A continuous process for the preparation of pyrroloindoline / furoindoline compounds

Abstract

The present invention discloses a continuous preparation method of a pyrroloindoline / furanindoline compound. Under room temperature, a compound represented by formula (I), a catalyst and a bromine source are respectively dissolved in corresponding solvents, and then pumped into the solvents through an infusion pump. After mixing in a T-type mixer, gas is introduced into the solvents, and the solvents enter a continuous flow microchannel reactor to react and generate a pyrroloindoline / furanindoline compound represented by formula (II). The catalyst is nitrite, and the reaction process is as follows: wherein the substituent R 1 is an acyl group or an ester group, and the substituent R 2 Substituted or unsubstituted, if substituted, the substituent R 2 It is an alkyl or aryl group, and the H on the benzene ring is substituted by R 3 Substituted or unsubstituted, when substituted R 3 is halogen, methoxy, benzyloxy or alkyl, and Y is NR 4 or O, R 4 is an acyl group or an ester group, and the substituent R 5 Substituted or unsubstituted, when substituted R 5 The present invention uses cheap and readily available reagents to carry out the bromination reaction, and the reaction conditions are mild, without the need to add an additional oxidant.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a continuous preparation method of pyrrole indoleline / furan indoleline compounds. Background Art

[0002] Pyrroloindoline and furanoindoline are important indole alkaloids with extensive structural diversity and high biological activity. They are ubiquitous in nature and have important applications in anticancer drugs. For example, (-)-Acetylardeemin is a drug that can enhance the cytotoxicity of the anticancer agent vincristine against multidrug-resistant human tumor cells. Pseudoakuammigine is an alkaloid extracted from the seeds of Picralima nitida with anti-inflammatory and analgesic effects. (+)-Madindoline A is extracted from the metabolites of Streptomyces nitrosporus and has the ability to inhibit tumor cell growth.

[0003]

[0004] Among the oxidative cyclization strategies for tryptamines, tryptols, and their derivatives, bromocyclization is one of the most widely used reactions for constructing pyrroloindoline and furanoindole structures. Furthermore, the bromine atom at the C3 position can be further transformed to form new C—C, C—N, or C—O bonds while preserving the structure, providing opportunities for the preparation of biologically active compounds. However, this process often requires the use of stoichiometric halogenating agents or terminal oxidants, resulting in the generation of numerous hazardous organic byproducts. Therefore, the development of a green, low-cost, and streamlined method for the preparation of bromopyrroloindoline and furanoindoline derivatives is of great importance. Summary of the Invention

[0005] In view of the above problems, the object of the present invention is to provide a continuous preparation method of pyrroloindoline / furanindoline compounds.

[0006] The specific technical solutions are as follows:

[0007] A continuous preparation method for pyrroloindoline / furanindoline compounds comprises the following steps: at room temperature, dissolving a compound represented by formula (I), a catalyst, and a bromine source in corresponding solvents, respectively, pumping the mixture into the solvents through an infusion pump, mixing the mixture in a T-type mixer, introducing gas, and then entering a continuous flow microchannel reactor to react and generate a pyrroloindoline / furanindoline compound represented by formula (II). The catalyst is nitrite, and the reaction process is as follows:

[0008]

[0009] Among them, the substituent R1 is an acyl group or an ester group, and the substituent R 2 Substituted or unsubstituted, if substituted, the substituent R 2 It is an alkyl or aryl group, and the H on the benzene ring is substituted by R 3 Substituted or unsubstituted, when substituted R 3 is halogen, methoxy, benzyloxy or alkyl, and Y is NR 4 or O, R 4 is an acyl group or an ester group, and the substituent R 5 Substituted or unsubstituted, when substituted R 5 It is an ester group.

[0010] Preferably, the substituent R 1 is acetyl, benzoyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyloxycarbonyl or methoxycarbonyl; R 2 is methyl or phenyl; R 3 is fluorine, chlorine, bromine, methyl, ethyl, methoxy or benzyloxy; R 4 is acetyl, benzoyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, benzyloxycarbonyl, tert-butyloxycarbonyl or methoxycarbonyl; R 5 It is methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl.

[0011] Furthermore, the nitrite is any one of sodium nitrite, potassium nitrite, calcium nitrite, silver nitrite, ammonium nitrite, copper nitrite, lead nitrite, and zinc nitrite, or a combination thereof. Preferably, the nitrite is potassium nitrite.

[0012] Furthermore, the bromine source is any one of hydrobromic acid (aq. 33%), hydrobromic acid (aq. 40%), hydrobromic acid (aq. 48%), hydrobromic acid (33% in AcOH), pyridine hydrobromic acid, and triethylamine hydrobromic acid, or a combination thereof. Preferably, the bromine source is hydrobromic acid (aq. 48%).

[0013] Further, the solvent for dissolving the substrate shown in formula (I), the catalyst and the bromine source is ethyl acetate, butyl acetate, methyl acetate, methyl formate, ethyl formate, butyl formate, acetonitrile, butyronitrile, valeronitrile, benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, ether, acetone, methyl butanone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, pyridine, phenol, or any one or a combination of any of the above. Preferably, the solvent for dissolving the substrate shown in formula (I) and the bromine source is acetonitrile, and the solvent for dissolving the catalyst is water.

[0014] Furthermore, the molar amount of the catalyst is 1-60% of the amount of the compound represented by formula (I), preferably 10%, and the molar ratio of the compound represented by formula (I) to the bromine source is 1:1-1:5, preferably 1:1.2.

[0015] Furthermore, the molar number of the solute of the compound represented by formula (I) in the total solvent is 0.1-2, preferably 0.2.

[0016] Furthermore, after the compound represented by formula (I) and the catalyst are dissolved in the corresponding solvents, they are pumped into the T-type mixer through an infusion pump at a flow rate of 10-300 μL / min, preferably 75 μL / min, and the bromine source solution is pumped into the T-type mixer through an infusion pump at a flow rate of 5-200 μL / min, preferably 75 μL / min.

[0017] Furthermore, the gas is oxygen, hydrogen, chlorine, methane, ethylene, acetylene, carbon dioxide, nitrogen, ammonia, helium, nitric oxide, nitrogen dioxide, hydrogen fluoride, sulfur dioxide, sulfur trioxide, hydrogen chloride or air, preferably oxygen, the gas is fed at a flow rate of 10-300 SCCM, preferably 75 SCCM, the reaction temperature is 10-90°C, preferably 25°C, the reaction pressure is 5-30 bar, preferably 25 bar, and the reaction time is 10-600 min, preferably 26 min.

[0018] Furthermore, the microchannel reactor is a PTFE coil reactor with an inner diameter of 0.5-6.0 mm, preferably 0.8 mm, an outer diameter of 1.6-8 mm, preferably 1.6 mm, and an internal volume of 15-157 mL, preferably 25 mL.

