NL2029459A - Tetrahydrofuro(2,3-b) indoline compound, preparation method and application thereof - Google Patents

Abstract

The present disclosure discloses a structurally novel tetrahydrofuro[2,3—b]indoline compound of formula I H, taz/\Rs | , a preparation method and an application thereof. The synthesis can be carried out under mild 5 conditions and at room temperature, the operation is simple and the yield is as high as 99%. The results of the anti— tumor cytotoxicity test of compounds Ia—Ih show that these compounds have certain inhibitory activity against cancer cells, including breast cancer cells MDArMB—23l and MCF—7, 10 osteosarcoma cancer cell U205, leukemia cell HL—60, lymphoma cell JeKo—l, HepG2 cell and. melanoma. cell .A375, etc. The compounds lb and. Id. have exhibited. significant inhibitory activity against JeKo—l, and the compound Ie has exhibited significant inhibitory activity against HL—60. 15 (+ Fig. l)

Description

TETRAHYDROFURO[2,3-B] INDOLINE COMPOUND, PREPARATION METHOD AND

APPLICATION THEREOF

TECHNICAL FIELD The present disclosure relates to the field of medical tech- nology, and more particularly to a tetrahydrofuro[2,3-b]indoline compound, and a preparation method and an application thereof.

BACKGROUND ART Cancer is a leading cause of death worldwide. It is particu- larly important to develop new anti-cancer drugs and more effec- tive strategies for cancer treatment. Natural products are an im- portant part of modern medicine and a source of discovery of new medicines. According to statistics, more than 50% of modern clini- cal anti-tumor drugs are directly or indirectly derived from natu- ral products. Based on the molecular structure of active natural products, designing and synthesizing natural products, screening and discovering compounds with high efficiency, high selectivity, and low toxic and side effects for drug preclinical research is one of the most important approaches for drug research and devel- opment. Tetrahydrofuro[2,3-b] indoline structural units are widely present in natural products and synthetic drug molecules, and have a wide range of pharmacological activities. For example, in the prior art, many biologically active tetrahydrofuro[2,3-b] indoline compounds have been developed, including: H CO,Me H Me Me Cra =r Ons "On ee H LN Me Me : R= Ph, phensvenine aspidophylline AH R = Me, physovenine physovenol and

Hoo PO Howl 20

H H Ny we

HT (+) -Madindolines A and B (*)-Madindoline A (+)-Madindoline B | Therefore, it is of great significance to design and synthesize more tetrahydrofuro[2,;3-b] indoline compounds and study their bio- logical activities.

Intramolecular carbon alkoxylation of alkynes catalyzed by transition metals has attracted much attention in the past decades because of its high bond formation efficiency and atom economy in the rapid assembly of functionalized cyclic compounds. This reac- tion usually involves the intramolecular carbon alkoxylation through external cyclization or internal cyclization, then inter- nal or external migration, resulting in the difunctionalization of alkynes. However, compared with the 1,2-carbon alkoxylation of al- kynes established by Fürstner, Yamamoto, Toste, et al., the relat- ed 1,1-carbon alkoxylation has a much lower degree of development and utilization. It is worth mentioning that 1,1-carbon alkoxyla- tion reaction of alkynes may involve the formation of metal car- bene. In 2002, Yamamoto, et al. reported a kind of palladium- catalyzed carbon alkoxylation of o-alkynylbenzaldehyde dialkyl ac- etals to form indan ethers, which was the first 1,1-carbon alkoxy- lation reaction of alkynes {Angew. Chem., Int. Ed. 2002, 41, 4328- 4331). In 2014, Liu, et al. demonstrated an ingenious scheme that could catalyze the 1,1-carbon alkoxylation of 2-ethynylbenzyl ether to control the synthesis of indanone (Adv. Synth. Catal. 2014, 356, 144-152). Almost at the same time, Davies et al. dis- closed a gold-catalyzed 1,1-carbon alkoxylation reaction of al- kynamine, involving 1,2-N-transfer, to obtain functionalized in- denes (Chem.-Eur. J. 2014, 20, 7262-7266.). Despite these achieve- ments, these 1,1-carbon alkoxylation reactions are only limited to internal cyclization, which ultimately leads to the formation of intra-ring metal carbene after internal migration. In particular, it is proposed to generate carbocation intermediates in these 1,1- carbon alkoxylation reactions.

