CN113200999A - Derivative containing trifluoroethyl azetidine and preparation method thereof - Google Patents

Derivative containing trifluoroethyl azetidine and preparation method thereof Download PDF

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CN113200999A
CN113200999A CN202110473966.7A CN202110473966A CN113200999A CN 113200999 A CN113200999 A CN 113200999A CN 202110473966 A CN202110473966 A CN 202110473966A CN 113200999 A CN113200999 A CN 113200999A
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azetidine
trifluoroethyl
methyl
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朱钢国
周根来
商甜波
柏一慧
罗芳
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Zhejiang Normal University CJNU
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Zhejiang Normal University CJNU
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a trifluoroethyl azetidine derivative and a preparation method thereof, which are obtained by mixing alkynylamine with a structure shown in a formula II, 1- (trifluoromethyl) -1, 2-phenyliodoacyl-3 (1H) -ketone with a structure shown in a formula III, 10-methyl-9-mesityleneacridine perchlorate with a structure shown in a formula IV and cesium carbonate in a solvent and reacting. The invention adopts a photocatalytic trifluoromethylation/cyclization tandem reaction strategy to realize the stereoselective synthesis of the derivative containing trifluoroethyl azetidine by one step. The reaction condition is mild, the application range of the substrate is wide, the structural diversity synthesis of the preparation method of the trifluoroethyl-containing azetidine derivative can be realized by changing the substituent, the reaction yield is good, the operation is simple, and a new way is provided for the cyclization of N-allylcyclic amide and the synthesis of fluorine-containing azetidine.

Description

Derivative containing trifluoroethyl azetidine and preparation method thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a derivative containing trifluoroethyl azetidine and a preparation method thereof.
Background
The nitrogen-containing heterocyclic compound is a core composition structure of a plurality of medicines, pesticides and functional material molecules, and the azetidine and the derivatives thereof are widely existed in a plurality of natural products or medicine molecules and have biological activities of hypertension resistance, inflammation resistance, arrhythmia resistance, depression resistance and the like. Introduction of fluorine-containing groups into drug molecules is one of the important strategies for drug modification. On one hand, due to the strong electron withdrawing property of fluorine, the introduction of fluorine into a drug molecule can change the acid-base property of fluorine, thereby improving the lipid solubility of the drug molecule. On the other hand, fluorine has strong electron-withdrawing ability and maximum electronegativity, so that the introduction of fluorine into drug molecules can enhance the oxidation resistance of the drug molecules and improve the stability of the drug molecules. With the development of fluorine chemistry, more and more fluorine-containing compounds are widely applied to the fields of medicines, pesticides, materials and the like. Fluorine element is introduced into the molecule of the azetidine segment, so that good pharmaceutical activity is obtained. Compound A is a novel drug cobicistinib (Cobimetinib), is a kinase inhibitor, and is suitable for treating patients with melanoma with a BRAF V600E or V600K mutation. The compound B is CCR2 antagonist JNJ-41443532, and has moderate blood sugar improving effect on type 2 diabetes mellitus patients. The compound C is TGR5 agonist, and has certain therapeutic effect on diabetes.
Figure BDA0003046671850000011
However, as a class of small ring nitrogen-containing backbone molecules, the synthesis of azetidine and its derivatives faces significant challenges, subject to their ring tensions. The current common synthesis methods of azetidine and derivatives thereof include nucleophilic substitution reactions, cycloaddition reactions, intramolecular carbon-hydrogen bond amination reactions catalyzed by transition metals, and the like. Unfortunately, the use of substrate pre-functionalization, strong bases, excess reducing agents, high temperatures, or expensive transition metal catalysts limits the application of these methods.
In recent years, the free radical addition reaction of alkynylamine is one of the effective routes for synthesizing nitrogen-containing heterocyclic compounds, and although this method has received much attention, there are still some problems to be solved. The current mode of free-radical cyclisation of alkynylamines is generally 5-exo-dig or 6-exo-dig cyclisation, giving what is often an aza five-or six-membered ring compound. However, the formation of quaternary nitrogen heterocycles by 4-exo-dig cyclization reactions has not been reported. Therefore, a reasonable free radical catalytic system is designed, the fluorinated serial cyclization reaction of the N-allylalkynylamine is realized, the trifluoromethyl is selectively introduced, and the construction of the azetidine compound is realized, so that the method has important significance in theoretical research and practical application.
