A method for synthesizing 1-trifluoromethylindole compounds from 2-alkynyl aryl isothiocyanate

Abstract

This invention discloses a method for synthesizing 1-trifluoromethylindole compounds from 2-alkynylaryl isothiocyanate as a starting material, belonging to the field of organic chemistry. The method uses o-alkynylphenylthioisocyanate as a substrate and readily available silver fluoride as a fluorine source. Under the action of a catalyst, the 1-trifluoromethylindole skeleton can be constructed in one step to obtain the target compound. This method has broad substrate applicability, uses simple and readily available raw materials, and has low economic cost. Furthermore, the method requires only 3-10 hours of reaction time to achieve a good yield of the target product. 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-trifluoromethylindole compounds from 2-alkynylaryl isothiocyanate, belonging to the field of organic chemistry. Background Technology

[0002] Since the discovery in the 1950s that introducing fluorine atoms into specific sites on drug molecules could improve their biological activity, a large number of fluorine-containing drugs have sprung up. From accounting for only 2% of the pharmaceutical market in 1970, they now account for approximately 20%. In 2019, the U.S. Food and Drug Administration (FDA) approved 35 chemical drugs, 14 of which contained fluorine atoms and 7 contained trifluoromethyl groups. In addition, indole drugs also constitute a significant proportion of pharmaceuticals, and in the past few decades, numerous new strategies for introducing CF3 groups into organic molecules have been explored. In the last decade, research on N-trifluoromethylation methods has attracted widespread attention. Summary of the Invention

[0003] This invention develops a novel method for synthesizing N-trifluoromethylindole, specifically a method for synthesizing polysubstituted-1-trifluoromethylindole compounds. This invention utilizes a tandem N-trifluoromethylation / cyclization reaction between a 2-alkynylaryl thioisocyanate compound and silver fluoride under the catalysis of a catalyst to synthesize polysubstituted-1-trifluoromethylindole compounds, thus conveniently achieving the synthesis of 1-trifluoromethylindole derivatives.

[0004] The purpose of this invention is to provide a method for synthesizing a polysubstituted-N-trifluoromethylindole compound. The method involves using a 2-alkynylaryl isothiocyanate compound of formula (1) and silver fluoride of formula (2) as reactants in an organic solvent, and carrying out a 1-trifluoromethylation / cyclization reaction under the catalysis of a catalyst to synthesize the polysubstituted-1-trifluoromethylindole compound of formula (3).

[0005]

[0006] 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 It is selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups and heterocycles.

[0007] In one embodiment of the present invention, the aryl group includes a substituted or unsubstituted benzene ring or a naphthalene ring; 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, and heterocycles.

[0008] In one embodiment of the present invention, the acyl group is -COR. a R a It is H or C1-8 alkyl.

[0009] In one embodiment of the present invention, the amide group is -NHCOR. b R b It is H or C1-8 alkyl.

[0010] 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.

[0011] In one embodiment of the present invention, the organic solvent includes any one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone. Acetonitrile is preferred.

[0012] In one embodiment of the present invention, the catalyst is any one or more of tris(triphenylphosphine)rhodium chloride, zinc chloride, copper acetate, bis(triphenylphosphine)palladium chloride, and ruthenium dichloride. Tris(triphenylphosphine)rhodium chloride is preferred.

[0013] In one embodiment of the invention, the reaction temperature is 25°C-100°C, preferably 35-45°C.

[0014] In one embodiment of the present invention, the reaction time is 3-10 hours. Specifically, 5 hours may be selected.

[0015] In one embodiment of the present invention, the molar ratio of 2-alkynylaryl isothiocyanate compound to silver fluoride is 1:(3.0-4.0); preferably 1:3.2.

[0016] In one embodiment of the present invention, the molar ratio of the 2-alkynylaryl isothiocyanate compound to the catalyst is 1:(0.001-0.1); further optionally, it is 1:0.005-0.01.

[0017] In one embodiment of the present invention, the reaction concentration of the 2-alkynylaryl isothiocyanate compound is 0.05-5 mmol / mL. Specifically, 0.1 mmol / mL is preferred.

[0018] In one embodiment of the invention, the 1-trifluoromethylation / cyclization reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere.

[0019] In one embodiment of the present invention, the molar ratio of 2-alkynylaryl isothiocyanate and silver fluoride is 1:(2-5); further optionally 1:(3.0-4.0); specifically optionally 1:3.2.