[0019] The beneficial effects of the present invention are:

[0020] a) The compounds of the present invention can be prepared by continuous flow, are practical, and have broad application prospects;

[0021] b) Catalysts and bromine source reagents are cheap, readily available, and stable;

[0022] c) The steps are simple and the reaction can be carried out at room temperature and in air, which is a relatively mild condition;

[0023] d) The reaction is relatively green and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A schematic diagram of the equipment used in the present invention;

[0025] In the figure: 1. Infusion pump; 2. T-type mixer; 3. Microchannel reactor. DETAILED DESCRIPTION

[0026] The present invention is further described in detail with reference to the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and are protected by the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products. The purity of the product is identified by nuclear magnetic resonance.

[0027] Use Figure 1 The device shown is used to prepare pyrroloindoline / furanindoline compounds, comprising the following steps: at room temperature, the compound represented by formula (I), a catalyst, and a bromine source are dissolved in corresponding solvents, respectively, and then pumped into the solvents through an infusion pump 1. After mixing through a T-type mixer 2, gas is introduced into a continuous flow microchannel reactor 3, which is a PTFE coil reactor. The pyrroloindoline / furanindoline compound represented by formula (II) is reacted, and the catalyst is nitrite. The reaction process is as follows:

[0028]

[0029] Example 1

[0030] (3a,8a)-3a-Bromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0031]

[0032] A solution of tert-butyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indole-1-carboxylate (876 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and EA (15 mL x 3) was added and the product was extracted. The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in a 90% yield. 1 H NMR(400MHz, CDCl3)δ7.51(s,1H),7.29(d,J=7.7Hz,1H),7.24–7.19(m,1H),7.02(t,J=7 .5Hz,1H),6.36(s,1H),3.71–3.60(m,1H),2.79–2.62(m,3H),1.51(s,9H),1.42(s,9H). 13 CNMR(100MHz, CDCl3)δ153.6,152.3,142.2,132.8,130.4,124.2,123.9,117.6,83.9,82.2,80.9,62.3,46.3,41.5,28.5,28.4.HRMS(ESI)m / z Calcd for[C 20 H 27 BrN2NaO4,M+Na] + :461.1046,found 461.1044.

[0033] Example 2

[0034] tert-Butyl (3a,8a)-3a-bromo-8-toluenesulfonyl-3,3a,8,8a-tetrahydropyrrolo[2,3b]indole-1(2H)-carboxylate

[0035]

[0036] A solution of tert-butyl (2-(1-tosyl-1H-indol-3-yl)ethyl)aminocarboxylate (828 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure for 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in a 94% yield. 1 H NMR(400MHz, CDCl3)δ7.70(d,J=7.9Hz,2H),7.55(d,J=8.1Hz,1H),7.34–7.24(m,2H),7.22 –7.05(m,3H),6.31(s,1H),3.89–3.66(m,1H),2.81–2.57(m,3H),2.32(s,3H),1.56(s,9H). 13 C NMR (100MHz, CDCl3) δ153.2,144.2,141.2,135.6,133.7,130.6,129.4,127.8 ,125.9,124.3,117.7,86.7,81.8,62.1,45.9,42.4,28.3,21.5.HRMS(ESI)m / z Calcd for[C 22 H 25 BrN2NaO4S,M+Na] + :515.0611,found 515.0610.

[0037] Example 3

[0038] 8-tert-Butyl-1-methyl-2,3,3a-bromo,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate

[0039]

[0040] A solution of tert-butyl 3-(2-((methoxycarbonyl)amino)ethyl)-1H-indole-1-carboxylate (636 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in a 91% yield. 1 H NMR (400MHz, CDCl3) δ7.65(d,J=8.3Hz,1H),7.37(d,J=7.6Hz,1H),7.33–7.28(m,1H),7.10(t,J=7.6Hz ,1H),6.40(s,1H),3.83–3.76(m,1H),3.74(s,3H),2.93–2.80(m,2H),2.79–2.67(m,1H),1.60(s,9H). 13 C NMR (100MHz, CDCl3) δ154.6,152.1,141.9,132.3,130.5,124.2,123.7,117.3,83.9,82.1,62.1,52.7,46.3,41.0,28.2.HRMS(ESI)m / z Calcd for[C 17 H 21 BrN2NaO4,M+Na] + :419.0577,found 419.0582.

[0041] Example 4

[0042] (3a,8a)-3a-Bromo-8-toluenesulfonyl-3,3a,8,8a-tetrahydropyrrolo[2,b]indole-1(2H)-carboxylic acid methyl ester

[0043]

[0044] A solution of methyl (2-(1-tosyl-1H-indol-3-yl)ethyl)carbamate (722 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure for 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in a 92% yield. 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.1Hz,2H),7.57(d,J=8.2Hz,1H),7.32–7.24(m,2H),7.18–7.11(m, 3H), 6.25 (s, 1H), 3.75 (m, J = 18.3Hz, 1H), 3.75 (s, 3H), 2.78 (m, 1H), 2.74–2.60 (m, 2H), 2.29 (s, 3H). 13 C NMR (100MHz, CDCl3) δ154.2,144.2,140.9,135.3,133.4,130.6,129.4,127.7 ,125.9,124.2,117.8,86.6,61.5,52.8,45.8,41.9,21.5.HRMS(ESI)m / zCalcd for[C 19 H 19 BrN2NaO4S,M+Na] + :473.0141,found 473.0144.

[0045] Example 5

[0046] (3a,8a)8-Benzoyl-3a-bromo-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylic acid methyl ester

[0047]

[0048] A solution of methyl (2-(1-benzoyl-1H-indol-3-yl)ethyl)carbamate (645 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure for 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in a 91% yield. 1 H NMR(400MHz, CDCl3)δ8.05(d,J=8.2Hz,1H),7.78(d,J=7.2Hz,2H),7.50–7.40(m,4H),7.33(t,J=7.8Hz, 1H),7.17(t,J=7.5Hz,1H),6.35(s,1H),3.65(m,1H),3.42(s,3H),2.95–2.82(m,2H),2.79–2.64(m,1H). 13 C NMR (100MHz, CDCl3) δ170.3,154.3,142.3,136.2,132.2,131.0,131.0,128 .5,128.3,125.4,123.5,117.7,84.4,62.0,52.5,46.4,39.3.HRMS(ESI)m / z Calcd for[C 19 H 17 BrN2NaO3,M+Na] + :423.0315,found 423.0320.

[0049] Example 6

[0050] (3a,8a)-8-Acetyl-3a-bromo-3,3a,8,8a-tetrahydropyrrolo[2,3b]indole-1(2H)-carboxylic acid methyl ester

[0051]

[0052] A solution of methyl (2-(1-acetyl-1H-indol-3-yl)ethyl)carbamate (520 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=20:1) to obtain the desired product in a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.36 (d, J = 7.6Hz, 1H), 7.31 (m, 1H), 7.14 (t, J = 7 .5Hz,1H),6.12(s,1H),3.68(s,4H),2.91–2.82(m,2H),2.76(m,1H),2.66(s,3H). 13 C NMR (100MHz, CDCl3) δ170.74,154.78,141.93,132.21,130.65,125.33,123.28,119.36,85.31,61.85,52.94,46.58,40.27,23.42.HRMS (ESI) m / z Calcd for[C 14 H 15 BrN2NaO3,M+Na] + :361.0158,found.361.0160.

