NL2029460B1 - Tetrahydrofuroindole compound and preparation method and application thereof - Google Patents

Abstract

The present disclosure discloses a new synthetic method to obtain various tetrahydrofuroindole compounds with high atom economy and diversified strategies through l,l—carbon alkoxylation of a gold— catalyzed propargylamine compound and exo—cyclization at room temperature to obtain an exo—cyclized gold carbene, followed by migration to gold carbene via l,2—H for the first time. This method, only requires one—step reaction to construct a ternary nitrogen—containing heterocyclic compound. The reaction only needs to be carried out at room temperature and does not need additional auxiliary agents. It only takes 1 hour to complete the reaction. The reaction conditions are mild and simple, with a high efficiency, a high yield of target products, and a good adaptability of reaction substrate groups.

Description

TETRAHYDROFUROINDOLE COMPOUND AND PREPARATION METHOD AND APPLICA- TION THEREOF

TECHNICAL FIELD The present disclosure relates to the technical field of pharmaceutical chemistry, and more particularly to a tetrahydrofu- roindole compound, and a preparation method and an application thereof.

BACKGROUND ART Intramolecular carbon alkoxylation catalyzed by transition metals has attracted much attention from chemists in the past dec- ades because of its high bond formation efficiency and atomic economy in the rapid construction of functionalized cyclic com- pounds. This reaction usually involves exo- or endo-cyclization alkoxylation followed by internal or external migration to obtain alkyne difunctionalized products. However, compared with the 1,2- carbon alkoxylation of alkynes established by Fürstner, Yamamoto, Toste, et al. ((1) Angew. Chem. Int. Ed. 2020, 59, 8522; (2) J. Am. Chem. Soc. 2001, 123, 11863; (3) Adv. Synth. Catal. 2009, 351, 1089; (4) J. Am. Chem. Soc. 2013, 135, 12600, etc.), there is very few development on the related 1,1-carbon alkoxylation ( (5) Angew. Chem. Int. Ed. 2002, 41, 4328; (6) J. Am. Chem. Soc. 2004, 126, 15423; (7) Adv. Synth. Catal. 2014, 356, 144; (8) Chem. Eur. J. 2014, 20, 7262) . It is worth noting that in the aforementioned preparation methods, in order to obtain the desired 1,1-carbon alkoxylation products of alkynes, it is probably necessary to in- volve the formation of metal carbene. Despite these achievements, these 1,1-carbon alkoxylations are limited to endo-cyclization, which ultimately leads to the formation of intra-ring metal car- bene after internal migration. In particular, it is proposed to generate carbocation intermediates in these 1,1-carbon alkoxyla- tion reactions. Inspired by these research achievements and the research on alkynamine chemistry for the synthesis of heterocycles develop by the inventor’s research group recently, the inventor envisages that, under the catalysis of transition metals, the ring expansion of the oxetane structural units of the oxetane-tethered alkynamine compounds may provide exo-cyclized carbene ((9) Chem. Rev. 2016, 116, 12150; (10) ACS Catal. 2013, 3, 272; (11) Chem. Soc. Rev. 2012, 41, 3318; (12) J. Org. Chem. 2011, 7, 767; (13) Angew. Chem. Int. Ed. 2010, 49, 9052) . It is worth noting that, as far as the inven- tor knows, there is only one example involving the catalytic reac- tion of oxetane and alkynes through ring expansion, which involves the typical 1,2-carbonyl alkoxylation reaction of alkynes ((14) Adv. Synth. Catal. 2014, 356, 2411.). Therefore, the inventor re- ports a gold-catalyzed 1,1-carbon alkoxylation of alkynamine com- pounds, which obtains exo-cyclized gold carbene by exocyclization at room temperature, followed by 1,2-N migration and 1, 2-H migra- tion to gold carbene, and constructs through high atom economy and diversified strategies to obtain various tetrahydrofuro 1,4- dihydroquinoline compounds and tetrahydrofuroindole compounds. These important heterocyclic skeleton structures are widely pre- sent in various biologically active molecules and natural prod- ucts. In addition, the enantiomeric synthesis of these tricyclic N heterocycles can be achieved through chiral transfer strategies. In the present disclosure, as an aspect of the investor’s re- search, a tetrahydrofuroindole compound and a preparation method and an application thereof are reported.

