CN108794344B - Difluoro acetate substituted imine compound and preparation method thereof - Google Patents

Difluoro acetate substituted imine compound and preparation method thereof Download PDF

Info

Publication number
CN108794344B
CN108794344B CN201810802897.8A CN201810802897A CN108794344B CN 108794344 B CN108794344 B CN 108794344B CN 201810802897 A CN201810802897 A CN 201810802897A CN 108794344 B CN108794344 B CN 108794344B
Authority
CN
China
Prior art keywords
cdcl
ppm
nmr
reaction
preparation
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.)
Active
Application number
CN201810802897.8A
Other languages
Chinese (zh)
Other versions
CN108794344A (en
Inventor
李方怿
邱昌福
郭静敏
侯欣鑫
尹光伟
王春华
李正
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin University of Traditional Chinese Medicine
Original Assignee
Tianjin University of Traditional Chinese Medicine
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tianjin University of Traditional Chinese Medicine filed Critical Tianjin University of Traditional Chinese Medicine
Priority to CN201810802897.8A priority Critical patent/CN108794344B/en
Publication of CN108794344A publication Critical patent/CN108794344A/en
Application granted granted Critical
Publication of CN108794344B publication Critical patent/CN108794344B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a difluoroacetate substituted imine compound and a preparation method thereof. The preparation method comprises the following steps: dissolving enamine compound shown as formula A in an organic solvent, adding electrophilic fluorine reagent, and filtering, washing and separating after the reaction is completed to obtain the imine compound shown as formula B containing difluoroacetic ester substitution. The preparation method disclosed by the invention is simple to operate, the raw materials are simple and easy to obtain, the reaction steps are few, the conversion rate and the reaction yield are high, the compatibility of functional groups is good, the application range of the substrate is wide, the use of alkali and noble metal can be avoided, and the preparation method is green and environment-friendly. The obtained compound contains imine and difluoroacetic ester structures, can be used as an important synthetic building block of active molecules, and has a wide application prospect in the field of biological medicines.

