Fluorine-containing polysubstituted pyrrole compound and photocatalytic synthesis method thereof

Abstract

The invention provides a synthesis method of a fluorine-containing polysubstituted pyrrole compound. The fluorine-containing polysubstituted pyrrole compound has the following structural formula: # imgabs0 #, wherein R1 is selected from one of phenyl, 4-methylphenyl, 2-methylphenyl and 4-tert-butylphenyl; r2 is an amino protecting group, and the amino protecting group is a Boc protecting group, a benzoyl group or a substituted benzoyl group. The preparation method comprises the following steps: adding a compound 1 # imgabs 1 #, a compound 2 # imgabs 2 # alkali and a catalyst into an organic solvent to form a reaction solution; and in an inert atmosphere, irradiating the reaction liquid with visible light, and purifying after the reaction is finished to obtain the compound 3 # imgabs3 #. According to the synthesis method disclosed by the invention, the activation of a very stable C-F bond is realized through photocatalysis, and a new method is provided for the synthesis of the fluorine-containing polysubstituted pyrrole compound.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis. Specifically, it relates to a fluorine-containing polysubstituted pyrrole compound and its photocatalytic synthesis method, especially 1-phenyl-2-(pyridin-4-yl-thio)-3-trifluoromethyl-2-aminopyrrole and its analogs, as well as the photocatalytic synthesis method. Background Art

[0002] Pyrrole and its derivatives widely exist in natural products and drug molecules. The synthesis of polysubstituted pyrroles containing specific substituents has important uses and remains a difficult point in organic synthesis methods to date. Fluorine-containing compounds have important uses in medicine, pesticides, and materials science due to their special physical and chemical properties and biological activities. However, there is currently no effective synthesis method for such compounds. Summary of the Invention

[0003] Aiming at the defects in the prior art, the purpose of the present invention is to provide a fluorine-containing polysubstituted pyrrole compound and its photocatalytic synthesis method.

[0004] The purpose of the present invention is achieved through the following scheme:

[0005] The first aspect of the present invention provides a fluorine-containing polysubstituted pyrrole compound, specifically 1-phenyl-2-(pyridin-4-yl-thio)-3-trifluoromethyl-2-aminopyrrole and its analogs, having the following structural formula:

[0006] Wherein, R1 is selected from phenyl or substituted phenyl, and the substituted phenyl includes but is not limited to 4-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, etc.; R2 is an amino protecting group, and the amino protecting group is a Boc protecting group, benzoyl group, or substituted benzoyl group.

[0007] Preferably, the substituted benzoyl group includes but is not limited to 4-methylbenzoyl group, 4-fluorobenzoyl group, or 4-chlorobenzoyl group, etc.

[0008] The second aspect of the present invention provides a photocatalytic synthesis method of a fluorine-containing polysubstituted pyrrole compound, including the following steps:

[0009] (1) Add compound 1 Compound 2 Base, catalyst into an organic solvent to form a reaction solution;

[0010] (2) Under an inert gas, irradiate the reaction solution with visible light, and after the reaction is completed, perform purification treatment to obtain compound 3 Among them, R1 is selected from one of phenyl, 4-methylphenyl, 2-methylphenyl, and 4-tert-butylphenyl; R2 is an amino protecting group, and the amino protecting group is a Boc protecting group, benzoyl group, or substituted benzoyl group.

[0011] Preferably, the substituted benzoyl group is 4-methylbenzoyl group, 4-fluorobenzoyl group, or 4-chlorobenzoyl group.

[0012] Furthermore, the molar ratio of Compound 1, Compound 2, base, and catalyst is 1:(2 - 3):(2 - 3):(0.01 - 0.02).

[0013] Preferably, the molar ratio of Compound 1, Compound 2, base, and catalyst is 1:2:2:0.01.

[0014] Preferably, the base is DABCO (triethylenediamine), and the catalyst is a photosensitive catalyst Ir(ppy)3 (tris(2-phenylpyridine)iridium(III)) or [Ir(ppy)2(dtbbpy)]PF6 ((4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate).

[0015] Furthermore, the visible light is blue light or blue-green light.

[0016] Preferably, the wavelength range of the blue light is 450 - 460 nm, and the range of the blue-green light is 480 - 490 nm.

[0017] Furthermore, the organic solvent is acetonitrile, DMF, acetone, or DMSO.

