CN110627718B - Synthesis method of (E) -beta-monofluoroalkyl-beta, gamma-unsaturated amide - Google Patents

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

A kind of synthetic method of (E)-β-monofluoroalkyl-β,γ-unsaturated amide

technical field

The invention belongs to the technical field of chemical organic synthesis, in particular to a method for synthesizing (E)-β-monofluoroalkyl-β,γ-unsaturated amide.

Background technique

Fluorine-containing organic molecules are widely used in medicine, agricultural chemicals and materials. The introduction of fluorine atoms or fluorine functional groups can significantly improve their lipophilicity and metabolic stability, and improve the efficacy of biomedicine. According to statistics, 20% of commercially available medical drugs contain at least one fluorine atom, and the proportion of fluorine-containing compounds in agricultural chemicals is also as high as 30-40%. However, the number of fluorine-containing organic compounds in natural products is limited and the structure is simple. Therefore, the development of practical methods that can effectively introduce fluorine atoms or fluorine-containing functional groups to synthesize new fluorine-containing organic compounds is equivalent to the development of medicines, agrochemicals and materials. important.

The introduction of fluorine atoms or fluorine-containing functional groups through transition metal-catalyzed fluorination, trifluoromethylation, and difluoroalkylation reactions has attracted extensive research interest and has become an important method for the synthesis of fluorine-containing compounds. In comparison, transition metal-catalyzed monofluoroalkylation reactions are less studied. In addition, according to statistics, C-F-centered drugs account for less than 1% of fluorine-containing drugs currently on the market or in clinical development, mainly due to less research on methods for introducing monofluoroalkyl groups and the construction of C-F centers. There are big challenges. The inventors have studied a method for the formation of β,γ-unsaturated amides by difunctionalization of terminal alkynes at the 1,1-position (Yunhe Lv, Weiya Pu, Lihan Shi, Org. Lett. 2019, 21, 6034). The research method did not obtain fluorine-containing compounds in the end, but the introduction of fluorine atoms into organic molecules can well improve the pharmacological and toxicological properties of drugs. This application improves the research method and introduces C-F bonds in the terminal alkyne to make it Generate β-monofluoroalkyl-β,γ-unsaturated amides, a new class of compounds that may be used in clinical medicine or agrochemicals, and so far, one-step synthesis of C-F bond-containing unsaturated fluorides (E)-β The method of -monofluoroalkyl-β,γ-unsaturated amide has not been reported.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a kind of synthetic method of (E)-β-monofluoroalkyl-β,γ-unsaturated amide, which is through copper catalyzed terminal alkyne, 2-chloroacetamidoquinoline and 2-fluoro Dialkyl malonate reaction, one-step synthesis of (E)-β-monofluoroalkyl-β,γ-unsaturated amide compound, the synthetic route is as follows:

The specific steps of the synthetic method of the present invention are as follows:

Add compound 1 into a sealed tube, add solvent, and add compound 2 and compound 3, mix well, then add copper catalyst and alkali in turn, fill with N ₂ for 2-3 minutes with a glass tube connected to nitrogen, fully drive out the air, The mouth of the tube was sealed with a stopcock, and the reaction was performed under magnetic stirring for 1.5 h under the condition of 80°C-100°C. After the reaction was completed, the system was cooled to room temperature, distilled water was added to the reaction system, extracted, the organic phases were combined, the solvent of the organic phase was distilled off under reduced pressure, and the product was obtained by silica gel column chromatography.

Preferably, 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-yne, 1-hexyne.

Preferably, the compound 2 is 2-chloroacetamidoquinoline.

Preferably, the compound 3 is dimethyl 2-fluoromalonate and diethyl 2-fluoromalonate.

Preferably, the amount of the reactants is as follows: the molar ratio of compound 1, compound 2, and compound 3 is 1.1-1.2:1:1.5-2.0.

Preferably, the copper catalyst is CuI; the amount of the copper catalyst is 10 mol%.

Preferably, the base is Cs ₂ CO ₃ ; the amount of the base is 1.2 equiv.

Preferably, the solvent is tetrahydrofuran.