Description

Difluoro acetate substituted imine compound and preparation method thereof
Technical Field
The invention relates to a difluoroacetate substituted imine compound and a preparation method thereof.
Background
When fluorine atoms or fluorine-containing groups are introduced into molecules of organic compounds, the physical, chemical and physiological properties of the parent compounds are usually changed significantly. In particular, difluoromethylene (-CF)2-) are often used in the design synthesis of drugs and biologically active molecules as bioisosteres of methylene, oxygen and carbonyl groups due to their good metabolic stability. The method for preparing imine compounds containing a difluoromethylene group at the ortho-position is very limited compared to the method for introducing a difluoromethylene group at the ortho-position of aldehydes, ketones, and hydrazones. Organic Letters 2006,8,4767-4770 reported the preparation of imine compounds containing difluoromethylene substitution, but the reaction was limited to imine substratesAnd both the reaction substrate and the reaction product have the disadvantage of unstable structure due to the instability of imine and the strong electron-withdrawing ability of difluoromethylene. Fluorine chem.2014,167,152-158 reports the preparation of difluorophosphate substituted imine compounds, the reaction substrate is limited to imine-enamine phosphate reaction substrate, the preparation of the reaction substrate is difficult, the yield of the reaction product is not high, the functional group transformation of the reaction product is not easy, and the like.
Therefore, the method for synthesizing the difluoroacetate substituted imine compound by the method has obvious significance for exploring a method which has the advantages of simple and easily obtained raw materials, high conversion rate and reaction yield, good functional group compatibility, wide substrate application range and environmental protection.
Disclosure of Invention
The invention aims to provide a difluoroacetate substituted imine compound and a preparation method thereof.
The present invention provides a method for preparing difluoroacetate substituted imine compounds, comprising the steps of:
Figure BDA0001737521790000011
dissolving the compound shown as the formula A in an organic solvent, adding an electrophilic fluorine reagent, and after the reaction is completed, filtering, washing and separating to obtain the difluoroacetate substituted imine compound shown as the formula B.
Wherein in the compound shown as the formula A and the compound shown as the formula B, R1Is an aromatic group or a heteroaromatic group; r2Is an aromatic group or an aliphatic alkyl group; r3Is a fatty alkyl group.
The electrophilic fluorine reagent is 1-chloromethyl-4-fluoro-1, 4-diazotization bicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), 1-fluoro-4-hydroxy-1, 4-diazotization bicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Accufluor), N-fluoro-bis-benzenesulfonamide (NFSI) and N-fluoropyridine trifluoromethanesulfonate.
The molar ratio of the enamine compound shown in the formula A to the electrophilic fluorine reagent is 1: 2.5-3.
The organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1, 4-dioxane, N, N-dimethylformamide
Said R1Is an aromatic group or a heteroaromatic group, wherein the aromatic group is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 3-bromophenyl, 2-bromophenyl, 3-chloro-4-fluoro-phenyl, 3, 4-methylenedioxyphenyl, 1-naphthyl, and 2-naphthyl; heteroaromatic groups are 2-furyl, 2-thienyl and 2-thiazolyl.
Said R2Is aromatic group or aliphatic alkyl, wherein the aromatic group is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 1-naphthyl, 2-naphthyl; wherein the aliphatic alkyl is allyl, propargyl, isopropyl, cyclopropyl and 4-nitrobenzyl.
Said R3Is aliphatic alkyl, wherein the aliphatic alkyl is methyl, ethyl, isopropyl, tertiary butyl and benzyl.