[0053] Example 7

[0054] 1-Benzyl-8-tert-butyl (3a,8a)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3,b]indole-1,8-dicarboxylate

[0055]

[0056] A solution of tert-butyl 3-((benzyloxy)carbonyl)amino)ethyl)-1H-indole-1-carboxylate (788 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=20:1) to obtain the desired product in a yield of 89%. 1 H NMR(400MHz, CDCl3)δ7.68(s,1H),7.45–7.29(m,7H),7.11(t,J=7.6Hz,1H),6.50(s,1H),5.21(s,2H) ,3.80(dd,J=10.9,7.6Hz,1H),2.94–2.87(m,1H),2.85–2.80(m,1H),2.78–2.70(m,1H),1.58(s,9H). 13 CNMR (100MHz, CDCl3) δ153.86,151.99,141.85,136.38,132.29,130.41,128.37,127.97,127 .85,124.14,123.67,117.30,83.93,82.07,67.09,61.93,46.24,40.89,28.10.HRMS(ESI)m / z Calcd for[C 23 H 25 BrN2NaO4,M+Na] + :495.0890,found495.0889.

[0057] Example 8

[0058] 3a-Bromo-8-(p-toluenesulfonyl)-3,3a,8,8a-tetrahydropyrrolo[2,3b]indole-1(2H)-carboxylic acid benzyl ester

[0059]

[0060] A solution of benzyl (2-(1-tosyl-1H-indol-3-yl)ethyl)carbamate (896 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in an 87% yield. 1 H NMR(400MHz, CDCl3) δ7.61(d,J=8.2Hz,3H),7.56–7.41(m,2H),7.40–7.30(m,5H),7.17–7.12(m,J=14.3,7.5Hz,3H),6.30(s ,1H),5.30(s,1H),5.18(d,J=11.7Hz,1H),3.80(dd,J=11.1,7.1Hz,1H),2.85–2.78(m,1H),2.76–2.60(m,2H),2.31(s,3H). 13 C NMR (100MHz, CDCl3) δ153.8,144.4,141.1,136.2,135.4,133.5,130.8,129.5,128.7,128 .5,128.3,127.9,126.0,124.3,117.9,86.8,67.8,61.7,46.0,42.3,21.6.HRMS(ESI)m / z Calcd for[C 25 H 23 BrN2NaO4S,M+Na] + :549.0454,found 549.0460.

[0061] Example 9

[0062] tert-Butyl (3a,8a)-1-acetyl-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-8(1H)-carboxylate

[0063]

[0064] A solution of tert-butyl 3-(2-acetylaminoethyl)-1H-indole-1-carboxylate (605 mg, 2 mmol, 1.0 equiv., 0.4 mL MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow rate of 75 μL / min of hydrobromic acid (407 μL of 48% HBr in 7.5 mL MeCN). The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=20:1) to obtain the desired product in a yield of 89%. 1 H NMR (400MHz, CDCl3) δ7.47(s,1H),7.40(d,J=7.6Hz,1H),7.31(d,J=8.0Hz,1H),7. 16(s,1H),6.38(s,1H),4.09(s,1H),2.87–2.65(m,3H),2.36(s,3H),1.60(s,9H). 13 C NMR (100MHz, CDCl3) δ170.5,152.6,141.3,132.9,130.4,125.0,123.7,118.3,84.9,83.2,62.4,45.1,40.3,28.1,22.2.HRMS(ESI)m / z Calcd for[C 17 H 21 BrN2NaO3,M+Na] + :403.0628,found 403.0630.

[0065] Example 10

[0066] 1-((3a,8a)-3a-Bromo-8-tosyl-3,3a,8,8a-tetrahydropyrrolo[2,3b]indol-1(2H)-yl)ethan-1-one

[0067]

[0068] A solution of N-(2-(1-tosyl-1H-indol-3-yl)ethyl)acetamide (712 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=5:1) to obtain the target product in a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.2Hz,1H),7.54(d,J=8.0Hz,2H),7.37(t,J=7.8Hz,1H),7.27(d,J=7.6Hz,1H),7.24–7.19( m,1H),7.14(d,J=8.1Hz,2H),6.13(s,1H),4.07–4.03(m,1H),2.68(d,J=7.0Hz,2H),2.55(s,2H),2.52(s,3H),2.31(s,3H). 13 C NMR (100MHz, CDCl3) δ170.8,145.0,140.8,134.5,130.9,129.6,128.3,127.1,124.4,119.2,87.7,62.0,45.0,41.5,23.0,21.7.HRMS(ESI)m / z Calcd for[C 19 H 19 BrN2NaO3S,M+Na] + :457.0192,found457.0193.

[0069] Example 11

[0070] (3a,8a)-3a-Bromo-4-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0071]

[0072] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-4-methyl-1H-indole-1-carboxylate (748 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 5: 1) with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.47(d,J=7.6Hz,1H),7.18(t,J=7.9Hz,1H),6.84(d,J=7.6Hz,1H),6.47(s,1H),3.73(dd,J=11.1 ,7.7Hz,1H),3.00(dd,J=12.3,4.7Hz,1H),2.85–2.77(m,1H),2.69–2.59(m,1H),2.47(s,3H),1.57(s,9H),1.48(s,9H). 13 C NMR (100MHz, CDCl3) δ153.6,152.3,142.7,135.2,130.3,129.1,126.4,115.0,84.5,82.1,80.8,63.6,46.2,40.2,28.5,28.4,18.6.HRMS (ESI) m / z Calcd for[C 21 H 29 BrN2NaO4,M+Na] +:475.1203,,found475.1209.

[0073] Example 12

[0074] (3a,8a)-3a-Bromo-4-chloro-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0075]

[0076] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-4-chloro-1H-indole-1-carboxylate (788 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 5: 1) with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.56 (s, 1H), 7.21 (t, J = 8.1Hz, 1H), 7.02 (d, J = 8.1Hz, 1H), 6.46 (s, 1H), 3.76 –3.71(m,1H),3.42–3.37(m,1H),2.87–2.76(m,1H),2.61–2.53(m,1H),1.56(s,9H),1.47(s,9H). 13 CNMR(100MHz, CDCl3)δ153.5,151.9,144.2,131.5,131.1,128.0,125.1,115.8,84.7,82.7,80.9,61.9,46.4,39.2,28.4,28.3.HRMS(ESI)m / z Calcdfor[C 20 H 27 BrClN2O4,M+H] +:473.0837,found 473.0835.

