qd , J 1 =8.4Hz, J 2 =2.4Hz, 2H), 4.71(s, 1H), 1.38-1.34(m, 1H), 1.24(s, 6H), 1.19-1.13(m, 2H), 1.02- 0.98 (m, 1H). 13 CNMR (150MHz, DMSO-d 6 ): δ 174.8, 157.8, 147.4, 132.9, 131.5, 130.4, 129.9, 129.3, 129.2, 128.7, 127.6, 124.0 (q, 1 J CF = 276.2 Hz ), 123.5, 114.2, 112.4, 90.7, 88.3, 69.2, 60.8 (q, 2 J CF = 34.8 Hz), 49.0, 32.8, 25.6, 19.6, 15.8, 7.6. 19 F NMR (565 MHz, DMSO-d 6 ): δ-72.20(t, J=8.5Hz).HRMS(ESI)m/z: [M+H] + Calcd for C 31 H 28 F 3 N 2 O 2 517.2097; Found 517.2087.
在15mL反应管中依次加入4ga(48.5mg,0.098mmol)、苯乙炔(16μL,0.15mmol)、三苯基膦(5.1mg,0.02mmol)、磷酸钾(25.5mg,0.12mmol)、醋酸钯(1.1mg,0.005mmol)和二甲基亚砜(2mL)，置于80℃油浴中于氩气氛围下反应24h。反应结束后冷却至室温，缓慢加入碳酸氢钠溶液淬灭反应。用乙酸乙酯萃取，有机相水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝30/1)得到淡黄色固体9(30.9mg,61％)。1H NMR(400MHz,CDCl3):δ7.55-7.50(m,4H),7.41-7.39(m,2H),7.37-7.34(m,3H),7.29-7.25(m,4H),6.89-6.85(m,1H),4.66(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.2Hz,2H),1.41-1.38(m,1H),1.35(s,3H),1.33(s,3H),1.62-1.12(m,2H),0.91-0.87(m,1H).13C NMR(100MHz,CDCl3):δ175.6,155.3,147.4,131.8,131.7,130.6,129.0,128.5,128.4,127.0,124.1,123.1,122.9(q,1JC-F＝276.0Hz),119.6,114.3,91.0,89.0,69.6,60.6(q,2JC-F＝36.9Hz),49.1,32.5,25.8,18.9,16.4,7.4.19F NMR(376MHz,CDCl3):δ-73.55(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd forC31H28F3N2O2 517.2097；Found 517.2088.4ga (48.5 mg, 0.098 mmol), phenylacetylene (16 μL, 0.15 mmol), triphenylphosphine (5.1 mg, 0.02 mmol), potassium phosphate (25.5 mg, 0.12 mmol), palladium acetate ( 1.1 mg, 0.005 mmol) and dimethyl sulfoxide (2 mL) were placed in an oil bath at 80 °C and reacted under an argon atmosphere for 24 h. After the reaction was completed, it was cooled to room temperature, and sodium bicarbonate solution was slowly added to quench the reaction. Extracted with ethyl acetate, the organic phase was washed with water, dried, filtered, concentrated, and separated by silica gel column (petroleum ether/ethyl acetate=30/1) to obtain pale yellow solid 9 (30.9 mg, 61%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.55-7.50 (m, 4H), 7.41-7.39 (m, 2H), 7.37-7.34 (m, 3H), 7.29-7.25 (m, 4H), 6.89- 6.85(m, 1H), 4.66(s, 1H), 4.51(qd, J 1 =8.4Hz, J 2 =1.2Hz, 2H), 1.41-1.38(m, 1H), 1.35(s, 3H), 1.33 (s, 3H), 1.62-1.12 (m, 2H), 0.91-0.87 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 175.6, 155.3, 147.4, 131.8, 131.7, 130.6, 129.0, 128.5, 128.4, 127.0, 124.1, 123.1, 122.9 (q, 1 J CF = 276.0Hz), 119.6, 114.3, 91.0, 89.0, 69.6, 60.6 (q, 2 J CF = 36.9 Hz), 49.1, 32.5, 25.8, 18.9, 16.4, 7.4. 19 F NMR (376 MHz, CDCl 3 ): δ-73.55 (t, J=8.6 Hz). HRMS (ESI) m/z: [M+H] + Calcd for C 31 H 28 F 3 N 2 O 2 517.2097; Found 517.2088.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments. The above-mentioned embodiments and descriptions only illustrate the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will also have various Variations and improvements all fall within the scope of the present invention.