[0020] In one embodiment of the present invention, the structure of 2-alkynylaryl isothiocyanate is specifically as follows:

[0021] The definitions of R1 and R2 are the same as above, specifically 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.

[0022] In one embodiment of the present invention, the steps of a novel green and economical synthesis method are as follows:

[0023] Using 2-alkynylaryl isothiocyanate and silver fluoride as raw materials, a catalyst was added, and the mixture was stirred at 25℃-50℃ for a period of time to obtain a crude product of polysubstituted-1-trifluoromethylindole. Then, the pure polysubstituted-1-trifluoromethylindole compound was obtained by filtration, washing, vacuum distillation and column chromatography.

[0024] In one embodiment of the present invention, the separation method is to use rapid column chromatography to obtain the final product, a polysubstituted 1-trifluoromethylindole compound.

[0025] In one embodiment of the present invention, the method is preferably carried out as follows: 2-alkynylaryl isothiocyanate compound, silver fluoride, and catalyst are added to a reaction vessel containing acetonitrile solvent at a molar ratio of 1:3.2:0.01, stirred at 25°C-50°C for 3-10 hours, and then separated and purified to obtain the target product.

[0026] In one embodiment of the present invention, the reaction mechanism is as follows: 2-alkynylaryl isothiocyanate undergoes desulfurization and fluorination with silver fluoride to form an ArN(CF3)Ag intermediate, which, under the action of a catalyst, undergoes nucleophilic addition / cyclization with the alkynyl group adjacent to the aromatic ring to generate a polysubstituted -1-trifluoromethylindole compound.

[0027] The target compound obtained by the method of this invention—a polysubstituted 1-trifluoromethylindole compound—can be used as a synthetic intermediate to prepare many bioactive drug molecules, such as the nicotinic acetylcholine receptor allosteric modulator reported in patent document WO2012131031A1.

[0028] The present invention also provides the application of the above method in the fields of pharmaceuticals, pesticides and functional materials preparation.

[0029] This invention also provides a method for synthesizing an important intermediate of a nicotinic acetylcholine receptor positive allosteric modulator, the structure of which is shown below: The reaction route of the method is as follows:

[0030]

[0031] The definitions of R1 and R2 are the same as above.

[0032] In one embodiment of the present invention, R1 may specifically be H, and R2 may specifically be methyl.

[0033] 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:

[0034] (1) In an organic solvent, 2-alkynylaryl isothiocyanate compound and silver fluoride were used as reactants to carry out 1-trifluoromethylation / cyclization reaction under the catalysis of a catalyst to synthesize polysubstituted-1-trifluoromethyl-5-cyanoindole compounds.

[0035] (2) The obtained polysubstituted-1-trifluoromethyl-5-cyanoindole compounds were hydrogenated and reduced to obtain an important intermediate of the nicotinic acetylcholine receptor orthoallometric regulator.

[0036] In one embodiment of the present invention, the conditions involved in step (1) are the same as those in the above-described method for synthesizing polysubstituted-1-trifluoromethylindole compounds.

[0037] In one embodiment of the present invention, the hydrogenation reduction in step (2) involves dissolving a polysubstituted -1-trifluoromethyl-5-cyanoindole compound in MeOH·NH3, then adding Raney-Ni, and reacting at room temperature for a period of time under hydrogen atmosphere.

[0038] In one embodiment of the present invention, the concentration of MeOH·NH3 is 5M.

[0039] In one embodiment of the present invention, the amount of Raney-Ni added relative to the 1-trifluoromethyl-5-cyanoindole compound is 0.2 g / mmol.

[0040] Beneficial effects:

[0041] The method of this invention, in a nitrogen atmosphere, using 2-alkynylaryl isothiocyanate as a substrate and silver fluoride as a fluorinating agent, can achieve the construction of the N-trifluoromethylindole skeleton in one step under the action of a catalyst, to obtain the target compound.

[0042] The method of this invention uses silver fluoride as the fluorine source, which has wide substrate applicability, simple and readily available raw materials, and low economic cost. In addition, the method of this invention can achieve the synthesis of the target product in good yield with only 3-10 hours of reaction, and the method is fast and efficient.

[0043] The synthesis method of this invention converts readily available 2-alkynylaryl isothiocyanate into the corresponding polysubstituted -N-trifluoromethylindole compound under relatively simple conditions, realizing the synthesis of N-trifluoromethylindole derivative in one step. The target compound has wide applications in the fields of medicine, pesticides and functional materials. Attached Figure Description

[0044] Figure 1 This is a synthesis route diagram for the method of the present invention. Detailed Implementation

[0045] The following are specific embodiments of the present invention.

