A method for synthesizing 1-trifluoromethylthioindole compounds

Abstract

This invention discloses a method for synthesizing 1-trifluoromethylthioindole compounds from 2-alkynylarylamines, belonging to the field of organic chemistry. The method uses 2-alkynylarylamine compounds and N-trifluoromethylthiosaccharin as raw materials, and achieves rapid one-pot synthesis of 1-trifluoromethylthioindole compounds under the action of an inorganic base. This method has broad substrate applicability, uses readily available and simple raw materials, and is economically cost-effective. Furthermore, the synthesis of the target product does not require a catalyst and only needs 8-10 hours of reaction time to obtain the target product in good yield. The target compound has wide applications in pharmaceuticals, pesticides, and functional materials.

Description

Technical Field

[0001] This invention specifically relates to a method for synthesizing 1-trifluoromethylthioindole compounds from 2-alkynylarylamines, belonging to the field of organic chemistry. Background Technology

[0002] The trifluoromethyl thio group (-SCF3) is an important fluorine-containing functional group with excellent lipophilicity, strong electron-withdrawing properties, and bioactivity, making it widely used in organic synthesis, medicinal chemistry, and materials science. The stability and relatively easy introduction of the trifluoromethyl thio group make it one of the most popular functional groups. Furthermore, indole and its derivatives exhibit broad-spectrum bioactivity in anti-inflammatory, insecticidal, bactericidal, and antitumor activities. Combining the advantages of both indole and indole in these areas, introducing a trifluoromethyl thio group into the indole skeleton would undoubtedly endow the compound with some novel and unique properties. However, no methods for introducing a trifluoromethyl thio group onto the nitrogen atom of indole have been reported to date.

[0003] In existing technologies, the introduction of trifluorine groups into compounds often involves the use of catalysts. For example, patent CN117865869A uses various metal compounds as catalysts. Similarly, the synthesis of indole compounds often employs catalysts, such as the metal catalyst used in CN 115322132B. However, catalysts suffer from drawbacks such as high cost, toxicity, and environmental damage during recycling. Furthermore, the catalytic reaction readily generates byproducts, making subsequent separation and purification of the products difficult and impacting product quality.

[0004] Therefore, developing a simple, mild, catalyst-free direct trifluoromethylthiolation method for the rapid construction of 1-trifluoromethylthioindole skeletons is of great importance and practical value. Summary of the Invention

[0005] This invention develops a novel method for synthesizing 1-trifluoromethylthioindole compounds. The method involves the addition cyclization of N-trifluoromethylthioindole compounds with 2-alkynyl aromatic amines and N-trifluoromethylthiosaccharin and an inorganic base, thus conveniently achieving the synthesis of 1-trifluoromethylthioindole derivatives.

[0006] The first objective of this invention is to provide a method for synthesizing 1-trifluoromethylthioindole compounds, comprising the following steps: in an organic solvent, a 2-alkynyl aromatic amine compound of formula (1), N-trifluoromethylthiosaccharin and an inorganic base undergo a cyclization reaction to synthesize the 1-trifluoromethylthioindole compound of formula (2);

[0007]

[0008] Among them, R 1Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br), cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 It is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles.

[0009] In one embodiment of the present invention, the aryl group includes substituted or unsubstituted benzene rings, naphthalene rings, and heteroaryl rings; the substitution can be one to three substitutions; the substituted group is selected from halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, ester groups, cyano groups, nitro groups, and heterocycles.

[0010] In one embodiment of the present invention, the acyl group is -COR. a R a It is H or C1-8 alkyl.

[0011] In one embodiment of the present invention, the amide group is -NHCOR. b R b It is H or C1-8 alkyl.

[0012] In one embodiment of the present invention, the heterocycle is a three- to six-membered ring containing 1 to 3 heteroatoms. The heteroatoms include N, O, and S.

[0013] In one embodiment of the present invention, the ester group is -COOR. c R c It is a C1-8 alkyl group.