In the invention, CuI is used as a catalyst, Cs ₂ CO ₃ is used as a base, and tetrahydrofuran (THF) is used as a solvent, and a terminal alkyne and Cu I are used to generate an acetylenic copper compound under the action of Cs ₂ CO ₃ . The acetylenic copper compound and 2-chloroacetamidoquinoline The 8-aminoquinoline group in the 2-chloroacetamidoquinoline is an auxiliary group, and the α-haloacetamide is an electron withdrawing group, and the allenamide compound is generated under the action of a base. This step is as follows: Sonogashira coupling reaction, followed by transmetallation reaction with 2-fluoromalonate dialkyl ester, carburization and proton decomposition to obtain the final product, that is, allenamide compound and 2-fluoromalonate dialkyl ester are hydrogenated Monofluoroalkylation reaction, and finally a new type of (E)-β-monofluoroalkyl-β,γ-unsaturated amide compound was obtained due to steric interaction and regioselectivity.

Compared with the prior art, the present invention has the following advantages:

(1) The present invention fills the blank of the method for synthesizing (E)-β-monofluoroalkyl-β,γ-unsaturated amide compounds through gem-bifunctionalization reaction of alkynes, and provides a direct, efficient and economical method. A method for the synthesis of (E)-β-monofluoroalkyl-β,γ-unsaturated amide compounds.

(2) The present invention directly and effectively synthesize (E)-β-monofluoroalkyl-β,γ-unsaturated amide compounds from alkynes, 2-chloroacetamidoquinoline, and 2-fluoromalonate dialkyl ester The method has simple reaction steps, cheap and easy-to-obtain raw materials, and a wide range of substrates, and is suitable for industrial production.

(3) The novel (E)-β-monofluoroalkyl-β,γ-unsaturated amide compound prepared by the present invention provides a new direction for the research and development of novel fluorine-containing drugs.

(4) The method for synthesizing fluorine-containing compounds of the present invention can also be used to rationally modify natural products containing alkynes, so as to increase the biological activity and drug-like properties of the natural products.

Description of drawings

Figure 1 is the ¹ H NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4b;

Figure 2 is the ¹³ C NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4b;

Figure 3 is the ¹⁹ F NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4b;

Figure 4 is the ¹ H NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4c;

Figure 5 is the ¹³ C NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4c;

Fig. 6 is the ¹⁹ F NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4c;

Fig. 7 is the ¹ H NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4e;

Figure 8 is the ¹³ C NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4e;

Figure 9 is a ¹⁹ F NMR spectrum of (E)-β-monofluoroalkyl-β,γ-unsaturated amide 4e.

Detailed ways

The technical solutions of the present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and implement it, but the examples are not intended to limit the present invention.

Example 1

First, a stirring bar was placed in a 35 mL sealed tube, followed by adding phenylacetylene (38 μL, 0.33 mmol), 0.9 mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg, 0.3 mmol), 2 - Dimethyl fluoromalonate (70.4 mg, 0.45 mmol), CuI (5.7 mg, 0.03 mmol) and Cs ₂ CO ₃ (117.3 mg, 0.36 mmol) were added to the mixed solution, followed by nitrogen The glass tube was filled with N ₂ for 3 minutes, the air was fully expelled, the mouth of the tube was sealed with a cock, and the reaction was stirred at 80 °C for 1.5 hours. After the reaction was completed, the system was cooled to room temperature, and 2 ml of distilled water was added to the reaction system. Ester extraction, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 123.1 mg of product 4a was obtained by silica gel column chromatography with a yield of 94%. ¹ H NMR (400 MHz, CDCl ₃ ): δ=3.77 (d, J=1.6 Hz, 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,J1 ₌ 1.6Hz,J2=8.0Hz,1H ₎ ,8.74(dd,J1 ₌ 2.4Hz,J2=6.4Hz,1H ₎ ,8.78(dd, J ₁ =1.2 Hz, J ₂ =4.0 Hz, 1H), 9.98 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ=37.3 (d, J=4.0 Hz), 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=25.0 Hz), 167.9; ¹⁹ F NMR (376 MHz, 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 stirring bar was placed in a 35 mL sealed tube, and 4-ethynylbiphenyl (60.6 mg, 0.33 mmol), 0.9 mL of tetrahydrofuran (0.9 mL), and 2-chloroacetamidoquinoline (66.2 mg) were added accordingly. , 0.3 mmol), dimethyl 2-fluoromalonate (70.4 mg, 0.45 mmol), CuI (5.7 mg, 0.03 mmol) and Cs ₂ CO ₃ (117.3 mg, 0.36 mmol) were added to the mixed solution accordingly ), fill with _N2 for 3 minutes with a glass tube connected to nitrogen, fully drive out the air, seal the nozzle with a cock, and stir the reaction at 80°C for 1.5 hours. After the reaction is completed, the system is cooled to room temperature, and 2 ml of Distilled water, extracted with ethyl acetate, combined the organic phases, distilled off the solvent of the organic phase under reduced pressure, and isolated 139.9 mg of product 4b by silica gel column chromatography with a yield of 91%. ¹ H NMR (400 MHz, 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 =1.2 Hz, J ₂ =8.4 Hz, 1H), 8.75-8.77 (m, 2H), 10.01 (s, 1H); ¹³ C NMR (100 MHz, 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=26.0 Hz), 167.9; ¹⁹ F NMR (376 MHz, 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 stirring bar was placed in a 35 mL sealed tube, and 2-ethynylpyridine (34 μL, 0.33 mmol), 0.9 mL of tetrahydrofuran (0.9 mL), and 2-chloroacetamidoquinoline (66.2 mg, 0.3 mmol) were added accordingly. ), dimethyl 2-fluoromalonate (70.4 mg, 0.45 mmol), CuI (5.7 mg, 0.03 mmol) and Cs ₂ CO ₃ (117.3 mg, 0.36 mmol) were added to the mixed solution, followed by The glass tube connected with nitrogen was filled with N ₂ for 3 minutes, the air was fully driven out, the mouth of the tube was sealed with a cock, and the reaction was stirred at 80°C for 1.5 hours. Extracted with ethyl acetate, combined the organic phases, distilled off the solvent of the organic phase under reduced pressure, and isolated 103.6 mg of product 4c by silica gel column chromatography with a yield of 79%. ¹ H NMR (400 MHz, 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=8.0 Hz) ,1H),7.38(dd,J1 ₌ 4.0Hz,J2=8.4Hz,1H ₎ ,7.43-7.51(m,2H),7.71(dt,J1 ₌ 1.6Hz, _J2 =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 = 7.2 Hz, 1H), 8.88 (d, J = 4.0 Hz, 1 H), 11.39 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 37.6 (d, J = 3.0 Hz), 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=26.0 Hz), 168.6; ¹⁹ F NMR (376 MHz, 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 stirring bar was placed in a 35 mL sealed tube, and methyl propargyl ether (28 μL, 0.33 mmol), 0.9 mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg, 0.3 mmol) were added accordingly. mmol), dimethyl 2-fluoromalonate (70.4 mg, 0.45 mmol), CuI (5.7 mg, 0.03 mmol) and Cs ₂ CO ₃ (117.3 mg, 0.36 mmol) were added to the mixed solution accordingly, Fill with N ₂ for 3 minutes with a glass tube connected to nitrogen, fully drive out the air, seal the mouth of the tube with a cock, and stir the reaction at 80°C for 1.5 hours. After extraction with ethyl acetate, the organic phases were combined, the solvent of the organic phase was distilled off under reduced pressure, and 86.1 mg of product 4d was isolated by silica gel column chromatography with a yield of 71%. ¹ H NMR (400 MHz, CDCl ₃ ): δ=3.36 (s, 3H), 3.62 (s, 2H), 3.81 (s, 6H), 4.25 (dd, J ₁ =2.0 Hz, J ₂ =6.0 Hz, 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 =1.2 Hz, 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 (100 MHz, CDCl ₃ ): δ=36.9 (d, J=3.0 Hz), 53.6, 58.5, 69.0, 94.8 (d, J=200.0 Hz), 116.4, 121.6, 121.7, 127.2, 127.9, 128.0, 132.9 (d, J=11.0 Hz), 134.3, 136.2, 138.4, 148.2, 165.4 (d, J=26.0 Hz), 167.0; ¹⁹ F NMR (376 MHz, 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, put a stirring bar into a 35 mL sealed tube, and then add 2-methyl-1-butene-3-yne (32 μL, 0.33 mmol), 0.9 mL tetrahydrofuran (0.9 mL), 2-chloroacetamido Quinoline (66.2 mg, 0.3 mmol), dimethyl 2-fluoromalonate (70.4 mg, 0.45 mmol), CuI (5.7 mg, 0.03 mmol) and Cs ₂ CO ₃ ( 117.3 mg, 0.36 mmol), fill N ₂ with a glass tube connected to nitrogen for 3 minutes, fully drive out the air, seal the mouth of the tube with a cock, and stir the reaction at 80 °C for 1.5 hours. 2 ml of distilled water was added to the reaction system, extracted with ethyl acetate, the organic phases were combined, the solvent of the organic phase was distilled off under reduced pressure, and 84.1 mg of product 4e was isolated by silica gel column chromatography with a yield of 70%. ¹ H NMR (400 MHz, CDCl ₃ ): δ=1.89 (s, 3H), 3.77 (d, J=1.2 Hz, 2H), 3.80 (s, 6H), 5.11 (s, 1H), 5.17 (s, 1H) ), 6.63(s, 1H), 7.44(dd, J1 ₌ 4.4Hz, J2=8.4Hz, 1H ₎ , 7.48-7.53(m, 2H), 8.14(dd, J1 ₌ 1.6Hz, _J2 = 8.4Hz, 1H), 8.73 (dd, J1 ₌ 2.4Hz, J2=6.4Hz, 1H ₎ , 8.79 (dd, J1 ₌ 1.6Hz, J2=4.0Hz, 1H ₎ , 9.97 (s, 1H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ=22.8, 37.2 (d, J=4.0 Hz), 53.6, 95.1 (d, J=201.0 Hz), 116.3, 117.7, 121.5, 121.6, 126.0, 126.2, 127.3 , 127.9, 134.4, 136.2 (d, J=12.0 Hz), 138.4, 139.8, 148.2, 165.7 (d, J=26.0 Hz), 167.9; ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ=-159.1.HRMS( ESI-TOF).Calcd forC ₂₁ H ₂₁ FN ₂ O ₅ Na,[M+Na] ⁺ m/z 423.1332,Found 423.1344.

