LU503507B1 - Indolo [3,2-c] quinoline compound and synthetic method thereof - Google Patents

Indolo [3,2-c] quinoline compound and synthetic method thereof Download PDF

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Publication number
LU503507B1
LU503507B1 LU503507A LU503507A LU503507B1 LU 503507 B1 LU503507 B1 LU 503507B1 LU 503507 A LU503507 A LU 503507A LU 503507 A LU503507 A LU 503507A LU 503507 B1 LU503507 B1 LU 503507B1
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indolo
reaction
synthesis method
quinoline compound
indole
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LU503507A
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German (de)
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Pinggui Li
Lianghua Zou
Yingying Song
Xia Wang
Kailing Zhang
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Wuxi Univ
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Indole Compounds (AREA)
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Abstract

The disclosure discloses an indolo[3,2-c]quinolinium compound and its synthesis method, the indolo[3,2-c]quinolinium compound contains benzamide group and has potential applications in anti-malaria and anti- cancer; the synthesis method is based on 2-(2-aminophenyl)indole or its derivatives as raw materials, copper salt as catalyst, and air as reaction atmosphere, and the reaction is carried out at 70-90°C in organic solvent to obtain indolo[3 ,2-c]quinolines containing benzamide groups; and the raw materials used in the synthesis method are easy to prepare, low in price, green and environment-friendly, and the catalyst is low in price, small in using amount, high in catalytic efficiency and wide in substrate application range.

Description

BL-5624
LU503507
Indolo [3,2-c] quinoline compound and synthetic method thereof
Technical Field
[0001] The disclosure relates to a synthesis method of quinoline compounds, in particular to an indolo [3,2-c] quinoline compound and a synthesis method thereof.
Background Art
[0002] The indoloquinoline compound widely exists in natural products and synthetic drugs with broad-spectrum biological activity, and attracts people's wide attention. Among them, the 11H-indolo [3,2-c] quinoline compound can be used as a candidate drug for malaria resistance and cancer resistance and a high-efficiency inhibitor of protein kinase DYRK1A, and can also be used as a DNA intercalator for inhibiting the replication and transcription of DNA, so it has an important application value in the fields such as biology, medicine and the like. In addition, the indolo [3,2-c] quinoline compound has potential of antibacterial, antifungal, antimalarial, anticancer and antitumor effects, and is also a key intermediate for synthesizing some important compounds. The synthesis method of the indolo [3,2-c] quinoline compound reported in the related literature is mainly obtained by palladium-catalyzed isocyanic insertion reaction, gold- catalyzed cyclization reaction of acyclic alkynes and aza wittig reaction of isocyanate. These literature methods have the disadvantages of difficult availability of starting materials, use of expensive catalysts, narrow substrate application, harsh reaction conditions, and low yield, which 1
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LU503507 greatly limits the scope of application of such synthetic methods.
Disclosure
[0003] The purpose of the disclosure is as follows: the disclosure aims to provide an indolo [3,2-c] quinoline compound containing benzamido, which has potential application value in the aspects of malaria resistance and cancer resistance; and the disclosure also aims to provide a synthetic method for preparing the indolo [3,2-c] quinoline compound, which has high selectivity and simple operation.
[0004] The technical solutions is as follows: the molecular structural formula of the indolo [3,2-c] quinoline compound is
NH
Oya)
RY Fen { Hal
Sen
Rx i i & nd
[0005] H
[0006] Where R! is any one of H, F, Cl or CHz.
[0007] The synthesis method of the indolo [3,2-c] quinoline compound comprises the following steps: taking 2-(2-aminophenyl) indole or derivatives thereof as raw materials, copper salt as a catalyst, reacting in an organic solvent in the reaction atmosphere of air, wherein the reaction temperature is 70-90 °C, and the benzamido-containing indolo [3,2-c] 2
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LU503507 quinoline compound 1s obtained by purifying after the reaction, and the reaction equation is as follows: 3 IN
FRE By #
A RR lyzed Cr J 7 wu i IC \ copper-cata lyre RTL SS &_e” >N + N EN
HN a 5 54 % # S ke =i Ts
[0008] H
[0009] Where R! is any one of H, F, Cl or CHz.
[0010] The copper salt is a metal salt with bivalent copper ions, and is preferably any one of copper bromide, copper chloride or copper acetate.
[0011] Preferably, the molar ratio of the indole or the derivative thereof to the copper catalyst is 1: 0.1-0.3.
[0012] Preferably, the organic solvent is selected from one or more of ethanol, ethylene glycol dimethyl ether, n-butanol or dimethyl sulfoxide.