Inspired by these findings and the inventor’s latest research on the development of alkynamine chemistry for the synthesis of heterocyclic rings, the inventor predicts that the formation of the outer-ring carbene can be carried out by the carbon alkoxyla- tion reaction of the alkynamine with the oxetane structural unit catalyzed by the transition metal, and the ring expansion reaction of the oxetane ring. It should be noted 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-carbon alkoxylation reaction of alkynes (Adv.

Synth. Catal . 2014, 356, 2411-2416). In the present disclosure, the inventor describes the exo-cyclization reaction and gold- catalyzed 1,1-carbonyl alkoxylation reaction of alkynamine at room temperature to generate exocyclic gold carbene, and then 1,2-H mi- grates into the gold carbine, leading to the atom-economic synthe- sis of various tetrahydrofuro[2,3-blindulines. This is an im- portant N heterocyclic skeleton, and is widely present in various biologically active molecules and natural products. In addition, the asymmetric synthesis of these tricyclic N heterocycles can be achieved through chiral transfer strategies and enantioselective cyclization of chiral gold-catalyzed kinetic resolution. In the present disclosure, the inventor discloses the detailed research results of 1,;1-carbon alkoxylation reaction of alkynamine com- pounds, including the range of substrates, synthetic applications, biological tests and studies on mechanism.

SUMMARY The object of the present disclosure is to provide a struc- turally novel tetrahydrofuro[2,3-b]indoline compound, a prepara- tion method and an application thereof.

In one aspect, the present disclosure provides a tetrahydro- furo[2,3-b]indoline compound of formula I as indicated below:

H == R, Rs l Wherein, R; represents a substituent on a connected benzene ring; n represents the number of R, substituents, selected from 1, 2, 3, or 4; each Ri is the same or different, and is independently selected from hydrogen, halogen, and C:g alkyl , Ci. alkoxy; R: is selected from any one of Ts (p-toluenesulfonyl), MBS (p-methoxybenzenesulfonyl), S0:Ph (benzenesulfonyl), Bs (4- bromobenzenesulfonyl), Ms (methylsulfonyl}; R3 is selected from C:4 alkyl, Cis alkoxy-C, ¢ alkyl, and ben- zyloxy-Ci.g alkyl. Preferably, n is selected from 1, and R; is selected from hy- drogen, fluorine, chlorine, bromine, methoxy, and methyl; R; is selected from Ts (p-toluenesulfonyl); R: is selected from methyl, ethyl, n-propyl, benzyloxzypropyl. Most preferably, the compound of formula I is selected from the following compounds of formulae Ia-Ij:

H H H N “= N == == rs rs ON Ts ON la Ib Ic

H H H N “== 4p N “== rs NT rs No Ts ON Id le if O2 Cr ork re NR Ts 308 Br Is Vp Ce ; — In a second aspect, the present disclosure provides a method for preparing the compound of formula I, comprising the following steps: dissolving alkynamine of formula II in an organic solvent at room temperature, then adding a gold catalyst and stirring to react at room temperature, after completion of reaction by TLC monitoring, concentrating the reaction mixture, separating the residue by silica gel column chromatography, to give a tetrahydrofuro[2,3-b]lindoline compound of formula I, with a reaction formula as follows: > 7 Rs A R, Ps EN sed ( N = " TR, R, |?

I 5 Wherein, R;-R;, n in the formula II are as defined in any one of the foregoing herein.

According to the preparation method of the present disclo- sure, wherein the gold catalyst is selected from any one of IPrAuNTf,, Ph;PAuUNTf., Cy-JohnPhosAulNTf,, XPhosAuNTf,, BrettPho- sAuNTf., most preferably, IPrAuNTf.. The feeding molar ratio of the gold catalyst to the compound of formula II is 0.01-0.2:1, preferably 0.05-0.1:1, most preferably 0.05 :1.

According to the preparation method of the present disclo- sure, wherein the organic solvent is selected from any one of dichloromethane, dichloroethane, chlorobenzene, toluene, and acetonitrile, preferably dichloromethane or dichloroethane, most preferably dichloromethane.

According to the preparation method of the present disclo- sure, wherein the time required for completion of reaction by TLC monitoring is 0.5-2 hours, most preferably 1 hour.

According to the preparation method of the present disclo- sure, wherein the elution solvent for silica gel column chromatography is a mixed solvent of n-hexane/ethyl acetate.