[0014] In one embodiment of the present invention, the organic solvent includes any one or more of acetonitrile (CH3CN), dichloromethane (DCM), tetrahydrofuran (THF), and 1,2-dichloroethane (DCE). CH3CN is preferred.

[0015] In one embodiment of the present invention, the inorganic base is any one or more of potassium tert-butoxide, sodium bicarbonate, copper acetate, and potassium fluoride. Potassium fluoride is preferred.

[0016] In one embodiment of the invention, the reaction temperature is 25°C-70°C, preferably 45°C-55°C.

[0017] In one embodiment of the present invention, the reaction time is 8-10 hours. Specifically, 8 hours may be selected.

[0018] In one embodiment of the present invention, the molar ratio of the 2-alkynyl aromatic amine compound, N-trifluoromethylthiosaccharin, and inorganic base is 1:(1.5-2.5):(0-3.0). Preferably, it is 1:2.5:3.

[0019] In one embodiment of the present invention, the reaction concentration of the 2-alkynyl aromatic amine compound is 0.05-5 mmol / mL, more preferably 0.05-2 mmol / mL. Specifically, 0.1 mmol / mL is preferred.

[0020] In one embodiment of the present invention, the N-trifluoromethyl sulfidation / cyclization reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere.

[0021] The second objective of this invention is to provide a novel, green, and economical synthesis method, comprising the following steps:

[0022] Using 2-alkynyl aromatic amines, N-trifluoromethylthiosaccharin, and potassium fluoride as raw materials, a crude product of 1-trifluoromethylthiosindo compound was obtained by stirring and reacting at 45-55℃ for a period of time. Then, pure 1-trifluoromethylthiosindo compound was obtained by filtration, washing, vacuum distillation, and column chromatography.

[0023] In one embodiment of the present invention, the separation and purification method employs rapid column chromatography to obtain the final product 1-trifluoromethylthioindole compound.

[0024] In one embodiment of the present invention, the method is preferably carried out as follows: 2-alkynyl aromatic amine compound, N-trifluoromethylthiosaccharin, and potassium fluoride are added to a reaction vessel containing acetonitrile solvent in a molar ratio of 1:2.5:3, stirred at 50°C for 8-10 hours, and then separated and purified to obtain the target product.

[0025] In one embodiment of the present invention, the reaction mechanism of the method is as follows: 2-alkynyl aromatic amine compounds undergo N-electrophilic substitution with the trifluoromethylthio cation provided by N-trifluoromethylthiosaccharin, and under the action of a base, a proton is deprotonated to form a nitrogen anion, which then undergoes nucleophilic addition / cyclization of the alkynyl group, ultimately generating a 1-trifluoromethylthioindole compound.

[0026] A third objective of this invention is to provide a method for preparing an indole derivative, the method comprising:

[0027] (1) First, 1-trifluoromethylthioindole compounds are prepared and synthesized using the method of the present invention; specifically:

[0028] In an organic solvent, the 2-alkynyl aromatic amine compound shown in formula (1), N-trifluoromethylthiosaccharin and an inorganic base undergo a cyclization reaction to synthesize the 1-trifluoromethylthiosindo compound shown in formula (2);

[0029]

[0030] Among them, R 1Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br), cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles;

[0031] (2) Using the 1-trifluoromethylthioindole compound obtained in step (1) as a reactant, indole derivatives are prepared.

[0032] In one embodiment of the present invention, the indole derivative uses a 1-trifluoromethylthioindole compound as a synthetic intermediate; optionally, the indole derivative can be a bioactive drug molecule. For example, the indole derivative of a CRAC modulator reported in patent document CN102574788A. A fourth object of the present invention is to provide an application of the method in the fields of pharmaceuticals, pesticides, and functional materials preparation.

[0033] In one embodiment of the present invention, the application is for preparing 1-trifluoromethylthioindole compounds, or indole compounds that can be obtained by further reaction using 1-trifluoromethylthioindole compounds as raw materials.