[0013] Preferably, the reaction time is 10 to 14 hours.
[0014] Preferably, the reaction temperature is 70-80 °C.
[0015] The purification method comprise: washing with a sodium carbonate aqueous solution, extracting with ethyl acetate, and finally separating by adopting a column chromatography; and wherein a solid phase of the column chromatography is column chromatography silica gel, and a mobile phase is a mixture of petroleum ether and ethyl acetate, and a volume ratio of the petroleum ether to the ethyl acetate 1s 3-10: 1. 3
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[0016] A preparation method of the 2-(2-aminophenyl) indole or the derivative thereof comprises the following steps, and the reaction formula 1s as follows:
RL A + NY “Mie ci À EEN WW al Nb lL £5 Nid, H NN
[0017] ë
[0018] Where R' is any one of H, F, Cl or CH3.
[0019] (1) 5mmol of o-aminoacetophenone, 5mmol of phenylhydrazine or phenylhydrazine derivative, 10mL of ethanol and 2mL of acetic acid were added into a 100mL reaction flask, heated to 80 °C, and stirred for reflux reaction for 12 hours. After reaction, 10mL of saturated sodium bicarbonate solution was added to quench the reaction, the solid was precipitated and was filtered to obtain a precipitate, and then the precipitate was air-dried.
[0020] (2) 10mL of methanesulfonic acid aqueous solution with the mass fraction of 50% was prepared, 200mg of phosphorus pentoxide was added, and then the precipitate prepared in the step (1) was added to react at 80 °C for 30 min. After the reaction was finished and the temperature was cooled to room temperature, a sodium hydroxide ice solution with the mass fraction of 10% was added until the PH value is more than 7, then was stood to precipitate a solid, and was filtered. The solid obtained by filtering was recrystallized with toluene to obtain the product of 2- (2(2-amino aryl) indole and derivatives thereof.
[0021] The advantages are as follows. Compared with the prior art, the 4
BL-5624
LU503507 disclosure has the following remarkable advantages: (1) the benzamido indolo [3,2-c] quinoline-containing compound has potential application value in the aspects of malaria resistance and cancer resistance; and (2) the raw materials used in the synthesis method are easy to prepare, low in price, green and environment-friendly, and the catalyst is low in price, small in using amount, high in catalytic efficiency and wide in substrate application range.
Brief Description of Drawings
[0022] FIG. 1 is a view of the synthetic process of the disclosure.
[0023] FIG. 2 is a nuclear magnetic hydrogen spectrum of N- (2- (11H- indole [3,2-c] quinoline-6-oxy) phenyl) -2-aminobenzamide synthesized in example 1.
[0024] FIG. 3 is a nuclear magnetic carbon spectrum of N- (2- (11H-indole [3,2-c] quinoline-6-oxy) phenyl) -2-aminobenzamide synthesized in example 1.
[0025] FIG. 4 is a view of the structure of single crystal of N- (2- (11H- indole [3,2-c] quinoline-6-oxy) phenyl) -2-aminobenzamide synthesized in example 1.
[0026] FIG. 5 is a nuclear magnetic hydrogen spectrum of N- (4-fluoro-2- (8-fluoro-11H-indole [3,2-c] quinolin-6-oxy) phenyl) -2-aminobenzamide synthesized in example 2. 5
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[0027] FIG. 6 is a nuclear magnetic carbon spectrum of N- (4-fluoro-2- (8- fluoro-11H-indole [3,2-c] quinolin-6-oxy) phenyl) -2-aminobenzamide synthesized in example 2.
[0028] FIG. 7 is a nuclear magnetic hydrogen spectrum of N- (4-chloro-2- (8-chloro-11H-indole [3,2-c] quinolin-6-oxy) phenyl) -2-aminobenzamide synthesized in example 3.
[0029] FIG. 8 is a nuclear magnetic carbon spectrum of N- (4-chloro-2- (8- chloro-11H-indole [3,2-c] quinolin-6-oxy) phenyl) -2-aminobenzamide synthesized in example 3.
[0030] FIG. 9 is a nuclear magnetic hydrogen spectrum of N- (4-methyl-2- (8-methyl-11H-indole [3,2-c] quinolin-6-oxy) phenyl) -2-aminobenzamide synthesized in example 4.
[0031] FIG. 10 is a nuclear magnetic carbon spectrum of N- (4-methyl-2- (8-methyl-11H-indole [3,2-c] quinolin-6-oxy) phenyl) -2-aminobenzamide synthesized in example 4.