SUMMARY The object of the present disclosure is to enrich the syn- thetic strategies of the prior art. A new synthetic method to ob- tain various tetrahydrofuroindole compounds with high atom economy and diversified strategies through 1,1-carbon alkoxylation of a gold-catalyzed propargylamine compound and exo-cyclization at room temperature to obtain an exo-cyclized gold carbene, followed by migration to gold carbene via 1,2-H, is reported. According to the present disclosure, a method for preparing a tetrahydrofuroindole compound, comprising the following steps:

dissolving a propargylamine compound of formula 3 in an or- ganic solvent under an inert atmosphere, adding a gold catalyst at room temperature, and then stirring the reaction mixture to react at room temperature, and after completion of reaction, performing post-treatment to obtain a tetrahydrofurcindole compound of formu- la 4; with a reaction formula as follows: (Rijn Py rR? (R)n H ba pc R 3 4 Wherein, in formula 3 and formula 4, n represents 0, 1, 2, 3 or 4; R; is selected from hydrogen, halogen, Cis alkyl, C, alkoxy, Ceo aryl, C:4 haloalkyl, -CN, -NO;, C:i4 acyl; it can be understood that when n is an integer greater than 2 selected from the above, each R, can be the same or differently selected from the above de- fined groups.

R; is selected from Ci. alkyl, substituted Cis alkyl, wherein the substituent is selected from halogen, Cis alkoxy, benzyloxy; PG is a protecting group. Preferably, R: is selected from fluorine, chlorine, bromine, methyl, and methoxy; R; is selected from methyl, ethyl, propyl, 3-benzyloxypropyl; PG is selected from 4-methylbenzenesulfonyl, 4- methoxybenzenesulfonyl, 4-bromobenzenesulfonyl, benzenesulfonyl, methylsulfonyl, preferably 4-methylbenzenesulfonyl.

According to the preparation method of the present disclo- sure, wherein the gold catalyst is selected from any one or more of Ph;PAuUNTf., Cy-JohnPhosAuNTf-, XPhosAuNTf,, BrettPhosAuNTf., IPrAuUNTf,.

According to the preparation method of the present disclo- sure, wherein, the organic solvent is selected from any one of chlorobenzene, toluene, dichlorcethane, dichloromethane, tetrahy- drofuran or acetonitrile. Preferably, the organic solvent is se- lected from dichloroethane.

According to the preparation method of the present disclo-

sure, wherein the feeding molar ratio of the propargylamine com- pound of formula 3 to the gold catalyst is 1:0.01-0.2. Preferably, the feeding molar ratio of the propargylamine compound of formula 3 to the gold catalyst is 1:0.05-0.1, most preferably 1:0.05.

According to the preparation method of the present disclo- sure, wherein the reaction time of the stirring reaction at room temperature is 0.5-24 h, preferably 0.5-1 h.

According to the preparation method of the present disclo- sure, wherein the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.

According to the preparation method of the present disclo- sure, wherein the post-treatment operation is as follows: concen- trating the reaction mixture, separating the residue by silica gel column chromatography, to give a target product of formula 4, wherein the elution solvent for silica gel column chromatography is a mixed solvent of n-hexane/ethyl acetate.

As another object of the present disclosure, the biological activity of the tetrahydrofuroindole compound synthesized in the following specific embodiments is tested herein. The inhibitory activity of these compounds against different cancer cells is pre- liminarily evaluated, wherein the cancer cells include breast can- cer cells MDA-MB-231 and MCF-7, osteosarcoma cancer cell U20S, leukemia cell HL-60, lymphoma cell JeKo-1, HepG2 cell and melanoma cell A375. Our preliminary studies have shown that most of these compounds have significant cytotoxic effects on JeKo-1 and HepG2, while a few compounds have cytotoxic effects on U208, HL-60 and A375, thus indicating that the tetrahydrofuroindole compound of the present disclosure has potential application prospects in chemical drugs.