[0077] Example 13

[0078] (3a,8a)-3a,4-dibromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0079]

[0080] A solution of tert-butyl 3-(2-(((tert-Butyloxycarbonyl)amino)ethyl)-4-bromo-1H-indole-1-carboxylate (876 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 10: 1) with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ7.63(s,1H),7.21(d,J=8.0Hz,1H),7.13(t,J=8.1Hz,1H),6.47(s,1H),3.7 3(dd,J=11.3,7.8Hz,1H),3.53–3.48(m,1H),2.82(m,1H),2.54(m,1H),1.56(s,9H),1.47(s,9H). 13 C NMR (100MHz, CDCl3) δ153.4,151.8,144.2,131.5,129.3,128.4,119.5,116.4,84.7,82.6,80.8,63.0,46.3,39.1,28.4,28.3.HRMS(ESI)m / z Calcdfor[C 20 H 26 Br2N2NaO4,M+Na] +:539.0152,found 539.0150.

[0081] Example 14

[0082] (3a,8a)-3a-Bromo-5-methoxy-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0083]

[0084] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-5-methoxy-1H-indole-1-carboxylate (780 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 5: 1) with a yield of 82%.

[0085] 1 H NMR (400MHz, CDCl3) δ7.45(s,1H),6.88–6.79(m,2H),6.39(s,1H),3.78(s,3H),3.73–3.68(m,1H),2.85–2.63(m,3H),1.55(s,9H),1.47(s,9H). 13 C NMR (100MHz, CDCl3) δ156.7,153.5,152.4,135.8,133.8,118.6,116.3,108.5,84.1,81.9,80.8,62.4,55.8,46.1,41.1,28.5,28.4.HRMS (ESI) m / z Calcd for[C 21 H 29 BrN2NaO5,M+Na] +:491.1152,found491.1157.

[0086] Example 15

[0087] (3a,8a)-3a,5-dibromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0088]

[0089] A solution of tert-butyl 3-(2-(((tert-Butyloxycarbonyl)amino)ethyl)-5-bromo-1H-indole-1-carboxylate (876 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 5: 1) with a yield of 82%. 1 H NMR(400MHz, CDCl3)δ7.45(s,2H),7.39–7.33(m,1H),6.41(s,1H),3.81–3. 66(m,1H),2.85–2.76(m,1H),2.76–2.61(m,2H),1.56(s,9H),1.46(s,9H). 13 C NMR (100MHz, CDCl3) δ153.3,151.9,141.3,134.8,133.3,127.0,118.8,116.3,84.3,82.6,81.0,61.1,46.3,41.8,28.4,28.3.HRMS(ESI)m / z Calcd for[C 20 H 26 Br2N2NaO4,M+Na] + :539.0152,found539.0155.

[0090] Example 16

[0091] (3a,8a)-3a-Bromo-5-chloro-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0092]

[0093] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-5-chloro-1H-indole-1-carboxylate (789 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 5: 1) with a yield of 89%. 1 H NMR(400MHz, CDCl3)δ7.52(s,1H),7.31(d,J=2.2Hz,1H),7.25–7.20(m,1H),6.42(s,1 H),3.81–3.65(m,1H),2.85–2.77(m,1H),2.75–2.62(m,2H),1.56(s,9H),1.46(s,9H). 13 C NMR (400MHz, CDCl3) δ153.3,151.9,140.7,134.4,130.4,129.0,124.0,118.5,84.3,82.5,80.9,61.2,46.2,41.7,28.4,28.3.HRMS(ESI)m / z Calcd for[C 20 H 26 BrClN2NaO4,M+Na] + :495.0657,found 495.0653.

[0094] Example 17

[0095] (3a,8a)-3a-Bromo-6-fluoro-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0096]

[0097] A solution of tert-butyl 3-(2-(((tert-Butyloxycarbonyl)amino)ethyl)-6-fluoro-1H-indole-1-carboxylate (789 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 5: 1) with a yield of 83%.

[0098] 1 H NMR (400MHz, CDCl3) δ7.35–7.29(m,2H),6.81–6.76(m,1H),6.46(s,1H),3.76(dd,J=11.2,7.2Hz,1H),2.85–2.67(m,3H),1.59(s,9H),1.49(s,9H). 13 CNMR (100MHz,CDCl3)δ164.1(d, 1 J C-F =245Hz),153.3,151.7,143.6(d, 2 J C-F =20Hz),128.3,125.0(d, 3 J C-F =10Hz),111.1(d, 2 J C-F =24Hz),105.1,84.7,82.7,80.9,61.7,46.3,28.4,28.2. 19F NMR(376MHz,CDCl3)δ-109.95.HRMS(ESI)m / zCalcd for[C 20 H 26 BrFN2NaO4,M+Na] + :479.0952,found 479.0949.

[0099] Example 18

[0100] (3a,8a)-3a-Bromo-6-chloro-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0101]

[0102] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-6-chloro-1H-indole-1-carboxylate (788 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 8: 1) with a yield of 90%.

[0103] 1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.27 (d, J = 8.2Hz, 1H), 7.07 (dd, J = 8.2, 1.8Hz, 1H), 6.44 (s,1H),3.77-3.74(m,1H),2.84-2.79(m,1H),2.75-2.67(m,2H),1.59(s,9H),1.48(s,9H); 13C NMR(100MHz, CDCl3)δ153.2,151.7,143.0,136.1,131.1,124.7,124.1,117.6,84.4,82.7,80.9,61.4,46.2,28.3,28.2; HRMS(ESI)(m / z)[M+Na] + Calcd for C 20 H 26 O4N2BrClNa:495.0657, found 495.0651.

[0104] Example 19

[0105] (3a,8a)-3a-Bromo-7-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0106]

[0107] A solution of tert-butyl 3-(2-(((tert-Butyloxycarbonyl)amino)ethyl)-7-methyl-1H-indole-1-carboxylate (748 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 8: 1) with a yield of 89%.

[0108] 1 H NMR(400MHz, CDCl3)δ7.17(dd,J=6.4,2.5Hz,1H),7.12–7.06(m,2H),6.22(s,1H),3.57–3 .44(m,1H),2.81–2.74(m,1H),2.73–2.61(m,2H),2.28(s,3H),1.51(s,9H),1.48(s,9H). 13C NMR (100MHz, CDCl3) δ153.7,141.6,135.1,132.4,130.9,126.2,120.3,86.0,82.0,80.6,62.2,45.5,37.9,28.6,28.2,19.3.HRMS(ESI)m / z Calcd for[C 21 H 29 BrN2NaO4,M+Na] + :475.1203,found 475.1200.

[0109] Example 20

[0110] (3a,8a)-3a,7-Dibromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0111]

[0112] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-7-bromo-1H-indole-1-carboxylate (748 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 8: 1) with a yield of 91%.

[0113] 1 H NMR (400MHz, CDCl3) δ7.46(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),7.04(t,J=7.8Hz ,1H),6.16(s,1H),3.57–3.48(m,1H),2.81–2.63(m,3H),1.51(s,9H),1.48(s,9H). 13C NMR (100MHz, CDCl3) δ153.5,152.4,142.0,137.7,134.6,127.3,122.0,115.7,86.4,82.6,81.1,61.6,45.5,37.7,28.5,28.1.HRMS(ESI)m / zCalcd for[C 20 H 26 Br2N2NaO4,M+Na] + :539.0152,found 539.0160.

[0114] Example 21

[0115] (3a,8a)-3a-Bromo-7-benzyloxy-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0116]

[0117] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-7-benzyloxy-1H-indole-1-carboxylate (933 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 8: 1) with a yield of 83%.

[0118] 1H NMR (400MHz, CDCl3) δ7.57 -6.98(m,7H),6.76(d,J=8.7Hz,1H),6.16(s,1H),5.23-4.72(dd,2H),3.70-3.39(m,2H),2 .75(td,J=11.1,10.7,5.3Hz,1H),2.49(td,J=12.4,8.4Hz,1H),1.41(s,9H),1.33(s,9H). 13 C NMR (100MHz, CDCl3) δ153.7,152.9,150.2,136.5,134.2,133.3,130.9,128.5,128.1,127. 5,117.8,109.5,86.6,82.0,81.0,70.6,63.3,45.7,36.0,28.6,28.0.HRMS(ESI)m / z[M+Na] + calcd for C 27 H 33 BrN2NaO5:576.1603, found 576.1611.

[0119] Example 22

[0120] (3a,8a)-3a-Bromo-8a-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0121]

[0122] A solution of tert-butyl 3-(2-(((tert-Butyloxycarbonyl)amino)ethyl)-2-methyl-1H-indole-1-carboxylate (748 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 8: 1) with a yield of 93%.

[0123] 1 H NMR (400MHz, CDCl3) δ7.67(s,1H),7.36(d,J=7.7Hz,1H),7.27–7.23(m,1H),7.07(t,J=7.5Hz,1H) ,3.47–3.39(m,1H),2.92–2.80(m,2H),2.69–2.59(m,1H),2.16(s,3H),1.59(s,9H),1.42(s,9H). 13 C NMR(100MHz, CDCl3)δ152.9,151.7,142.3,132.1,130.1,123.6,123.1,118.6,88.2,81.7,80.4,77.4,70.5,45.8,36.0,28.5,24.2.HRMS(ESI)m / zCalcd for[C 21 H 29 BrN2NaO4,M+Na] + :475.1203,found475.1197.

[0124] Example 23

[0125] (3a,8a)-3a-Bromo-8a-phenyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylic acid di-tert-butyl ester

[0126]

[0127] A solution of tert-butyl 3-(2-(((tert-Butoxycarbonyl)amino)ethyl)-2-phenyl-1H-indole-1-carboxylate (872 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-type mixer 2 at a flow rate of 75 μL / min and mixed with hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL) at a flow rate of 75 μL / min. The effluent was transferred to a T-type mixer 2 and mixed with oxygen (flow rate 75 SCCM). In a PTFE coil reactor (inner diameter 0.8 mm, outer diameter 1.6 mm, internal volume 25 mL), a flow diazotization reaction occurred at 25 ° C and 25 bar pressure within 26 minutes. The reaction mixture was quenched with a saturated Na2S2O3 aqueous solution (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product (eluent polarity: PE: EA = 8: 1) with a yield of 87%.

[0128] 1 H NMR (400MHz, CDCl3) δ8.06(d,J=8.3Hz,1H),7.69(s,1H),7.39(d,J=7.7Hz,1H),7.37–7.28(m,4H),7.19(s,1H),7.10( t,J=7.5Hz,1H),3.79–3.58(m,1H),3.27–3.13(m,1H),2.87–2.71(m,1H),2.50–2.33(m,1H),1.37(s,9H),1.29(s,9H). 13 C NMR (100MHz, CDCl3) δ151.9,142.9,136.4,133.1,131.5,130.4,128.1,126.8,125.6,12 5.6,123.3,123.2,118.0,92.5,81.4,80.2,73.4,47.4,35.8,28.4,27.8.HRMS(ESI)m / z Calcd for[C 26 H 32 BrN2O4,M+H] + :515.1540,found 515.1541.

[0129] Example 24

[0130] tert-Butyl (3a,8a)-3a-bromo-2,3,3a,8a-tetrahydro-8H-furo[2,3b]indole-8-carboxylate

[0131]

[0132] A solution of tert-butyl 3-(2-hydroxyethyl)-1H-indole-1-carboxylate (522 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow rate of 75 μL / min of hydrobromic acid (407 μL of aq. 48% HBr in 7.5 mL MeCN). The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 87%. 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.42 (d, J = 7.6Hz, 1H), 7.30 (t, J = 7.0Hz, 1H), 7.09 (t, J = 7.5Hz, 1H), 6 .20(s,1H),4.01(t,J=8.2Hz,1H),3.58–3.41(m,1H),3.00–2.85(m,1H),2.85–2.75(m,1H),1.62(s,9H). 13 C NMR(100MHz, CDCl3)δ151.8,141.9,131.7,130.5,124.9,123.8,115.0,100.8,82.1,67.8,61.8,45.1,28.4.HRMS(ESI)m / z Calcd for[C 15 H 18 BrNNaO3,M+Na] + :362.0363,found 362.0367.

[0133] Example 25

[0134] tert-Butyl (3a,8a)-3a-bromo-8a-methyl-2,3,3a,8a-tetrahydro-8H-furo[2,3b]indole-8-carboxylate

[0135]

[0136] A solution of tert-butyl 3-(2-hydroxyethyl)-2-methyl-1H-indole-1-carboxylate (550 mg, 2 mmol, 1.0 equiv., 0.4 mL MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 84%. 1 H NMR(400MHz, CDCl3)δ7.70(d,J=8.4Hz,1H),7.41(d,J=7.7Hz,1H),7.25–7.18(m,1H),7.06–6.98(m,1H) ,3.92–3.88(m,1H),3.43–3.37(m,1H),2.87–2.79(m,1H),2.78–2.71(m,1H),2.08(s,3H),1.58(s,9H). 13 C NMR(100MHz, CDCl3)δ151.9,142.0,131.3,130.4,125.2,123.4,115.2,103.9,82.3,71.5,66.3,46.3,28.5,26.6.HRMS(ESI)m / z Calcd for[C 16 H 20 BrNNaO3,M+Na] + :376.0519,found 376.0522.

[0137] Example 26

[0138] tert-Butyl (3a,8a)-3a-bromo-8a-phenyl-2,3,3a,8a-tetrahydro-8H-furo[2,3b]indole-8-carboxylate

[0139]

[0140] A solution of tert-butyl 3-(2-hydroxyethyl)-2-phenyl-1H-indole-1-carboxylate (674 mg, 2 mmol, 1.0 equiv., 0.4 mL MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 85%. 1 H NMR (400MHz, CDCl3) δ7.97(d,J=8.1Hz,1H),7.66(d,J=7.9Hz,1H),7.45–7.40(m,2H),7.36–7.28(m,3H),7.22(s,1H) ,7.10(t,J=7.5Hz,1H),4.23(t,J=7.5Hz,1H),3.71–3.65(m,1H),2.96–2.88(m,1H),2.86–2.80(m,1H),1.17(s,9H). 13 C NMR (100MHz, CDCl3) δ151.8,142.5,142.3,131.1,130.5,128.1,127.8,127.5,127 .1,125.5,125.4,123.7,114.7,106.7,81.8,72.5,67.1,46.9,27.9.HRMS(ESI)m / z Calcd for[C 21 H 22 BrNNaO3,M+Na] + :438.0675,found 438.0682.

[0141] Example 27

[0142] (3a,8a)-3a-Bromo-8-p-toluenesulfonyl-3,3a,,8a-tetrahydro-2H-furo[2,3b]indole

[0143]

[0144] A solution of 2-(1-toluenesulfonyl-1H-indol-3-yl)ethyl-1-ol (630 mg, 2 mmol, 1.0 equiv., 0.4 mL MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 83%. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=8.4Hz,2H),7.45(d,J=8.2Hz,1H),7.34(d,J=7.7Hz,1H),7.30–7.21(m,3H),7 .09(t,J=7.6Hz,1H),6.24(s,1H),4.00(t,J=7.4Hz,1H),3.41(m,1H),2.83(m,1H),2.72(m,1H),2.35(s,3H). 13 C NMR (100MHz, CDCl3) δ144.5,140.5,135.5,132.4,130.7,129.8,127.4,125.3,124.9,114.2,103.3,68.1,61.5,44.7,21.6.HRMS(ESI)m / z Calcd for[C 17 H 16 BrNNaO3S,M+Na] + :415.9926,found 415.9931.

[0145] Example 28

[0146] (3a,8a)-3a-Bromo-8-(4-nitrobenzenesulfonyl)-3,3a,,8a-tetrahydro-2H-furo[2,3b]indole

[0147]

[0148] A solution of 2-(1-nitrobenzenesulfonyl-1H-indol-3-yl)ethyl-1-ol (672 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in an 80% yield. 1 H NMR (400MHz, CDCl3) δ8.30(d,J=9.0Hz,2H),8.12(d,J=8.9Hz,2H),7.47(d,J=8.1Hz,1H),7.37(d,J=7.8Hz,1H),7.34– 7.27(m,1H),7.15(t,J=7.6Hz,1H),6.22(s,1H),4.10–3.93(m,1H),3.36(m,1H),2.90–2.79(m,1H),2.79–2.71(m,1H). 13 C NMR(100MHz, CDCl3)δ150.5,144.2,139.7,132.6,131.0,128.8,125.7,125.6,124.4,114.1,103.2,68.4,61.0,44.3.HRMS(ESI)m / z Calcd for[C 16 H 13 BrN2NaO5S,M+Na] + :446.9621,found 446.9626.

[0149] Example 29

[0150] tert-Butyl (3a,8a)-3a-bromo-4-fluoro-2,3a,8a-tetrahydro-8H-furo[2,3b]indole-8-carboxylate

[0151]

[0152] A solution of tert-butyl 4-fluoro-3-(2-hydroxyethyl)-1H-indole-1-carboxylate (558 mg, 2 mmol, 1.0 equiv., 0.4 mL MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow rate of 75 μL / min of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN). The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 83%. 1 H NMR (400MHz, CDCl3) δ8.02(s,1H),7.68–7.63(m,J=8.2,5.6Hz,1H),7.11(t,J=8.9Hz,1H),6.55(s ,1H),4.41(t,J=8.3Hz,1H),4.06–3.82(m,1H),3.40–3.35(m,1H),3.25–3.17(m,1H),1.97(s,9H). 13 C NMR (100 MHz, CDCl3) δ 158.8 (d, 1 J C-F =249Hz),151.5,143.9,132.6(d, 2 J C-F =9.2Hz),118.1,110.9(d, 3 J C-F =3.2Hz),110.5(d, 2 J C-F =19.2Hz),101.5,82.6,68.2,58.4,43.1,28.3. 19FNMR(376MHz,CDCl3)δ-117.59.HRMS(ESI)m / z Calcd for[C 15 H 17 BrFNNaO3,M+Na] + :380.0268,found 380.0267.

[0153] Example 30

[0154] 1,8-Di-tert-butyl-2-methyl(2,3a,8a)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,2,8-tricarboxylate

[0155]

[0156] A solution of tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (836 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow rate of 75 μL / min of hydrobromic acid (407 μL of 48% HBr in 7.5 mL MeCN). The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure for 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and EA (15 mL x 3) was added and the product was extracted. The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 10:1) to obtain the desired product in yields of 84% (exo), 7% (endo).

[0157] 30(exo):[α] 25 D =-138.0 (c = 1.0, CHCl3); 1H NMR (400MHz, CDCl3) δ: 7.54 (s, 1H), 7.41-7.27 (m, 2H), 7.12 (t, J = 7.5Hz, 1H), 6.39 (s, 1H), 3.88 (dd, J = 1 0.3, 6.3Hz, 1H), 3.20 (dd, J=12.6, 6.3Hz, 1H), 2.81 (dd, J=12.5, 10.4Hz, 1H), 1.58 (s, 9H), 1.40 (s, 9H). 13 C NMR (100MHz, CDCl3) δ: 171.7, 152.3, 141.7, 133.0, 130.7, 124.5, 123.4, 118.7, 83.9, 82.4, 81.7, 59.7, 59.6, 52.5, 42.1, 28.4; HRMS (CI + )(m / z)calcd.for C 22 H 29 BrN2O6[M] + 496.1209; found 496.1203.

[0158] Example 31

[0159] tert-Butyl (3a,8a)-3a,5-dibromo-2,3a,8a-tetrahydro-8H-furo[2,3b]indole-8-carboxylate

[0160]

[0161] A solution of tert-butyl 5-bromo-3-(2-hydroxyethyl)-1H-indole-1-carboxylate (678 mg, 2 mmol, 1.0 equiv., 0.4 mL MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was mixed with a flow rate of 75 μL / min of hydrobromic acid (407 μL of aq. 48% HBr in 7.5 mL MeCN). The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 84%. 1H NMR (400MHz, CDCl3) δ7.72(s,1H),7.51(d,J=1.9Hz,1H),7.38(d,J=6.6Hz,1H),6.15(s,1H ),4.03–3.99(m,1H),3.52–3.46(m,1H),2.91–2.83(m,1H),2.78–2.74(m,1H),1.59(s,9H). 13 C NMR(100MHz, CDCl3)δ151.6,141.0,133.7,133.4,127.9,116.5,115.9,101.0,82.5,67.8,60.5,44.9,28.4.HRMS(ESI)m / z Calcd for[C 15 H 17 Br2NNaO3,M+Na] + :439.9467,found 439.9473.

[0162] Example 32

[0163] (3-Bromo-8-methylphenyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-1(2H)-yl)(phenyl)methanone

[0164]

[0165] A solution of N-(2-(1-tosyl-1H-indol-3-yl)ethyl)benzamide (837 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL aq. 48% HBrin in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and EA (15 mL x 3) was added and the product was extracted. The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in an 85% yield. 1H NMR(400MHz,Chloroform-d)δ7.71(d,J=8.3Hz,3H),7.59–7.51(m,2H),7.50–7.42(m,1H),7.42–7.29(m,4H) ,7.22–7.12(m,3H),6.82(s,1H),3.64(s,1H),3.14(td,J=11.5,5.6Hz,1H),2.72–2.57(m,2H),2.32(s,3H). 13 C NMR(100MHz,Chloroform-d)δ170.0,144.4,141.5,135.1,134.5,132.9,131.2,130.8, 129.7,128.5,128.3,127.7,125.6,124.7,116.7,85.2,61.6,44.5,21.6.HRMS(ESI)m / z Calcd for[C 24 H 21 BrN2NaO3S,M+Na] + :519.0348,found519.0353.

[0166] Example 33

[0167] Benzyl-3a-bromo-8a-methyl-8-tosyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

[0168]

[0169] A solution of benzyl (2-(2-methyl-1-tosyl-1H-indol-3-yl)ethyl)carbamate (925 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was mixed with a flow of hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL MeCN) solution at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and EA (15 mL x 3) was added and the product was extracted. The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 20:1) to obtain the desired product in an 85% yield. 1 H NMR(400MHz,Chloroform-d)δ7.84–7.70(m,1H),7.63(d,J=8.3Hz,2H),7.55 (dd,J=8.1,3.7Hz,1H),7.42–7.21(m,6H),7.19–7.06(m,3H),5.23(d,J=12.1 Hz, 2H), 3.50 (t, J=9.5Hz, 1H), 2.90 (td, J=10.6, 6.1Hz, 1H), 2.74 (dd, J=12. 9, 6.2Hz, 1H), 2.56 (ddd, J = 13.1, 11.1, 8.6Hz, 1H), 2.31 (s, 3H), 2.15 (s, 3H). 13 C NMR(100MHz,Chloroform-d)δ153.9,143.8,141.0,137.5,136.6,133.2,130.6,129.3,128.4,12 8.6,128.0,127.3,125.4,123.6,118.6,90.9,69.4,67.2,45.8,36.19,23.0,21.5.HRMS(ESI)m / z Calcd for[C 26 H 25 BrN2NaO4S],M+Na] + :563.0611,found.563.0616.

[0170] Example 34

[0171] tert-Butyl 3a-bromo-5-methoxy-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate

[0172]

[0173] A solution of tert-butyl 3-(2-hydroxyethyl)-5-methoxy-1H-indole-1-carboxylate (582 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=20:1) to obtain the desired product in 85% yield. 1 H NMR (400MHz, CDCl3) δ7.72(s,1H),6.91(d,J=2.7Hz,1H),6.83(dd,J=8.9,2.7Hz,1H),6.14(s,1H),3.9 8(t,J=7.2Hz,1H),3.79(s,3H),3.58–3.36(m,1H),2.92–2.80(m,1H),2.78–2.74(m,1H),1.58(s,9H). 13 C NMR(100MHz, CDCl3)δ156.4,151.8,135.6,132.6,116.3,115.8,109.8,101.0,81.9,67.8,62.1,55.8,45.0,28.4.HRMS(ESI)m / z Calcd for[C 16 H 20 BrNNaO4,M+Na] + :392.0468,found392.0473.

[0174] Example 35

[0175] tert-Butyl 3a-bromo-6-chloro-2,3,3a,8a-tetrahydro-8H-furo[2,3-b]indole-8-carboxylate

[0176]

[0177] A solution of tert-butyl 6-chloro-3-(2-hydroxyethyl)-1H-indole-1-carboxylate (591 mg, 2 mmol, 1.0 equiv., 0.4 min MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. The mixture was then mixed with a flow of hydrobromic acid (407 μL of 48% aq. HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=20:1) to obtain the desired product in an 80% yield. 1 H NMR (400MHz, CDCl3) δ7.89(s,1H),7.30(d,J=8.2Hz,1H),7.04(dd,J=8.2,2.0Hz,1H),6.16(s,1 H), 4.00 (t, J = 7.6Hz, 1H), 3.50–3.44 (m, 1H), 2.91–2.83 (m, 1H), 2.77–2.73 (m, 1H), 1.59 (s, 9H). 13 C NMR(100MHz, CDCl3)δ151.6,142.9,136.5,130.2,125.7,123.9,115.4,101.3,82.7,67.9,61.0,45.0,28.4.HRMS(ESI)m / z Calcd for[C 15 H 17 BrClNNaO3,M+Na] + :395.9973,found395.9970.

[0178] Example 36

[0179] 2-Isopropyl-1,8-di-tert-butyl 3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate

[0180]

[0181] A solution of tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-3-isopropoxy-3-oxopropyl)-1H-indole-1-carboxylate (893 mg, 2 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL of eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was sent to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). The flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and EA (15 mL x 3) was added and the product was extracted. The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 5:1) to obtain the desired product in yields of 76% (exo), 6% (endo).

[0182] 36(exo): 1 H NMR (400MHz, CDCl3) δ7.79–7.33(m,1H),7.32–7.27(m,1H),7.26–7.19(m,1H),7.04(t,J=7.5Hz,1H),6.32(s,1H),5.08–4. 71(m,1H),3.92–3.67(m,1H),3.21–3.06(m,1H),2.81–2.61(m,1H),1.51(s,9H),1.46–1.23(s,9H),1.18(t,J=6.2Hz,6H). 13 CNMR (100MHz, CDCl3) δ170.2,153.3,152.2,151.0,141.5,133.1,130.6,123.3,1 19.2,118.0,83.8,82.3,81.4,69.0,59.9,59.8,41.8,28.3,21.7.HRMS(ESI)m / z Calcd for[C 24 H 33BrN2NaO6,M+Na] + :547.1414,found547.1420.

[0183] Example 37

[0184] Continuous Flow Preparation of Some Intermediates in the Total Synthesis of the Natural Product (-)-Physostigmine

[0185] 2-Methyl-1,8-di-tert-butyl 3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate

[0186]

[0187] The intermediate 38 in the total synthesis of the natural product (-)-Physostigmine was prepared by continuous flow, as follows:

[0188] A solution of tryptamine derivative 37 (837 mg, 2.0 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL of 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.56 (s, 1H), 7.37–7.27 (m, 2H), 7.10 (t, J = 7.6Hz, 1H), 6.39 (s, 1H), 3.9 0–3.86(m,1H),3.73(s,3H),3.23–3.19(m,1H),2.84–2.78(m,1H),1.58(s,9H),1.39(s,9H). 13C NMR (100MHz, CDCl3) δ171.3,152.0,141.3,132.6,130.5,124.3,123.2,118.0,83.7,82.1,81.2,59.6,59.3,52.3,41.9,28.1.HRMS(ESI)m / z Calcd for[C 22 H 29 BrN2NaO6,M+Na] + :519.1101,found 519.1100.

