CN110627718B - Synthesis method of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide - Google Patents
Synthesis method of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide Download PDFInfo
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Abstract
The invention relates to a method for synthesizing (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide, which comprises the steps of catalyzing terminal alkyne, 2-chloroacetamidoquinoline and 2-fluoro-malonic acid dialkyl ester by copper to react to synthesize a novel (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound in one step; the structural formula of the (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide is as follows:
the method has the advantages of simple reaction steps, cheap and easily-obtained raw materials, wide substrate range and suitability for industrial production, and the prepared (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound can be applied to the fields of medicines, pesticides and materials.
Description
Technical Field
The invention belongs to the technical field of chemical organic synthesis, and particularly relates to a synthesis method of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide.
Background
The fluorine-containing organic molecules are widely applied to medicines, agricultural chemicals and materials, and the introduction of fluorine atoms or fluorine functional groups can obviously improve the lipophilic property and metabolic stability of the fluorine-containing organic molecules and improve the drug effect of biological medicines. According to statistics, 20% of the commercially available medical medicines contain at least one fluorine atom, and the proportion of the fluorine-containing compound in the agricultural chemicals is up to 30-40%. However, since the natural products have a limited amount of fluorine-containing organic compounds and a simple structure, it is important to develop a practical method for efficiently introducing fluorine atoms or functional groups to synthesize novel fluorine-containing organic compounds for the development of medicines, agrochemicals and materials.
The introduction of fluorine atoms or fluorine-containing functional groups by transition metal catalyzed fluorination, trifluoromethylation and desflurane reactions has attracted considerable research interest and is an important method for the synthesis of fluorine-containing compounds. In comparison, transition metal catalyzed monofluoroalkylation reactions were less studied. In addition, it is statistically determined that C-F-centered drugs account for less than 1% of the fluorine drugs currently on the market or in clinical development, mainly due to the few studies of methods for introducing monofluoroalkyl groups and the large challenges in constructing C-F centers. The inventor researches a method for generating beta, gamma-unsaturated amide by a 1,1-site bifunctional reaction of terminal alkyne (Yunhe Lv, weiya Pu, lihan Shi, org.Lett.2019,21, 6034), wherein a fluorine-containing compound is not obtained finally by the research method, and fluorine atoms are introduced into organic molecules to well improve the pharmacological and toxicological properties of the medicine.
Disclosure of Invention
The invention aims to provide a method for synthesizing (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide, which is characterized in that a copper-catalyzed terminal alkyne, 2-chloroacetamidoquinoline and 2-fluoro-malonic acid dialkyl ester are reacted to synthesize the (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound in one step, and the synthetic route is as follows:
the synthesis method comprises the following specific steps:
adding the compound 1 into a sealed tube, adding a solvent, adding the compound 2 and the compound 3, uniformly mixing, sequentially adding a copper catalyst and alkali, and filling N into the sealed tube by using a glass guide tube connected with nitrogen 2 Fully driving out in 2-3 minutesAir, sealing the tube opening by a cock, and magnetically stirring the mixture to react for 1.5 hours at the temperature of between 80 and 100 ℃. After the reaction is finished, cooling the system to room temperature, adding distilled water into the reaction system, extracting, combining organic phases, distilling under reduced pressure to remove the solvent of the organic phase, and performing silica gel column chromatography to obtain the product.
Preferably, the compound 1 is phenylacetylene, 4-ethynylbiphenyl, 2-ethynylpyridine, 3-ethynylpyridine, 4-ethynylpyridine, 2-ethynylthiophene, 3-ethynylthiophene, methylpropargyl ether, propargylphenyl ether, 2-methyl-1-buten-3-yne, 1-hexyne.
Preferably, the compound 2 is 2-chloroacetamidoquinoline.
Preferably, the compound 3 is dimethyl 2-fluoro malonate or diethyl 2-fluoro malonate.
Preferably, the reactants are used in amounts of: the molar ratio of compound 1 to compound 2 to compound 3 is 1.1 to 1.2.
Preferably, the copper catalyst is CuI; the amount of copper catalyst used was 10mol%.
Preferably, the base is Cs 2 CO 3 (ii) a The amount of the base used was 1.2equiv.
Preferably, the solvent is tetrahydrofuran.