[0034] The fifth objective of this invention is to provide a method for synthesizing a CRAC regulator indole derivative, the structure of which is shown below: The reaction route of the method is as follows:

[0035]

[0036] Among them, R 1 R 2 The definition is the same as above, R 1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br), cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 It is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles.

[0037] In one embodiment of the present invention, R 1 Specifically, hydrogen can be selected, R 2 Specifically, phenyl can be selected.

[0038] In one embodiment of the present invention, the method for synthesizing the important intermediate of the nicotinic acetylcholine receptor allosteric modulator includes the following steps:

[0039] (1) In an organic solvent, 2-alkynyl aromatic amines and N-trifluoromethylthiosaccharin reactants were reacted and potassium fluoride was added to carry out a cyclization reaction to synthesize 1-trifluoromethylthios-2-phenylindole compounds;

[0040] (2) The obtained 1-trifluoromethylthio-2-phenylindole compounds were oxidized to obtain CRAC regulator indole derivatives.

[0041] In one embodiment of the present invention, the conditions involved in step (1) are the same as those in the above-described synthesis method of 1-trifluoromethylthioindole compounds.

[0042] In one embodiment of the present invention, the oxidation in step (2) involves dissolving a 1-trifluoromethylthio-2-phenylindole compound in dichloromethane, then adding mCPBA dissolved in dichloromethane dropwise over 30 minutes under ice / water cooling, and reacting at room temperature for a period of time under nitrogen atmosphere.

[0043] In one embodiment of the present invention, the mass concentration of mCPBA is 80%.

[0044] In one embodiment of the present invention, the amount of mCPBA added relative to the 1-trifluoromethylthio-2-phenylindole compound is 0.54 g / mmol.

[0045] Beneficial effects:

[0046] (1) The method of the present invention uses 2-alkynylarylamine and N-trifluoromethylthiosaccharin as reactants in a nitrogen atmosphere and an inorganic base to carry out a one-pot reaction to achieve the construction of the 1-trifluoromethylthiosindo skeleton and obtain the target compound.

[0047] (2) The method of the present invention uses N-trifluoromethylthiosaccharin as a fluorine source, which has wide substrate applicability, simple and readily available raw materials, and low economic cost. In addition, the method of the present invention does not require a catalyst to achieve the synthesis of the target product and only requires 8-10 hours of reaction to obtain the target product in good yield. The method is fast and efficient.

[0048] (3) The synthesis method of the present invention converts readily available 2-alkynyl aromatic amines into corresponding 1-trifluoromethylthioindole compounds under relatively simple conditions, thereby achieving the synthesis of 1-trifluoromethylthioindole derivatives in one step. The target compounds have wide applications in the fields of medicine, pesticides and functional materials. Attached Figure Description

[0049] Figure 1 This is a synthesis route diagram for the method of the present invention. Detailed Implementation

[0050] The following are specific embodiments of the present invention.

[0051] 1. The following examples involve 2-phenylethynylaniline (CAS: 13141-38-3), 2-p-nitrophenylethynylaniline (CAS: 157869-12-0), 2-p-methoxyphenylethynylaniline (CAS: 157869-15-3), 2-octynylaniline (CAS: 157869-10-8), and 2-phenylethynyl-4-chloroaniline (CAS: 92878). 2-97-2), 2-p-chlorophenylethynyl-4-methylaniline (1019842-29-5), N-trifluoromethylthiosaccharin (CAS: 1647073-46-8), N-trifluoromethylthiophthalimide (CAS: 719-98-2), and N-trifluoromethylthiobisbenzenesulfonylimide (CAS: 1902154-93-1) were synthesized by methods reported in existing literature.

[0052] Potassium fluoride, acetonitrile, ethyl acetate, mCPBA, sodium thiosulfate (Na2S2O3), and anhydrous MgSO4 were all purchased from Adamas.

[0053] 2. The chromatographic separation and purification methods involved in the following examples: Column type: G3, stationary phase: silica gel (particle size 200-300 mesh), mobile phase: V 石油醚 :V 乙酸乙酯 =100:1.