In a third aspect, the present disclosure provides an application of the compound of formula I. The results of the anti- tumor cytotoxicity test of compounds Ia-Ih show that these compounds have certain inhibitory activity against cancer cells, including breast cancer 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, etc. It is worth mentioning that the compounds Ib and Id have exhibited significant inhibitory activity against JeKo-1, and the compound Ie has exhibited significant inhibitory activity against HL-60, indicating that the compounds of the present disclosure can be applied to the preparation of anti-cancer drugs.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a single crystal diffraction pattern of compound Ij of the present disclosure.

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 methods used are conventional methods in the art, and the reagents used are all commercially available without further purification. The synthetic route of the reaction substrates IIa-IIj is as follows: r OH O R 3 ‚ Ry RL COOH do LDA (2 equiv) OE! GG EtOAc (2 equiv) R _ „52 NH, > y THF, 78°C - 11, 4 h N 2 | 75-90%

R OH 3

R 1) NaBH, (12 equiv) OMs BuOK RI 0 R MeOH, 0°C-1t, 2h Re (1.1 equiv) 3 2) MSCI (1.1 equiv) ‘BuO, it, 1h N Ps ELN (1.5 equiv) | | Fy DCM, 0°C-1t, 3h 2 Ry 790 58-72%, 2 steps 0 40-50% {one chromatography) Sh N= js ON la Example 1 Synthesis of compound Ia

QO Cr 4

N The alkynamine of formula IIa Ts {0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf, (0.01 mmol) was added, and stirred to react for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 70.4 mg of the target product having the formula Ia, with a yield of 99%. The product was a colorless oily liquid. ‘{ NMR (400 MHz, CDCl3) & 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, 3H), 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, CDCls) & 143.4,

141.9, 137.4, 132.4, 129.7, 12%.0, 128.3, 127.9, 126.0, 124.56,

123.0, 112.7, 106.6, 67.8, 53.7, 33.6, 21.4, 17.4; IR (neat): 2920, 2871, 1599, 1478, 1460, 1361, 1170, 660, 578; HRESIMS Calcd for [C;sH::NNa0:S]" (M + Na’) 378.1134, found 378.1114.

Real N “== rs Example 2 Synthesis of compound Ib Ib © Br Et The alkynamine of formula IIb Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf,; (0.01 mmol) was added, and stirred to react for 24 hours at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 55.6 mg of the target product having the formula Tb, with a yield of 64%. 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, ZH), 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) & 143.7, 141.2, 137.1, 132.1,

132.0, 131.2, 129.1, 127.%, 127.7, l1l2e¢.6, 115.4, 114.2, 107.0,

67.9, 53.4, 33.5, 21.5, 17.5; IR (neat): 2983, 2868, 1597, 1471, 1363, 1275, 1260, 1167, 764, 750, 662, 584; HRESIMS Calcd for [C:9H:oBrNNa0:S]" (M + Na’) 456.0239, found 456.0238. “Or N == js ON Example 3 Synthesis of compound Ic Ic Oo “OL Et wd The alkynamine of formula IIc Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf, (0.0lmmel) was added, and stirred to re- act for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography {elution solvent: n-hexane/ethyl acetate), to obtain 73.2 mg of the target product having the formula Ic, with a yield of 99%. The product was a white solid (mp 155-156 °C). ‘H NMR (400 MHz, CDCI1:) 5 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:) 5

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; IR (neat): 2949, 2919, 2872, 1598, 1486, 1360, 1168, 764, 661; HRESIMS Calcd for [C:H-:NNa0:S]* (M + Na’) 392.1291, found 292.1292. wers N “== Ts ON Example 4 Synthesis of compound Id ld

Oo “OL Et wd The alkynamine of formula IId Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf: (0.0lmmol) was added, and stirred to re- act for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 64.8 mg of the target product having the formula Id, with a yield of 84%. The product was a white solid (mp 115-116°C). GH NMR (400 MHz, CDC1:) & 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, J = 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.) & 156.1, 143.2, 137.5, 135.5, 132.3,

131.1, 128.9, 127.8, 126.1, 113.5, 113.3, 110.6, 106.8, 67.9,

55.6, 53.9, 33.5, 21.4, 17.4; IR (neat): 2951, 2873, 2835, 1598, 1488, 1359, 1216, 1167, 662; HRESIMS Calcd for [C,:;H;;NNaO;3]" (M + Na’) 408.1240, found 408.1241.

lest N “= j Ts ON Example 5 Synthesis of compound Ie le Oo oo

F AE The alkynamine of formula IIe Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf, (0.0lmmcl) was added, and stirred to react for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 70.9 mg of the target product having the formula Ie, with a yield of 95%. 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;) & 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; IR (neat): 2949, 2872, 1601, 1493, 1362, 1171, 663, 582; HRESIMS Calcd for [C:sHzsFNNa0:s]" (M + Na*) 396.1040, found 396.1041.