The method of the present disclosure has the following bene- ficial effects: {1} The present disclosure firstly reports a new synthetic method to obtain various tetrahydrofuroindole compounds with high atom economy and diversified strategies through 1,1-carbon alkoxy- lation of a gold-catalyzed propargylamine compound and exo- cyclization at room temperature to obtain an exo-cyclized gold carbene, followed by migration to gold carbene via 1,2-H. This method only requires one-step reaction to construct a ternary ni- trogen-containing heterocyclic compound. The reaction only needs to be carried out at room temperature and does not need additional auxiliary agents. It only takes 1 hour to complete the reaction.

5 The reaction conditions are mild and simple, with a high efficien- cy, a high yield of target products, and a good adaptability of reaction substrate groups.

(2) The tetrahydrofuroindole compound prepared in the present disclosure exhibits good inhibitory activity against a variety of cancer cells.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram of the reaction mechanism of the reactions of the present disclosure. FIG. 2 is a single crystal diffraction pattern of compound 4j.

DETAILED DESCRIPTION OF THE EMBODIMENTS The present disclosure will be further described in detail below in conjunction with specific embodiments. In the following, unless otherwise specified, the raw material compounds used are prepared by classical organic synthesis methods in the art, and the reagents used are all commercially available. Example 1 Synthesis of compound 4a A — : a Je 3a 4a IPrAuNTf, (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3a in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3a was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4a, with a yield of 99% (70.4 mg). The product was color- less oily liquid. ‘YH NMR (400 MHz, CDCl) & 7.92 (d, J = 8.4 Hz, 2H}, 7.54 (d, J=8.0 Hz, 1H), 7.24 - 7.15 (m, 3H), 7.09 (d, J =

7.2 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.06 - 5.82 {(m, 2H), 3.92 (t, J = 7.6 Hz, 1H), 3.67 (d, J = 8.8 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.35 (s, ZH), 2.31 - 2.22 (m, 1H), 1.90 - 1.82 (m, 1H), 1.77 (dd, J =

6.4, 1.2 Hz, 3H); *c NMR (100 MHz, CDCl.) & 143.4, 141.9, 137.4,

132.4, 129.7, 129.0, 128.3, 127.9, 126.0, 124.6, 123.0, 112.7,

106.6, 67.8, 53.7, 33.6, 21.4, 17.4; HRESIMS Calcd for [C-oHsiNNa0:S]* (M + Na’) 378.1134, found 378.1114. Example 2 Synthesis of compound 4b zz re Ni ts Me 3b 4b IPrAUNTf: (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3b in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 24 hours. When the raw material of formula 3b was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4b, with a yield of 64% (55.6 mg). The product was a white solid (mp 122-123 °C). *H NMR (400 MHz, CDCl:) & 7.88 (d, J = 8.4 Hz, 2H), 7.43 (d, J= 8.8 Hz, 1H), 7.32 - 7.28 {(m, 1H), 7.25 -

7.17 {(m, 3H), 6.02 - 5.86 (m, 2H), 3.92 (t, J= 8.0 Hz, 1H), 3.64 (d, J = 8.8 Hz, 1H), 3.02 - 2.93 (m, 1H), 2.37 (s, 3H), 2.33 -

2.21 (m, 1H), 1.88 — 1.81 (m, 1H), 1.77 (d, J = 5.2 Hz, 3H); *C NMR {100 MHz, CDCl.) ò 143.7, 141.2, 137.1, 132.1, 132.0, 131.2,

