CN109293657B - Alpha-carboline ketone compound and preparation method and application thereof - Google Patents
Alpha-carboline ketone compound and preparation method and application thereof Download PDFInfo
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- 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
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Abstract
The present invention provides a compound of formula i or a pharmaceutically acceptable salt thereof: wherein R is1Is selected from C1～C10Alkyl, substituted or unsubstituted aryl, cycloalkyl, -C.ident.C-R5、‑(CH2)aR6Each of said substituted or unsubstituted phenyl groups being independently substituted by one or more groups selected from alkoxy, C1～C6Alkyl, nitro and halogen; r2Is selected from C1～C6Alkyl, - (CH)2)bR3；R3Is selected from-OR4Substituted or unsubstituted phenyl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, alkoxy; r4Selected from benzyl, R5、R6Is selected from phenyl; a is 2; b is 1, 2. The invention also provides a preparation method and application of the compound. Experimental results show that the alpha-carboline compound is successfully synthesized, and the compound has the advantages of simple and convenient preparation method, mild reaction, high yield, antitumor activity and wide market application prospect.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to an alpha-carboline ketone compound and a preparation method and application thereof.
Background
Tumor refers to a new organism formed by clonal abnormal hyperplasia caused by the loss of normal regulation and control of local tissue cells on the gene level under the action of various tumorigenic factors. Tumors have a high incidence and mortality rate worldwide. Statistically, in 70 hundred million people worldwide, about 1000 or more million people suffer from tumors each year, and millions of people die due to tumors. Therefore, the prevention and treatment of tumors has become a public health problem which is highly valued by society.
In recent decades, people have been making continuous efforts to treat tumors, and the current tumor treatments mainly include surgery, chemotherapy, radiotherapy and cellular immunotherapy, and the combined application of the methods can increase the survival rate of patients. Metastasis of tumor cells between organs is a problem facing the treatment of cancer, however, surgery and radiotherapy have limited therapeutic effects on it, and thus chemotherapy, i.e., drug therapy, is mainly adopted. Many chemotherapeutic drugs have been reported, and these tumor drugs are roughly classified into the following categories: an antitumor antimetabolite represented by 5-fluorouracil, an antitumor antibiotic represented by doxorubicin hydrochloride, a plant-derived antitumor drug represented by vinblastine and paclitaxel, an antitumor platinum complex represented by cisplatin, and the like.
Indole compounds are important heterocyclic derivative alkaloids, most of the indole compounds have obvious physiological activity, a large number of domestic and foreign researches show that indole or indole-like structures have an anti-cancer effect, and reported indole anti-cancer compounds comprise vinblastine, melatonin, indomethacin, indirubin and other indole substances from cruciferous vegetables. At present, the research on indole antitumor drugs is greatly progressed, but the clinical application still has many defects, such as serious damage to normal cells of a human body, inhibition of the immune function of an organism, easy generation of drug resistance of heavy cells and the like. Therefore, the synthesis of the antitumor drug with high curative effect and low toxicity is still a research hotspot.
Disclosure of Invention
The invention aims to provide an alpha-carboline ketone compound and a preparation method and application thereof.
The present invention provides a compound of formula i or a pharmaceutically acceptable salt thereof:
wherein R is1Is selected from C1～C10Alkyl, substituted or unsubstituted aryl, cycloalkyl, -C.ident.C-R5、-(CH2)aR6Each of said substituted or unsubstituted phenyl groups being independently substituted by one or more groups selected from alkoxy, C1～C6Alkyl, nitro and halogen;
R2is selected from C1～C6Alkyl, - (CH)2)bR3；
R3Is selected from-OR4Substituted or unsubstituted phenyl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, alkoxy;
R4selected from benzyl, R5、R6Is selected from phenyl;
a＝2；b＝1，2。
further, the compound of formula I has the structure shown in formula II:
wherein R is1Is selected from C1～C10Alkyl, substituted or unsubstituted aryl, cycloalkyl, -C.ident.C-R5、-(CH2)aR6Each of said substituted or unsubstituted phenyl groups being independently substituted by one or more groups selected from alkoxy, C1～C6Alkyl, nitro and halogen;
R2is selected from C1～C6Alkyl, - (CH)2)bR3；
R3Is selected from-OR4Substituted or unsubstituted phenyl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, alkoxy;
R4selected from benzyl, R5、R6Is selected from phenyl;
a＝2；b＝1，2。
further, said R2Selected from benzyl.
Further, the aryl group is selected from phenyl, naphthyl, thiophene, pyridine.
Further, the compound is selected from one of the following structural formulas:
the present invention also provides a process for preparing the aforementioned compound, comprising the steps of:
(1) dissolving indole electron-deficient olefin, alpha-chloroaldehyde, potassium phosphate and a catalyst in tetrahydrofuran for reaction; wherein the molar ratio of the indole electron-deficient olefin substrate, the alpha-chloroaldehyde, the potassium phosphate and the catalyst is 0.1:0.25:0.15: 0.005;
(2) decompressing after the reaction is completed, removing the reaction solvent, eluting, collecting the eluent, and removing the solvent to obtain the product;
the synthetic route is as follows:
wherein R is2Is selected from C1～C6Alkyl, - (CH)2)bR3；R3Is selected from-OR4Substituted or unsubstituted phenyl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, alkoxy; r4Is selected from benzyl; b is 1, 2; NHC 3a is catalyst with the structural formula
THF is in tetrahydrofuran;
preferably, in the step (1), the reaction is carried out for 8 hours at 60 ℃ under the condition of argon gas with stirring;
and/or, in step (1), monitoring the reaction by TLC;
and/or, in the step (2), a silica gel column is used for elution, and the eluent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 35: 1;
and/or in the step (2), the conditions for collecting the eluent are that Rf is 0.4-0.5, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 6: 1.