The invention has the advantages that: the invention discloses a method for synthesizing difluoroacetic ester substituted imine compound, which overcomes the defects of reaction substrate limitation and unstable reaction product in the prior art, and has the advantages of simple preparation method operation, simple and easily obtained raw materials, few reaction steps, high conversion rate and reaction yield, good functional group compatibility, wide substrate application range, no alkali and noble metal, environmental protection and no need of using alkali and noble metal. The obtained compound contains imine and difluoroacetic ester structures, can be used as an important synthetic building block of active molecules, and has a wide application prospect in the field of biological medicines.
Detailed Description
The invention will be further understood by reference to the following examples, which are not intended to limit the scope of the invention.
Example 1
Figure BDA0001737521790000021
In a dry 25mL reaction flask, A-1(179mg,0.6mmol) was dissolved in acetonitrile (6mL), and after cooling the system to 0 deg.C, Selectfluor (532mg,1.5mmol) was added in one portion and the reaction was stirred at 0 deg.C for an additional 1 h. After TLC detection reaction is completed, diethyl ether (5mL) is added into the system, then insoluble substances are removed by filtration, the filter cake is washed three times with diethyl ether (5mL), and the target product (190mg, yield 95%) is obtained by column chromatography after the filtrate is dried by spinning (eluent: petroleum ether/ethyl acetate: 20/1to 10/1).1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.32(m,3H),7.28–7.26(m,2H),6.69(s,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),159.81(t,J＝30Hz),157.86,140.02,131.00,130.04,128.91,128.72,123.64,114.01,113.13(t,J＝253Hz),63.07,55.45,14.19；19F NMR(376MHz,CDCl3)δ(ppm):–105.11
Example 2
Figure BDA0001737521790000022
In a dry 25mL reaction flask, A-1(179mg,0.6mmol) was dissolved in acetonitrile (6mL), and after cooling the system to 0 deg.C, Accufluor (483mg,1.5mmol) was added in one portion and the reaction was stirred at room temperature for an additional 2 h. After TLC detection reaction, ether (5mL) was added to the system, and then insoluble matter was removed by filtration, the filter cake was washed three times with ether (5mL), and the target product (106mg, yield 53%) was obtained as a bright yellow oily liquid after spin-drying the filtrate and column chromatography (eluent: petroleum ether/ethyl acetate: 20/1to 10/1).1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.32(m,3H),7.28–7.26(m,2H),6.69(s,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),159.81(t,J＝30Hz),157.86,140.02,131.00,130.04,128.91,128.72,123.64,114.01,113.13(t,J＝253Hz),63.07,55.45,14.19；19F NMR(376MHz,CDCl3)δ(ppm):–105.11
Example 3
Figure BDA0001737521790000023
In a dry 25mL reaction flask, A-1(179mg,0.6mmol) was dissolved in 1, 4-dioxane (6mL), Selectfluor (532mg,1.5mmol) was added in one portion at room temperature, and the reaction was stirred for an additional 1 h. After TLC detection reaction, ether (5mL) was added to the system, and then insoluble matter was removed by filtration, the filter cake was washed three times with ether (5mL), and the objective product (137mg, yield 69%) was obtained by column chromatography after spin-drying the filtrate (eluent: petroleum ether/ethyl acetate: 20/1to 10/1).1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.32(m,3H),7.28–7.26(m,2H),6.69(s,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.40(t,J＝7Hz,3H)；13CNMR(125MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),159.81(t,J＝30Hz),157.86,140.02,131.00,130.04,128.91,128.72,123.64,114.01,113.13(t,J＝253Hz),63.07,55.45,14.19；19F NMR(376MHz,CDCl3)δ(ppm):–105.11
Example 4
Figure BDA0001737521790000031
In a dry 25mL reaction flask, A-1(179mg,0.6mmol) was dissolved in 1, 4-dioxane (6mL), after the system was cooled to 0 deg.C, NFSI (473mg,1.5mmol) was added in one portion and the reaction was stirred at 0 deg.C for an additional 2 h. After the TLC detection reaction is completed, the reaction liquid is dried by spinning and then is subjected to column chromatography (eluent: petroleum ether/ethyl acetate: 20/1to 10/1) to obtain the target product (182mg, yield 91%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.32(m,3H),7.28–7.26(m,2H),6.69(s,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),159.81(t,J＝30Hz),157.86,140.02,131.00,130.04,128.91,128.72,123.64,114.01,113.13(t,J＝253Hz),63.07,55.45,14.19；19FNMR(376MHz,CDCl3)δ(ppm):–105.11