The invention takes CuI as catalyst and Cs 2 CO 3 Is alkali, tetrahydrofuran (THF) is used as solvent, and the terminal alkyne and CuI react in Cs 2 CO 3 The method comprises the steps of generating a copper alkyne compound under the action, combining the copper alkyne compound and 2-chloroacetamidoquinoline, wherein an 8-aminoquinoline group in the 2-chloroacetamidoquinoline is an auxiliary group, alpha-haloacetamide is an electron-withdrawing group, generating a dienamide compound under the action of alkali, carrying out Sonogashira coupling reaction, then carrying out transmetallation reaction, carbon coppering and proton decomposition on the dienamide compound and 2-fluoro-malonic acid dialkyl ester to obtain a final product, namely carrying out hydrogenation monofluoroalkylation reaction on the dienamide compound and the 2-fluoro-malonic acid dialkyl ester, and finally obtaining the novel (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound due to space interaction and region selection.
Compared with the prior art, the invention has the following advantages:
(1) The invention fills the blank of the method for synthesizing the (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound by alkyne through the gem-bifunctional reaction, and provides the method for synthesizing the (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound with direct, high-efficiency and high economical efficiency.
(2) The (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound is directly and effectively synthesized from alkyne, 2-chloroacetamide quinoline and 2-fluoro-malonic acid dialkyl ester, and the method has the advantages of simple reaction steps, cheap and easily-obtained raw materials, wide substrate range and suitability for industrial production.
(3) The novel (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide compound prepared by the invention provides a new direction for the research and development of novel fluorine-containing medicaments.
(4) The synthetic method of the fluorine-containing compound can also be used for reasonably modifying a natural product containing alkyne so as to increase the biological activity and the drug-like property of the natural product.
Drawings
FIG. 1 is a schematic representation of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide 4b 1 H NMR spectrum;
FIG. 2 is a schematic representation of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide 4b 13 C NMR spectrum;
FIG. 3 is a schematic representation of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide 4b 19 F NMR spectrum;
FIG. 4 is a schematic representation of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide 4c 1 H NMR spectrum;
FIG. 5 is a schematic representation of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide 4c 13 C NMR spectrogram;
FIG. 6 is a schematic representation of (E) - β -monofluoroalkyl- β, γ -unsaturated amide 4c 19 F NMR spectrum;
FIG. 7 is a schematic representation of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide 4E 1 H NMR spectrum;
FIG. 8 is a schematic representation of (E) - β -monofluoroalkyl- β, γ -unsaturated amide 4E 13 C NMR spectrum;
FIG. 9 is a schematic representation of (E) - β -monofluoroalkyl- β, γ -unsaturated amide 4E 19 F NMR spectrum.
Detailed Description
The following detailed description of the present invention is provided in connection with the accompanying drawings and specific embodiments for the purpose of better understanding and enabling those skilled in the art to practice the present invention, which are not intended to limit the present invention.
Example 1
First, a 35mL sealed tube was charged with a stirrer, phenylacetylene (38. Mu.L, 0.33 mmol), tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg,0.3 mmol), dimethyl 2-fluoromalonate (70.4 mg, 0.45mmol), cuI (5.7 mg, 0.03mmol) and Cs to the well-mixed solution 2 CO 3 (117.3mg, 0.36mmol), N-filled with a glass tube connected to nitrogen 2 And 3 minutes, fully removing air, sealing a pipe orifice by using a cock, stirring and reacting at 80 ℃ for 1.5 hours, cooling the system to room temperature after the reaction is finished, adding 2ml of distilled water into the reaction system, extracting by using ethyl acetate, combining organic phases, removing the solvent of the organic phase by reduced pressure distillation, and separating by silica gel column chromatography to obtain 123.1mg of a product 4a with the yield of 94 percent. 1 H NMR(400MHz,CDCl 3 ):δ＝3.77(d,J＝1.6Hz,2H),3.84(s,6H),7.24-7.33(m,4H),7.42-7.45(m,3H),7.48-7.52(m,2H),8.14(dd,J 1 ＝1.6Hz,J 2 ＝8.0Hz,1H),8.74(dd,J 1 ＝2.4Hz,J 2 ＝6.4Hz,1H),8.78(dd,J 1 ＝1.2Hz,J 2 ＝4.0Hz,1H),9.98(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝37.3(d,J＝4.0Hz),53.7,95.1(d,J＝201.0Hz),116.3,121.6(d,J＝6.0Hz),127.3,127.6,127.8,127.9,128.1,128.5,128.7,134.4,134.6(d,J＝12.0Hz),135.1,136.2,138.4,148.2,165.7(d,J＝25.0Hz),167.9； 19 F NMR(376MHz,CDCl 3 ):δ＝-158.9.HRMS(ESI-TOF).Calcd for C 24 H 21 FN 2 O 5 Na,[M+Na] + m/z 459.1332,Found 459.1327.