[0046] The synthesis route diagram of this invention embodiment is as follows: Figure 1 As shown:

[0047] The target compound can be obtained by reacting 2-alkynylaryl isothiocyanate and silver fluoride as raw materials, using rhodium tris(triphenylphosphine)chloride as a catalyst and acetonitrile as a reaction solvent at 25℃-50℃ for 3-10 hours. The reaction formula is as follows: Figure 1 .

[0048] Example 1: Synthesis of 2-phenyl-1-trifluoromethylindole

[0049]

[0050] Under nitrogen protection, p-2-phenylethynylphenyl isothiocyanate (80 mg, 0.5 mmol), silver fluoride (202 mg, 1.6 mmol), rhodium tris(triphenylphosphine) chloride (5 mg, 0.005 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 45 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated sodium chloride solution, respectively. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 104 mg of product, with a yield of 80% (90% yield according to fluorine chromatography).

[0051] 1 H NMR (400MHz, CDCl3) δ7.79-7.69(m,1H),7.69-7.62(m,1H),7.57(dd,J=6.5,2.8Hz,2H),7.52-7.44(m,3H),7.43-7.30(m,2H),6.69-6.61(m,1H).19 F NMR(376MHz, CDCl3)δ-49.82(s,3F). 13 C NMR (101MHz, CDCl3) δ138.18,134.81,131.18,128.37,128.07,127.59,126.99,123.1 6,121.83,119.90,119.52(q,J=263.2Hz),111.97(q,J=4.3Hz),108.62.HRMS(AP)m / z calcd.for C 15 H 11 F3N[M+H] + :262.0844; found:262.0838.

[0052] Example 2: Synthesis of 2-cyclohexyl-1-trifluoromethylindole

[0053]

[0054] Under nitrogen protection, p-2-cyclohexylethynylphenyl isothiocyanate (121 mg, 0.5 mmol), silver fluoride (202 mg, 1.6 mmol), rhodium tris(triphenylphosphine) chloride (5 mg, 0.005 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 45 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated sodium chloride solution, respectively. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 104 mg of product, with a yield of 78% (90% yield according to fluorine chromatography).

[0055] 1 H NMR (400MHz, CDCl3) δ7.64-7.57(m,1H),7.56-7.50(m,1H),7.31-7.18(m,2H),6.45(s,1H),2.85(s,1H),2. 11(t,J=9.7Hz,2H), 1.89(dd,J=5.3,2.5Hz,2H), 1.81(ddt,J=11.1,3.0,1.4Hz,1H), 1.45(p,J=11.7Hz,5H). 19 F NMR (376MHz, CDCl3) δ-51.35 (s, 3F). 13C NMR (101MHz, CDCl3) δ146.03,135.16,129.26,123.29,122.35,121.02(q,J=260.2Hz),12 0.37,112.57(q,J=5.1Hz),104.50,36.95(q,J=2.9Hz),34.18,26.66,26.16.HRMS(AP)m / z calcd.for C 15 H 16 F3N[M] + :267.1235; found:267.1235.

[0056] Example 3: Synthesis of 6-chloro-2-phenyl-1-trifluoromethylindole

[0057]

[0058] Under nitrogen protection, 5-chloro-2-phenylethynylphenyl isothiocyanate (135 mg, 0.5 mmol), silver fluoride (202 mg, 1.6 mmol), rhodium tris(triphenylphosphine) chloride (5 mg, 0.005 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 45 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated sodium chloride solution, respectively. The solvent was removed by vacuum concentration, and the target analytes were purified by column chromatography to obtain 96 mg of the product, with a yield of 65% (76% yield according to fluorine chromatography).

[0059] 1 H NMR (400MHz, CDCl3) δ7.68 (s, 1H), 7.55-7.48 (m, 3H), 7.48-7.42 (m, 3H), 7.28 (dd, J = 8.4, 1.8Hz, 1H), 6.58 (s, 1H). 19 F NMR (376MHz, CDCl3) δ-49.97 (s, 3F). 13 C NMR(101MHz, CDCl3)δ140.0(s),136.2(s),131.8(s),130.2(s),129.5(s),129.1(s),128.3(s),1 27.7(s),123.7(s),121.8(s),120.4(q,J=263.9Hz),113.4(q,J=4.7Hz),109.4(s).HRMS(ESI)m / z calcd.for C 15 H 10 ClF3N(M+H) +:296.0454; found:296.0448.