[0054] 3. The synthesis route diagram of the embodiments of the present invention, as follows: Figure 1 As shown, specifically:

[0055] The target compound is obtained by reacting o-alkynylaniline and N-trifluoromethylthiosaccharin as raw materials, adding potassium fluoride, and using acetonitrile as the reaction solvent at 50°C for 8-10 hours. The reaction formula is as follows: Figure 1 .

[0056] Example 1: Synthesis of 2-phenyl-1-trifluoromethylthioindole

[0057]

[0058] Under nitrogen protection, p-2-phenylethynylaniline (97 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (354 mg, 1.25 mmol), potassium fluoride (124 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C and 800 rpm for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by vacuum distillation. The crude product was then purified by column chromatography to obtain 129 mg of the target compound, with a yield of 88%.

[0059] The obtained product was analyzed and characterized, and the specific data are as follows:

[0060] 1 H NMR (400MHz, CDCl3) δ7.54(dd,J=6.7,3.0Hz,2H),7.47–7.40(m,2H),7.39–7.35(m,3H),7.34(t,J=8.7Hz,1H),6.93(t,1H),6.01(s,1H). 19 F NMR (376MHz, CDCl3) δ-52.66 (s, 3F). 13 C NMRδ146.18(s),132.39(s),131.87(s),130.09(s),129.50(q,J=317.2Hz),129.04(s),128 .73(s),122.72(s),121.54(s),113.57(s),110.92(s),96.33(s),84.22(s).HRMS(APCI)m / z calculated for C 15 H 10 F3NSH[M+H] + :294.0564,found:294.0560.

[0061] Example 2: Synthesis of 2-p-nitrophenyl-1-trifluoromethylthioindole

[0062]

[0063] Under nitrogen protection, p-2-nitrophenylethynylaniline (119 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (354 mg, 1.25 mmol), potassium fluoride (124 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C and 800 rpm for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by vacuum distillation. The crude product was then purified by column chromatography to obtain 152 mg of the target compound, with a yield of 90%.

[0064] The obtained product was analyzed and characterized, and the specific data are as follows:

[0065] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=8.8Hz,2H),7.68(d,J=8.8Hz,2H),7.50–7.35(m,3H),6.97(t,J=7.5Hz,1H),5.94(s,1H).19 F NMR (376MHz, CDCl3) δ-52.56 (s, 3F). 13 CNMR(101MHz, CDCl3)δ147.53(s),146.48(s),132.78(s),132.51(s),131.15(s),129.54(s),129.41 (q, J=317.0Hz),123.97(s),121.77(s),113.91(s),109.74(s),94.27(s),89.52(s).HRMS(APCI)m / z calcd.for C 15 H9F3N2O2SH(M+H) + :339.0415; found:339.0420.

[0066] Example 3: Synthesis of 2-p-methoxyphenyl-1-trifluoromethylthioindole

[0067]

[0068] Under nitrogen protection, 2-p-methoxyphenylethynylaniline (112 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (354 mg, 1.25 mmol), potassium fluoride (124 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C and 800 rpm for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by vacuum distillation. The crude product was then purified by column chromatography to obtain 126 mg of the target compound, with a yield of 78%.

[0069] The obtained product was analyzed and characterized, and the specific data are as follows:

[0070] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=8.8Hz,2H),7.42(dd,J=13.7,8.0Hz,2H),7.35–7.27(m,1H),6.92(dd,J=13.2,8.2Hz,3H),6.02(s,1H),3.84(s,3H). 19 F NMR (376MHz, CDCl3) δ-52.66 (s, 3F). 13C NMR (101MHz, CDCl3) δ160.20(s), 145.97(s), 133.35(s), 132.24(s), 129.76(s), δ129.46(q, J=317.2Hz), 121.45(s),114.68(s),114.33(s),113.39(s),111.15(s),96.32(s),82.85(s),55.56(s).HRMS(APCI)m / z calculated forC 16 H 12 F3NOSH[M+H] + :324.0670,found:324.0669.