Disclosure of Invention
The invention provides a trifluoroethyl-containing azetidine derivative and a preparation method thereof, wherein a trifluoromethylation/cyclization tandem reaction strategy is adopted to realize stereoselective synthesis of the trifluoroethyl-containing azetidine derivative in one step. The method is synthesized to have a multi-element parallel ring framework structure based on a free radical serial cyclization reaction strategy, and realizes one-step construction of azetidine and benzothiazines in a high-efficiency reaction manner. The reaction condition is mild, the substrate application range is wide, the structural diversity synthesis of the preparation method of the trifluoroethyl-containing azetidine derivative can be realized by changing the substituent, the reaction yield is good, the operation is simple, and a new way is provided for the cyclization of N-allyl cyclic amide and the synthesis of fluorine-containing azetidine.
A trifluoroethyl-containing azetidine derivative has a structure of formula I:
Figure BDA0003046671850000021
wherein R is1Is one of phenyl, p-acetylphenyl, p-benzoylethoxy, p-cyanophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl and p-methoxyphenyl; r2Is one of hydrogen atom, chlorine and methyl; r3Is one of hydrogen atom, methyl, butyl and tert-butyl dimethyl siloxy.
A preparation method of a derivative containing trifluoroethyl azetidine comprises the following steps:
adding alkynylamine with a structure shown in a formula II, 1- (trifluoromethyl) -1, 2-phenyliodoacyl-3 (1H) -ketone with a structure shown in a formula III, 10-methyl-9-mesitylacridine perchlorate with a structure shown in a formula IV and cesium carbonate into an acetonitrile solvent, forming a reaction system in a certain reaction environment, and carrying out post-treatment after the reaction is finished to obtain the derivative containing trifluoroethyl azetidine with the structure shown in the formula I;
Figure BDA0003046671850000031
wherein R is1Is one of phenyl, p-acetylphenyl, p-benzoylethoxy, p-cyanophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl and p-methoxyphenyl; r2Is one of hydrogen atom, chlorine and methyl; r3Is one of hydrogen atom, methyl, butyl and tert-butyl dimethyl siloxy.
The specific synthetic route involved in the reaction is shown below:
Figure BDA0003046671850000032
according to the preparation method, due to addition of trifluoromethyl radicals to alkenyl in N-allyl alkynylamide, rare 4-exo-dig cyclization of generated alkyl radicals is carried out to obtain an alkenyl radical intermediate of the azetidine containing nitrogen, and the intermediate carries out intramolecular functionalization cyclization reaction through spin polarization and single electron transfer.
The reaction environment is nitrogen atmosphere, and the blue light irradiation is carried out at the temperature of 5-35 ℃ by 20-40W, and the blue light irradiation is preferably carried out at the room temperature by 30W.
The molar ratio of the alkynylamine with the structure shown in the formula II, the 1- (trifluoromethyl) -1, 2-phenyliodoacyl-3 (1H) -ketone with the structure shown in the formula III, the 10-methyl-9-mesitylacridine perchlorate with the structure shown in the formula IV and the cesium carbonate is 1: 1.5-3: 0.01-0.1: 1.5 to 3, and more preferably 1: 1.8-2.2: 0.03-0.05: 1.8 to 2.2. Most preferably 1: 2: 0.04: 2.
the reaction time of the reaction system is 20 to 40 hours, more preferably 32 to 38 hours, and most preferably 36 hours.
The post-treatment comprises the following steps: quenching, suction filtering, extracting, washing organic phase, drying and column chromatography separation.
The quenching adopts water and ethyl acetate for quenching, the suction filtration is methyl diatomite suction filtration, the extraction adopts ethyl acetate for extraction for three times, the washing organic phase adopts saturated edible water for washing, the drying adopts anhydrous sodium sulfate for drying, and the column chromatography separation adopts silica gel column chromatography separation.
Compared with the prior art, the invention has the following advantages:
1. the 4-exo-dig cyclization of the alkynylamide is realized for the first time.
2. The synthetic method has a multi-element parallel-ring framework structure based on a free radical serial cyclization reaction strategy, and realizes one-step construction of azetidine and benzothiazines for the first time.
3. The reaction condition is mild, the operation is simple, the application range of the substrate is wide, the compatibility of functional groups is good, and the application prospect is good; therefore, the invention has higher theoretical innovation value and implementation value.