129.1, 127.9, 127.7, 126.6, 115.4, 114.2, 107.0, 67.9, 53.4, 33.5,

21.5, 17.5; HRESIMS Calcd for [C::H:;BrNNa0:S]* (M + Na*) 456.0239, found 456.0238. Example 3 Synthesis of compound 4c

== — pl 3 ú ds We Ss 3c 4c IPrAuNTf, {0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3c in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3c was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4c, with a yield of 99% (73.2 mg). The product was a white solid (mp 155-156°C). 'H NMR (400 MHz, CDCl3) & 7.90 (d, J = 8.4 Hz, 2H), 7.43 (d, J= 8.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 - 6.95 (m, 1H), 6.90 (s, 1H), 6.03 - 5.84 (m, 2H), 3.89 (t, J =

7.6 Hz, 1H), 3.62 (d, J= 8.4 Hz, 1H), 2.03 - 2.93 (m, 1H), 2.34 (s, 3H), 2.31 - 2.19 (m, 4H), 1.88 - 1.80 (m, 1H), 1.76 (dd, J =

6.0, 1.2 Hz, 3H); “°C NMR (100 MHz, CDCL:) & 143.2, 139.6, 137.5,

132.6, 132.4, 129.7, 128.9, 128.8, 127.8, 126.0, 125.2, 112.5,

106.7, 67.8, 53.7, 33.6, 21.4, 20.7, 17.4; HRESIMS Calcd for [C:iH:3NNa03s]" (M + Na’) 392.1291, found 392.1292. Example 4 Synthesis of compound 4d a ess FZ TTT ga Ni rs Me 3d 4d IPrAuNTf. (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3d in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3d was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4d, with a yield of 84% {64.8 mg). The product was a white solid (mp 115-116 °C). 'H NMR (400 MHz, CDCl;) & 7.88 (d, J = 8.4 Hz, 2H), 7.48 (d, J= 8.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.74 (dd, = 8.8, 2.8 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 6.02 - 5.85 (m, 2H), 3.88 (t, J= 7.6 Hz, 1H), 3.74 (s, 3H), 3.63 (d, J= 8.8 Hz, 1H), 3.00 - 2.90 {m, 1H), 2.35 (s, 3H), 2.30 - 2.18 (m, 1H),

1.88 — 1.81 (m, 1H), 1.76 (dd, J= 6.0, 0.8 Hz, 3H); *’C NMR (100 MHz, CDCl;) ò 156.1, 143.2, 137.5, 135.5, 132.3, 131.1, 128.9,

127.8, 126.1, 113.5, 113.3, 110.86, 106.8, 67.9, 55.6, 53.9, 33.5,

21.4, 17.4; HRESIMS Calcd for [C::H;3NNa0S]* (M + Na’) 408.1240, found 408.1241. Example 5 Synthesis of compound 4e 9 Me H ts Ts Me 1 3e 4e IPrAuNTf; (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound {0.2 mmol) of formula 3e in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3e was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4e, with a yield of 95% (70.9 mg). The product was a white solid (mp 118-119 °C). 'H NMR (400 MHz, CDCl:) & 7.90 (d, J = 8.4 Hz, 2H), 7.30 (dd, J= 10.4, 2.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.01 (ddd, J = 8.4, 6.0, 0.8 Hz, 1H), 6.69 - 6.61 (m, 1H),

6.01 - 5.86 (m, 2H), 3.92 (t, J= 8.0 Hz, 1H), 3.62 (d, J = 8.4 Hz, 1H), 3.04 - 2.95 {(m, 1H), 2.38 (s, 3H), 2.33 - 2.18 (m, 1H),

1.86 — 1.76 (m, 1H), 1.77 (d, J = 4.8 Hz, 3H); ‘°C NMR (100 MHz, CDCl;) ò 163.0 (d, J = 242.0 Hz), 143.8, 143.2 (d, J = 12.0 Hz),