Best Mode
[0032] The technical solution of the disclosure is further explained with the accompanied drawings.
[0033] The molecular structural formula of the indolo [3,2-e] quinoline compound is as follows: — HD
FN
[0034] (À 6
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LU503507
[0035] Where R! is any one of H, F, Cl or CH3.
[0036] The synthesis method of the indolo [3,2-c] quinoline compound takes 2- (2-aminophenyl) indole or derivatives thereof as raw materials, copper salt as a catalyst, air as reaction atmosphere, and the reaction 1s carried out in an organic solvent, wherein the reaction temperature is 70-90 °C, and the indolo [3,2-c] quinoline compound containing benzamido is obtained by purifying after the reaction, and the reaction equation is as follows: 3-7 ‘ — {rin 3 mu Sef > copper-catalyzed EA FN “sr SN pa Tr = No
HB ph wf pS
[0037] 9
[0038] Where R'is H, F, Cl or CH3.
[0039] A preparation method of the 2-(2-aminophenyl) indole or the derivative thereof comprises the following steps, and the reaction formula 1s as follows: 5 pee Fm,
RN à À ve KK E %
RY a + rage néant ER RRER RR E Ri an us NM Lt CR an
ES HN
[0040] ©
[0041] Where R! is any one of H, F, Cl or CH3.
[0042] (1) 5mmol of o-aminoacetophenone, 5mmol of phenylhydrazine or phenylhydrazine derivative, 10mL of ethanol and 2mL of acetic acid were added into a 100mL reaction flask, heated to 80 °C, and stirred for reflux 7
BL-5624
LU503507 reaction for 12 hours. After reaction, 10mL of saturated sodium bicarbonate solution was added to quench the reaction, the solid was precipitated and was filtered to obtain a precipitate, and then the precipitate was air-dried.
[0043] (2) 10mL of methanesulfonic acid aqueous solution with the mass fraction of 50% was prepared, 200mg of phosphorus pentoxide was added, and then the precipitate prepared in the step (1) was added to react at 80 °C for 30 min. After the reaction was finished and the temperature was cooled to room temperature, a sodium hydroxide ice solution with the mass fraction of 10% was added until the PH value is more than 7, then was stood to precipitate a solid, and was filtered. The solid obtained by filtering was recrystallized with toluene to obtain the product of 2- (2(2-amino aryl) indole and derivatives thereof.
[0044] Example 1
[0045] Regarding to indolo [3,2-c] quinoline compound of the disclosure, when R'is H, it will be N- (2- (11H-indole [3, 2-c] quinoline-6-oxygen) phenyl) -2-aminobenzamide with the structural formula
FF
FEE, N La 3 & FOUT aa Me
So
[0046] H
[0047] The synthesis method of the compound comprises the following steps.
[0048] Step 1 Preparation of 2- (2-aminophenyl) indole 8
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LU503507
[0049] 0 “en
[0050] (1) 5mmol of o-aminoacetophenone, 5mmol of phenylhydrazine or phenylhydrazine derivative, 10mL of ethanol and 2mL of acetic acid were added into a 100mL reaction flask, the temperature was raised to 80 °C, and the reaction was carried out under stirring and refluxing for 12 hours. After reaction, 10mL of saturated sodium bicarbonate solution was added to quench the reaction, the solid was precipitated and was filtered to obtain a precipitate, and then the precipitate was air-dried.
[0051] (2) 10mL of methanesulfonic acid aqueous solution with the mass fraction of 50% was prepared, 200mg of phosphorus pentoxide was added, and then the precipitate prepared in the step (1) was added to react at 80 °C for 30 min. After the reaction was finished and the temperature was cooled to room temperature, a sodium hydroxide ice solution with the mass fraction of 10% was added until the PH value is more than 7, then was stood to precipitate a solid, and was filtered. The solid obtained by filtering was recrystallized with toluene to obtain the product of 2- (2-aminophenyl) indole.
[0052] The nuclear magnetic data of the compound was: 'H NMR (400MHz,CDCls) 88.43(s, 1H), 7.63(d,J= 7.9Hz,1H), 7.37(ddd,J = 7.7,5.6,1.3Hz,2H), 7.22-7.18(m,1H), 7.18-7.11(m,2H), 6.86(td,J = 7.5,1.2Hz,1H), 6.80(dd,J = 8.1,1.2Hz, 1H), 6.71(dd,J = 2.2,0.9Hz,1H), 3.82(s,2H) : 9
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BC NMR(101MHz,CDCI3) 8144.1, 136.2, 135.9, 129.3, 129.1, 128.9, 122.2, 120.4, 120.2, 119.1, 118.8, 116.6, 110.8, 101.6.