H Ts Example 6 Synthesis of compound If If Oo

CL Br 7 The alkynamine of formula IIf Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf, (0.0lmmcl) was added, and stirred to react for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 80.0 mg of the target product having the formula If, with a yield of 92%. The product was a white solid (mp 174-175°C). 'H NMR (400 MHz, CDCl;) & 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, IH), 1.85 - 1.78 (m, 1H), 1.77 (d, J = 5.2 Hz, 3H); HPC NMR (100 MHz, CDCl:) ò 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; IR (neat): 2950, 2872, 1597, 1474, 1410, 1362, 1170, 661, 579; HRESIMS Calcd for [CsH:sBrNNa0:S]* (M + Na) 456.0239, found

456.0241.

H Example 7 Synthesis of compound Ig Ts Et Oo on 7 The alkynamine of formula IIg Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf: (0.01 mmol) was added, and stirred to react for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 70.9 mg of the target product having the formula Ig, with a yield of 96%. 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); YC 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; IR (neat): 2964, 2872, 1599, 1478, 1460, 1361, 1170, 749, 662, 578; HRESIMS Calcd for [C1HsNNa03S]" (M + Na‘) 392.1291, found 392.1291.

H C IL yee Example 8 Synthesis of compound Ih Ts VP

Oo Cr"

NZ The alkynamine of formula IIh Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf: (0.01 mmol) was added, and stirred to react for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 72.1 mg of the target product having the formula Ih, with a yield of 94%. The product was a white solid (mp 95-96°C). ‘H NMR (400 MHz, CDCl.) & 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, 3H), 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, CDCl,;) & 143.4, 142.0, 137.5, 131.3,

131.1, 12%.7, 12%.0, 128.3, 127.9, 124.6, 123.0, 112.7, 106.7,

67.8, 53.9, 33.9, 33.6, 21.9, 21.4, 13.6; IR (neat): 2956, 2928, 2871, 1599, 1478, 1459, 1361, 1170, 749, 662, 579; HRESIMS Calcd for [C22H;sNNa0sS]" (M + Na’) 406.1447, found 406.1448.

H re 081 Example 9 Synthesis of compound Ii li or OBn 4

EE The alkynamine of formula IIi Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf: (0.01 mmol) was added, and stirred to react for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 79.3 mg of the target product having the formula Ii, with a yield of 81%. The product was a colorless oily liquid. i'H NMR (400 MHz, CDCls) & 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 (ss, 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 - 2.62 (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; IR (neat): 2928, 2866, 1599, 1478, 1460, 1361, 1169, 751, 662, 579; HRESIMS Calcd for [CsH3:NNa0,48]* (M + Nat) 512.1866, found 512.1872. Jans. Br Ne Mpp Example 10 Synthesis of compound Ij i Oo Br 7 The alkynamine of formula II] Ts (0.2 mmol) was dissolved in dichloromethane (4 mL) at room temperature, then a gold catalyst IPrAuNTf.: (0.01 mmol) was added, and stirred to re- act for 1 hour at at room temperature, after completion of reaction by TLC monitoring, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate), to obtain 74.9 mg of the target product having the formula Ij, with a yield of 81%. The product was a white solid (mp 119-120°C). *H NMR (400 MHz, CDC1:) &

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) &

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; IR (neat): 2956, 2928, 2871, 1597, 1474, 1363, 1171, 661, 579; HRESIMS Calcd for [C::H:,BrNNa0:S]* (M + Na‘) 484.0552, found

484.0553.

Application Example The biological activities of newly synthesized compounds Ia- Th as anti-tumor agents were tested, to evaluate the cytotoxic ef- fects of these compounds on a group of cancer cells, including breast cancer cells MDA-MB-231 and MCF-7, osteosarcoma cancer cell U208, leukemia cell HL-60, lymphoma cell JeKo-1, HepG2 cell and melanoma cells A375, etc. A cell viability assay was performed us- ing a commercially available proliferation assay kit (Promega, US). Briefly, cells were inoculated in a medium in a 96-well cul- ture plate at an appropriate density, allowed to adhere overnight. After treating the control group (0.1% DMSO as a control) or test- ing the compounds according to the specified time and concentra- tion, 20 pL of MTS reaction solution (3-(4,5-dimethylthiazol-2- yl)-5-{(3-carboxymethoxyphenyl) -2-{4-sulfophenyl) -2H-tetrazolium, inner salt; MTS (a) and 100 pg/mL phenazine methosulfate (PES) were added to each well, after incubation for 1-4 hours, the OD values at a wavelength of 490 nm were read from a spectrophotome- ter (Varioskan Flash, Thermo, US). The cell viability was calcu- lated according to the formula: cell viability=(ODtest compouna— ODpiank) / (ODcontso1 ODpianr) 51008. The results were summarized in Table