137.1, 132.0, 129.1, 127.8, 126.4, 125.3 (d, J = 10.0 Hz), 125.1

(d, J= 3.0 Hz), 109.6 (d, J = 23.0 Hz), 107.7, 101.0 (d, J= 29.0 Hz), 67.8, 53.1, 33.7, 21.4, 17.4; HRESIMS Calcd for [CsoH:9FNNa0:S]" (M + Na’) 396.1040, found 396.1041. Example 6 Synthesis of compound 4f

D CIR Br Nv Br re Me i 3f 4f IPrAuUNTf, (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3f in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3f was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4f, with a yield of 92% (80.0 mg). The product was a white solid (mp 174-175 °C). ‘H NMR (400 MHz, CDCls) & 7.90 (d, J = 8.4 Hz, 2H), 7.72 (d, J= 1.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.09 (dd, J= 8.0, 1.6 Hz, 1H), 6.94 (dd, J= 8.0, 0.8 Hz, 1H), 6.01 -

5.85 {m, 2H), 3.92 (t, J= 8.0 Hz, 1H), 3.60 (d, J = 8.8 Hz, 1H),

3.02 - 2.93 (m, 1H), 2.38 (s, 3H), 2.32 - 2.19 (m, 1H), 1.85 -

1.78 (m, 1H), 1.77 (d, J = 5.2 Hz, 3H); "C NMR (100 MHz, CDCl;) &

143.8, 143.2, 137.1, 131.9, 129.2, 128.8, 127.8, 126.5, 126.0,

125.8, 121.9%, 115.8, 107.3, 67.8, 53.3, 33.5, 21.4, 17.4; HRESIMS Calcd for [C9H:;BrNNa03s]* (M + Nat) 456.0239, found 456.0241. Example 7 Synthesis of compound 4g 9 Et H ts Ts H 3g 4g IPrAuNTf. (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3g in dichloromethane, to proceed reaction under nitrogen protec-

tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3g was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4g, with a yield of 96% (70.9 mg). The product was a white solid (mp 104-108 °C). 'H NMR (400 MHz, CDCl;) & 7.92 (d, J = 8.4 Hz, 2H), 7.53 (d, J= 8.4 Hz, 1H), 7.24 - 7.14 (m, 3H), 7.09 (d, J = 7.2 Hz, 1H), 7.01 - 6.92 (m, 1H), 6.02 - 5.91 (m, 2H), 3.93 (t, J = 8.0 Hz, 1H), 3.68 (d, J= 8.8 Hz, 1H), 3.08 - 2.96 (m, 1H),

2.35 {s, 3H), 2.32 - 2.22 (m, 1H), 2.18 - 2.08 (m, 2H), 1.91 -

1.82 (m, 1H), 1.03 (t, J = 7.6 Hz, 3H); Cc NMR (100 MHz, CDCL:) &

143.4, 142.0, 137.5, 132.7, 130.2, 129.7, 129.0, 128.3, 127.9,

124.7, 123.0, 112.7, 106.8, 67.8, 53.8, 33.7, 24.8, 21.4, 13.0; HRESIMS Calcd for [C:H-:NNa0:S]* (M + Na’) 392.1291, found 292.1291. Example 8 Synthesis of compound 4h © pr H ts Ts Pr 3h 4h IPrAuNTf, (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3h in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3h was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4h, with a yield of 94% (72.1 mg). The product was a white solid (mp 95-96 °C). 'H NMR (400 MHz, CDCl:) ò 7.92 (d, J = 8.4 Hz, 2H), 7.52 (d, J= 8.4 Hz, 1H), 7.24 - 7.14 (m, 3H), 7.09 (d, J =

7.6 Hz, 1H), 7.00 - 6.93 {(m, 1H), 6.04 - 5.85 (m, 2H), 3.92 (t, J = 7.6 Hz, 1H), 3.67 (d, J= 8.4 Hz, 1H), 3.06 - 2.97 (m, 1H), 2.35 (s, ZH), 2.32 - 2.22 (m, 1H), 2.13 - 2.04 (m, 2H), 1.90 - 1.83 (m,