[0018] The novel method for the visible-light-catalyzed synthesis of 1-phenyl-2-(pyridin-4-yl-thio)-3-trifluoromethyl-2-aminopyrrole and its analogs according to the present invention has the following reaction general formula:

[0019]

[0020] Speculation on the reaction mechanism: Generally, reactions under photocatalysis proceed through radical intermediates. The [Ir]Ⅲ catalyst generates the excited state *[Ir]Ⅲ under visible light irradiation. Then 1a is reduced by *[Ir]Ⅲ through single electron transfer to obtain the Ir(IV) species and the radical anion A. Subsequently, it undergoes a spin center shift (SCS) process, accompanied by the departure of the fluoride ion, to generate the radical B. The radical B is captured by the enamine to generate the radical C. The radical C is oxidized by the high-valent photosensitizer to generate the corresponding cation D while completing the catalytic cycle of the photosensitizer. The cation D then undergoes deprotonation and subsequent β-fluorine elimination to obtain the intermediate E, and finally undergoes intramolecular cyclization to obtain the final product. The reaction of the present invention realizes the activation of very stable C-F bonds through photocatalysis, providing a new method for the synthesis of fluorine-containing polysubstituted pyrrole compounds.

[0021]

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The synthesis method of the present invention has a low reaction temperature, mild conditions, high reaction safety, high reaction yield, and low cost.

[0024] 2. The synthesis method of the present invention realizes the activation of very stable C-F bonds through photocatalysis, providing a new method for the synthesis of fluorine-containing polysubstituted pyrrole compounds.

[0025] 3. The synthesis method of the present invention can synthesize pyrrole compounds with specific substituents starting from commercially available raw materials, providing an efficient synthesis method for the synthesis of pharmaceutical intermediates. Description of the drawings

[0026] By reading the following detailed description of the non-limiting embodiments with reference to the accompanying drawings, other features, objects, and advantages of the present invention will become more apparent:

[0027] Figure 1 1H NMR spectrum of compound 3a in Example 1;

[0028] Figure 2 13C NMR spectrum of compound 3a in Example 1;

[0029] Figure 3 19F NMR spectrum of compound 3a in Example 1. Detailed implementation manners

[0030] The present invention will be described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several changes and improvements can still be made. These all belong to the protection scope of the present invention.

[0031] The present invention provides a new method for the visible-light-catalyzed synthesis of 1-phenyl-2-(pyridin-4-ylthio)-3-trifluoromethyl-2-aminopyrrole and its analogs starting from commercially available raw materials. The reaction general formula is as follows:

[0032]

[0033] R1 is phenyl and substituted phenyl, including but not limited to phenyl, 4-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, etc. R2 is an amino protecting group, including Boc (tert-butoxycarbonyl), substituted benzoyl group. The substituted benzoyl group includes but not limited to benzoyl group, 4-methylbenzoyl group, 4-fluorobenzoyl group, 4-chlorobenzoyl group, etc.

[0034] General experimental procedure: Compound 1 (1 mmol), compound 2 (2 mmol), DABCO (2 mmol), Ir(ppy)3 (0.01 mmol) and acetonitrile (20 mL) were added to a 50 mL glass reaction flask equipped with a magnetic stir bar. After deoxygenation by bubbling with argon for ten minutes, the reaction was terminated after irradiation with a 10 W blue LED (450 - 460 nm) for 24 hours. The organic solvent was removed using a rotary evaporator, and finally the final product compound 3 was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent.

[0035] Taking the following reaction as a template reaction, the reaction conditions were screened.

[0036]

[0037] (1) Screening of organic solvents: Using the template reaction, other conditions were the same as those in the general experimental procedure except for the solvent.

[0038] Table 1. Screening experiments of organic solvents

[0039]

[0040]

[0041] When THF was used as the solvent, compound 1 was completely consumed, but the target product compound 3 was not detected. From the data in the table, it can be seen that acetonitrile gave the highest yield of the target product compound 3 as the reaction solvent.

[0042] (2) Screening of catalysts: Using a template reaction, except for the catalyst, other conditions are the same as those in the general experimental process.

[0043] Table 2. Screening experiments of catalysts

[0044] Entry Catalyst Yield 1 None 0％ 2 <![CDATA[[Ir(ppy)2(dtbbpy)]PF6]]> 17％ 3 <![CDATA[[Ru(bpy)3]Cl2]]> N.D. 4 4-CzIPN N.D. 5 <![CDATA[Ir(ppy)3]]> 77％

[0045] It can be seen from the data in the table that in the absence of a catalyst, the raw materials did not undergo conversion and no products were formed; when the catalyst (4,4'-di-tert-butyl-2,2'-bipyridine) bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate was selected, the raw material I was completely converted and the product yield was 17%; when [Ru(bpy)3]Cl2 (ruthenium(II) tris(bipyridine)) or 4-CzIPN (2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile) was selected as the catalyst, compound 1 was completely converted, and the target product compound 3 was not detected. When Ir(ppy)3 was selected as the catalyst, the yield of the target product compound 3 was the highest.

