Synthesis process of polyfluorinated amino acid compound

Abstract

The invention discloses a synthesis process of a polyfluorinated amino acid compound. Under the condition of nitrogen and the irradiation of a blue light source, polyfluoroalkyl bromide, aryl olefin and amino-acid ester are subjected to a coupling reaction under the action of an iridium catalyst and alkali to generate the polyfluoroamino acid compound. The method provided by the invention has the advantages of mild conditions, simple and easily available raw materials and simple operation, can be widely applied to drug synthesis in industrial and academic industries, and has high application potential.

Description

Technical Field

[0001] The invention relates to the technical field of organic intermediate synthesis, and in particular to a synthesis process of polyfluoroamino acid compounds. Background Art

[0002] Fluorinated amino acids and their derivatives have high biological and pharmacological activities. Fluorine is the most electronegative element, and the CF bond has a significant dipole moment and a low polarizability. Introducing fluorine into amino acids and peptides can improve the charge distribution of the molecules, increase lipophilicity, solubility and metabolic stability, change the primary and secondary structures of proteins, and make fluorinated peptides and proteins have unusual biological activities and structural states. The traditional strategy for synthesizing fluorinated amino acids and their derivatives is to make amino acids into metal reagents and undergo transition metal-catalyzed cross-coupling with polyfluorinated halides. In recent years, methods for direct modification of amino acids and their derivatives with the participation of photocatalytic free radicals have also made great progress, and have attracted much attention due to their green environmental protection, high atom economy and mild reaction conditions. The specific synthetic methods that have been reported for synthesizing polyfluorinated amino acid compounds and their derivatives are:

[0003] Method 1: Using α-bromoketone as the fluorine source, Synthesis of fluorinated amino acid esters under acid-cocatalyzed conditions.

[0004]

[0005] The disadvantage of this reaction is that it requires the use of Molecular sieves are used to ensure good anhydrous conditions, and α-bromoketone needs to be pre-prepared. The preparation steps are cumbersome, the reaction cost is high, and only a single fluorocarbonyl group can be introduced.

[0006] Method 2: Using fluoroalkyl peroxyesters as the fluorine source, free radical coupling occurs under thermal induction to directly synthesize fluorinated amino acid esters and their derivatives.

[0007]

[0008] The disadvantages of this reaction are that it needs to be carried out at high temperature, and the peroxide is highly dangerous, which places high demands on the experiment. At the same time, the substrate range is limited, and only the introduction of difluorobenzyl groups can be achieved, which limits the synthesis scope of fluorinated amino acids.

[0009] Method 3: Using Togni reagent as fluorine source and olefin as linker, the corresponding fluorinated amino acid ester and its derivative compounds are synthesized under the condition of copper catalyst.

[0010]

[0011] The disadvantage of this reaction is that the Togni reagent needs to be prepared in advance, the steps are cumbersome, the cost is high, and it is not the most ideal fluorine-containing free radical precursor; and heavy metal salts need to be added during the reaction, which is not environmentally friendly. More importantly, this method can only introduce trifluoromethyl groups but not other fluorine-containing groups. Summary of the invention

[0012] In view of the above problems, the present invention aims to provide a synthesis process of polyfluoroamino acid compounds which is low in cost, simple to operate, has mild reaction conditions and is easy to promote in industrial production.

[0013] In order to achieve the above object, the technical solution adopted by the present invention is as follows: A synthesis process of polyfluoroamino acid compounds, specifically as follows:

[0014]

[0015] Among them, R f An alkyl group in which all H atoms in C6 to C8 are replaced by F atoms, 4-bromo-1,1,2,2-tetrafluorobutyl; R 1 is selected from H, methyl; R 2 The alkyl radical is selected from C1-C2 and the phenyl radical; Ar is selected from phenyl radical and substituted phenyl radical; the photocatalyst is an iridium catalyst; the light source is a blue light source; the reaction is carried out under nitrogen protection; and the solvent is selected from dichloromethane, dimethyl sulfoxide and dichloroethane.

[0016] In the process of the present invention, R f The alkyl group in is preferably a straight-chain alkyl group in which all H atoms in C6 to C8 are replaced by F atoms; the substituent of the phenyl group in Ar is preferably a para-methyl group or a methoxy group; the iridium catalyst is preferably Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir[(dFCF3ppy)2-(5,5'-dCF3bpy)]PF6; the inorganic base is selected from K2CO3, Na2CO3, NaHCO3, Cs2CO3; the preferred wavelength of the blue light source is 390 to 462 nm.