1H), 1.52 - 1.39 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); *C NMR (100 MHz, CDCls;) © 143.4, 142.0, 137.5, 131.3, 131.1, 129.7, 129.0,

128.3, 127.9, 124.6, 123.0, 112.7, 106.7, 67.8, 53.9, 33.9, 33.¢,

21.9, 21.4, 13.6; HRESIMS Calcd for [C::H;;NNa0:S]* (M + Na%)

406.1447, found 406.1448. Example 9 Synthesis of compound 4i OBn > H ts NI. 3i H IPrAUNTf: (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 31 in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3i was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel colum chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 4i, with a yield of 81% (79.3 mg). The product was a col- orless oily liquid; *H NMR (400 MHz, CDCl:) & 7.92 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.37 - 7.15 (m, 8H), 7.07 (d, J =

7.2 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.03 - 5.85 (m, 2H), 4.51 (s, 2H), 3.91 (t, J= 8.0 Hz, 1H), 3.61 (d, J = 8.4 Hz, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.06 - 2.97 {(m, 1H), 2.35 (s, 3H), 2.29 - 2.862 (m, 3H), 1.89 — 1.82 (m, 1H), 1.80 - 1.71 (m, 2H); *c NMR (100 MHz, CDCl.) & 143.4, 142.0, 138.7, 137.5, 131.8, 130.5, 129.7,

129.1, 128.4, 128.3, 127.9, 127.7, 127.4, 124.7, 123.0, 112.7,

106.6, 72.8, 69.5, 67.9, 53.9, 33.6, 28.8, 28.4, 21.4. HRESIMS Calcd for [CzsH::NNa0,S]* (M + Na’) 512.1866, found 512.1872.

Example 10 Synthesis of compound 47

© Pr H OC Oe ts Ts Fr 3j 4 IPrAuUNTf, (0.01 mmol, 8.7 mg) was added to the solution (4 mL, 0.05 M) of the propargylamine compound (0.2 mmol) of formula 3j in dichloromethane, to proceed reaction under nitrogen protec- tion condition. The reaction mixture was stirred to react at room temperature for 1 hour. When the raw material of formula 3j was consumed completely by TLC monitoring, the reaction mixture was concentrated to obtain a residue, and the residue was separated by silica gel column chromatography with n-hexane/ethyl acetate as the elusion solvent, to obtain a tetrahydrofuroindole compound of formula 47, with a yield of 81% (74.9 mg). The product was a white solid (mp 119-120 °C). 'H NMR (400 MHz, CDCl:;) & 7.90 (d, J = 8.4 Hz, 2H), 7.71 (d, J= 1.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.08 (dd, J = 8.0, 1.6 Hz, 1H), 6.95 (dd, J = 8.0, 0.8 Hz, 1H), 5.99 -

5.84 {(m, 2H), 3.92 (t, J= 8.0 Hz, 1H), 3.60 (d, J = 8.8 Hz, 1H),

3.02 - 2.93 (m, 1H), 2.38 (s, 3H), 2.32 - 2.20 (m, 1H), 2.13 -

2.03 (m, 2H), 1.86 - 1.78 (m, 1H), 1.51 - 1.38 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); Cc NMR (100 MHz, CDCl;) 5 143.8, 143.2, 137.1,

131.4, 130.9, 129.2, 128.8, 127.8, 125.9, 125.8, 121.9, 115.8,

107.4, 67.8, 53.4, 33.8, 33.5, 21.9, 21.4, 13.6; HRESIMS Calcd for [C:2H:aBrNNa038]* (M + Na®) 484.0552, found 484.0553.