[0046] (3) Screening of visible light wavelengths: Using a template reaction, except for the wavelength, other conditions are the same as those in the general experimental process.

[0047] Table 3. Screening experiments of visible light wavelengths

[0048] Entry Wavelength Yield 1 410 - 420 nm (violet light) N.D. 2 480 - 490 nm (cyan - blue light) 21％ 3 450 - 460 nm (blue light) 77％

[0049] It can be seen from the data in the table that when the reaction solution was irradiated with ultraviolet light, compound 1 was completely converted, but the target product compound 3 was not detected. When blue light with a wavelength range of 450 - 460 nm was selected, the yield of the target product compound 3 was the highest.

[0050] Next, the technical solution of the present invention will be further described in combination with specific embodiments.

[0051] Synthesis reference of raw material compound 1: Tao Wang, Yuan-Yuan Zong, Tao Huang, Xiao-Ling Jin, Li-Zhu Wu and Qiang Liu. Chem. Sci., 2023, 14, 11566 - 11572.

[0052] Raw material compound 2 is a commercially available compound.

[0053] The reaction conditions of the following examples all adopt those of the general experimental process.

[0054] Example 1

[0055]

[0056] R1 is phenyl, R2 is Boc (tert-butoxycarbonyl), and the yield of the target product 3a is 77%.

[0057] tert-butyl(1-phenyl-5-(pyridin-4-ylthio)-4-(trifluoromethyl)-1H-pyrrol-2-yl)carbamate

[0058] As Figure 1 shown, the 1H NMR data: 1 H NMR(400MHz,Chloroform-d)δ(ppm): 8.28(dd,J1 = 1.7Hz and J2 = 4.6Hz,2H), 7.46–7.42(m,1H), 7.41–7.34(m,2H), 7.07(d,J = 7.3Hz,2H), 6.76(dd,J1 = 1.7 and J2 = 4.7Hz,2H), 6.73(brs,1H), 6.38(s,1H), 1.42(s,9H).

[0059] As Figure 2 shown, the 13C NMR data: 13 C NMR(101MHz,Chloroform-d)δ(ppm) = 152.2, 149.5, 149.3, 134.0, 131.2, 129.8, 129.4, 128.3, 123.1(q,J = 35.7Hz), 122.8(q,J = 268.1Hz), 120.0, 111.0, 100.1, 81.7, 28.0.

[0060] As Figure 3 shown, the 19F NMR data: 19 F NMR(376MHz,Chloroform-d)δ(ppm) = -57.42.

[0061] High resolution mass spectrum: 435.1233 (theoretical value: 435.1228).

[0062] Example 2

[0063]

[0064] R1 is 4-methylphenyl, R2 is Boc (tert-butoxycarbonyl), and the yield of the target product 3b is 78%.

[0065] tert-butyl(5-(pyridin-4-ylthio)-1-(p-tolyl)-4-(trifluoromethyl)-1H-pyrrol-2-yl)carbamate

[0066] Hydrogen spectrum data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)=8.32–8.28(m,2H),7.17(d,J=7.9Hz,2H),6.95(d,J=8.0Hz,2H),6.81–6.77(m,2H),6.74(s,1H),6.34(s,1H),2.37(s,3H),1.43(s,9H).

[0067] Carbon spectrum data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)=152.0,149.8,149.2,140.1,131.5,131.2,130.1,128.0,123.0(q,J=36.4Hz),122.8(q,J=268.1Hz),119.9,110.6,99.2,81.7,28.0,21.2.

[0068] Fluorine spectrum data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)=-57.45.

[0069] High resolution mass spectrum: 449.1389 (theoretical value: 449.1385).

[0070] Example 3

[0071]

[0072] R1 is 2-methylphenyl, R2 is Boc (tert-butoxycarbonyl), and the yield of the target product 3c is 72%.