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210068950.2A CN114349704A (en) | 2022-01-21 | 2022-01-21 | Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210068950.2A CN114349704A (en) | 2022-01-21 | 2022-01-21 | Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114349704A true CN114349704A (en) | 2022-04-15 |
Family
ID=81090938
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210068950.2A Pending CN114349704A (en) | 2022-01-21 | 2022-01-21 | Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114349704A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040209896A1 (en) * | 2001-04-20 | 2004-10-21 | Peter Jeschke | Novel insecticidal azoles |
| CA2547887A1 (en) * | 2003-12-05 | 2005-06-16 | Tokai University Educational System | Protein modifier production inhibitor |
| CN1671698A (en) * | 2002-07-25 | 2005-09-21 | 拜尔作物科学有限公司 | 4-trifluoromethylpyrazole substituted pyridines and pyrimidines |
| US20090076049A1 (en) * | 2006-02-07 | 2009-03-19 | Astrazeneca Ab | Novel Spiro [Imidazolidine-4, 3' -Indole] 2, 2', 5' (1H) Triones for Treatment of Conditions Associated with Vanilloid Receptor 1 |
| WO2010103065A1 (en) * | 2009-03-11 | 2010-09-16 | Basf Se | Fungicidal compositions and their use |
| CN113717179A (en) * | 2021-10-12 | 2021-11-30 | 湖北科技学院 | Spiropyrazoline pyrrolidone derivative and synthesis method thereof |
-
2022
- 2022-01-21 CN CN202210068950.2A patent/CN114349704A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040209896A1 (en) * | 2001-04-20 | 2004-10-21 | Peter Jeschke | Novel insecticidal azoles |
| CN1671698A (en) * | 2002-07-25 | 2005-09-21 | 拜尔作物科学有限公司 | 4-trifluoromethylpyrazole substituted pyridines and pyrimidines |
| CA2547887A1 (en) * | 2003-12-05 | 2005-06-16 | Tokai University Educational System | Protein modifier production inhibitor |
| US20090076049A1 (en) * | 2006-02-07 | 2009-03-19 | Astrazeneca Ab | Novel Spiro [Imidazolidine-4, 3' -Indole] 2, 2', 5' (1H) Triones for Treatment of Conditions Associated with Vanilloid Receptor 1 |
| WO2010103065A1 (en) * | 2009-03-11 | 2010-09-16 | Basf Se | Fungicidal compositions and their use |
| CN113717179A (en) * | 2021-10-12 | 2021-11-30 | 湖北科技学院 | Spiropyrazoline pyrrolidone derivative and synthesis method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王猛 等: "氮叶立德高立体选择性地合成螺[环丙烷-1, 4\'-吡唑啉-5\'-酮] 衍生物的研究", 《有机化学》, vol. 29, no. 10, pages 1611 - 1616 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102786448B (en) | Method of synthesizing belinostat | |
| CN111471047A (en) | Method for the selective synthesis of pyrazolo[1,2-a]pyrazolones or 2-acylindole compounds | |
| CN111675712A (en) | A kind of synthetic method of pyrazolone benzodiazepine compounds | |
| CN111606849B (en) | A kind of synthetic method of 2-(2-aminophenyl) quinoline compounds | |
| CN110577457B (en) | A kind of copper-catalyzed carboxylation method of arylboronic acid and carbon dioxide | |
| CN107266457A (en) | Ketone compounds of two indoline of a kind of 2,3 ' spiral shell 2 and preparation method thereof | |
| CN114349704A (en) | Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof | |
| CN107033106B (en) | A kind of preparation method of sulfamide compound | |
| CN109574906A (en) | A kind of preparation method of 3,3 '-two Indoleacetic esters | |
| CN115385858B (en) | Photocatalytic preparation method of 2-phenyl-2H-indazole-3-carboxamide compound | |
| CN104945305A (en) | Method for achieving indole derivative selective aromatic thiolation | |
| CN113105401B (en) | 1, 2, 3-triazole derivative and preparation method and application thereof | |
| CN110642689B (en) | 3, 6-dibromo-2-methylbenzaldehyde and chemical synthesis method thereof | |
| CN104327025B (en) | A kind of preparation method of 4-arylnaphthalene lactone derivative | |
| CN103272638A (en) | Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof | |
| CN113698349A (en) | Water-phase photocatalytic preparation method of 2- (2-phenyl-2H-indazole-3-yl) acetate compounds | |
| CN115353514B (en) | Fluoro-pyridopyrimidinone compounds and synthesis method thereof | |
| CN107033073B (en) | Method for synthesizing 2-(4'-hydroxy)phenyl-quinoline compounds with 2-methylquinoline compounds | |
| CN111960961A (en) | Synthetic method of alpha-amidoketone compound | |
| CN101245040B (en) | Process for producing 4-ethynyl benzene sulfonamide (I) | |
| CN113717107B (en) | Synthesis method of N-acyl benzimidazole compound | |
| CN104311495B (en) | Method for synthesizing NH-1,2,3-triazole | |
| CN115626861B (en) | Method for synthesizing trifluoromethyl aromatic compounds | |
| JP7209808B2 (en) | Method for producing cyclic butane compound, photosensitizer, and pyrazole compound | |
| CN109810069B (en) | A kind of preparation method of polysubstituted 1,3,5-triazine |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220415 |
|
| WD01 | Invention patent application deemed withdrawn after publication |