Example 2
First, a 35mL sealed tube was charged with a stirrer, and thus 4-ethynylbiphenyl (60.6 mg, 0.33mmol), 0.9mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg, 0.3mmol), and dimethyl 2-fluoromalonate (70.4 mg, 0.45mmol) were added, and thus CuI (5.7 mg, 0.03mmol) and Cs were added to the uniformly mixed solution 2 CO 3 (117.3mg, 0.36mmol), N-filled with a glass tube connected to nitrogen 2 And 3 minutes, fully removing air, sealing a pipe orifice by using a cock, stirring and reacting for 1.5 hours at the condition of 800 ℃, cooling the system to room temperature after the reaction is finished, adding 2ml of distilled water into the reaction system, extracting by using ethyl acetate, combining organic phases, removing the solvent of the organic phase by reduced pressure distillation, and separating by silica gel column chromatography to obtain 139.9mg of a product 4b with the yield of 91%. 1 H NMR(400MHz,CDCl 3 ):δ＝3.82(s,2H),3.85(s,6H),7.29-7.32(m,2H),7.38-7.44(m,3H),7.48-7.56(m,8H),8.13(dd,J 1 ＝1.2Hz,J 2 ＝8.4Hz,1H),8.75-8.77(m,2H),10.01(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝37.4(d,J＝4.0Hz),53.7,95.1(d,J＝201.0Hz),116.3,121.6,126.9,127.1,127.3,127.4,127.6,127.8,127.8,128.7,129.2,134.1,134.2,134.3,136.2,138.4,140.3,140.8,148.2,165.7(d,J＝26.0Hz),167.9； 19 F NMR(376MHz,CDCl 3 ):δ＝-159.1.HRMS(ESI-TOF).Calcd for C 30 H 25 FN 2 O 5 Na,[M+Na] + m/z 535.1645,Found 535.1660.
Example 3
First, a 35mL sealed tube was charged with a stirrer, and 2-ethynylpyridine (34. Mu.L, 0.33 mmol), 0.9mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg,0.3 mmol), and dimethyl-2-fluoromalonate (70.4 mg, 0.45mmol) were added, and CuI (5.7) was added to the well-mixed solutionmg,0.03 mmol) and Cs 2 CO 3 (117.3mg, 0.36mmol), N-filled with a glass tube connected to nitrogen 2 And 3 minutes, fully removing air, sealing a pipe orifice by using a cock, stirring and reacting for 1.5 hours under the condition of 800 ℃, cooling the system to room temperature after the reaction is finished, adding 2ml of distilled water into the reaction system, extracting by using ethyl acetate, combining organic phases, removing the solvent of the organic phase by reduced pressure distillation, and separating by silica gel column chromatography to obtain 103.6mg of a product 4C with the yield of 79%. 1 H NMR(400MHz,CDCl 3 ):δ＝3.87(s,6H),4.26(s,2H),6.99(s,1H),7.23-7.26(m,1H),7.33(d,J＝8.0Hz,1H),7.38(dd,J 1 ＝4.0Hz,J 2 ＝8.4Hz,1H),7.43-7.51(m,2H),7.71(dt,J 1 ＝1.6Hz,J 2 ＝7.6Hz,1H),8.10(dd,J 1 ＝1.6Hz,J 2 ＝8.4Hz,1H),8.66(dd,J 1 ＝1.6Hz,J 2 ＝4.4Hz,1H),8.76(dd,J 1 ＝1.2Hz,J 2 ＝7.2Hz,1H),8.88(d,J＝4.0Hz,1H),11.39(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝37.6(d,J＝3.0Hz),53.7,95.4(d,J＝200.0Hz),116.9,121.2(d,J＝5.0Hz),122.6,126.0,127.3,128.0,130.1(d,J＝11.0Hz),132.4,132.6,135.6,136.0,136.7,138.9,147.7,149.5,153.8,165.5(d,J＝26.0Hz),168.6； 19 F NMR(376MHz,CDCl 3 ):δ＝-157.3.HRMS(ESI-TOF).Calcd for C 23 H 20 FN 3 O 5 Na,[M+Na] + m/z 460.1285,Found 460.1284.