Example 5
Figure BDA0001737521790000032
In a dry 25mL reaction flask, A-1(179mg,0.6mmol) was dissolved in tetrahydrofuran (6mL), and after the system was cooled to 0 deg.C, NFSI (473mg,1.5mmol) was added in one portion and the reaction was stirred at 0 deg.C for an additional 2 h. After the TLC detection reaction is completed, the reaction liquid is dried by spinning and then is subjected to column chromatography (eluent: petroleum ether/ethyl acetate: 20/1to 10/1) to obtain the target product (170mg, yield 85%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.32(m,3H),7.28–7.26(m,2H),6.69(s,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),159.81(t,J＝30Hz),157.86,140.02,131.00,130.04,128.91,128.72,123.64,114.01,113.13(t,J＝253Hz),63.07,55.45,14.19；19FNMR(376MHz,CDCl3)δ(ppm):–105.11
Example 6
Figure BDA0001737521790000033
In a dry 25mL reaction flask, A-1(179mg,0.6mmol) was dissolved in N, N-dimethylformamide (6mL), and after the system was cooled to 0 deg.C, N-fluoropyridine trifluoromethanesulfonate (445mg,1.8mmol) was added in one portion and the reaction was stirred at room temperature for 2 h. After the TLC detection reaction was completed, ether (15mL) was added to the system, and the mixture was washed three times with saturated brine (20mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and then subjected to column chromatography (eluent: petroleum ether/ethyl acetate: 20/1to 10/1) to obtain the objective product (186mg, yield 93%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.32(m,3H),7.28–7.26(m,2H),6.69(s,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),159.81(t,J＝30Hz),157.86,140.02,131.00,130.04,128.91,128.72,123.64,114.01,113.13(t,J＝253Hz),63.07,55.45,14.19；19F NMR(376MHz,CDCl3)δ(ppm):–105.11
Example 7
Figure BDA0001737521790000041
In a similar manner to experiment 1, A-2(160mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-2(169mg, yield 93%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.36–7.25(m,5H),7.17(t,J＝8Hz,2H),7.02(t,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,2H),4.45(q,J＝7Hz,2H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.14(t,J＝31Hz),161.51(t,J＝30Hz),147.39,130.36,130.15,129.01,128.80,128.50,125.33,120.86,112.82(t,J＝254Hz),63.17,14.16；19F NMR(376MHz,CDCl3)δ(ppm):–105.28
Example 8
Figure BDA0001737521790000042
In a similar manner to experiment 1, A-3(172mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-3(185mg, 96% yield) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.36(m,1H),7.33–7.30(m,2H),7.25–7.24(m,2H),6.88–6.84(m,2H),6.70–6.67(m,2H),4.44(q,J＝7Hz,2H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.09(t,J＝31Hz),161.88(t,J＝31Hz),160.57(d,J＝244Hz),143.26(d,J＝3Hz),130.32,128.92,128.70,122.95(d,J＝8Hz),115.70(d,J＝23Hz),112.76(t,J＝254Hz),63.21,14.17；19F NMR(376MHz,CDCl3)δ(ppm):–105.31,–117.18
Example 9
Figure BDA0001737521790000043
In a similar manner to experiment 1, A-4(181mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-4(193mg, 95% yield) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.39–7.36(m,1H),7.33–7.30(m,2H),7.25–7.23(m,2H)，7.14(d,J＝9Hz,2H),6.65(d,J＝9Hz,2H),4.44(q,J＝7Hz,2H),1.39(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.00(t,J＝31Hz),162.30(t,J＝30Hz),145.83,130.99,130.44,130.05,129.02,128.93,128.71,122.41,112.63(t,J＝254Hz),63.27,14.17；19F NMR(376MHz,CDCl3)δ(ppm):–105.31
Example 10
Figure BDA0001737521790000044
In a similar manner to experiment 1, A-5(201mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-5(209mg, yield 94%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.47(d,J＝8Hz,2H),7.40–7.38(m,1H),7.34–7.32(m,2H),7.28–7.26(m,2H),6.82(d,J＝8Hz,2H),4.47(q,J＝7Hz,2H),1.41(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.12(t,J＝30Hz),162.82(t,J＝31Hz),150.55,130.64,129.66,128.90,128.69,127.21(q,J＝33Hz),126.16(q,J＝4Hz),124.14(q,J＝270Hz),120.61,112.40(t,J＝254Hz),63.36,14.11；19F NMR(376MHz,CDCl3)δ(ppm):–62.25,–105.37
Example 11
Figure BDA0001737521790000051