[0053] Step 2 Preparation of N- (2- (11H-indole [3,2-c] quinoline-6-oxy) phenyl) -2-aminobenzamide 8 5 7 SNC 4 5 MH,
A Nd Seeman ; wl,
Ha ey FY 2 ANF
A Ke
[0054] 4
[0055] 0.2mmol of 2-(2-aminophenyl) indole, 0.02mmol of copper bromide and 2mL of ethanol were added to a 25mL schlenk tube, and the mixture was sealed in an air atmosphere, the temperature was raised to 70 °C, and the reaction was carried out under stirring for 14 hours. After the reaction, the mixture was washed with a sodium carbonate solution, extracted with ethyl acetate, finally added with column chromatography silica gel, and distilled under reduced pressure to remove a solvent. A crude product was separated by silica gel column chromatography, and was eluted with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3: 1). Through TLC (thin layer chromatography) elution tracking detection, an eluent containing a target product was collected, combined, evaporated and concentrated to obtain the N- (2- (11H-indole [3,2-c] quinoline-6-oxygen) phenyl) -2-aminobenzamide.
[0056] According to Fig. 2, the nuclear magnetic hydrogen spectrum data of the compound was: 10
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LU503507
IH NMR(400MHz,DMSO-d6) 613.04(s,1H), 11.51(s, 1H), 8.62(d,J = 7.7Hz,1H), 8.44(d,J = 8.2Hz, 1H), 8.24(d,J = 8.2Hz, 1H), 7.92(dd,J = 7.7,1.6Hz 1H), 7.86(ddd,J = 8.4,6.9,1.5Hz,1H), 7.79-7.73(m,2H), 7.71(d.J = 8.1Hz, 1H), 7.67-7.61(m,1H), 7.51-7.46(m,1H), 7.41tdJ = 7.5,1.2Hz 1H), 7.37(d,J= 8.0Hz, 1H), 7.23-7.17(m,1H), 7.14-7.08(m,1H), 6.67(dd,J=8.3,1.1Hz,1H), 6.43(s,2H).
[0057] According to Fig. 3, the nuclear magnetic carbon spectrum data of the compound was: 13C NMR(101MHz,DMSO-d6) 6167.2, 154.1, 150.6, 144.4, 142.5, 139.6, 136.8, 132.8, 131.6, 130.3, 129.5, 129.1, 129.0, 127.7, 126.7, 126.2, 123.8, 122.8, 122.6, 121.9, 121.8, 121.0, 117.3, 116.7, 115.3, 114.6, 112.9, 112.6.
[0058] The mass spectrum data of the compound was: HRMS m/z (ESI) calcd for C23H2:N40(M+H}" 429.1710, found429.1712.
[0059] As shown in Fig. 4, the single crystal structure of N-(2-(11H-indole [3,2-c] quinoline-6-oxy) phenyl)-2-aminobenzamide is shown in Table 1.
[0060] TABLE 1 Crystal Structure data for N-(2-(11H-indole [3,2-c] quinolin-6-oxy) phenyl)-2-aminobenzamide 11
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Identification code : in : : Enguiricel formula CHa RG ;
A
: Formula weicht : AIN 48 ; seems
Temperature NTR :
NEE i sad a Pe à + rte tes :
PLUS Asien à XEAC AIRE \ : Space group DE : i $32 ä ou FR Ep en Ÿ 3 : LA Che BRASS A :
Pog i À £a ee Ÿ :
EE Poe 248A : a” ss, \ a | = TR2BHRE 3 > :X 3 à FOV ay an 3X Ï
Vale A INTER A \
A - - - - - - -—_—_-—- i 2 ios : i ; $ = à FEY LE Ss * : : men +
From : FIG | 44x00 .
Vn ee doc EN UNE ON Ra 5 ERE 3 :
Crystal Ste 5.106 x LEO GOR ra” ; : Radiation 1071073 : bodes nous pepe 1 2, diem 3, démoli
E PO 2 bie fa éteinte à ave ga san : : Diatereostriitie;parsimeïers : 3727507298 ;
Gdedness-ef-iit on FQ : 10: : 12
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Final B indexes (he (IM | Be GONG wRI = 188
Final R indexes fall dia RES 00703, wR = 0170 :
Largest JE peakrhole se AN OA and 0105 AY
CONC 2085379
[0063] Example 2
[0064] In indolo [3,2-c] Quinoline compound of the disclosure, when R! is F, it will be N-(4-fluoro-2-(8-fluoro-11H-indole [3, 2-c] quinoline-6-oxy) phenyl)-2-aminobenzamide with the structural formula a H 73
PSN AV dy FE i ï RL 5 NH,
SAT
PE MY
[0065] H
[0066] The synthesis method of the compound comprises the following steps.