[0189] Example 38

[0190] Continuous Flow Preparation of Some Intermediates in the Total Synthesis of the Natural Product (-)-Psychotriasine

[0191] 8-(tert-Butyl)-1,2-dimethyl-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate

[0192]

[0193] The intermediate 42 in the total synthesis of the natural product (-)-Psychotriasine was prepared by continuous flow as follows:

[0194] A solution of tryptamine derivative 41 (753 mg, 2.0 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL H2O) and then pumped into T-mixer 2 at a flow rate of 75 μL / min. It was then mixed with a flow of hydrobromic acid (407 μL eq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was transferred to T-mixer 2 and mixed with oxygen (flow rate 75 SCCM). A flow diazotization reaction was carried out in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA=15:1) to obtain the desired product in a yield of 84%. 1H NMR (400MHz, CDCl3) δ7.57 (s, 1H), 7.38–7.26 (m, 2H), 7.08 (t, J = 7.5Hz, 1H), 6.34 (s, 1H), 4.0 0–3.86(m,1H),3.71(s,3H),3.67(s,3H),y3.31–3.15(m,1H),2.94–2.75(m,1H),1.57(s,9H). 13 C NMR (100MHz, CDCl3) δ171.1,154.2,151.9,141.1,132.3,130.8,124.5,123. 3,118.2,83.6,82.2,59.7,59.4,52.9,52.6,41.7,28.2.HRMS(ESI)m / zCalcd for[C 19 H 23 BrN2NaO6,M+Na] + :477.0632,found 477.0636.

[0195] Example 39

[0196] Continuous Flow Preparation of Some Intermediates in the Total Synthesis of Natural Product WIN64821

[0197] 1,8-di-tert-butyl-2-methyl-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate

[0198]

[0199] Intermediate 46, from the total synthesis of natural product WIN64821, was prepared via continuous flow. A solution of tryptamine derivative 45 (837 mg, 2.0 mmol, 1.0 equiv., 0.4 M in MeCN) was directly mixed with an aqueous solution of KNO2 (17 mg in 100 μL HO). The mixture was then pumped into a T-mixer (2) at a flow rate of 75 μL / min and mixed with a solution of hydrobromic acid (407 μL aq. 48% HBr in 7.5 mL MeCN) at a flow rate of 75 μL / min. The effluent was then transferred to a T-mixer (2) and mixed with oxygen (at a flow rate of 75 sccm). The flow diazotization reaction took place in a PTFE coil reactor (0.8 mm inner diameter, 1.6 mm outer diameter, 25 mL internal volume) at 25°C and 25 bar pressure over 26 minutes. The reaction mixture was quenched with saturated aqueous Na2S2O3 (20 mL), and the product was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent polarity: PE:EA = 15:1) to obtain the desired product in an 82% yield. 1 H NMR(400MHz, CDCl3)δ7.53(s,1H),7.29–7.25(m,2H),7.08–6.98(m,1H),6.43(s,1H),4.53(d,J =9.1Hz,1H),3.26(d,J=13.0Hz,1H),3.11(s,3H),3.10–3.02(m,1H),1.59(s,9H),1.46(s,9H). 13 C NMRδ170.9,152.7,152.3,142.6,132.6,130.8,124.0,118.4,84.4,82.3,81.5,60.4,59.7,52.2,43.4,28.4,28.3.HRMS(ESI)m / z Calcdfor[C 22 H 29 BrN2NaO6,M+Na] + :519.1101,found 519.1100.

Claims

1. A continuous preparation method of pyrroloindoline / furanindoline compounds, characterized in that, The method comprises the following steps: dissolving a compound represented by formula (I), a catalyst and a bromine source in corresponding solvents respectively at room temperature, pumping the mixture into the solvents through an infusion pump (1), mixing the mixture through a T-type mixer (2), introducing gas, and then entering a continuous flow microchannel reactor (3) to react and generate a pyrrole indole / furan indole compound represented by formula (II). The catalyst is nitrite, and the reaction process is as follows: Among them, the substituent R 1 is an acyl group or an ester group, and the substituent R 2 Substituted or unsubstituted, if substituted, the substituent R 2 It is an alkyl or aryl group, and the H on the benzene ring is substituted by R 3 Substituted or unsubstituted, when substituted R 3 is halogen, methoxy, benzyloxy or alkyl, and Y is NR 4 or O, R 4 is an acyl group or an ester group, and the substituent R 5 Substituted or unsubstituted, when substituted R 5 is an ester group; The bromine source is any one of 33% hydrobromic acid, 40% hydrobromic acid, 48% hydrobromic acid, 33% hydrobromic acid in acetic acid, pyridine hydrobromic acid, and triethylamine hydrobromic acid, or any combination thereof; The solvent for dissolving the substrate represented by formula (I), the catalyst and the bromine source is any one or a combination of any two of ethyl acetate, butyl acetate, methyl acetate, methyl formate, ethyl formate, butyl formate, acetonitrile, butyronitrile, valeronitrile, benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, ethyl ether, acetone, methyl butanone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, pyridine, phenol and water; The molar amount of the catalyst is 1-60% of the amount of the compound represented by formula (I), and the molar ratio of the compound represented by formula (I) to the bromine source is 1:1-1:5; The molar number of the solute of the compound represented by formula (I) in the total solvent is 0.1-2; The gas is oxygen and the reaction pressure is 5-30 bar.

2. The continuous preparation method according to claim 1, wherein Substituent R 1 is acetyl, benzoyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butyloxycarbonyl or methoxycarbonyl; R 2 is methyl or phenyl; R 3 is fluorine, chlorine, bromine, methyl, ethyl, methoxy or benzyloxy; R 4 is acetyl, benzoyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, benzyloxycarbonyl, tert-butyloxycarbonyl or methoxycarbonyl; R 5 It is methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl or tert-butyloxycarbonyl.

3. The continuous preparation method according to claim 1 or 2, wherein The nitrite is any one of sodium nitrite, potassium nitrite, calcium nitrite, silver nitrite, ammonium nitrite, copper nitrite, lead nitrite and zinc nitrite, or a combination of any two of them.

4. The continuous preparation method according to claim 1, wherein After the compound represented by formula (I) and the catalyst are dissolved in corresponding solvents, they are pumped into the T-type mixer (2) through the infusion pump (1) at a flow rate of 10-300 μL / min, and the bromine source solution is pumped into the T-type mixer (2) through the infusion pump (1) at a flow rate of 5-200 μL / min.

5. The continuous preparation method according to claim 1, wherein The flow rate of the gas is 10-300 SCCM, the reaction temperature is 10-90° C., and the reaction time is 10-600 min.

6. The continuous preparation method according to claim 1, wherein The microchannel reactor (3) is a PTFE coil reactor with an inner diameter of 0.5-6.0 mm, an outer diameter of 1.6-8 mm, and an inner volume of 15-157 mL.

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