Similar procedure as in experiment 1, A-6(179mg,0.6mmol), Selectfluor (532mg,1.5mmol), acetonitrile as solventThe reaction was carried out at 0 ℃ for 1 hour to obtain the objective product B-6(191mg, yield 96%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.37–7.27(m,5H),7.05(t,J＝9Hz,1H),6.58–6.56(m,1H),6.28–6.27(m,2H),4.44(q,J＝7Hz,2H),3.79(s,3H),3.65(s,3H),1.39(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.11(t,J＝31Hz),161.62(t,J＝30Hz),160.02,148.62,130.39,130.20,129.64,128.92,128.51,113.18,112.78(t,J＝254Hz),111.20,106.51,63.20,55.32,14.16；19F NMR(376MHz,CDCl3)δ(ppm):–105.30
Example 12
Figure BDA0001737521790000052
In a similar manner to experiment 1, A-7(179mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-7(190mg, yield 95%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.35–7.26(m,5H),7.01(td,J＝8Hz,2Hz,1H),6.79(td,J＝8Hz,1Hz,1H),6.76(d,J＝8Hz,1H),6.65(dd,J＝8Hz,2Hz,1H),4.46(q,J＝7Hz,2H),3.63(s,3H),1.42(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.14(t,J＝31Hz),162.80(t,J＝30Hz),148.87,137.27,131.22,130.03,128.20,128.14,126.02,120.93,120.64,112.68(t,J＝254Hz),111.79,63.11,55.44,14.09；19F NMR(376MHz,CDCl3)δ(ppm):–104.89
Example 13
Figure BDA0001737521790000053
In a similar manner to experiment 1, A-8(261mg,0.8mmol), Selectfluor (710mg,2mmol), acetonitrile as solvent, was reacted at 70 ℃ for 1h to give the desired product B-8(197mg, yield 68%) as a white solid.1H NMR(500MHz,CDCl3)δ(ppm):1H NMR(500MHz,CDCl3)δ(ppm):8.17(d,J＝9Hz,2H),7.53–7.47(m,3H),7.39(d,J＝9Hz,2H),7.31–7.29(m,2H),4.65(s,2H),4.41(q,J＝7Hz,2H),1.35(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):164.91(t,J＝30Hz),163.17(t,J＝31Hz),147.18,146.03,130.54,129.95,129.06,128.03,127.79,123.77,112.58(t,J＝253Hz),63.18,55.69,14.13；19F NMR(376MHz,CDCl3)δ(ppm):–105.92
Example 14
Figure BDA0001737521790000061
In a similar manner to experiment 1, A-9(139mg,0.6mmol), Selectfluor (531mg,1.5mmol), acetonitrile as solvent, was reacted at room temperature for 2h to give the desired product B-9(144mg, yield 90%) as a pale yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.48–7.44(m,3H),7.41–7.39(m,2H),4.35(q,J＝7Hz,2H),2.92–2.88(m,1H),1.33(t,J＝7Hz,3H),0.97–0.86(m,4H)；13C NMR(125MHz,CDCl3)δ(ppm):163.40(t,J＝31Hz),159.65(t,J＝30Hz),130.85,129.81,128.70,128.50,113.15(t,J＝251Hz),62.68,35.07,14.02,10.65；19F NMR(376MHz,CDCl3)δ(ppm):–105.63
Example 15
Figure BDA0001737521790000062
In a similar manner to experiment 1, A-10(187mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-10(193mg, yield 93%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.17(d,J＝8Hz,2H),7.13(d,J＝8Hz,2H),6.70(s,4H),4.43(q,J＝7Hz,2H),3.73(s,3H),2.33(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.45(t,J＝31Hz),159.94(t,J＝30Hz),157.72,140.28,140.26,129.41,128.87,127.88,123.48,114.01,113.23(t,J＝253Hz),63.01,55.44,21.57,14.18；19F NMR(376MHz,CDCl3)δ(ppm):–105.05
Example 16
Figure BDA0001737521790000063
In a similar manner to experiment 1, A-11(197mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-11(204mg, yield 94%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.23(d,J＝9Hz,2H),6.82(d,J＝9Hz,2H),6.71(s,4H),4.43(q,J＝7Hz,2H),3.79(s,3H),3.73(s,3H),1.39(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.45(t,J＝31Hz),160.82,159.45(t,J＝30Hz),157.60,140.42,130.69,123.28,122.73,114.11,114.07,113.35(t,J＝253Hz),62.97,55.41,55.32,14.14；19F NMR(376MHz,CDCl3)δ(ppm):–104.80
Example 17
Figure BDA0001737521790000064
In a similar manner to experiment 1, A-12(226mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-12(235mg, yield 95%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.47(d,J＝8.5Hz,2H),7.22(d,J＝8.5Hz,2H),6.73–6.67(m,4H),4.44(q,J＝7Hz,2H),3.74(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.09(t,J＝31Hz),158.63(t,J＝30Hz),158.05,139.67,132.09,130.57,129.72,124.72,123.50,114.18,112.95(t,J＝253Hz),63.18,55.47,14.17；19F NMR(376MHz,CDCl3)δ(ppm):–104.95
Example 18
Figure BDA0001737521790000071
Similar to experiment 1, A-13(254mg,0.6mmol), Selectfluor (532mg,1.5mmol), acetonitrile as solvent, 0 deg.CThe reaction was carried out for 1h to obtain the target product B-13(265mg, yield 96%) as a bright yellow oily liquid.1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J＝8Hz,2H),7.01(d,J＝8Hz,2H),6.73–6.67(m,4H),4.44(q,J＝7Hz,2H),3.73(s,3H),1.39(t,J＝7Hz,3H)；13C NMR(100MHz,CDCl3)δ(ppm):163.04(t,J＝31Hz),158.67(t,J＝30Hz),158.01,139.61,137.96,130.49,130.25,123.48,114.14,112.89(t,J＝253Hz),96.77,63.14,55.42,14.14；19F NMR(376MHz,CDCl3)δ(ppm):–104.93；
Example 19