[0067] Step 1 Preparation of 2-(2-aminophenyl) -5-fluoro-indole 9
NS + Ne SR ES
[0068] HN
[0069] (1) 5mmol of o-aminoacetophenone, Smmol of 4- fluorophenylhydrazine hydrochloride, 10mL of ethanol and 2mL of acetic acid were added into a 100mL reaction flask, the temperature was raised to 80 °C, and the reaction was carried out under stirring and refluxing for 12 13
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LU503507 hours. After the reaction, 10mL of saturated sodium bicarbonate solution was added to quench the reaction, and the solid was precipitated, filtered to obtain a precipitate, and then air-dried.
[0070] (2) 10mL of methanesulfonic acid aqueous solution with the mass fraction of 50% was prepared, 200mg of phosphorus pentoxide was added, then the solid prepared in the step (1) was added, and the mixture was reacted at 80 °C for 30 min. And after the reaction, the temperature was cooled to room temperature, a sodium hydroxide ice solution with the mass fraction of 10% was added until the PH value is more than 7, the mixture was stood to precipitate a solid, and the solid was filtered. The solid obtained by filtration is recrystallized from toluene to obtain the product of 2-(2-aminophenyl)-5-fluoro indole.
[0071] The nuclear magnetic data of the compound were:
IH NMR(400MHz,CDCI3) 88.48(s, 1H), 7.35(ddJ = 7.7,14Hz,1H), 7.27(ddd,J=9.7,5.7,1.9Hz,2H), 7.18(ddd,J= 8.2,7.4,1.6Hz,1H), 6.93(td,J= 9.1,2.5Hz,1H), 6.86(td,J = 7.5,1.2Hz,1H), 6.80(dd,J = 8.0,1.2Hz,1H), 6.66(dd,J= 2.2,0.9Hz,1H), 4.04(s,2H) ;
BC NMR(101MHz,CDC13) 8159.3, 157.0, 144.0, 137.8, 132.7, 129.3(d,J= 7.AHz), 119.2, 118.5, 116.7, 111.4(d,J= 9.8Hz), 110.5, 110.3, 105.2(d,J= 23.5Hz), 101.6(d,J= 4.6H7).
[0072] Step 2 preparation of N- (4-fluoro-2- (8-fluoro-11H-indole [3,2-c] quinoline-6-oxy) phenyl)-2-aminobenzamide 14
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Key Sn ; ps * yy Ned
[0073] H
[0074] 0.2mmol of 2- (2-aminophenyl) -5-fluoro-indole, 0.03mmol of copper bromide, 2mL of ethanol and ethylene glycol dimethyl ether were added to a 25mL schlenk tube, and the mixture was sealed in an air atmosphere, the temperature was raised to 80 °C, and the reaction was carried out under stirring for 12 hours. After the reaction, the resultant was washed with a sodium carbonate solution, extracted with ethyl acetate, finally added with column chromatography silica gel, and distilled under reduced pressure to remove a solvent. A crude product was separated by silica gel column chromatography, eluted with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5: 1), and an eluent containing a target product was collected through TLC (thin layer chromatography) elution tracking detection. The target product eluent was combined, and evaporated and concentrated to obtain N- (4-fluoro-2- (8-fluoro-11H-indole[3,2-c]quinoline-6-oxygen)phenyl)-2- aminobenzamide.
[0075] According to Fig. 5, the nuclear magnetic hydrogen spectrum data of the compound was:
IH NMR(400MHz,DMSO-d6) 613.07(s,1H), 11.08(s,1H), 8.60(d,J = 8.1Hz,1H), 8.33(d,J = 8.2Hz,1H), 8.21(d,J = 84Hz,1H), 7.85(tJ = 15
BL-5624
LU503507 9.3Hz,2H), 7.79-7.72(m,2H), 7.68(t,J = 7.9Hz,1H), 7.46(t,J = 7.5Hz,1H), 7.34(t,J=8.2Hz,1H), 7.27(d,J= 9.9Hz,1H), 7.05-6.93(m,2H), 6.67(dd,J = 8.7,4.8Hz,1H), 6.16(s,2H).