[0017] In the process method of the present invention, the photocatalyst is preferably Ir[dF(CF3)ppy]2(dtbbpy)PF6; when the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, the yield of the final product is the highest.

[0018] The inorganic base in the process of the present invention is preferably K2CO3.

[0019] In the process method of the present invention, the molar concentration of polyfluoroalkyl bromide in the solvent is 0.05 mmol / mL; the molar concentration of aromatic olefin in the solvent is 0.1 mmol / mL; the molar concentration of amino acid ester in the solvent is 0.1 mmol / mL; the solvent is preferably dichloromethane; when the solvent is dichloromethane, the yield of the final product is the highest.

[0020] In the process of the present invention, the molar ratio of polyfluoroalkyl bromide, aryl olefin and amino acid ester is 1:1-3:1-3; the molar ratio of polyfluoroalkyl bromide, inorganic base and photocatalyst is 1:1-3:0.01-0.03. The molar ratio of polyfluoroalkyl bromide, aryl olefin and amino acid ester is 1:2:2; the molar ratio of polyfluoroalkyl bromide, inorganic base and photocatalyst is 1:1.5:0.02; when the preferred molar ratio of photocatalyst, aryl olefin and amino acid ester compound is selected, the yield of the final product is the highest.

[0021] In the process of the present invention, the reaction temperature is 16-25° C. and the reaction time is 12-14 hours. After the reaction is completed, the reaction solution is washed with saturated brine and extracted three times with dichloromethane, and then separated by column chromatography to obtain a refined polyfluoroamino acid compound.

[0022] The advantages of the present invention are: the present invention uses a simple and easily available polyfluoroalkyl bromide compound as a reaction substrate, uses commercially available stable Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, uses cheap and easily available K2CO3 as a base, and after adding the materials at 25°C, polyfluoroamino acid compounds are simply and efficiently synthesized under nitrogen conditions.

[0023] Compared with other methods for synthesizing polyfluoroamino acid compounds, the reaction raw materials used in the present invention are cheap and easy to obtain, the reaction yield is high, and it has the characteristics of low cost, environmental friendliness, safe operation, and convenient industrial promotion. The method of the present invention has good compatibility with aliphatic, aromatic and heterocyclic raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The H NMR spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoate described in Example 1;

[0025] Figure 2 The NMR carbon spectrum of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoic acid ethyl ester described in Example 1;

[0026] Figure 3The NMR fluorine spectrum of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoic acid ethyl ester described in Example 1;

[0027] Figure 4 The H NMR spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-((4-methoxyphenyl)amino)-3,3-diphenyldecanoate described in Example 2;

[0028] Figure 5 The NMR carbon spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-((4-methoxyphenyl)amino)-3,3-diphenyldecanoate described in Example 2;

[0029] Figure 6 The NMR fluorine spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-((4-methoxyphenyl)amino)-3,3-diphenyldecanoate described in Example 2;

[0030] Figure 7 The H NMR spectrum of 5,5,6,6,7,7,8,8,9,10,10,10-trifluoro-3,3-diphenyl-2-(p-tolylamino)phenyl decanoate described in Example 3;

[0031] Figure 8 The H NMR spectrum of (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoyl)glycine ethyl ester described in Example 4;

[0032] Fig. 9 The H NMR spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-pentadecafluoro-3,3-diphenyl-2-(phenylamino)undecanoate described in Example 5;

[0033] Fig.10 The H NMR spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluoro-3,3-diphenyl-2-(phenylamino)dodecanoate described in Example 6;

[0034] Fig.11 The H NMR spectrum of 8-bromo-5,5,6,6-tetrafluoro-3,3-diphenyl-2-(phenylamino)octanoic acid ethyl ester described in Example 7;

[0035] Fig.12This is the H NMR spectrum of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3-phenyl-2-(phenylamino)decanoate described in Example 8. DETAILED DESCRIPTION

[0036] The present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0037] In the present invention, "amino acid ester" compounds have the meaning commonly understood by those skilled in the art, ie, compounds containing R-NH-CH2-CO2R', such as N-phenylglycine methyl ester, N-phenylglycine ethyl ester and various derivatives thereof.

[0038] In the present invention, "aryl olefin" compounds have the meaning commonly understood by those skilled in the art, that is, compounds with an aromatic ring connected to at least one end of a carbon-carbon double bond, such as styrene and its various derivatives.