Detailed Description
Example 1
To a dry reaction tube were added allylalkynylamide compound 1a (60mg,0.2mmol), 1- (trifluoromethyl) -1, 2-phenyliodoyl-3 (1H) -one (trifluoromethylating agent 2, 126mg,0.4mmol), 10-methyl-9-mesitylacridine perchlorate (Acr-Mes)+ClO4 -,0.008mmol,3.3mg), Cs2CO3(0.4mmol,130mg), vacuumized and nitrogen-exchanged three times, 3mL of acetonitrile is added under the protection of nitrogen, and the mixture is reacted for 36h at room temperature and 25 ℃ under a 30W blue lamp. The reaction was quenched by adding 10mL of water and 10mL of ethyl acetate to the reaction system after the reaction was complete. After adding celite and suction filtration, the filter cake was washed with ethyl acetate, and the mixture was allowed to stand for liquid separation, the aqueous phase was extracted with ethyl acetate (15 mL. times.3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was spin dried and column chromatographed (EA: PE ═ 1:10) to give 51mg of 3a as a pale yellow solid in 70% yield. Product spectral analysis1H NMR(600MHz,CDCl3)δ8.06(d, J＝7.9Hz,1H),7.53–7.51(m,1H),7.49–7.43(m,4H),7.32–7.30(m,2H),7.15 (d,J＝8.0Hz,1H),4.44–4.42(m,1H),4.39–4.37(m,1H),3.97–3.93(m,1H), 2.38–2.28(m,1H),2.06–1.98(m,1H)；13C NMR(151MHz,CDCl3)δ144.3, 134.9,132.7,131.8,131.3,129.6,129.3,128.6,127.4,125.8,125.7(q,J＝277.3 Hz),123.7,115.7,49.9,34.4(q,J＝3.2Hz),33.8(q,J＝29.0Hz)；19F NMR(565 MHz,CDCl3)δ-65.6；HRMS(ESI)Calcd for C18H15F3NO2S[M+H]+366.0770, found 366.0774。
The reaction formula is as follows:
Figure BDA0003046671850000041
example 2
The procedure of example 1 was followed, except that the allylalkynamide compound of the formula 1b was used instead of the allylalkynamide compound of the formula 1a in example 1, to give a yield: 70% pale yellow solid 3 b. Product spectral analysis1H NMR(600MHz,CDCl3)δ8.07(d,J＝8.2 Hz,3H),7.54(t,J＝7.7Hz,1H),7.48(t,J＝7.6Hz,1H),7.44(d,J＝8.2Hz, 2H),7.11(d,J＝7.9Hz,1H),4.46–4.39(m,2H),4.05–3.93(m,1H),2.67(s,3H), 2.40–2.32(m,1H),2.05–2.00(m,1H)；13C NMR(151MHz,CDCl3)δ197.2, 145.2,137.0,137.0,134.2,132.9,131.3,129.8,129.2,127.7,125.6,125.6(q,J＝ 277.4Hz),123.9,114.8,50.0,34.5(q,J＝3.0Hz),33.8(q,J＝29.1Hz),26.7；19F NMR(565MHz,CDCl3)δ-65.5；HRMS(ESI)Calcd for C20H17F3NO2S[M+ H]+408.0876found,408.0873。
The reaction formula is as follows:
Figure BDA0003046671850000051
example 3
Except that allylalkynylamides of the formula 1c are used instead of the formula 1a of example 1The remaining procedure was as in example 1 except for the allylalkynamide compound shown, yield: 79% grey solid 3 c. Product spectral analysis1H NMR(600MHz,CDCl3)δ8.15(d,J＝8.2Hz, 2H),8.07(d,J＝7.7Hz,1H),7.53(t,J＝7.3Hz,1H),7.48(t,J＝7.5Hz,1H), 7.48(t,J＝7.5Hz,1H),7.41(d,J＝8.2Hz,2H),7.11(d,J＝7.9Hz,1H), 4.46–4.38(m,4H),4.05–3.96(m,1H),2.47–2.17(m,1H),2.11–1.94(m,1H), 1.43(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ165.9,145.1,136.7, 134.3,132.9,131.3,130.7,130.5,129.6,127.6,125.6,125.6(q,J＝277.4Hz), 123.9,114.9,61.3,50.0,34.5(q,J＝3.1Hz),33.4(q,J＝29.0Hz),14.3；19F NMR(565MHz,CDCl3)δ-65.5；HRMS(ESI)calcd for C21H19F3NO4S(M+H)+ 438.0981,found 438.0968。
The reaction formula is as follows:
Figure BDA0003046671850000061
example 4
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1d was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 75% and grey solid 3 d. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.08(d,J＝7.9Hz, 1H),7.79(d,J＝8.2Hz,2H),7.56(t,J＝7.7Hz,1H),7.50(t,J＝7.6Hz,1H), 7.47(d,J＝8.2Hz,2H),7.07(d,J＝7.9Hz,1H),4.46–4.43(m,1H),4.43–4.41 (m,1H),3.97–3.95(m,1H),2.40–2.32(m,1H),2.00–1.96(m,1H)；13C NMR (151MHz,CDCl3)δ145.7,137.1,133.8,133.1,133.0,131.4,130.4,127.9, 125.4(q,J＝277.4Hz),125.4,124.0,118.1,114.2,112.6,50.1,34.4(q,J＝3.1 Hz),33.9(q,J＝29.2Hz)；19F NMR(565MHz,CDCl3)δ-65.5；HRMS(ESI) calcd for C19H14F3N2O2S(M+H)+391.0723,found 391.0723。
the reaction formula is as follows:
Figure BDA0003046671850000062
example 5
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1e was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 63% as a pale yellow solid 3 e. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.08(d,J＝7.1Hz, 1H),7.75(d,J＝8.1Hz,2H),7.55(t,J＝7.2Hz,1H),7.49(d,J＝7.4Hz,1H), 7.47(d,J＝8.3Hz,2H),7.08(d,J＝7.9Hz,1H),4.46–4.40(m,2H),3.99–3.96 (m,1H),2.40–2.34(m,1H),2.04–1.96(m,1H)；13C NMR(151MHz,CDCl3)δ 145.3,136.0,134.2,133.0,131.4,130.9(q,J＝30Hz),130.1,127.7,126.3(q,J＝ 3.6Hz),125.6(q,J＝277.5Hz),125.5,123.9,123.9(q,J＝272.3Hz),114.5, 50.0,34.4(q,J＝3.1Hz),34.0(q,J＝29.1Hz)；19F NMR(565MHz,CDCl3)δ -62.7,-65.5；HRMS(ESI)calcd for C19H13F6NO2S(M+H)+434.0644,found 434.0646.。
the reaction formula is as follows:
Figure BDA0003046671850000071
example 6
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1f was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 64% as a pale yellow solid 3 f. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.9Hz, 1H),7.53(t,J＝7.7Hz,1H),7.46(t,J＝7.6Hz,1H),7.32–7.28(m,2H),7.18(t, J＝8.5Hz,2H),7.10(d,J＝8.0Hz,1H),4.43–4.37(m,2H),3.95–3.91(m,1H), 2.38–2.32(m,1H),2.10–1.95(m,1H)；13C NMR(151MHz,CDCl3)δ162.7(d, J＝249.1Hz),144.5,134.8,132.8,131.4(d,J＝8.2Hz),131.3,127.8(d,J＝3.4 Hz),127.5,125.6(q,J＝277.4Hz),125.6,123.8,116.5(d,J＝21.6Hz),114.7, 49.9,34.3(q,J＝3.2Hz),33.9(q,J＝28.9Hz)；19F NMR(565MHz,CDCl3)δ -65.56,-112.18；HRMS(ESI)Calcd for C18H14F4NO2S[M+H]+384.0676,found 384.0675。
the reaction formula is as follows:
Figure BDA0003046671850000072
example 7
The procedure of example 1 was followed, except that the allylalkynamide compound of the formula 1g was used instead of the allylalkynamide compound of the formula 1a in example 1, to give a yield: 65% of a pale yellow solid (3 g). Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.9Hz, 1H),7.53(t,J＝7.7Hz,1H),7.48–7.45(m,3H),7.26(d,J＝8.4Hz,2H),7.10(d, J＝7.9Hz,1H),4.44–4.38(m,2H),4.00–3.89(m,1H),2.45–2.28(m,1H), 2.11–1.98(m,1H)；13C NMR(151MHz,CDCl3)δ144.7,134.7,134.5,132.8, 131.3,131.0,130.4,129.6,127.6,125.6(q,J＝277.4Hz),125.6,123.8,114.6, 49.9,34.4(q,J＝3.1Hz),33.9(q,J＝29.0Hz)；19F NMR(565MHz,CDCl3)δ -65.5；HRMS(ESI)Calcd for C18H14ClF3NO2S[M+H]+400.0380,found 400.0382。
the reaction formula is as follows:
Figure BDA0003046671850000081
example 8