[0076] According to Fig. 5, the nuclear magnetic carbon spectrum data of the compound was:
BC NMR(101MHz DMSO-d6) 8166.3, 158.6, 156.3, 154.2, 151.8, 146.9, 144.8, 143.4, 136.6, 136.1, 131.3, 130.3, 129.6, 129.2, 126.7, 124.5, 123.7, 122.6, 122.5(d,J=10.3Hz), 120.2(d,J= 22.5Hz), 118.3(d,J= 7.0Hz), 116.8, 115.0(d,J= 5.4Hz), 114.0(d,J=25.6Hz), 113.5(d,J=1 Hz), 113.3, 112.9(d,J =44Hz), 107.2(d,J=25.0Hz).
[0077] The mass spectrum data of the compound was: HRMS m/z (ESI) calcd for C23H19F2N40(M+H)'465.1521, found 465.1517.
[0078] Example 3
[0079] In indolo [3,2-c] Quinoline of the disclosure, when R! is CI, it will be N- (4-chloro-2-(8-chloro-11H-indole[3, 2-c)]quinoline-6-oxygen) phenyl)-2-aminobenzamide with the structural formula [EN NA cq 4 XE
Ng Ne
Ohne AS
[0080] H
[0081] The synthesis method of the compound comprises the following steps. 16
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[0082] Step 1 preparation of 2-(2-aminophenyl)-5-chloro-indole © “EUNRNH, SE AN
[0083] HN
[0084] (1) 5mmol of o-aminoacetophenone, 5mmol of 4- chlorophenylhydrazine hydrochloride, 10mL of n-butanol and 2mL of acetic acid were added into a 100mL reaction flask, the temperature is raised to 90 °C, and the reaction was carried out under stirring and refluxing for 10 hours. After the reaction, 10mL of saturated sodium bicarbonate solution was added to quench the reaction, and the solid was precipitated, filtered to obtain a precipitate, and then the precipitate was air-dried.
[0085] (2)10mL of methanesulfonic acid aqueous solution with the mass fraction of 50% was prepared, 200mg of phosphorus pentoxide was added, then the solid prepared in the step (1) was added, and the reaction was carried out at 80 °C for 30 min. And after the reaction, the temperature was cooled to room temperature, a sodium hydroxide solution ice with the mass fraction of 10% was added until the PH value is more than 7, the resultant was stood to precipitate a solid, and the solid was filtered. The solid obtained by filtration is recrystallized from toluene to obtain the product of 2-(2-aminophenyl)-5-chloro-indole.
[0086] The nuclear magnetic data of the compound was: 'H NMR(400MHz,CDC13) 88.54(s,1H), 7.58(d,J=2.0Hz, 1H), 7.36(dd,J = 7.7,1.5Hz,1H), 7.29(d,J= 8.6Hz,1H), 7.18(td,J=8.0,1.5Hz 1H), 7.14(dd.J 17
BL-5624
LU503507 = 8.6,2.0Hz, 1H), 6.87(td,J = 7.5,1.1Hz,1H), 6.81(dd,J = 8.0,0.9Hz, 1H), 6.65(dd,J=2.1,0.8Hz,1H), 4.05(s,2H) ;
BC NMR(101MHz,CDCI3) 8144.0, 137.4, 134.5, 130.0, 129.4, 129.2, 125.74, 122.4, 119.8, 119.3, 118.4, 116.8, 111.8, 101.1.
[0087] Step 2: preparation of N- (4-chloro-2- (8-chloro-11H-indole [3,2-c] quinoline-6-oxy) phenyl) -2-aminobenzamide
Ce J | AL 1 A040 2 Mo NH
CH
[0088] ER =
[0089] 0.2mmol of 2-(2-aminophenyl)-5-chloro-indole, 0.06mmol of copper chloride, 2mL of ethanol were added to a 25mL schlenk tube, and the mixture was heated to 80 °C under a sealed atmosphere and stirred to react for 12 hours. After the reaction, the resultant was washed with a sodium carbonate solution, extracted with ethyl acetate, finally added with column chromatography silica gel, distiled under reduced pressure to remove a solvent. A crude product was separated by silica gel column chromatography, eluted with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate: 10: 1), an eluent containing a target product was collected through TLC (thin layer chromatography) elution tracking detection. The target product eluent was combined, and evaporated and concentrated to obtain the N- (4-chloro-2- (8-chloro-11H- indole [3,2-c] quinoline-6-oxygen) phenyl) -2-aminobenzamide. 18
BL-5624
LU503507
[0090] According to Fig. 7, the nuclear magnetic hydrogen spectrum data of the compound was:
IH NMR(400MHz,DMSO-d6) 613.10(s,1H), 10.96(s,1H), 8.53(d,J = 79Hz,1H), 8.23(d,J = 8.0Hz,1H), 8.18(d,J = 84Hz,1H), 7.79(t,J = 7.5Hz,2H), 7.71(t,J = 9.0Hz 2H), 7.63(t,J = 7.5Hz,1H), 7.50(s,1H), 7.45- 7.35(m,2H), 7.07-7.03(m,2H), 6.60(d,J= 8.7Hz,1H), 6.32(s,2H).