Example 4
First, a 35mL sealed tube was charged with a stirrer, whereupon methylpropargyl ether (28. Mu.L, 0.33 mmol), 0.9mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg,0.3 mmol), and dimethyl 2-fluoromalonate (70.4 mg, 0.45mmol) were added, whereupon CuI (5.7 mg, 0.03mmol) and Cs were added to the well-mixed solution 2 CO 3 (117.3mg, 0.36mmol), N-filled with a nitrogen-connected glass tube 2 3 minutes, fully driving out air, sealing the pipe orifice by a cock, stirring and reacting for 1.5 hours under the condition of 800 ℃, and reactingAfter completion, the reaction system was cooled to room temperature, 2ml of distilled water was added to the reaction system, extraction was performed with ethyl acetate, the organic phases were combined, the solvent of the organic phase was removed by distillation under the reduced pressure, and 86.1mg of the product 4d was isolated by silica gel column chromatography, with a yield of 71%. 1 H NMR(400MHz,CDCl 3 ):δ＝3.36(s,3H),3.62(s,2H),3.81(s,6H),4.25(dd,J 1 ＝2.0Hz,J 2 ＝6.0Hz,2H),6.34(t,J＝2.0Hz,1H),7.45(dd,J 1 ＝4.0Hz,J 2 ＝8.4Hz,1H),7.50-7.52(m,2H),8.15(dd,J 1 ＝1.2Hz,J 2 ＝8.4Hz,1H),8.72(dd,J 1 ＝3.6Hz,J 2 ＝5.2Hz,1H),8.81(dd,J 1 ＝1.2Hz,J 2 ＝4.0Hz,1H),10.02(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝36.9(d,J＝3.0Hz),53.6,58.5,69.0,94.8(d,J＝200.0Hz),116.4,121.6,121.7,127.2,127.9,128.0,132.9(d,J＝11.0Hz),134.3,136.2,138.4,148.2,165.4(d,J＝26.0Hz),167.0； 19 F NMR(376MHz,CDCl 3 ):δ＝-158.6.HRMS(ESI-TOF).Calcd for C 20 H 21 FN 2 O 6 Na,[M+Na] + m/z 427.1281,Found 427.1272.
Example 5
First, a 35mL sealed tube was charged with a stirrer, and then 2-methyl-1-buten-3-yne (32. Mu.L, 0.33 mmol), 0.9mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg,0.3 mmol), and dimethyl 2-fluoromalonate (70.4 mg, 0.45mmol) were added, and then CuI (5.7mg, 0.03mmol) and Cs were added to the uniformly mixed solution 2 CO 3 (117.3mg, 0.36mmol), N-filled with a glass tube connected to nitrogen 2 And 3 minutes, fully removing air, sealing a pipe orifice by using a cock, stirring and reacting for 1.5 hours at the condition of 800 ℃, cooling the system to room temperature after the reaction is finished, adding 2ml of distilled water into the reaction system, extracting by using ethyl acetate, combining organic phases, removing the solvent of the organic phase by reduced pressure distillation, and separating by silica gel column chromatography to obtain 84.1mg of product 4e with the yield of 70%. 1 H NMR(400MHz,CDCl 3 ):δ＝1.89(s,3H),3.77(d,J＝1.2Hz,2H),3.80(s,6H),5.11(s,1H),5.17(s,1H),6.63(s,1H),7.44(dd,J 1 ＝4.4Hz,J 2 ＝8.4Hz,1H),7.48-7.53(m,2H),8.14(dd,J 1 ＝1.6Hz,J 2 ＝8.4Hz,1H),8.73(dd,J 1 ＝2.4Hz,J 2 ＝6.4Hz,1H),8.79(dd,J 1 ＝1.6Hz,J 2 ＝4.0Hz,1H),9.97(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝22.8,37.2(d,J＝4.0Hz),53.6,95.1(d,J＝201.0Hz),116.3,117.7,121.5,121.6,126.0,126.2,127.3,127.9,134.4,136.2(d,J＝12.0Hz),138.4,139.8,148.2,165.7(d,J＝26.0Hz),167.9； 19 F NMR(376MHz,CDCl 3 ):δ＝-159.1.HRMS(ESI-TOF).Calcd for C 21 H 21 FN 2 O 5 Na,[M+Na] + m/z 423.1332,Found 423.1344.