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1h was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 68% of light yellow solid for 3 h. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.9Hz, 1H),7.62(d,J＝8.3Hz,2H),7.53(t,J＝7.7Hz,1H),7.47(t,J＝7.6Hz,1H), 7.20(d,J＝8.3Hz,2H),7.10(d,J＝8.0Hz,1H),4.44–4.38(m,2H), 3.96–3.92(m,1H),2.43–2.29(m,1H),2.15–2.00(m,1H)；13C NMR(151MHz, CDCl3)δ144.7,134.4,132.8,132.6,131.3,131.2,130.9,127.6,125.6(q,J＝ 277.4Hz),125.6,123.8,122.9,114.6,49.9,34.4(q,J＝3.1Hz),33.9(q,J＝29.0 Hz)；19F NMR(565MHz,CDCl3)δ-65.5；HRMS(ESI)Calcd for C18H14BrF3NO2S[M+H]+443.9875,found 443.9875。
the reaction formula is as follows:
Figure BDA0003046671850000082
example 9
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1i was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 72% as pale yellow solid 3 i. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.9Hz, 1H),7.51(t,J＝7.7Hz,1H),7.45(t,J＝7.6Hz,1H),7.27(d,J＝7.8Hz,2H), 7.19(d,J＝8.0Hz,2H),7.16(d,J＝8.0Hz,1H),4.43–4.36(m,2H),3.95–3.93 (m,1H),2.42(s,3H),2.39–2.28(m,1H),2.14–1.99(m,1H)；13C NMR(151 MHz,CDCl3)δ144.0,138.6,135.1,132.7,131.4,130.0,129.5,128.7,127.3, 125.9,125.8(q,J＝277.2Hz),123.7,115.7,49.8,34.5(q,J＝3.3Hz),33.9(q,J ＝28.9Hz),21.3；19F NMR(565MHz,CDCl3)δ-65.6；HRMS(ESI)Calcd for C19H17ClF3NO2S[M+H]+380.0927,found 380.0925。
the reaction formula is as follows:
Figure BDA0003046671850000091
example 10
Structure for removingThe procedure of example 1 was followed except for substituting the allylalkynylamide compound of formula 1a in example 1 for the allylalkynylamide compound of formula 1j, in high yield: 60% light yellow solid 3 j. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.05(d,J＝7.9Hz, 1H),7.52(t,J＝7.9Hz,1H),7.44(t,J＝7.8Hz,1H),7.22(d,J＝8.7Hz,1H), 7.16(d,J＝8.0Hz,1H),6.99(d,J＝8.7Hz,1H),4.43–4.35(m,2H),3.94–3.87 (m,1H),3.87(s,3H),2.36–2.32(m,1H),2.09–2.04(m,1H)；13C NMR(151 MHz,CDCl3)δ159.7,143.8,135.2,132.7,131.4,130.8,127.3,125.8,125.8(q,J ＝277.4Hz),123.7,123.7,115.4,114.7,55.3,49.8,34.4(q,J＝3.2Hz),33.9(q, J＝28.8Hz)；19F NMR(565MHz,CDCl3)δ-65.5；HRMS(ESI)Calcd for C19H17F3NO3S[M+H]+396.0876,found 396.0864。
the reaction formula is as follows:
Figure BDA0003046671850000101
example 11
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1k was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 60% pale yellow solid 3 k. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.5Hz, 1H),7.53–7.45(m,3H),7.41(d,J＝8.5Hz,1H),7.29(d,J＝6.9Hz,2H),7.10 (d,J＝1.7Hz,1H),4.46–4.37(m,2H),4.01–3.88(m,1H),2.43–2.24(m,1H), 2.00(m,1H)；13C NMR(151MHz,CDCl3)δ145.8,139.5,136.7,131.1,129.6, 129.5,129.0,128.3,127.4,125.6,125.6(q,J＝277.3Hz),125.4,115.0,50.1, 34.5(q,J＝3.1Hz),33.8(q,J＝29.0Hz)；19F NMR(565MHz,CDCl3)δ-65.6； HRMS(ESI)Calcd for C18H13ClF3NO2SNa[M+Na]+422.0200,found 422.0180。
the reaction formula is as follows:
Figure BDA0003046671850000102
example 12
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1l was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 74% of a pale yellow solid, 3 l. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.95(d,J＝8.1Hz, 1H),7.48(t,J＝7.2Hz,2H),7.45(d,J＝7.1Hz,1H),7.32–7.28(m,2H), 7.28–7.22(m,1H),6.92(s,1H),4.41–4.34(m,2H),3.94–3.91(m,1H),2.33(s, 3H),2.31–2.24(m,1H),2.00-1.96(m,1H)；13C NMR(151MHz,CDCl3)δ144.3, 143.6,134.8,132.0,129.6,129.3,128.7,128.6,128.2,126.1,125.7(q,J＝277.3 Hz),123.8,115.6,49.8,34.4(q,J＝3.3Hz),33.9(q,J＝29.0Hz),21.7；19F NMR(565MHz,CDCl3)δ-65.6；HRMS(ESI)Calcd for C18H15F3NO2S[M+ H]+380.0927,found 380.0915。