[0039] In the present invention, "polyfluoroalkyl bromide" compounds have the meaning commonly understood by those skilled in the art, i.e., compounds in which the H atoms at one end of a long-chain alkane are replaced by a Br atom and the H atoms on multiple C atoms are all replaced by F atoms, such as 1-bromoperfluorohexane.

[0040] In the present invention, "polyfluoroamino acid" compounds have the meaning commonly understood by those skilled in the art, that is, compounds in which the hydrogen on the carbon atom adjacent to the amino group of the above-mentioned amino acid ester is replaced by a fluorine-containing group, such as 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoic acid ethyl ester.

[0041] The raw materials used in the following specific examples can all be purchased commercially, and each reagent is purified by means known in the art before use when necessary.

[0042] 1 H NMR and 13 C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform, and the reference was selected: 1 H NMR: CHCl3 7.260 ppm; 13 C NMR: CHCl3: 77.000 ppm.

[0043] Example 1: Synthesis of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoic acid ethyl ester

[0044] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), N-phenylglycine ethyl ester (72 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and nitrogen was pumped in and out three times. Then, ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluorohexane (42.6 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 125 mg of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoic acid ethyl ester with a yield of 92%.

[0045] The results are as follows Figure 1 , 2 As shown in 3; product 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoic acid ethyl ester: 1 H NMR(400MHz,Chloroform-d)δ7.42-7.36(m,5H),7.34-7.26(m,5H),7.25-7.19(m,2H),6.86-6.78(m,1H),6. 76-6.69(m,2H),5.37(s,1H),4.09-3.78(m,3H),3.58-3.41(m,1H),3.30-3.13(m,1H),1.01(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.5,146.3,141.5,141.4,129.4,129.4,129.1,127 .9,127.7,127.7,127.3,119.4,114.6,61.2,60.9,51.7,38.1(t,J=18.2Hz),13.7. 19 F NMR(376MHz,Chloroform-d)δ-80.8,-108.5,-111.0,-121.6,-122.8,-123.4,-126.2.

[0046] Example 2: Synthesis of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-((4-methoxyphenyl)amino)-3,3-diphenyldecanoate

[0047] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), (4-methoxyphenyl)glycine ethyl ester (83.6 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and nitrogen was pumped in and out three times. Then, ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluorohexane (42.6 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 104 mg of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-((4-methoxyphenyl)amino)-3,3-diphenyldecanoic acid ethyl ester with a yield of 73%.

[0048] The results are as follows Figure 4 , 5 As shown in 6; product 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-2-((4-methoxyphenyl)amino)-3,3-diphenyldecanoic acid ethyl ester: 1 H NMR(400MHz,Chloroform-d)δ7.56-7.49(m,4H),7.44-7.35(m,6H),6.76-6.60(m,4H),3 .98(q,J=7.1Hz,2H),3.78(s,3H),3.57(s,2H),2.95-2.81(m,2H),1.11(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ170.5,158.2,139.2,137.6,132.0,129.4,127.7,127.7,113.4,69.1,60.4,55.1,53.7,41.6(t,J=18.6Hz),13.9. 19 F NMR(376MHz,Chloroform-d)δ-81.1,-108.9,-121.8,-123.1,-124.0,-126.3.

[0049] Example 3: Synthesis of 5,5,6,6,7,7,8,8,9,10,10,10-trifluoro-3,3-diphenyl-2-(p-tolylamino) phenyl decanoate

[0050] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), p-toluene glycine phenyl ester (96.4 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and after nitrogen was pumped in and out three times, ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluorohexane (42.6 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 104 mg of 5,5,6,6,7,7,8,8,9,10,10,10-trifluoro-3,3-diphenyl-2-(p-tolylamino)decanoic acid phenyl ester with a yield of 70%.

[0051] The results are as follows Figure 7 As shown; product 5,5,6,6,7,7,8,8,9,10,10,10-trifluoro-3,3-diphenyl-2-(p-tolylamino) phenyl decanoate: 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J=8.1Hz,2H),7.52-7.44(m,3H),7.43-7.37(m,5H),7.34-7.28(m,2H),7.22-7.17(m, 1H),7.14(d,J=8.3Hz,2H),6.84-6.68(m,4H),5.64(s,1H),4.02(br,1H),3.78-3.59(m,1H),3.47-3.31(m,1H),2.35(s,3H). 13 C NMR(101MHz,Chloroform-d)δ170.6,150.3,143.8,141.5,141.2,130.1,129.5,129.4,129.3, 129.2,128.2,127.9,127.5,126.0,121.2,118.8,115.0,61.9,51.8,38.2(t,J=18.1Hz),20.5. 19 F NMR(376MHz,Chloroform-d)δ-80.8,-108.8,-110.6,-121.5,-122.8,-123.3,-126.1.

[0052] Example 4: Synthesis of (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoyl)glycine ethyl ester

[0053] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), phenylglycylglycine ethyl ester (94.4 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and nitrogen was pumped in and out three times. Then, ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluorohexane (42.6 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 106 mg of (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoyl)glycine ethyl ester with a yield of 72%.

[0054] The results are as follows Figure 8 As shown; product (5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3,3-diphenyl-2-(phenylamino)decanoyl)glycine ethyl ester: 1 H NMR (400MHz, Chloroform-d) δ7.40-7.27(m,8H),7.25-7.14(m,4H),6.86(t,J=7.3Hz,1H),6.75-6.66(m,1H),6.59(d ,J=7.5Hz,2H),4.69(s,1H),4.05(q,J=8.2,7.6Hz,3H),3.98-3.82(m,2H),3.50-3.13(m,2H),1.16(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ169.8,169.7,144.4,138.3,130.4,129.4,129.3,128.5,12 8.2,128.0,127.9,127.4,119.8,113.3,70.0,61.6,54.9,41.3,41.3(t,J=20.2Hz),14.1. 19F NMR(376MHz,Chloroform-d)δ-80.8,-107.8--108.8(m),-110.1--111.1(m),-121.7,-122.9,-123.4,-126.2.

[0055] Example 5: Synthesis of ethyl 5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-pentadecafluoro-3,3-diphenyl-2-(phenylamino)undecanoate

[0056] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), N-phenylglycine ethyl ester (72 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and nitrogen was pumped in and out three times. Then, ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluoroheptane (52.9 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 125 mg of 5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-pentadecafluoro-3,3-diphenyl-2-(phenylamino)undecanoic acid ethyl ester with a yield of 85%.

[0057] The results are as follows Fig. 9 As shown; product 5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-pentadecafluoro-3,3-diphenyl-2-(phenylamino)undecanoic acid ethyl ester; 1 H NMR(400MHz,Chloroform-d)δ7.47-7.34(m,10H),7.30-7.25(m,2H),6.88(t,J=7.3Hz,1H),6.79(d,J=8 .0Hz,2H),5.45(s,1H),4.10-3.88(m,3H),3.66-3.50(m,1H),3.42-3.15(m,1H),1.06(t,J=7.1Hz,3H). 13C NMR(101MHz,Chloroform-d)δ171.5,146.4,141.5,141.4,129.4,129.4,129.2,127 .9,127.8,127.7,127.3,119.4,114.7,61.2,61.0,51.7,38.2(t,J=18.3Hz),13.7. 19 F NMR(376MHz,Chloroform-d)δ-80.9,-108.5,-111.0,-121.5,-122.1,-122.8,-123.4,-126.2.

[0058] Example 6: Synthesis of 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-fluoro-3,3-diphenyl-2-(phenylamino)dodecanoic acid ethyl ester

[0059] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), N-phenylglycine ethyl ester (72 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, nitrogen was pumped in and out for 3 times, and then ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluorooctane (57.7 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 82 mg of 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-fluoro-3,3-diphenyl-2-(phenylamino)dodecanoic acid ethyl ester with a yield of 52%.

[0060] The results are as follows Fig.10 As shown; product 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-fluoro-3,3-diphenyl-2-(phenylamino) dodecanoic acid ethyl ester: 1H NMR(400MHz,Chloroform-d)δ7.50-7.41(m,5H),7.40-7.35(m,5H),7.32-7.26(m,2H),6.89(t,J=7.3Hz,1H),6. 81(d,J=8.0Hz,2H),5.47(s,1H),4.11-3.95(m,3H),3.67-3.52(m,1H),3.39-3.22(m,1H),1.08(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ171.5,146.4,141.6,141.4,129.4,129.4,129.2,127 .9,127.8,127.7,127.3,119.4,114.7,61.2,61.0,51.7,38.2(t,J=18.2Hz),13.6. 19 FNMR(376MHz,Chloroform-d)δ-81.0,-108.5,-111.0,-121.4,-122.0,-122.8,-123.4,-126.3.