Figure BDA0001737521790000072
In a similar manner to experiment 1, A-14(219mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-14(238mg, yield 99%) as a bright yellow oily liquid.1H NMR(400MHz,CDCl3)δ(ppm):7.61(d,J＝8Hz,2H),7.41(d,J＝8Hz,2H),6.89(q,J＝9Hz,4H),4.46(q,J＝7Hz,2H),3.74(s,3H),1.41(t,J＝7Hz,3H)；13C NMR(100MHz,CDCl3)δ(ppm):162.83(t,J＝31Hz),158.12,158.11(t,J＝31Hz),139.22,134.51,131.85(q,J＝33Hz),129.35,125.65(q,J＝4Hz),123.59(q,J＝271Hz),123.50,114.09,112.77(t,J＝253Hz),63.16,55.35,14.05；19F NMR(376MHz,CDCl3)δ(ppm):–63.07,–104.94
Example 20
Figure BDA0001737521790000073
In a similar manner to experiment 1, A-15(226mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-15(225mg, yield 91%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.51(dt,J＝8Hz,2Hz,1H),7.47(s,1H),7.21–7.16(m,2H),6.70(d,J＝3Hz,4H),4.44(q,J＝7Hz,2H),3.72(s,3H),1.40(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):162.96(t,J＝31Hz),158.17,157.83(t,J＝30Hz),139.35,133.17,132.90,131.54,130.29,127.58,123.68,122.80,114.12,112.84(t,J＝253Hz),63.15,55.42,14.12；19F NMR(376MHz,CDCl3)δ(ppm):–104.98
Example 21
Figure BDA0001737521790000081
In a similar manner to experiment 1, A-16(226mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-16(220mg, 89% yield) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.56(d,J＝8Hz,1H),7.41–7.36(m,2H),7.31–7.27(m,1H),6.81(d,J＝9Hz,2H),6.71(d,J＝9Hz,2H),4.54–4.43(m,2H),3.74(s,2H),1.44(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.09(t,J＝31Hz),158.49,157.49(dd,J＝33Hz,29Hz),139.40,133.33,133.28,131.27,130.72,127.47,124.07,121.61,113.86,112.44(dd,J＝255Hz,251Hz),63.15,55.40,14.21；19F NMR(376MHz,CDCl3)δ(ppm):–104.37(d,J＝277Hz),–106.78(d,J＝277Hz)
Example 22
Figure BDA0001737521790000082
In a similar manner to experiment 1, A-17(210mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-17(227mg, yield 98%) as a bright yellow oily liquid.1H NMR(400MHz,CDCl3)δ(ppm):7.40–7.38(m,1H),7.15–7.07(m,2H),6.74–6.67(m,4H),4.44(q,J＝7Hz,2H),3.75(s,3H),1.40(t,J＝7Hz,3H)；13CNMR(100MHz,CDCl3)δ(ppm):162.91(t,J＝31Hz),158.96(d,J＝252Hz),158.23,157.17(t,J＝30Hz),139.31,131.37,129.34(d,J＝8Hz),127.86(d,J＝4Hz),123.52,121.98(d,J＝18Hz),117.22(d,J＝21Hz),114.26,112.87(t,J＝253Hz),63.25,55.48,14.16；19F NMR(376MHz,CDCl3)δ(ppm):–104.90,–111.49
Example 23
Figure BDA0001737521790000083
In a similar manner to experiment 1, A-18(205mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-18(183mg, yield 81%) as a bright yellow oily liquid.1H NMR(400MHz,CDCl3)δ(ppm):6.80–6.72(m,7H),5.96(s,2H),4.43(q,J＝7Hz,2H),3.74(s,3H),1.39(t,J＝7Hz,3H)；13C NMR(100MHz,CDCl3)δ(ppm):163.36(t,J＝31Hz),158.99(t,J＝30Hz),157.80,149.08,147.90,140.09,124.10,123.69,123.41,114.11,113.19(t,J＝253Hz),109.21,108.73,101.59,63.04,55.45,14.17；19F NMR(376MHz,CDCl3)δ(ppm):–104.83
Example 24
Figure BDA0001737521790000084
In a similar manner to experiment 1, A-19(182mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-19(159mg, yield 78%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.57–7.56(m,1H),7.42(dd,J＝8Hz,1Hz,1H),7.01(dd,J＝5Hz,4Hz,1H),6.88(d,J＝9Hz,2H),6.73(d,J＝9Hz,2H),4.41(q,J＝7Hz,2H),3.81(s,3H),1.36(t,J＝7Hz,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.01(t,J＝31Hz),157.76,153.44(t,J＝30Hz),141.47,133.12(t,J＝4Hz),131.71,129.47(t,J＝3Hz),126.77,120.71,114.89,113.74(t,J＝256Hz),63.12,55.58,14.13；19F NMR(376MHz,CDCl3)δ(ppm):–103.98
Example 25
Figure BDA0001737521790000091
In a similar manner to experiment 1, A-20(216mg,0.6mmol), Selectfluor (532mg,1.5mmol) and acetonitrile as solvent were reacted at 0 ℃ for 1h to give the desired product B-20(204mg, yield 86%) as a bright yellow oily liquid.1H NMR(500MHz,CDCl3)δ(ppm):7.49–7.48(m,2H),7.43–7.38(m,4H),7.35(t,J＝8Hz,2H),7.29(d,J＝8Hz,2H),6.71(d,J＝9Hz,2H),6.64(d,J＝9Hz,2H),5.45(s,2H),3.75(s,3H)；13C NMR(125MHz,CDCl3)δ(ppm):163.27(t,J＝32Hz),159.58(t,J＝30Hz),157.86,139.80,134.76,130.84,130.04,128.84,128.74,128.73,128.70,128.67,123.68,113.92,113.28(t,J＝254Hz),68.38,55.38；19F NMR(376MHz,CDCl3)δ(ppm):–104.67
The above-described embodiments are preferred examples of the present invention, and it should be noted that modifications can be made by those skilled in the art without departing from the principle of the present invention, and these modifications should be construed as the protection scope of the present invention.