[0091] According to Fig. 8, the nuclear magnetic carbon spectrum data of the compound was:
BC NMR(126MHz DMSO-d6) 8166.2, 154.1, 149.0, 144.8, 143.0, 138.0, 136.6, 132.3, 131.3, 130.5, 130.4, 129.7, 129.6, 127.3, 126.8, 125.9, 125.2, 124.5, 123.9, 123.2, 122.6, 121.1, 118.6, 118.3, 116.6, 116.1, 114.0, 112.3.
[0092] The mass spectrum data of the compound is HRMS m/z (ESI) calcd for C2gH19Cl,N10(M+H)'497.0930, found 497.0928.
[0093] Example 4
[0094] In indolo [3,2-c] quinoline of of the disclosure, when R! is CH3, it will be N- (4-methyl-2- (8-methyl-11H-indole [3, 2-c)] quinoline-6-oxygen) phenyl)-2-aminobenzamide with the structural formula
LAD
ES \ N N ne =
SN
[0095] H 19
BL-5624
LU503507
[0096] The synthesis method of the compound comprises the following steps.
[0097] Step 1: preparation of 2-(2-aminophenyl)-5-methyl-indole
Mi 9 vi Fee < A A a ey IN
OU se. ED)
SHINE a TTT de a pl
[0098] HN
[0099] (I) 5mmol of o-aminoacetophenone, Smmol of 4- chlorophenylhydrazine hydrochloride, 10mL of dimethyl sulfoxide and 2mL of acetic acid were added into a 100mL reaction flask, the temperature was raised to 80 °C, and the reaction is stirred and refluxed for 12 hours.
After the reaction, 10mL of saturated sodium bicarbonate solution was added to quench the reaction, the solid was precipitated and filtered to obtain a precipitate, and the precipitate was then air-dried.
[00100] (2) 10mL of methanesulfonic acid aqueous solution with the mass fraction of 50% was prepared, 200mg of phosphorus pentoxide was added, then the solid prepared in the step (1) was added, and the mixture was reacted at 80 °C for 30 min. And after the reaction, the temperature was cooled to room temperature, a sodium hydroxide ice solution with the mass fraction of 10% was added until the PH value is more than 7, the resultant was stood to precipitate a solid, and the solid was filtered. The solid obtained by filtration is recrystallized from toluene to obtain the product of 2- (2(2-aminophenyl) -5-methyl-indole.
[00101] The nuclear magnetic data of the compound was: 20
BL-5624
LU503507
I} NMR(400MHz,CDCI3) 88.32(s, 1H), 7.41(s,1H), 7.35(ddJ = 7.6,1.6Hz,1H), 7.26(d, J = 8.3Hz,1H), 7.18-7.13(m,1H), 7.02(d,J = 82Hz, 1H), 6.84(t,J = 7.3Hz,1H), 6.78(d,J = 8.0Hz 1H), 6.62(s,1H), 4.05(s,2H), 2.45(s,3H) :
BCNMR(101MHz,CDCI3) 6144.0, 136.0, 134.5, 1294, 129.2, 129.0, 123.8, 120.1, 119.0, 119.0, 116.5, 110.5, 101.2, 21.5.
[00102] Step 2 preparation of N- (4-methyl-2- (8-methyl-11H-indole [3,2- c] quinoline-6-oxy) phenyl) -2-aminobenzamide
SN
MER wo LY
[00103] MT
[00104] 0.2mmol of 2- (2-aminophenyl) -5-methyl-indole, 0.03mmol of copper acetate, 2mL of ethanol were added to a 25mL schlenk tube, the mixture was sealed in an air atmosphere, the temperature was raised to 80 °C, and the reaction was carried out under stirring for 12 hours. After the reaction, the resultant was washed with a sodium carbonate solution, extracted with ethyl acetate, added with column chromatography silica gel, distilled under reduced pressure to remove a solvent, and a crude product was separated by silica gel column chromatography. The crude product was eluted with a mixed solution of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5: 1), an eluent containing a target product was collected through TLC (thin layer chromatography) elution tracking detection, and the target product eluent was combined, evaporated and 21
BL-5624
LU503507 concentrated to obtain the N- (4-methyl-2- (8-methyl-11H-indole [3,2-c] quinoline-6-oxygen) phenyl) -2-aminobenzamide.