[0071] Example 4: Synthesis of 1-trifluoromethylthio-2-hexylindole

[0072]

[0073] Under nitrogen protection, 2-octyrylaniline (101 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (354 mg, 1.25 mmol), potassium fluoride (124 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C and 800 rpm for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by vacuum distillation. The crude product was then purified by column chromatography to obtain 80 mg of the target compound, with a yield of 53%.

[0074] The obtained product was analyzed and characterized, and the specific data are as follows:

[0075] 1 H NMR(400MHz, CDCl3)δ7.38(d,J=8.2Hz,1H),7.32–7.24(m,2H),6.87(t,J=7.5Hz,1H),5.98( s,1H),2.48(t,J=7.0Hz,2H),1.65(s,2H),1.46(t,J=7.5Hz,2H),1.33(s,4H),0.91(s,3H). 19 F NMR(376MHz, CDCl3)δ-52.79(s,3F). 13C NMR(101MHz, CDCl3)δ145.99(s),132.16(s),129.15(s),127.89(q),127.02(s),124.73(s),121.26(s),113.11(s) ),111.60(s),97.90(s),75.72(s),31.54(s),28.86(d,J=2.1Hz),22.78(s),19.82(s),14.27(s).HRMS(APCI)m / z calculated for C 15 H 18 F3NSH[M+H] + :302.1190,found:302.1181.

[0076] Example 5: Synthesis of 1-trifluoromethylthio-2-phenyl-5-chloroindole

[0077]

[0078] Under nitrogen protection, 2-phenylethynyl-4-chloroaniline (114 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (354 mg, 1.25 mmol), potassium fluoride (124 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C and 800 rpm for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by vacuum distillation. The crude product was then purified by column chromatography to obtain 110 mg of the target compound, with a yield of 67%.

[0079] The obtained product was analyzed and characterized, and the specific data are as follows:

[0080] 1 H NMR (400MHz, CDCl3) δ7.56–7.52(m,2H),7.41–7.38(m,4H),7.37(t,J=4.4Hz,1H),7.28(dd,J=8.9,2.4Hz,1H),5.97(s,1H). 19 F NMR (376MHz, CDCl3) δ-52.56 (s, 3F). 13CNMR(101MHz, CDCl3)δ144.89(s),131.93(s),131.71(s),131.14(q),130.07(s),129.39(s),1 28.80(s),126.40(s),122.19(s),114.94(s),112.31(s),97.32(s),82.96(s).HRMS(APCI)m / z calculated for C 15 H9ClF3NSH[M+H] + :328.0175,found:328.0164.

[0081] Example 6: Synthesis of 1-trifluoromethylthio-2-p-chlorophenyl-5-methylindole

[0082]

[0083] Under nitrogen protection, 2-p-chlorophenylethynyl-4-methylaniline (121 mg, 0.5 mmol), N-trifluoromethylthiosaccharin (354 mg, 1.25 mmol), potassium fluoride (124 mg, 1.5 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 50 °C and 800 rpm for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was removed by vacuum distillation. The crude product was then purified by column chromatography to obtain 126 mg of the target compound, with a yield of 74%.

[0084] The obtained product was analyzed and characterized, and the specific data are as follows:

[0085] 1 H NMR (400MHz, CDCl3) δ7.48–7.42(m,2H),7.34(dd,J=8.4,4.4Hz,3H),7.24(d,J=7.7Hz,1H),7.14(d,J=8.5Hz,1H),5.84(s,1H),2.28(s,3H). 19 F NMR (376MHz, CDCl3) δ-52.73 (s, 3F). 13C NMR(101MHz, CDCl3)δ143.97(s),135.03(s),133.02(s),132.64(s),131.15(s),131.07(s),129.53(q,J= 317.3Hz),129.07(s),121.31(s),113.80(s),110.39(s),94.75(s),85.47(s),20.52(s).HRMS(APCI)m / z calculated for C 16 H 11 ClF3NSH[M+H] + :342.0331,found:342.0336.