Claims (3)

1. A method for preparing difluoroacetate substituted imine compounds, comprising the steps of: dissolving the compound shown as the formula A in an organic solvent, adding an electrophilic fluorine reagent, and after the reaction is completed, separating and purifying to obtain the compound shown as the formula B;
Figure FDA0002892473170000011
the electrophilic fluorine reagent is any one of 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo [2.2.2] octane bis (tetrafluoroborate) salt, 1-fluoro-4-hydroxy-1, 4-diazotized bicyclo [2.2.2] octane bis (tetrafluoroborate) salt, N-fluoro-bis-benzenesulfonamide and N-fluoropyridine trifluoromethanesulfonate;
in the compound shown as the formula A and the compound shown as the formula B, R is1Is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-tri-phenylAny one of fluoromethylphenyl, 4-nitrophenyl, 3-bromophenyl, 2-bromophenyl, 3-chloro-4-fluoro-phenyl, 3, 4-methylenedioxyphenyl, 1-naphthyl and 2-naphthyl, 2-furyl, 2-thienyl, 2-thiazolyl;
said R2Is any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorphenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 1-naphthyl, 2-naphthyl, allyl, propargyl, isopropyl, cyclopropyl and 4-nitrobenzyl;
said R3Is any one of methyl, ethyl, isopropyl, tertiary butyl and benzyl.
2. The method of claim 1, wherein: the molar ratio of the compound shown as the formula A to the electrophilic fluorinating reagent is 1: 2.5-3.
3. The method of claim 1, wherein: the organic solvent is any one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1, 4-dioxane and N, N-dimethylformamide.
CN201810802897.8A 2018-07-20 2018-07-20 Difluoro acetate substituted imine compound and preparation method thereof Active CN108794344B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810802897.8A CN108794344B (en) 2018-07-20 2018-07-20 Difluoro acetate substituted imine compound and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810802897.8A CN108794344B (en) 2018-07-20 2018-07-20 Difluoro acetate substituted imine compound and preparation method thereof