Among them, the compound 4j was subjected to single crystal cultivation, to obtain 4j crystals (CCDC Number = 2004907). The single crystal structure was shown in Figure 2. The crystallographic data were as follows:

Rod precision: 0-0 = 0.004% A Wevelemgihel S4183 Celi: 8=32 532118} h=8.2857F {2} C= ETER{5} alpha-30 bota-LlL00 738 {3} Sam =20 Tempsrature: 166 EK Calculate Eesported Volume AIDS ER{I8: 4135 2A{13) Spaces group c zie Coy Ried Hall ora =O Ey DC 2ye Muisty formula O22 H24 Br N 02 B USE H2Z4 Br NM 23 8 Sum formals CIE HZ4 Br N 03 8 C22 Hd Br W G3 5 Mr 482.38 483.3% Bx, gq om-3 1.48% IL48% Mu {mm-1} 3.848 A, Ea hk, Imax 25, 190,28 25, 19,35 Tuin, Tmax 715, 0.825 8.283, 1,090 Ccrrsction methmi- # Remmmted T Limits: Tuin=9.383% Tmax=1.000 AbaTory = MULTI -SUCAN Data cocmpletenegg=- 0.558 Thetaimani= £7,933 Rirefleciionsi= DO 04711 3234} whe {raflectionsl= DO 12&5: 2835}

The foregoing embodiments are only preferred embodiments ra- ther than all embodiments of the present disclosure.

For those skilled in the art, obvious changes may be made without departing from the principle and spirit of the present disclosure, and these changes shall be considered to be included in the protection scope as claimed in the claims of the present disclosure.

Claims (10)

CONCLUSIONS A process for preparing a tetrahydrofuroindole compound, comprising the steps of: dissolving a propargylamine compound of formula 3 in an organic solvent under an inert atmosphere, adding a gold catalyst at room temperature, and then stirring the reaction mixture to react at room temperature, and, after completion of the reaction, performing a post-treatment to obtain a tetrahydrofuroindole compound of formula 4; according to the following reaction formula: (Rhine 7 Re (Rn H PG pc R 3 4 | where, in Formula 3 and Formula 4, n represents 0, 1, 2, 3 or 4; R' is selected from hydrogen, halogen C1 alkyl, C1 alkoxy, C8-20 aryl, C18 haloalkyl, -CN, -NO1 , C16 acyl, R8 is selected from C18 alkyl, substituted C1-8 alkyl, wherein the substituent is selected from halogen, C1 : 4 alkoxy, benzyloxy, PG represents a protecting group, wherein the gold catalyst is selected from one or more of Ph3PAUNTf2, Cy-JohnPhosAuNT{f2, XPhosAuNTf2, BrettPhosAuNTf2, IPrAUNTf2. The method of claim 1, wherein R' is selected from fluorine, chlorine, bromine, methyl and methoxy; R 2 is selected from methyl, ethyl, propyl, 3-benzyloxypropyl; PG is selected from 4-methylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-bromobenzenesulfonyl, benzenesulfonyl, methylsulfonyl, preferably 4-methylbenzenesulfonyl. Process according to any one of claims 1 to 2, wherein the gold catalyst is selected from IPrAuNTf2. Process according to any one of claims 1 to 3, wherein the organic solvent is selected from chlorobenzene, toluene, dichloroethane, dichloromethane, tetrahydrofuran or acetonitrile. The method of claim 4, wherein the organic solvent is selected from dichloromethane. A process according to any one of claims 1 to 5, wherein the molar ratio in the feed of the propargylamine compound of formula 3 to the gold catalyst is 1:0.01-0.2. A process according to claim 6, wherein the molar ratio in the feed of the propargylamine compound of formula 3 to the gold catalyst is 1:0.05-0.1, most preferably 1:0.05. A method according to any one of claims 1 to 7, wherein the reaction time of the stirring reaction at room temperature is 0.5-24 hours, preferably 0.5-1 hour. A method according to any one of claims 1 to 7, wherein the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere. A process according to any one of claims 1 to 7, wherein the post-treatment is as follows: concentrating the reaction mixture, separating the residue by silica gel column chromatography, to give a target product of formula 4, wherein the elution solvent for silica gel column chromatography is a mixed solvent of n-hexane/ethyl acetate.