[0086] In this invention, we also replaced 2-p-chlorophenylethynyl-4-methylaniline with other substitutions to obtain more corresponding poly-1-trifluoromethylthioindole target compounds. Through the synthesis of dozens of extended compounds, we found that the method of this invention is universal and can effectively prepare the target compounds.

[0087] Example 7: Effects of different inorganic bases on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0088] Referring to Example 1, the inorganic base was replaced by potassium tert-butoxide, sodium bicarbonate, and copper acetate, respectively, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylthioindole. Specific yield results are shown in Table 1.

[0089] Table 1 Effect of different inorganic bases on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0090] Inorganic base Separation yield (%) KF (Example 1) 88 t-BuOK 23 <![CDATA[NaHCO3]]> 35 <![CDATA[(CH3COO)2Cu]]> 33

[0091] The results showed that using potassium tert-butoxide, sodium bicarbonate, or copper acetate instead of potassium fluoride in Example 1 as the inorganic base could yield the target product, but the product yield was worse than that in Example 1.

[0092] Example 8: Effect of different solvents on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0093] Referring to Example 1, the solvent was replaced by acetonitrile with 1,2-dichloroethane, tetrahydrofuran, and dichloromethane, respectively, while keeping other conditions unchanged, to synthesize 2-phenyl-1-trifluoromethylthioindole. Specific yield results are shown in Table 2.

[0094] Table 2 Effect of different solvents on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0095] solvent Separation yield (%) <![CDATA[CH3CN (Example 1)]]> 88 DCE 25 THF 40 DCM 60

[0096] The results showed that replacing acetonitrile in Example 1 with 1,2-dichloroethane, tetrahydrofuran, or dichloromethane as the solvent could yield the target product, but the product yield was worse than that of Example 1.

[0097] Example 9: Synthesis of 2-phenyl-1-trifluoromethylthioindole at different reaction temperatures

[0098] Referring to Example 1, the reaction temperature was replaced from 50°C to 30°C, 70°C, and 90°C respectively, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylthioindole.

[0099] The specific yield results are shown in Table 3.

[0100] Table 3 Effect of different reaction temperatures on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0101] Temperature (°C) Separation yield (%) 30 63 50 (Example 1) 88 70 83 90 77

[0102] The results showed that replacing 50°C in Example 2 with 30°C, 70°C, or 90°C all yielded the target product, but the product yield was not significantly different from that in Example 1. However, the yield decreased considerably when the temperature reached 90°C.

[0103] Example 10: Synthesis of 2-phenyl-1-trifluoromethylthioindole from different trifluoromethylthio sources

[0104] Referring to Example 1, the trifluoromethyl thiocyanate source was replaced by N-trifluoromethyl thiocyanate saccharin with N-trifluoromethyl thiocyanate phthalimide, N-trifluoromethyl thiocyanate bisbenzenesulfonylimide, and silver trifluoromethyl thiocyanate, respectively, while keeping other conditions unchanged, to synthesize 2-phenyl-1-trifluoromethyl thiocyanate indole. The specific yield results are shown in Table 4.

[0105] Table 4. Effects of different trifluoromethyl sulfide sources on the synthesis of 2-phenyl-1-trifluoromethyl sulfide indole

[0106] Trifluoromethyl sulfide source Separation yield (%) N-Trifluoromethylsaccharin (Example 1) 88 N-Trifluoromethylthiophthalimide trace N-Trifluoromethylthiobisbenzenesulfonylimide trace Silver trifluoromethyl sulfide NR

[0107] The results showed that replacing N-trifluoromethylthiophthalimide, N-trifluoromethylthiobisbenzenesulfonimide, and silver trifluoromethylthiocyanate in Example 1 with N-trifluoromethylthiocyanate saccharin as the trifluoromethylthiocyanate source yielded the target product, except that the trifluoromethylthiocyanate source was silver trifluoromethylthiocyanate. However, the product yield was worse than that in Example 1.

[0108] Example 11: Molar ratio of different 2-alkynyl aromatic amine compounds, N-trifluoromethylthiosaccharin, and inorganic bases

[0109] Referring to Example 1, the molar ratios of 2-alkynyl aromatic amine compounds, N-trifluoromethylthiosaccharin, and inorganic base were adjusted to 1:1.5:1, 1:1.5:1.5, 1:2:1, 1:2:2, 1:2.5:2, and 1:2.5:2.5, while keeping other conditions unchanged, to synthesize 2-phenyl-1-trifluoromethylthiosindo. Specific yield results are shown in Table 5.

[0110] Table 5. Effect of different molar ratios of 2-alkynyl aromatic amines, N-trifluoromethylthiosaccharin, and inorganic bases on the synthesis of 2-phenyl-1-trifluoromethylthiosindol.

[0111]

[0112] The results showed that replacing the 1:2.5:3 ratio in Example 1 with 2-alkynyl aromatic amine compounds, N-trifluoromethylthiosaccharin and inorganic base in molar ratios of 1:1.5:1, 1:1.5:1.5, 1:2:1, 1:2:2, 1:2.5:2, and 1:2.5:2.5 all yielded the target product, but the yield of the product was worse than that of Example 1.

[0113] Example 12: Reaction concentrations of different 2-alkynyl aromatic amine compounds

[0114] Referring to Example 1, the reaction concentrations of the 2-alkynyl aromatic amine compounds were adjusted to 0.05, 1, 2, 3, 4, and 5 mmol / mL, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylthioindole. Specific yield results are shown in Table 6.

[0115] Table 6. Effect of reaction concentrations of different 2-alkynyl aromatic amine compounds on the synthesis of 2-phenyl-1-trifluoromethylthioindole.

[0116]

[0117] The results showed that replacing the 0.1 mmol / mL in Example 1 with 0.05, 1, 2, 3, 4, and 5 mmol / mL of 2-alkynyl aromatic amine compounds all yielded the target product, but the yield of the product was worse than that of Example 1.

[0118] Example 13: Different reaction times

[0119] Referring to Example 1, the reaction time was adjusted to 7 h, 9 h, 10 h, and 11 h, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylthioindole. Specific yield results are shown in Table 7.

[0120] Table 7. Effect of different reaction times on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0121] Reaction time (h) Separation yield (%) 7 71 9 83 10 80 11 81

[0122] The results showed that replacing the 8h reaction time in Example 1 with 7h, 9h, 10h, and 11h all yielded the target product, but the product yield was worse than that in Example 1, and extending the reaction time did not significantly change the reaction yield.

[0123] Example 14: Synthesis of an indole derivative (taking an indole derivative of a CRAC regulator as an example)

[0124] 1-Trifluoromethylthioindole compounds can be used as raw materials or synthetic intermediates to further synthesize indole derivatives, thus having wide applications in the fields of pharmaceuticals, pesticides, and functional materials. For example, 1-trifluoromethylthioindole compounds can be used as raw materials to prepare bioactive drug molecules—indole derivatives, such as the indole derivative of a CRAC modulator reported in patent document CN102574788A.

[0125] Therefore, this embodiment provides a method for preparing an indole derivative, the method comprising:

[0126] (1) First, 1-trifluoromethylthioindole compounds were prepared and synthesized; specifically:

[0127] In an organic solvent, the 2-alkynyl aromatic amine compound shown in formula (1), N-trifluoromethylthiosaccharin and an inorganic base undergo a cyclization reaction to synthesize the 1-trifluoromethylthiosindo compound shown in formula (2);

[0128]

[0129] Among them, R 1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen (F, Cl, Br), cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles;

[0130] (2) Using the 1-trifluoromethylthioindole compound obtained in the previous step as a reactant, indole derivatives were prepared.