Publications (2)

Publication Number Publication Date
CN108794344A CN108794344A (en) 2018-11-13
CN108794344B true CN108794344B (en) 2021-04-30

Family

ID=64077249

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810802897.8A Active CN108794344B (en) 2018-07-20 2018-07-20 Difluoro acetate substituted imine compound and preparation method thereof

Country Status (1)

Country Link
CN (1) CN108794344B (en)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
The synthesis of a,a-difluoroacetamides via electrophilic fluorination in the mixed-solvent of water and PEG-400;Zhiguo Zhang等;《Journal of Fluorine Chemistry》;20130330;第151卷;第45-49页 *

Also Published As

Publication number Publication date
CN108794344A (en) 2018-11-13

Similar Documents

Publication Publication Date Title
CN101993407B (en) Indoline compound for preparing silodosin and preparation method thereof
JP7097467B2 (en) Bribalacetam intermediate, its manufacturing method and bribalacetam manufacturing method
CN107674044B (en) Method for synthesizing carbamate by using carbon dioxide, amine and aryl diazo acetate
CN107141207B (en) Synthetic method of 3 '-acyl-2, 4' -dihydroxy benzophenone compound
JP2022552713A (en) 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6- was obtained by racemate separation with diastereomeric tartaric esters. Method for preparing naphthyridine-3-carboxylate
CN111087344A (en) Amino acid compound containing biaziridine group and synthesis method thereof
CN104086419B (en) Replace 3-xenol-2,4-dicarboxylic acid diethyl's ester compound and synthetic method thereof
CN101914052B (en) Oxiracetam compound and new method thereof
CN101209990B (en) Resolution method for 3-piperidine formic acid ester
CN105949118B (en) A kind of preparation method of 2- aryl quinoline derivatives
CN108794344B (en) Difluoro acetate substituted imine compound and preparation method thereof
KR101744046B1 (en) Process for preparing an intermediate useful for the synthesis of silodosin
CN106928149A (en) A kind of preparation method of olaparib
CN103298783A (en) 2-(alkoxy or aryloxy carbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-2-enoic acid compounds, its preparation and use
JP6676146B2 (en) Novel production method of chromanol derivative
CN106146271B (en) A method of diaryl ketone is prepared by aromatic yl sulphonate
CN111233750B (en) 3, 3-difluoro-1, 2,3, 6-tetrahydropiperidine derivative and preparation method thereof
CN100408554C (en) New technique for synthesizing hydrazinomethyl ester carbonate in high purity
CN112321514A (en) Chiral barbituric acid compound and preparation method thereof
CN105348062A (en) Preparation method of 3-aryl-1-indanone derivate
JP6038800B2 (en) Method for producing optically active alcohol
CN104592129B (en) A kind of improved method for preparing ambrisentan
CN101314574B (en) Process for synthesizing acylations enamine
CN108947909B (en) Chiral N-heterocyclic carbene precursor compound with imidazolone framework and synthesis method thereof
JPH02268191A (en) Production of d-mannosamine derivative

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant