Synthesis method of 1-trifluoromethylthio indole compound

Abstract

The invention discloses a method for synthesizing a 1-trifluoromethylthio indole compound by taking 2-alkynyl arylamine as a raw material, and belongs to the field of organic chemistry. According to the method disclosed by the invention, a 2-alkynyl arylamine compound and N-trifluoromethylthio saccharin are taken as raw materials, and under the action of inorganic alkali, the one-pot synthesis of the 1-trifluoromethylthio indole compound can be quickly realized. The method has the advantages of wide substrate applicability, simple and easily available raw materials and low economic cost; besides, the synthesis of the target product is realized by the method, the target product can be obtained at a relatively high yield only by 8-10 hours without catalysis of a catalyst, and the target product has wide application in the fields of medicines, pesticides, functional materials and the like.

Description

Technical Field

[0001] The invention specifically relates to a method for synthesizing a 1-trifluoromethylthioindole compound by taking 2-alkynyl aromatic amine as a raw material, and belongs to the field of organic chemistry. Background Art

[0002] Trifluoromethylsulfide group (-SCF3) is an important fluorine-containing functional group with excellent lipid solubility, strong electron absorption and biological activity, and is widely used in organic synthesis, medicinal chemistry, materials science and other fields. The stability of trifluoromethylsulfide group and its relatively easy chemical properties make it one of the most popular groups. In addition, indole and its derivatives also show broad-spectrum biological activity in anti-inflammatory, insecticidal, bactericidal and anti-tumor aspects. Combining the advantages of the two in the above-mentioned fields, the introduction of trifluoromethylsulfide group into the indole skeleton will inevitably give the compound some new special properties. However, there is no report on the method of introducing trifluoromethylsulfide group into the nitrogen atom of indole.

[0003] In the prior art, when introducing trifluoro groups into compounds, catalysts are mostly used, such as various metal compounds used as catalysts in patent CN117865869A; when synthesizing indole compounds, catalysts are mostly used, such as metal catalysts used in CN 115322132B. Due to the defects of the catalyst itself, such as high cost, toxicity, environmental damage during recycling, and the easy generation of by-products during the catalytic reaction, the separation of the two is difficult in the subsequent separation and purification of the product, which will affect the product quality.

[0004] Therefore, it is of great importance and practical value to develop a simple, mild, catalyst-free, direct trifluoromethylthiolation method to quickly construct the 1-trifluoromethylthioindole skeleton. Summary of the invention

[0005] The present invention develops a new method for synthesizing 1-trifluoromethylthioindole compounds. The N-trifluoromethylthioindole compounds are obtained by addition cyclization of 2-alkynyl aromatic amine compounds with N-trifluoromethylthiosaccharin and inorganic base, thereby conveniently realizing the synthesis of 1-trifluoromethylthioindole derivatives.

[0006] The first object of the present 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 represented by formula (1), N-trifluoromethylthiosaccharin and an inorganic base undergo a cyclization reaction to synthesize a 1-trifluoromethylthioindole compound represented by formula (2);

[0007]

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

[0009] In one embodiment of the present invention, the aromatic group includes a substituted or unsubstituted benzene ring, a naphthalene ring, a heteroaromatic ring; the substitution may be one to three substitutions; the substituted group is selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, ester group, cyano group, nitro group and heterocycle.

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

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

[0012] In one embodiment of the present invention, the heterocycle is a three- to six-membered ring containing 1-3 heteroatoms, including 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), preferably CH3CN.

[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, preferably potassium fluoride.

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

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

[0018] In one embodiment of the present invention, the molar ratio of the 2-alkynyl aromatic amine compound, N-trifluoromethylthiosaccharin and the inorganic base is 1:(1.5-2.5):(0-3.0), preferably 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, and particularly preferably 0.1 mmol / mL.

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

[0021] A second object of the present invention is to provide a novel green and economical synthesis method comprising the steps of:

[0022] With 2-alkynyl aromatic amine compounds, N-trifluoromethylthiosaccharin and potassium fluoride as raw materials, the crude product of 1-trifluoromethylthioindole compound is obtained after stirring and reacting at 45-55° C. for a period of time, and then the pure 1-trifluoromethylthioindole compound is obtained by filtering, washing, vacuum distillation and column chromatography separation.

[0023] In one embodiment of the present invention, the separation and purification method is to use 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 in the following steps: adding 2-alkynyl aromatic amine compounds, N-trifluoromethylthiosaccharin, and potassium fluoride in a molar ratio of 1:2.5:3 to a reaction vessel containing acetonitrile solvent, stirring at 50°C for 8-10 hours, separating and purifying 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 trifluoromethylsulfonium cation provided by N-trifluoromethylthiosaccharin, and under the action of a base, protons are deprotonated to form nitrogen anions, and then nucleophilic addition / cyclization is performed on the alkynyl group to ultimately generate 1-trifluoromethylthioindole compounds.

[0026] The third object of the present invention is to provide a method for preparing an indole derivative, the method comprising:

[0027] (1) First, the method of the present invention is used to prepare and synthesize 1-trifluoromethylthioindole compounds; specifically,

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

[0029]

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

[0031] (2) Using the 1-trifluoromethylthioindole compound prepared in step (1) as a reactant, an indole derivative is prepared.

[0032] In one embodiment of the present invention, the indole derivative uses 1-trifluoromethylthioindole compound as a synthetic intermediate; optionally, the indole derivative can be a drug molecule with biological activity. For example, the indole derivative of CRAC regulator reported in patent document CN102574788A. The fourth object of the present invention is to provide an application of the method in the fields of medicine, pesticide and functional material 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 with 1-trifluoromethylthioindole compounds as raw materials.

[0034] The fifth object of the present 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:

[0035]

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

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

[0038] In one embodiment of the present invention, the synthesis method of the important intermediate of the nicotinic acetylcholine receptor positive allosteric modulator comprises the following steps:

[0039] (1) In an organic solvent, 2-alkynyl aromatic amine compounds and N-trifluoromethylthio saccharin reactants are reacted with potassium fluoride to carry out a cyclization reaction to synthesize 1-trifluoromethylthio-2-phenylindole compounds;

[0040] (2) The obtained 1-trifluoromethylthio-2-phenylindole compound is oxidized to obtain a CRAC regulator indole derivative.

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

[0042] In one embodiment of the present invention, the oxidation in step (2) is to dissolve the 1-trifluoromethylthio-2-phenylindole compound in dichloromethane, then dropwise add mCPBA dissolved in dichloromethane under ice / water cooling within 30 minutes, and react at room temperature under nitrogen environment for a period of time.

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

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

[0045] Beneficial effects:

[0046] (1) The method of the present invention uses 2-alkynyl aromatic amine and N-trifluoromethylthio saccharin as reactants in a nitrogen atmosphere, and under the action of an inorganic base, a one-pot reaction is performed to construct a 1-trifluoromethylthio indole skeleton to obtain the target compound.

[0047] (2) The method of the present invention uses N-trifluoromethylthiosaccharin as a fluorine source, has a wide substrate applicability, and the raw materials are simple and easy to obtain, and the economic cost is low. 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 a good yield. The method is fast and efficient.

[0048] (3) The synthetic method of the present invention converts the readily available 2-alkynyl aromatic amine into the corresponding 1-trifluoromethylthioindole compound under relatively simple conditions, thereby achieving the synthesis of 1-trifluoromethylthioindole derivatives in one step. The target compound has a wide range of applications in the fields of medicine, pesticides and functional materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 The synthetic route diagram of the method of the present invention is shown in FIG. DETAILED DESCRIPTION

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

[0051] 1. 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, 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 purchased from Adamas.

[0053] 2. The chromatographic separation and purification method involved in the following examples: column model: 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 synthetic route diagram of the embodiment of the present invention is as follows: Figure 1 As shown, specifically:

[0055] Using o-alkynylaniline and N-trifluoromethylthiosaccharin as raw materials, adding potassium fluoride, using acetonitrile as the reaction solvent, reacting at 50°C for 8-10 hours, the target compound can be obtained. The reaction expression is: 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 stirrer, and reacted at 50°C and 800 rpm for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through 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 distillation under reduced pressure. The crude product was then separated and 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 stirrer, and reacted at 50°C and 800 rpm for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through 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 distillation under reduced pressure. The crude product was then separated and 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 stirrer, and reacted at 50 ° C and 800 rpm for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure, and the crude product was separated and 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-octynylaniline (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 stirrer, and reacted at 50 ° C and 800 rpm for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through 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 distillation under reduced pressure. The crude product was separated and 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 stirrer, and reacted at 50 ° C and 800 rpm for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, and the filter residue was washed with 30 mL of ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure, and the crude product was separated and 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 stirrer, and reacted at 50°C and 800 rpm for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through 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 distillation under reduced pressure. The crude product was then separated and 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 the present invention, we also replace 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 the present invention is universal and can effectively prepare the target compound.

[0087] Example 7: Effect 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, and other conditions remained unchanged to synthesize 2-phenyl-1-trifluoromethylthioindole. The 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 Isolation yield (%) KF (Example 1) 88 t-BuOK 23 <![CDATA[NaHCO3]]> 35 <![CDATA[(CH3COO)2Cu]]> 33

[0091] The results show that the target product can be obtained by replacing the potassium fluoride in Example 1 with potassium tert-butoxide, sodium bicarbonate, and copper acetate as the inorganic base, but the product yield is 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 1,2-dichloroethane, tetrahydrofuran, and dichloromethane respectively, and other conditions remained unchanged to synthesize 2-phenyl-1-trifluoromethylthioindole. The 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 Isolation yield (%) <![CDATA[CH3CN (Example 1)]]> 88 DCE 25 THF 40 DCM 60

[0096] The results show that: using 1,2-dichloroethane, tetrahydrofuran, dichloromethane to replace the acetonitrile in Example 1 as the solvent can obtain the target product, but the product yield is worse than that in 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, and 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(℃) Isolation yield (%) 30 63 50 (Example 1) 88 70 83 90 77

[0102] The results showed that the target product could be obtained by replacing 50°C in Example 2 with 30°C, 70°C, or 90°C, but the product yield was not much different from that in Example 1. When the temperature reached 90°C, the yield decreased significantly.

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

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

[0105] Table 4 Effect of different trifluoromethylsulfide sources on the synthesis of 2-phenyl-1-trifluoromethylthioindole

[0106] Methyl trifluorosulfide source Isolation yield (%) N-trifluoromethylthiosaccharin (Example 1) 88 N-Trifluoromethylthiophthalimide trace N-Trifluoromethylthiobisbenzenesulfonimide trace Silver trifluoromethylthiothionate NR

[0107] The results showed that: by using N-trifluoromethylthiophthalimide, N-trifluoromethylthiobisbenzenesulfonimide, and silver trifluoromethylthiodide to replace N-trifluoromethylthiosaccharin in Example 1 as the trifluoromethyl sulfide source, except when the trifluoromethyl sulfide source was silver trifluoromethylthiodide, the target product could be obtained, but the product yield was worse than that in Example 1.

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

[0109] Referring to Example 1, the molar ratio of 2-alkynyl aromatic amine compound, N-trifluoromethylthio saccharin and inorganic base was adjusted to 1:1.5:1, 1:1.5:1.5, 1:2:1, 1:2:2, 1:2.5:2, 1:2.5:2.5, and other conditions remained unchanged to synthesize 2-phenyl-1-trifluoromethylthio indole. The specific yield results are shown in Table 5.

[0110] Table 5 Effect of different molar ratios of 2-alkynyl aromatic amine compounds, N-trifluoromethylthio saccharin and inorganic base on the synthesis of 2-phenyl-1-trifluoromethylthio indole

[0111]

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

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

[0114] Referring to Example 1, the reaction concentration of the 2-alkynyl aromatic amine compound was adjusted to 0.05, 1, 2, 3, 4, 5 mmol / mL, and other conditions were kept unchanged to synthesize 2-phenyl-1-trifluoromethylthioindole. The specific yield results are shown in Table 6.

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

[0116]

[0117] The results showed that the target product could be obtained by using 2-alkynyl aromatic amine compounds at reaction concentrations of 0.05, 1, 2, 3, 4, and 5 mmol / mL to replace 0.1 mmol / ml in Example 1, but the yield of the product was worse than that in 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, and other conditions were kept unchanged to synthesize 2-phenyl-1-trifluoromethylthioindole. The 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) Isolation yield (%) 7 71 9 83 10 80 11 81

[0122] The results showed that the target product could be obtained by replacing the 8h in Example 1 with a reaction time of 7h, 9h, 10h, or 11h, but the yield of the product was worse than that in Example 1, and there was no significant change in the reaction yield by extending the reaction time.

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

[0124] 1-Trifluoromethylthioindole compounds can be used as raw materials or synthetic intermediates to further synthesize indole derivatives, and therefore have wide applications in the direction of functional compounds in the fields of medicine, pesticides and functional materials. For example, 1-trifluoromethylthioindole compounds can be used as raw materials to prepare indole derivatives, which are biologically active drug molecules, such as the indole derivatives of CRAC regulators reported in patent document CN102574788A.

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

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

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

[0128]

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

[0130] (2) Using the 1-trifluoromethylthioindole compound prepared in the above step as a reactant, an indole derivative is prepared.

[0131] Take 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 of the indole derivative can be carried out as follows:

[0134]

[0135] Specifically:

[0136] First, 1-trifluoromethylthio-2-phenylindole was prepared according to the method of Example 1, and then the 1-trifluoromethylthio-2-phenylindole (0.5 mmol) prepared in Example 1 was dissolved in CH2Cl2 (5 mL), and a CH2Cl2 solution of mCPBA (0.161 g of mCPBA with a mass solubility of 80% was dissolved in 2 ml of CH2Cl2) was added dropwise under ice-water cooling within 30 minutes. After stirring at room temperature and a rotation speed of 800 for 2 hours, the oxidant was removed with 30 mL of a saturated aqueous solution of sodium thiosulfate (Na2S2O3), the organic layer in the reaction mixture was separated, washed three times with 30×3 mL of water, the organic phases were combined and then dried over anhydrous MgSO4, filtered, the filtrate was collected and the solvent was distilled off under reduced pressure, and the crude product was separated and purified by column chromatography to obtain 103 mg of the target compound in 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] Further, You can also use R 1 , R 2 More substitution expansions can be made to obtain more analogues, providing corresponding synthetic methods for exploring more indole derivatives of CRAC regulators.

[0140] Furthermore, the indole derivatives of the CRAC regulator can be prepared by referring to the patent document CN102574788A.

[0141] Comparative Example 1:

[0142] Referring to Example 1, potassium fluoride was not added, and the other conditions remained unchanged.

[0143] The results showed that without adding potassium fluoride, the yield decreased.

[0144] Comparative Example 2:

[0145] Referring to Example 1, copper iodide was additionally added as a catalyst while other conditions remained unchanged.

[0146] The results showed that the yield did not change significantly when cuprous iodide was added.

Claims

1. A method for synthesizing 1-trifluoromethylthioindole compounds, characterized in that: The method comprises the following steps: using a 2-alkynyl aromatic amine compound represented by formula (1) and N-trifluoromethylthio saccharin as reactants in an organic solvent, and carrying out an N-trifluoromethylthio / cyclization reaction in the presence of an inorganic base to synthesize a 1-trifluoromethylthio indole compound represented by formula (2); Among them, R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, nitro, C1-C8 alkoxy, acyl and amide, and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocyclic rings.

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 inorganic base is any one or more of potassium tert-butoxide, sodium bicarbonate, copper acetate, and potassium fluoride.

4. The method according to claim 1, characterized in that: The reaction temperature is 25°C-70°C.

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

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

7. The method according to claim 1, characterized in that The N-trifluoromethylthiolation / cyclization reaction is carried out under an inert gas atmosphere.

8. Application of the method according to any one of claims 1 to 7 in the fields of medicine, pesticide and functional material preparation.

9. A method for preparing an indole derivative, characterized in that: The preparation method comprises: (1) firstly prepare and synthesize 1-trifluoromethylthioindole compounds by the method described in any one of claims 1 to 7; (2) Using the 1-trifluoromethylthioindole compound prepared in step (1) as a reactant, an indole derivative is prepared.

10. 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 The reaction route of the method is: Among them, R 1 is selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, nitro, C1-C8 alkoxy, acyl and amide, and heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocyclic rings.

Images