the reaction formula is as follows:
Figure BDA0003046671850000111
example 13
The procedure of example 1 was followed, except that the allylalkynamide compound of the formula 1m was used instead of the allylalkynamide compound of the formula 1a in example 1, to give a yield: 76% as a pale yellow solid, 3 m. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.8Hz, 1H),7.54–7.40(m,5H),7.34–7.24(m,2H),6.94(d,J＝7.9Hz,1H),4.51(d,J＝ 7.6Hz,1H),4.08(d,J＝7.6Hz,1H),2.63–2.48(m,1H),2.11–1.84(m,1H), 1.52(s,3H)；13C NMR(151MHz,CDCl3)δ149.6,135.8,132.7,132.3,130.8, 130.3,129.1,128.7,127.2,126.1,125.7(q,J＝278.6Hz),123.5,114.5,55.3, 42.6(q,J＝2.1Hz),39.6(q,J＝27.7Hz),23.1；19F NMR(565MHz,CDCl3)δ -61.2；HRMS(ESI)Calcd for C19H17F3NO2S[M+H]+380.0927,found 380.0929。
the reaction formula is as follows:
Figure BDA0003046671850000112
example 14
The procedure of example 1 was followed, except that the allylalkynamide compound of the formula 1n was used instead of the allylalkynamide compound of the formula 1a in example 1, to give a yield: 63% as a pale yellow solid 3 n. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.05(dd,J＝7.8, 1.0Hz,1H),7.54–7.39(m,5H),7.29(m,1H),7.24(m,1H),6.95(d,J＝7.9Hz, 1H),4.47(d,J＝7.8Hz,1H),4.17(d,J＝7.8Hz,1H),2.59–2.54(m,1H), 2.07–2.03(m,1H),1.82–1.64(m,1H),1.56–1.49(m,2H),1.46(dd,J＝11.9,4.8 Hz,1H),1.34(tt,J＝13.9,6.9Hz,2H),0.91(t,J＝7.4Hz,3H)；13C NMR(151 MHz,CDCl3)δ148.0,135.7,132.6,132.5,130.8,130.3,129.1,128.7,127.2, 126.0,125.8(q,J＝278.8Hz),123.5,114.9,52.1,46.8,39.6(q,J＝27.6Hz), 34.9,26.7,22.8,13.8；19F NMR(565MHz,CDCl3)δ-60.6；HRMS(ESI)Calcd for C22H23F3NO2S[M+H]+422.1396,found 422.1401。
the reaction formula is as follows:
Figure BDA0003046671850000121
example 15
The procedure of example 1 was followed, except that the allylalkynamide compound of formula 1o was used instead of the allylalkynamide compound of formula 1a in example 1, to give a yield: 74% white solid 3 o. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.05(d,J＝7.8Hz, 1H),7.50–7.39(m,5H),7.31(m,2H),6.93(d,J＝7.1Hz,1H),4.49(d,J＝7.7 Hz,1H),4.29(d,J＝7.7Hz,1H),3.75(d,J＝10.4Hz,1H),3.61(d,J＝10.4Hz, 1H),2.39–2.25(m,2H),0.86(s,9H),0.05(d,J＝8.9Hz,6H)；13C NMR(151 MHz,CDCl3)δ146.3,135.7,132.5,130.9,130.5,130.2,128.9,128.6,127.2, 126.0,125.7(q,J＝278.2Hz),123.4,115.2,65.4,51.1,48.4,35.9(q,J＝28.7 Hz),25.7,18.2,-5.6(d,J＝12.3Hz)；19F NMR(565MHz,CDCl3)δ-60.9； HRMS(ESI)Calcd for C25H31F3NO3SSi[M+H]+510.1741,found 510.1743。
the reaction formula is as follows:
Figure BDA0003046671850000122
。

Claims (8)

1. a derivative containing trifluoroethyl azetidine is characterized by having a structure shown in formula I:
Figure FDA0003046671840000011
wherein R is1Is one of phenyl, p-acetylphenyl, p-benzoylethoxy, p-cyanophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl and p-methoxyphenyl;
R2is one of hydrogen atom, chlorine and methyl;
R3is one of hydrogen atom, methyl, butyl and tert-butyl dimethyl siloxy.