[0131] Taking the preparation of indole derivatives of CRAC regulators as an example: Indole derivatives of CRAC regulators are an important intermediate. The synthesis method of the intermediate reported in CN102574788A is as follows:

[0132]

[0133] Therefore, the synthetic reaction route for this indole derivative can be followed as follows:

[0134]

[0135] Specifically:

[0136] 1-Trifluoromethylthio-2-phenylindole was first prepared according to the method in Example 1. Then, 0.5 mmol of 1-trifluoromethylthio-2-phenylindole prepared in Example 1 was dissolved in CH2Cl2 (5 mL). Under ice-water cooling, a CH2Cl2 solution of mCPBA (0.161 g of 80% mCPBA dissolved in 2 mL of CH2Cl2) was added dropwise over 30 minutes. After stirring at room temperature and 800 rpm for 2 hours, the oxidant was removed with 30 mL of saturated aqueous solution of sodium thiosulfate (Na2S2O3). The organic layer in the reaction mixture was separated and washed three times with 30 × 3 mL of water. The organic phases were combined and dried over anhydrous MgSO4. The mixture was filtered, and the filtrate was collected and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain 103 mg of the target compound, with a yield of 70%.

[0137] The obtained product was analyzed and characterized, and the specific data are as follows:

[0138] 1 H NMR (400MHz, CDCl3) δ7.51 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.1 Hz, 2H), 7.31 (d, J = 8. 0Hz,1H),7.25(d,J=8.0Hz,1H),7.12(t,J=7.6Hz,2H),6.91(s,1H),6.89(s,1H). 19 FNMR(376MHz, CDCl3)δ-77.93.(s,3F).

[0139] Furthermore, It can also be used for R 1 R 2 Further substitutions can be made to obtain more analogs and provide corresponding synthetic methods for exploring more indole derivatives of CRAC regulators.

[0140] Furthermore, the indole derivative of the CRAC regulator can be prepared with reference to patent document CN102574788A.

[0141] Comparative Example 1:

[0142] Referring to Example 1, potassium fluoride was not added, and everything else remained the same.

[0143] The results showed that the yield decreased without the addition of potassium fluoride.

[0144] Comparative Example 2:

[0145] Referring to Example 1, cuprous iodide catalyst was added as an additional catalyst, while everything else remained the same.

[0146] The results showed that the addition of cuprous iodide did not significantly change the yield.

Claims

1. A method for synthesizing a 1-trifluoromethylthioindole compound, characterized in that, The method involves using 2-alkynyl aromatic amines of formula (1) and N-trifluoromethylthiosaccharin as reactants in an organic solvent and carrying out an N-trifluoromethylthiosylation / cyclization reaction in the presence of a base to synthesize 1-trifluoromethylthiosindo compounds of formula (2). Among them, R 1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles; The alkali is any one or more of potassium tert-butoxide, sodium bicarbonate, copper acetate, and potassium fluoride.

2. The method according to claim 1, characterized in that, The organic solvent includes any one or more of acetonitrile, dichloromethane, tetrahydrofuran, and 1,2-dichloroethane.

3. The method according to claim 1, characterized in that, The reaction temperature is 25℃-70℃.

4. The method according to claim 1, characterized in that, The molar ratio of the 2-alkynyl aromatic amine compound, N-trifluoromethylthiosaccharin and inorganic base is 1:(1.5-2.5):(0-3.0).

5. The method according to claim 1, characterized in that, The reaction concentration of the 2-alkynyl aromatic amine compounds is 0.05-5 mmol / mL.

6. The method according to claim 1, characterized in that, The N-trifluoromethyl sulfide / cyclization reaction was carried out under an inert gas atmosphere.

7. A method for synthesizing an indole derivative of a CRAC regulator, characterized in that, The structure of the indole derivative of the CRAC regulator is as follows: The reaction route of the method is as follows: Among them, R 1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, nitro, C1-C8 alkoxy, acyl and amide groups, and heterocycles; R 2 It is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles.

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