[0060] Example 4: Synthesis of 1-trifluoromethyl-2-methyl-5-cyano-indole

[0061]

[0062] Under nitrogen protection, 2-propynyl-4-cyanophenyl isothiocyanate (99.1 mg, 0.5 mmol), silver fluoride (202 mg, 1.6 mmol), rhodium tris(triphenylphosphine) chloride (5 mg, 0.005 mmol), and acetonitrile (5 mL) were added to a 25 mL reaction tube equipped with a stir bar and reacted at 45 °C 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 ethyl acetate. The solvent was removed by vacuum concentration, and the target analyte was purified by column chromatography to obtain 50.4 mg of the product, with a fluorine spectrum yield of 52% (yield 45.0%).

[0063] 1 H NMR (400MHz, CDCl3) δ7.96-7.72(m,1H),7.62(d,J=6.6Hz,1H),7.56-7.43(m,1H),6.45(s,1H),2.54(s,3H). 19 F NMR (376MHz, CDCl3) δ-51.75 (s, 3F). 13 C NMR(101MHz, CDCl3)δ137.67(s),137.04(s),129.10(s),126.45(s),δ124.65-115.35(m),125 .07(s),119.53(s),112.99(q,J=4.9Hz),107.27-107.13(m),106.11(s),14.12(q,J=3.6Hz).

[0064] By replacing 2-propynyl-4-cyanoaniline with other substitutions, more corresponding polysubstituted 1-trifluoromethylindole-like compounds were prepared.

[0065] Example 5: Effect of different catalysts on the synthesis of 2-phenyl-1-trifluoromethylindole

[0066] Referring to Example 1, the catalyst was changed from rhodium tris(triphenylphosphine)chloride to zinc chloride, copper acetate, palladium di(triphenylphosphine)chloride, and ruthenium triphenylphosphine chloride, respectively. In addition, an experiment without any catalyst was added, with other conditions remaining unchanged, to synthesize 2-phenyl-1-trifluoromethylindole. The specific yield results are shown in Table 1.

[0067] Table 1 Effect of different catalysts on the synthesis of 2-alkyl-1-trifluoromethylindole a

[0068] catalyst Yield (%) No addition 55 <![CDATA[ZnCl2]]> 50 <![CDATA[Cu(OAc)2]]> 66 <![CDATA[RuCl2(Ph3P)4]]> 67 <![CDATA[PdCl2(Ph3P)2]]> 50 <![CDATA[RhCl(Ph3P)3]]> 90

[0069] a. Yield is the yield of fluorine spectrum.

[0070] The results showed that the product yields obtained without a catalyst and by replacing rhodium chloride (triphenylphosphine) in Example 2 with zinc chloride, copper acetate, bis(triphenylphosphine) palladium chloride, or triphenylphosphine ruthenium chloride were all worse than those in Example 2, with yields not exceeding 70%.

[0071] Example 6: Effect of different solvents on the synthesis of 2-phenyl-1-trifluoromethylindole

[0072] Referring to Example 1, the solvent was replaced by dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, NMP, and water, respectively, while keeping other conditions unchanged, to synthesize 2-phenyl-1-trifluoromethylindole.

[0073] The specific yield results are shown in Table 2.

[0074] Table 2 Effect of different solvents on the synthesis of 2-phenyl-1-trifluoromethylindole a

[0075] solvent Yield (%) DMSO 60 <![CDATA[CH3CN]]> 90 DMAc 40 DMF 31 NMP 20 <![CDATA[H2O]]> 0

[0076] a. Yield is the yield of fluorine spectrum.

[0077] The results showed that when dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, NMP, and water were used instead of acetonitrile in Example 1 as solvents, the yields of the products obtained were all worse than those in Example 1, with yields not exceeding 60%.

[0078] Example 7: Synthesis of 2-phenyl-1-trifluoromethylindole at different reaction temperatures

[0079] Referring to Example 1, the reaction temperature was replaced from 45°C to 25°C, 65°C, and 90°C respectively, while other conditions remained unchanged, to synthesize 2-phenyl-1-trifluoromethylindole.

[0080] The specific yield results are shown in Table 3.

[0081] Table 3. Effects of different reaction temperatures on the synthesis of 2-phenyl-1-trifluoromethylindole a

[0082] Temperature (°C) Yield (%) 25 88 45 90 65 87 90 80

[0083] a. Yield is the yield of fluorine spectrum.