[0061] Example 7: Synthesis of 8-bromo-5,5,6,6-tetrafluoro-3,3-diphenyl-2-(phenylamino)octanoic acid ethyl ester

[0062] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), N-phenylglycine ethyl ester (72 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and nitrogen was pumped in and out three times. Then, ultra-dry DCM (4.0 mL), 1,1-diphenylethylene (70.6 μL, 2.0 eq, 0.4 mmol) and 1,4-dibromo-1,1,2,2-tetrafluorobutane (41.1 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 78 mg of 8-bromo-5,5,6,6-tetrafluoro-3,3-diphenyl-2-(phenylamino)octanoic acid ethyl ester with a yield of 69%.

[0063] The results are as follows Fig.11 As shown; the product 8-bromo-5,5,6,6-tetrafluoro-3,3-diphenyl-2-(phenylamino)octanoic acid ethyl ester: 1H NMR(400MHz,Chloroform-d)δ7.48-7.40(m,5H),7.39-7.32(m,5H),7.26(t,J=7.9Hz,2H),6.86(t,J=7.3Hz,1H),6.77(d,J=8 .1Hz,2H),5.41(s,1H),4.14-3.88(m,3H),3.50(t,J=8.2Hz,3H),3.27-3.10(m,1H),2.71-2.51(m,2H),1.06(t,J=7.1Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ171.6,146.4,142.0,129.5,129.4,129.2,128.3,127.8,127.6,127.0,1 25.5,119.2,114.5,61.1,60.9(d,J=3.8Hz),51.5,37.1(t,J=18.6Hz),33.8(t,J=22.6Hz),21.8,13.8. 19 FNMR(376MHz,Chloroform-d)δ-108.1--112.7(m),-114.0--115.8(m).

[0064] Example 8: Synthesis of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3-phenyl-2-(phenylamino)decanoic acid ethyl ester

[0065] Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.45 mg, 2 mmol%), N-phenylglycine ethyl ester (72 mg, 2.0 eq, 0.4 mmol) and anhydrous K2CO3 (41.5 mg, 1.5 eq, 0.3 mmol) were added to an 8 mL sample bottle equipped with a magnetic stirrer, the sample bottle was capped, and nitrogen was pumped in and out three times. Then, ultra-dry DCM (4.0 mL), styrene (46.0 μL, 2.0 eq, 0.4 mmol) and 1-bromoperfluorohexane (42.6 μL, 1.0 eq, 0.2 mmol) were added, and then stirred at room temperature and irradiated with LED blue light with a wavelength of 462 nm for 12 hours. After the reaction was completed, extraction was performed, the solvent was removed in vacuo, and then column chromatography was performed to obtain 72 mg of 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3-phenyl-2-(phenylamino)decanoic acid ethyl ester with a yield of 60%.

[0066] The results are as follows Fig.12As shown; product 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluoro-3-phenyl-2-(phenylamino)decanoic acid ethyl ester: 1 H NMR (400MHz, CDCl3) δ7.36-7.34(m,1H,minor isomer),7.34-7.33(m,1.1H,major isomer),7.32-7.28(m,3.3H,major isomer),7.25-7.22(m,3H,minor isomer),7.22-7.19(m,3H,minor isomer),7.19-7.15(m,3.3H,major isomer),6.83-6.79(m,1.1H,major isomer),6.79-6.76(m,1H,minor isomer),6.67(d,2.2H,major isomer),6.63(d,2H,minor isomer),4.41(d,1H,minor isomer),4.24(d,1.1H,major isomer),4.09(q,2.2H,major isomer),3.92(q,2H,minor isomer),3.85-3.80(m,1.1H,major isomer),3.51-3.43(m,1H,minor isomer),3.10-2.93(m,1.1H,major isomer),2.91-2.78(m,1H,minor isomer),2.74-2.66(m,1H,minor isomer),2.65-2.56(m,1.1H,major isomer),1.19(t,3.3H,major isomer),0.97(t,3H,minor isomer). 13 C NMR(101MHz,Chloroform-d)δ172.0,171.8,147.1,146.3,138.7,138.2,129.4,129.4,128.8,128.7,128.2,128.0,1 28.0,127.8,119.5,119.3,114.6,114.3,62.0,61.6,61.5,61.2,41.9,40.6,32.9(td,J=20.9,10.6Hz),14.1,13.8. 19 F NMR(376MHz,Chloroform-d)δ-80.8,-112.3,-121.8,-122.9,-123.3,-126.2.

[0067]

[0068]

[0069] From Examples 1-8, it can be seen that the product synthesized by the method in Example 1 has the highest yield, and the yield of polyfluoroamino acid compounds synthesized from other raw materials is also not low; this method starts from various cheap and readily available polyfluoroalkyl bromide compounds, reacts with aromatic olefins and amino acid esters, uses DCM as solvent, and the reaction temperature is room temperature. Under the conditions of blue light with a wavelength of 462nm, Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and K2CO3 as a base, it can most efficiently synthesize polyfluoroamino acid compounds.

[0070] Example 9: Comparative Example Group

[0071] Under the condition that other conditions remain unchanged, the technical solution in Example 1 is used with different iridium photocatalysts, bases, solvents and light sources of different wavelengths, and the results obtained are as follows:

[0072]

[0073]

[0074] DCM = dichloromethane; DMSO = dimethyl sulfoxide; DCE = dichloroethane.

[0075] As shown in the above table, compared with comparative examples 1-2, when the iridium catalyst is selected from Ir[dF(CF3)ppy]2(dtbbpy)PF6, the yield of polyfluoroamino acid is higher in Example 1; when the base is selected from K2CO3, the yield of polyfluoroamino acid is higher in Example 1 compared with comparative examples 3-5; when Example 1 is compared with comparative examples 6-7, when the solvent is selected from DCM, the yield of polyfluoroamino acid is higher in Example 1; when Example 1 is compared with comparative examples 8-10, when the wavelength of the blue light source is selected from 462nm, the yield of polyfluoroamino acid is higher in Example 1; the embodiment with the lowest yield in the above table is when the wavelength of the light source is 390-395nm, because the wavelength does not match the excitation wavelength of the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0076] It should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the protection scope of the present invention. Any combination or equivalent transformation made on the basis of the above embodiments shall fall within the protection scope of the present invention.

Claims

1. A synthesis process for polyfluoroamino acid compounds, characterized in that: Described synthesis process is as follows: Among them, R f Alkyl groups in which all H atoms in C6 to C8 are replaced by F atoms, and 4-bromo-1,1,2,2-tetrafluorobutyl; R 1 is selected from H, methyl; R 2 is selected from C1-C2 alkyl and phenyl; Ar is selected from phenyl and substituted phenyl; The photocatalyst is an iridium catalyst; the light source is a blue light source; the reaction is carried out under nitrogen protection; The solvent is selected from dichloromethane, dimethyl sulfoxide, and dichloroethane.

2. The synthesis process according to claim 1, characterized in that The R f The alkyl in is a straight-chain alkyl in which all H atoms in C6 to C8 are replaced by F atoms; the substituent of the substituted phenyl in Ar is a para-methyl or methoxy group; the iridium catalyst is selected from Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir[(dFCF3ppy)2-(5,5'-dCF3bpy)]PF6; the inorganic base is selected from K2CO3, Na2CO3, NaHCO3, Cs2CO3; The wavelength of the blue light source is 390-462nm.

3. The synthesis process according to claim 2, characterized in that The photocatalyst is preferably Ir[dF(CF3)ppy]2(dtbbpy)PF6.

4. The synthesis process according to claim 2, characterized in that The inorganic base is preferably K2CO3.

5. The synthesis process according to claim 2, characterized in that: The molar concentration of the polyfluoroalkyl bromide in the solvent is 0.05 mmol / mL; the molar concentration of the aromatic olefin in the solvent is 0.1 mmol / mL; the molar concentration of the amino acid ester in the solvent is 0.1 mmol / mL; and the solvent is preferably dichloromethane.

6. The synthesis process according to claim 1 or 2, characterized in that: The molar ratio of the polyfluoroalkyl bromide, aryl olefin and amino acid ester is 1:1-3:1-3; the molar ratio of the polyfluoroalkyl bromide, inorganic base and photocatalyst is 1:1-3:0.01-0.

03.

7. The synthesis process according to claim 6, characterized in that The molar ratio of the polyfluoroalkyl bromide, aromatic olefin and amino acid ester is 1:2:2; the molar ratio of the polyfluoroalkyl bromide, inorganic base and photocatalyst is 1:1.5:0.

02.

8. The synthesis process according to claim 1 or 2, characterized in that: The reaction temperature is 16-25°C.

9. The synthesis process according to claim 1 or 2, characterized in that: The reaction time is 12 to 14 hours.

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