1. Table 1: ID MDA-MB- MCF- 020 HL- JeKo- HepG A375 BGC- SK-GT- KYS 231 7 s 60 1 2 > 823 4 E-450 OD | es» | aes | eon ssa | oon | war ots | we | mo | sows Men [sas [aes 97 | 39 | mes 91 | se | mes | est TT as owns oa | | ses | an was | om | oun | wen | fe | tenn | os | 7707 | ass | wes | 9202 opn | 126 | 980 | 966 [es [ee [a eme | oar | sam [sess | mos | wa | ser |

The results shown in Table 1 were the mean values obtained in twice tests.

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 Tetrahydrofuro[2,;3-b]lindoline compound of formula I as indicated below: H == R, Rs1 where R; represents a substituent on a linked benzene ring; n represents the number of R 1 substituents selected from 1, 2, 3 or 4; each Ry is the same or different and is independently selected from hydrogen, halogen and C18 alkyl, C18 alkoxy; R; is selected from one of Ts (p-toluenesulfonyl), MBS (p-methoxybenzenesulfonyl), SO 2 Ph (benzenesulfonyl), Bs (4-bromobenzenesulfonyl), Ms (methylsulfonyl); R3 is selected from C18 alkyl, C18 alkoxy-C4; alkyl and benzyloxy-C18 alkyl. A tetrahydrofuro[2,3-b]indoline compound of formula I according to claim 1, wherein n is selected from 1 and R; is selected from hydrogen, fluoro, chloro, bromo, methoxy and methyl; R1 is selected from Ts (p-toluenesulfonyl); R 5 is selected from methyl, ethyl, n-propyl, benzyloxypropyl. A tetrahydrofuro[2,3-b]indoline compound of formula I according to claim 1 or 2, wherein the compound of formula I is selected from the following compounds of formulas Ia-Ij: H H H 1 = L Tl “Ors Ym N Ti me Ts A Ts A Ts DN la Ib lc H H H N “ee FE N eeen Br N ae Ts js js ON Id le If H H H Ts R Ts 3081 Ts "Pr lg, R=Et . . th R="Pr ti j A process for preparing the tetrahydrofuro[2,3-blindoline compound of formula I according to claim 1, comprising the steps of: dissolving alkynamine of formula II in an organic solvent at room temperature, then adding a gold catalyst and stirring to react at room temperature, after completion of the reaction by TLC monitoring, concentrating the reaction mixture, separating the residue by silica gel column chromatography, to obtain a tetrahydrofuro[2,3-b]lindoline compound with formula I with the following reaction formula: 9 Rs H (R DO ' N ON 8 Re Rs 2 I ll where R 1 -R 2 , n in formula II are as defined in any one of claims 1 to 3; gold catalyst is selected from one of IPrAuNTf2, Ph3PAUNTf2, Cy-JohnPhosAuNTf2, XPhosAuNTf2, BrettPhosAuNTf2. The method of claim 4, wherein the gold catalyst is selected from IPrAuNTf2. Process according to any one of claims 4 to 5, wherein the molar ratio in the feed of the gold catalyst to the compound of formula II is at a value of 0.01-0.2:1, preferably at a value of 0. 05-0.1:1, most preferably at a value of 0.05:1. A method according to claim 4, wherein the organic solvent is selected from one of dichloromethane, dichloroethane, chlorobenzene, toluene and acetonitrile, preferably dichloromethane or dichloroethane, most preferably dichloromethane. The method according to claim 4, wherein the time taken to complete the reaction by TLC monitoring is 0.5-2 hours, most preferably 1 hour. The method of claim 4, wherein the elution solvent for silica gel column chromatography is a mixed solvent of n-hexane/ethyl acetate. Use of the tetrahydrofuro[2,3-b]lindoline compound of formula I according to claim 1 in the preparation of antitumor drugs.