[0084] The results showed that replacing 45°C in Example 2 with 25°C, 65°C, and 90°C did not significantly alter the product yield compared to Example 1. However, the yield decreased considerably when the temperature reached 90°C.

[0085] Example 8: Synthesis of an important intermediate for a nicotinic acetylcholine receptor allosteric modulator

[0086] An important intermediate of nicotinic acetylcholine receptor orthoallosteric modulators (PAMs) Synthesis method of intermediate M18 (disclosed in China under WO2012131031A1):

[0087]

[0088] 1-Trifluoromethyl-2-methyl-5-cyanoindole (0.5 mmol) was added to Raney-Ni (100 mg) in MeOH·NH3 (10 mL, 5 M) at room temperature. The reaction mixture was stirred under H2 (60 psi) for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated to dryness. The crude compound was washed with pentane to give intermediate M18 (70.4 mg, yield 40%).

[0089] 1 H NMR (400MHz, CDCl3) δ7.56-7.37(m,2H),7.17(d,J=8.5Hz,1H),6.32(s,1H),3.87(br s,2H),2.48(s,3H). 19 F NMR(376MHz, CDCl3)δ-52.32(s,3F).

[0090] Furthermore, Further substitutions of R1 and R2 can be made to obtain more analogs, providing corresponding synthetic methods for exploring more small molecules with positive allosteric regulatory activity of nicotinic acetylcholine receptors.

[0091] Furthermore, nicotinic acetylcholine receptor orthoallosteric modulators (PAMs) can be prepared by referring to compounds 83-85 in WO2012131031A1.

Claims

1. A method for synthesizing a 1-trifluoromethylindole compound, characterized by, In an organic solvent, using the 2-alkynyl aryl isothiocyanate compound shown in formula (1) and silver fluoride shown in formula (2) as reactants, an N-trifluoromethylation / cyclization reaction was carried out under the action of a catalyst to synthesize the polysubstituted-1-trifluoromethylindole compound shown in formula (3). ， Among them, R 1 Selected from H, C1-C8 alkyl, C1-C8 haloalkyl, aryl, halogen, cyano, nitro, C1-C8 alkoxy, acyl and amide, heterocycle; R 2 Selected from C1-C8 alkyl, C1-C8 haloalkyl, aryl, C1-C8 alkoxy, acyl and amide groups, and heterocycles; The catalyst is any one or more of tris(triphenylphosphine) rhodium chloride, zinc chloride, copper acetate, di(triphenylphosphine) palladium chloride, and ruthenium dichloride.

2. The method of claim 1, wherein, The organic solvent includes any one or more of acetonitrile, N , N dimethylformamide, N , N dimethylacetamide, dimethylsulfoxide, N methylpyrrolidone.

3. The method of claim 1, wherein, The reaction temperature is 25℃-100℃.

4. The method of claim 1, wherein, The molar ratio of 2-alkynylaryl isothiocyanate compounds to silver fluoride is 1:(2.0-5.0).

5. The method of claim 1, wherein, The molar ratio of 2-alkynylaryl isothiocyanate compound to catalyst is 1:(0.001-0.1).

6. The method of claim 1, wherein, The reaction concentration of 2-alkynylaryl isothiocyanate compounds is 0.05-5 mmol / mL.

7. The method according to any one of claims 1 to 6, characterized in that, The N-trifluoromethylation / cyclization reaction was carried out under an inert gas atmosphere.

8. A method for synthesizing an important intermediate of a nicotinic acetylcholine receptor allosteric modulator, characterized in that, The structure of the important intermediate of the nicotinic acetylcholine receptor allosteric regulator is as follows: The reaction route of the method is as follows: ， The definitions of R1 and R2 are the same as in claim 1; Includes the following steps: (1) In an organic solvent, 2-alkynylaryl isothiocyanate compound and silver fluoride were reacted and 1-trifluoromethylation / cyclization reaction was carried out under the catalysis of a catalyst to synthesize polysubstituted-1-trifluoromethyl-5-cyanoindole compounds; (2) The obtained polysubstituted-1-trifluoromethyl-5-cyanoindole compounds were hydrogenated and reduced to obtain an important intermediate of the nicotinic acetylcholine receptor orthoallometric regulator; The catalyst is any one or more of tris(triphenylphosphine) rhodium chloride, zinc chloride, copper acetate, di(triphenylphosphine) palladium chloride, and ruthenium dichloride.

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