[00105] According to Fig. 9, the nuclear magnetic hydrogen spectrum data of the compound was: 'H NMR(400MHz,DMSO-d6) 612.93(s,1H), 11.33(s,1H), 8.60(d,J = 7.3Hz,1H), 8.47(d,J = 8.0Hz,1H), 8.24(d,J = 8.2Hz,1H), 7.91(dd,J = 7.6,1.3Hz, 1H), 7.84(t,J = 8.2Hz 1H), 7.76(t,J = 7.0Hz,1H), 7.64(d,J = 8.2Hz 2H), 7.49(s,1H), 7.41(t,J=7.5Hz,1H), 7.31(d,J=8.3Hz 1H), 6.97- 6.87(m,2H), 6.59(d,J= 8.3Hz,1H), 6.25(s,2H), 2.36(s,3H), 1.96(s,3H).
[00106] According to Fig. 10, the nuclear magnetic carbon spectrum data of the compound was:
BC NMR(101MHz DMSO-d6) 8167.1, 154.0, 148.4, 144.3, 142.6, 137.9, 136.7, 133.8, 131.5, 130.3, 130.1, 129.7, 129.3, 129.2, 127.6, 127.2, 126.6, 123.8, 123.6, 122.7, 122.6, 122.0, 121.7, 117.5, 116.7, 114.4, 112.7, 112.2, 21.9, 20.2.
[00107] The mass spectrum data of the compound was: HRMS m/z (ESI) calcd for CzoH25N4O(M+H)"457.2023, found457.2022. 22

Claims (9)

  1. BL-5624 LU503507 CLAIMS
    I. An indolo [3,2-c] quinoline compound, wherein a molecular structural formula is 7 ¢ A NEE} x ; ! ; R el HaN N > wherein R'is any one of H, F, CI or CH.
  2. 2. A synthesis method of indolo [3,2-c] quinoline compound of claim 1, comprising: taking 2- (2-aminophenyl) indole or derivatives thereof as raw materials, copper salt as a catalyst, reacting in an organic solvent in the reaction atmosphere of air, wherein a reaction temperature is 70-90 °C, and a benzamido-containing indolo [3,2-c] quinoline compound is obtained by purifying after reaction, and a reaction equation 1s as follows: £a FN, post Pb A Sal # a1 il Rx “A EN copper-catalyzed AI Hai T I Pf ee TN SEN SA IN HEN Rif MAL > H where R! is any one of H, F, Cl or CHz. 23
    BL-5624 LU503507
  3. 3.The synthesis method of indolo [3,2-c] quinoline compound of claim 2, wherein the copper salt is any one of copper bromide, copper chloride or copper acetate.
  4. 4 The synthesis method of indolo [3,2-c] quinoline compound of claim 2, wherein a molar ratio of the 2- (2-aminophenyl) indole or the derivative thereof to the copper salt is 1: 0.1-0.3.
  5. 5.The synthesis method of indolo [3,2-c] quinoline compound of claim 2, wherein the organic solvent is selected from one or more of ethanol, ethylene glycol dimethyl ether, n-butanol or dimethyl sulfoxide.
  6. 6.The synthesis method of indolo [3,2-c] quinoline compound of claim 2, wherein a method of the purifying is washing with aqueous sodium carbonate, followed by extraction with ethyl acetate and finally separation by column chromatography, wherein a solid phase of the column chromatography is column chromatography silica gel and a mobile phase is a mixture of petroleum ether and ethyl acetate
  7. 7. The synthesis method of indolo [3,2-c] quinoline compound of claim 2, wherein a reaction temperature is 70-80 °C.
  8. 8.The synthesis method of indolo [3,2-c] quinoline compound of claim 2, wherein a reaction time 1s 10 to 14 hours.
  9. 9.The synthesis method of indolo [3,2-c] quinoline compound of claim 6, wherein a volume ratio of the petroleum ether to the ethyl acetate is 3-10: 1. 24
LU503507A 2022-02-18 2023-02-17 Indolo [3,2-c] quinoline compound and synthetic method thereof LU503507B1 (en)

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CN109503572B (en) * 2017-09-15 2021-10-08 上海交通大学 Method for synthesizing indole quinoline compounds
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