[0073] tert-butyl(5-(pyridin-4-ylthio)-1-(o-tolyl)-4-(trifluoromethyl)-1H-pyrrol-2-yl)carbamate

[0074] Hydrogen spectrum data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)=8.27(d,J=5.6Hz,2H),7.40–7.30(m,2H),7.11(td,J=7.5,1.8Hz,1H),6.86(d,J=7.8Hz,1H),6.83–6.70(m,3H),6.29(s,1H),1.93(s,3H),1.43(s,9H).

[0075] Carbon spectrum data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)=151.8,149.1,137.1,132.8,131.3,131.3,130.3,128.7,126.9,123.1(q,J=36.0Hz),122.8(q,J=268.0Hz),120.4,110.0,98.7,81.8,28.0,17.3。

[0076] Fluorine spectrum data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)=-57.30。

[0077] High resolution mass spectrum: 449.1390 (theoretical value: 449.1385).

[0078] Example 4

[0079]

[0080] R1 is 4-tert-butylphenyl, R2 is Boc (tert-butoxycarbonyl), and the yield of the target product 3d is 71%.

[0081] tert-butyl

[0082] (1-(4-(tert-butyl)phenyl)-5-(pyridin-4-ylthio)-4-(trifluoromethyl)-1H-pyrrol-2-yl)carbamate

[0083] Hydrogen spectrum data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)=8.29(d,J=5.5Hz,2H),7.37(d,J=8.2Hz,2H),6.98(d,J=8.2Hz,2H),6.77(d,J=6.2Hz,2H),6.72(s,1H),6.29(s,1H),1.43(s,9H),1.31(s,9H)。

[0084] Carbon spectrum data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)=153.0,152.0,149.6,149.2,131.4,131.1,127.8,126.4,122.8(q,J=36.1Hz),122.8(q,J=268.1Hz),120.2,111.0,99.4,81.7,34.8,31.1,28.0。

[0085] Fluorine spectrum data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)= -57.39.

[0086] High-resolution mass spectrometry: 491.1857 (theoretical value: 491.1854).

[0087] Example 5

[0088]

[0089] R1 is phenyl, R2 is benzoyl, and the yield of the target product 3e is 78%.

[0090] N-(1-phenyl-5-(pyridin-4-ylthio)-4-(trifluoromethyl)-1H-pyrrol-2-yl)benzamide

[0091] Hydrogen spectrum data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)= 8.30–8.24(m,2H),8.00(s,1H),7.59–7.52(m,2H),7.56–7.43(m,2H),7.46–7.40(m,3H),7.37(d,J = 1.7Hz,1H),7.10(d,J = 7.3Hz,2H),7.06(s,1H),6.82–6.76(m,2H).

[0092] Carbon spectrum data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)= 164.8,149.4,149.3,133.8,133.0,132.4,130.8,130.1,129.7,128.8,128.2,126.9,123.4(q,J = 36.1Hz),122.7(q,J = 268.2Hz),120.1,111.6,101.3.

[0093] Fluorine spectrum data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)= -57.37.

[0094] High-resolution mass spectrometry: 439.0973 (theoretical value: 439.0966).

[0095] Example 6

[0096]

[0097] R1 is phenyl, R2 is 4-methylbenzoyl, and the yield of the target product 3f is 77%.

[0098] 4-methyl-N-(1-phenyl-5-(pyridin-4-ylthio)-4-(trifluoromethyl)-1H-pyrrol-2-yl)benzamide

[0099] 1H NMR data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)=8.34(s,1H),8.21(d,J=6.3Hz,2H),7.49(d,J=8.3Hz,2H),7.46–7.40(m,1H),7.34(t,J=7.5Hz,2H),7.16(d,J=8.0Hz,2H),7.07(d,J=7.4Hz,2H),6.98(s,1H),6.79–6.73(m,2H),2.35(s,3H).

[0100] 13C NMR data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)=165.3,149.1,143.0,133.9,130.9,130.1,129.8,129.4,129.4,128.1,127.3,127.0,123.2(q,J=36.1Hz),122.7(q,J=268.2Hz),120.1,111.5,101.8,21.4.

[0101] 19F NMR data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)=-57.30.

[0102] High resolution mass spectrum: 453.1125 (theoretical value: 453.1123).

[0103] Example 7

[0104]

[0105] R1 is phenyl, R2 is 4-fluorobenzoyl, and the yield of the target product 3g is 75%.

[0106] 4-fluoro-N-(1-phenyl-5-(pyridin-4-ylthio)-4-(trifluoromethyl)-1H-pyrrol-2-yl)benzamide

[0107] Hydrogen spectrum data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)=8.65(s,1H),8.20–8.15(m,2H),7.66–7.59(m,2H),7.46–7.40(m,1H),7.33(t,J=7.6Hz,2H),7.06–6.99(m,4H),6.96(s,1H),6.83–6.78(m,2H).