2. A preparation method of a derivative containing trifluoroethyl azetidine is characterized by comprising the following steps:
adding alkynylamine with a structure shown in a formula II, 1- (trifluoromethyl) -1, 2-phenyliodoacyl-3 (1H) -ketone with a structure shown in a formula III, 10-methyl-9-mesitylacridine perchlorate with a structure shown in a formula IV and cesium carbonate into an acetonitrile solvent to form a reaction system in a reaction environment, and performing post-treatment after the reaction is finished to obtain a derivative containing trifluoroethyl azetidine with a structure shown in a formula I;
Figure FDA0003046671840000012
wherein R is1Is one of phenyl, p-acetylphenyl, p-benzoylethoxy, p-cyanophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl and p-methoxyphenyl; r2Is one of hydrogen atom, chlorine and methyl; r3Is one of hydrogen atom, methyl, butyl and tert-butyl dimethyl siloxy.
3. The method for preparing the derivative containing trifluoroethyl azetidine according to claim 2, wherein the reaction environment is a nitrogen atmosphere and 20W to 40W of blue light irradiation is performed at 5 to 35 ℃.
4. The method for preparing trifluoroethyl azetidine-containing derivatives according to claim 2, wherein said alkynylamine of formula ii, 1- (trifluoromethyl) -1, 2-phenyliodoxy-3 (1H) -one of formula iii, 10-methyl-9-mesitylacridine perchlorate of formula iv, cesium carbonate are present in a molar ratio of 1: 1.5-3: 0.01-0.1: 1.5 to 3.
5. The method for preparing trifluoroethyl azetidine-containing derivatives according to claim 4, wherein said alkynylamine of formula ii, 1- (trifluoromethyl) -1, 2-phenyliodoxy-3 (1H) -one of formula iii, 10-methyl-9-mesitylacridine perchlorate of formula iv, cesium carbonate are present in a molar ratio of 1: 1.8-2.2: 0.03-0.05: 1.8 to 2.2.
6. The method for preparing trifluoroethyl azetidine-containing derivatives according to claim 2, wherein said reaction system has a reaction time of 20 to 40 hours.
7. The process of claim 2 wherein said post-treatment comprises: quenching, suction filtering, extracting, washing organic phase, drying and column chromatography separation.
8. The method for preparing the trifluoroethyl azetidine-containing derivative according to claim 7, wherein the quenching is performed by adding water and ethyl acetate, the suction filtration is performed by diatomite suction filtration, the extraction is performed by ethyl acetate extraction, the washed organic phase is washed by saturated edible water, the drying is performed by anhydrous sodium sulfate, and the column chromatography separation is performed by silica gel column chromatography.
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Citations (2)

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US3492299A (en) * 1968-02-21 1970-01-27 Mcneilab Inc Benzothiazine dioxide carboxylates
CN101203512A (en) * 2005-04-22 2008-06-18 第一三共株式会社 Heterocyclic compound

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Publication number Priority date Publication date Assignee Title
US3492299A (en) * 1968-02-21 1970-01-27 Mcneilab Inc Benzothiazine dioxide carboxylates
CN101203512A (en) * 2005-04-22 2008-06-18 第一三共株式会社 Heterocyclic compound

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Title
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