Example 6
First, a 35mL sealed tube was charged with a stirrer, phenylacetylene (38. Mu.L, 0.33 mmol), tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg,0.3 mmol), diethyl 2-fluoromalonate (82.7mg, 0.45mmol), and CuI (5.7mg, 0.03mmol) and Cs were added to the well-mixed solution 2 CO 3 (117.3mg, 0.36mmol), N-filled with a nitrogen-connected glass tube 2 And 3 minutes, fully removing air, sealing a pipe orifice by using a cock, stirring and reacting at 80 ℃ for 1.5 hours, cooling the system to room temperature after the reaction is finished, adding 2ml of distilled water into the reaction system, extracting by using ethyl acetate, combining organic phases, removing the solvent of the organic phase by reduced pressure distillation, and separating by silica gel column chromatography to obtain 133.8mg of product 4f, wherein the yield is 96%. 1 H NMR(400MHz,CDCl 3 ):δ＝1.27(t,J＝7.2Hz,6H),3.76(d,J＝1.6Hz,2H),4.25-4.34(m,4H),7.23-7.33(m,4H),7.41-7.53(m,5H),8.13(dd,J 1 ＝1.6Hz,J 2 ＝8.0Hz,1H),8.74(dd,J 1 ＝2.4Hz,J 2 ＝6.4Hz,1H),8.77(dd,J 1 ＝1.6Hz,J 2 ＝4.0Hz,1H),10.02(s,1H)； 13 C NMR(100MHz,CDCl 3 ):δ＝13.8,37.4(d,J＝4.0Hz),63.0,95.1(d,J＝200.0Hz),116.3,121.5(d,J＝7.0Hz),127.3,127.8,128.0,128.5,128.7,134.4,134.5,134.6,135.2,136.1,138.4,148.1,165.2(d,J＝26.0Hz),167.8； 19 F NMR(376MHz,CDCl 3 ):δ＝-159.0.HRMS(ESI-TOF).Calcd for C 26 H 26 FN 2 O 5 ,[M+H] + m/z 465.1826,Found 465.1832.
Finally, the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting, and other modifications or equivalent substitutions made by the technical solutions of the present invention by those of ordinary skill in the art should be covered within the scope of the claims of the present invention as long as they do not depart from the spirit and scope of the technical solutions of the present invention.
Claims (6)
1. A method for synthesizing (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide is characterized in that the synthetic route is as follows:
wherein the compound 1 is phenylacetylene, 4-ethynylbiphenyl, 2-ethynylpyridine, 3-ethynylpyridine, 4-ethynylpyridine, 2-ethynylthiophene, 3-ethynylthiophene, methyl propargyl ether, propargyl phenyl ether, 2-methyl-1-butene-3-alkyne or 1-hexyne;
compound 2 is
R' is methyl or ethyl.
2. The method for synthesizing (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide according to claim 1, comprising the following steps: adding the compound 1 into a sealed tube, adding a solvent, adding the compound 2 and the compound 3, uniformly mixing, sequentially adding a copper catalyst and alkali, and filling N into the sealed tube by using a glass guide tube connected with nitrogen 2 For 2-3 minutes, fully driving out air and using a screwSealing the pipe orifice by a plug, and reacting for 1.5 hours under the condition of magnetic stirring at the temperature of 80-100 ℃; after the reaction is finished, cooling the system to room temperature, adding distilled water into the reaction system, extracting, combining organic phases, distilling under reduced pressure to remove the solvent of the organic phase, and performing silica gel column chromatography to obtain the product.
3. The method for synthesizing (E) - β -monofluoroalkyl- β, γ -unsaturated amide according to claim 2, wherein the molar ratio of compound 1, compound 2, and compound 3 is 1.1 to 1.2.
4. The process for the synthesis of (E) - β -monofluoroalkyl- β, γ -unsaturated amide according to claim 2, wherein said copper catalyst is CuI; the amount of the copper catalyst is 10mol%.
5. The method for synthesizing (E) - β -monofluoroalkyl- β, γ -unsaturated amide according to claim 2, wherein the base is Cs 2 CO 3 (ii) a The amount of the base is 1.2equiv.
6. The method for synthesizing (E) - β -monofluoroalkyl- β, γ -unsaturated amide according to claim 2, wherein the solvent is tetrahydrofuran.
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