[0108] Carbon spectrum data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)=165.0(d,J=253.8Hz),164.6,150.1,148.8,134.0,130.7,129.8,129.5(d,J=9.1Hz),129.4,129.2(d,J=3.1Hz),127.9,123.3(q,J=36.2Hz),122.6(q,J=268.2Hz),120.1,115.8(d,J=22.0Hz),111.8,102.4.

[0109] Fluorine spectrum data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)=-57.36,-106.14.

[0110] High resolution mass spectrum: 457.0877 (theoretical value: 457.0872).

[0111] Example 8

[0112]

[0113] R1 is phenyl, R2 is 4-chlorobenzoyl, and the yield of the target product 3h is 70%.

[0114] 4-chloro-N-(1-phenyl-5-(pyridin-4-ylthio)-4-(trifluoromethyl)-1H-pyrrol-2-yl)benzamide

[0115] Hydrogen spectrum data: 1 H NMR(400MHz,Chloroform-d)δ(ppm)=8.45(s,1H),8.19(d,J=6.3Hz,2H),7.60–7.54(m,2H),7.45–7.39(m,1H),7.37–7.29(m,4H),7.07–7.00(m,2H),6.79–6.74(m,2H).

[0116] Carbon spectrum data: 13 C NMR(101MHz,Chloroform-d)δ(ppm)=164.4,149.8,149.0,138.7,133.9,131.4,130.6,129.9,129.5,129.0,128.5,128.0,123.3(q,J=36.1Hz),122.7(q,J=268.2Hz),120.1,111.9,102.2。

[0117] Fluorine spectrum data: 19 F NMR(376MHz,Chloroform-d)δ(ppm)=-57.38。

[0118] High resolution mass spectrum: 473.0581 (theoretical value: 473.0576).

[0119] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. Without conflict, the embodiments of the present application and the features in the embodiments can be combined with each other arbitrarily.

Claims

1. A fluorine-containing polysubstituted pyrrole compound, characterized in that, It has the following structural formula: Among them, R1 is selected from one of phenyl, 4-methylphenyl, 2-methylphenyl, and 4-tert-butylphenyl; R2 is an amino protecting group, and the amino protecting group is a Boc protecting group, benzoyl group or substituted benzoyl group.

2. The fluorine-containing polysubstituted pyrrole compound according to claim 1, characterized in that, The substituted benzoyl group is 4-methylbenzoyl, 4-fluorobenzoyl or 4-chlorobenzoyl.

3. A photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to claim 1, characterized in that, It includes the following steps: (1) Add compound 1 Compound 2 a base, and a catalyst to an organic solvent to form a reaction solution; (2) Under an inert gas, the reaction solution was irradiated with visible light, and after the reaction was completed, purification treatment was carried out to obtain Compound 3 Wherein, R1 is selected from one of phenyl, 4-methylphenyl, 2-methylphenyl, and 4-tert-butylphenyl; R2 is an amino protecting group, and the amino protecting group is a Boc protecting group, a benzoyl group or a substituted benzoyl group.

4. The photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to claim 3, characterized in that, The substituted benzoyl group is 4-methylbenzoyl, 4-fluorobenzoyl or 4-chlorobenzoyl.

5. The photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to claim 3, characterized in that, The molar ratio of Compound 1, Compound 2, base, and catalyst is 1:(2-3):(2-3):(0.01-0.02).

6. The photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to claim 5, characterized in that, The molar ratio of Compound 1, Compound 2, base, and catalyst is 1:2:2:0.

01.

7. The photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to any one of claims 3 to 6, characterized in that, The base is DABCO, and the catalyst is a photosensitive catalyst Ir(ppy)3 or [Ir(ppy)2(dtbbpy)]PF6.

8. The photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to claim 3, characterized in that, The visible light is blue light or greenish-blue light.

9. The photocatalytic synthesis method of a fluorine-containing polysubstituted pyrrole compound according to claim 8, characterized in that, The wavelength range of the blue light is 450-460 nm, and the range of the greenish-blue light is 480-490 nm.

10. The photocatalytic synthesis method of the fluorine-containing polysubstituted pyrrole compound according to claim 3, characterized in that, The organic solvent is acetonitrile, DMF, acetone or DMSO.

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