Example 6

First, a stirring bar was placed in a 35 mL sealed tube, followed by adding phenylacetylene (38 μL, 0.33 mmol), 0.9 mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg, 0.3 mmol), 2 - Diethyl fluoromalonate (82.7 mg, 0.45 mmol), CuI (5.7 mg, 0.03 mmol) and Cs ₂ CO ₃ (117.3 mg, 0.36 mmol) were added to the mixed solution, followed by nitrogen The glass tube was filled with N ₂ for 3 minutes, the air was fully expelled, the mouth of the tube was sealed with a cock, and the reaction was stirred at 80 °C for 1.5 hours. After the reaction was completed, the system was cooled to room temperature, and 2 ml of distilled water was added to the reaction system. Ester extraction, the organic phases were combined, the solvent of the organic phase was removed by distillation under reduced pressure, and 133.8 mg of product 4f was obtained by silica gel column chromatography with a yield of 96%. ¹ H NMR (400 MHz, CDCl ₃ ): δ=1.27 (t, J=7.2 Hz, 6H), 3.76 (d, J=1.6 Hz, 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 =1.6 Hz, J ₂ =4.0 Hz, 1H), 10.02 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ=13.8, 37.4 (d, J=4.0 Hz) ,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=26.0 Hz), 167.8; ¹⁹ F NMR (376 MHz, 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, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Other modifications or equivalent replacements made by those of ordinary skill in the art to the technical solutions of the present invention, as long as they do not depart from the spirit of the technical solutions of the present invention and The scope should be included in the scope of the claims 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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