Further, the preparation method of the indole electron-deficient olefin comprises the following steps:
a. dissolving indole and p-toluenesulfonyl azide in methanol for reaction, separating out a solid after the reaction is completed, filtering, and drying in vacuum to obtain a compound a; wherein the mol ratio of indole to p-toluenesulfonyl azide is 100: 50;
b. dissolving a compound a, substituted benzaldehyde and titanium tetrachloride in dichloromethane for reaction, precipitating a solid after the reaction is completed, filtering, and drying in vacuum to obtain the compound a; wherein the molar ratio of the compound a to the substituted benzaldehyde to the titanium tetrachloride is 17.5:52.5: 35;
the synthetic route is as follows:
wherein R is1Is selected from C1～C10Alkyl, substituted or unsubstituted aryl, cycloalkyl, -C.ident.C-R5、-(CH2)aR6Each of said substituted or unsubstituted phenyl groups being independently substituted by one or more groups selected from alkoxy, C1～C6Alkyl, nitro and halogen; r5、R6Is selected from phenyl; a is 2;
preferably, the reaction in step a is at 60 ℃ for 4 h;
and/or, in step a, the reaction is monitored by TLC method;
and/or in the step b, the reaction is carried out at room temperature for 4-16 h;
and/or, in step b, the reaction is monitored by TLC.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Further, the tumor is colon cancer, breast cancer, prostate cancer, melanoma.
The invention also provides a medicament which is a preparation prepared from the compound or the pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials or auxiliary components.
Experimental results show that the alpha-carboline compound is successfully prepared, and the compound has the advantages of simple preparation method, mild reaction, high yield, antitumor activity and wide market application prospect.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix (C)a～Cb) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C)1～C6) The alkyl group means an alkyl group having 1 to 6 carbon atoms.
Said C is1～C6Alkyl is C1、C2、C3、C4、C5、C6The alkyl group of (2) is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, etc.
The alkoxy group means an alkyl substituent attached to an oxygen atom, such as methoxy, ethoxy, propoxy, butoxy, and the like.
The halogen refers to fluorine atom, bromine atom, chlorine atom and iodine atom.
The term "pharmaceutically acceptable salts" refers to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the specific embodiment of the invention are all known products and can be purchased in the market.
The synthesis formula of indole electron-deficient olefin as a substrate is as follows:
wherein R is1Is selected from C1～C10Alkyl, substituted or unsubstituted aryl, cycloalkyl, -C.ident.C-R5、-(CH2)aR6Each of said substituted or unsubstituted phenyl groups being independently substituted by one or more groups selected from alkoxy, C1～C6Alkyl, nitro and halogen; r5、R6Is selected from phenyl; a is 2.
The compound of the invention has the following general synthesis formula:
wherein R is2Is selected from C1～C6Alkyl radical、-(CH2)bR3；R3Is selected from-OR4Substituted or unsubstituted phenyl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, alkoxy; r4Is selected from benzyl; b is 1, 2; NHC 3a is catalyst with the structural formula
THF was in tetrahydrofuran.
EXAMPLE 1 preparation of Compound 1
1. Preparation of substrate indole electron-deficient olefin
At 60 ℃, 50mL of methanol, 11.7g of indole (100mmol) and 9.9g of p-toluenesulfonyl azide (50mmol) are sequentially added into a 100mL flask, the reaction is carried out for 4 hours, the TLC method is used for monitoring the reaction until the reaction is completed, solid is separated out, the filtration and the vacuum drying are carried out, and the compound a, 13.0g of pink solid product and 90% yield are obtained.
At room temperature, 50mL of dichloromethane, 5.0g of compound a (17.5mmol) and benzaldehyde (52.5mmol) are sequentially added into a 100mL flask, 3.5mL of titanium tetrachloride (35.0mmol) is added to promote the reaction to occur, the reaction is carried out for 8 hours, the reaction is monitored by a TLC method until the reaction is complete, a solid is separated out, a solid product is obtained by filtration, and vacuum drying is carried out, so that the substrate 1a of the compound 1 is obtained, 4.9g of yellow powder is obtained, and the yield is 71%.
2. Preparation of Compound 1 of the present invention
Under argon, the substrate 1a (0.1mmol), (0.15mmol, 31.0mg) potassium phosphate, carbene catalyst 3a (0.005mmol, 2.4mg), 1mL tetrahydrofuran and α -chloroaldehyde (0.25mmol) were added sequentially to the reaction tube, the tube was sealed and stirred at 60 ℃, the reaction was monitored by TLC method, after completion of the reaction, the reaction solvent was removed under reduced pressure, and the residue was subjected to silica gel column with petroleum ether: eluting with 35:1 ethyl acetate, collecting eluent with Rf of 0.4-0.5, and eluting with PE, EA, 6:1, removing the solvent to obtain the compound 1 shown as the following.
Compound 1 is a white solid in 99% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.56(s,1H),7.99(d,J＝7.8Hz,2H),7.39(d,J＝8.4,3H),7.30–7.25(m,3H),7.22(t,J＝12.0,4.2Hz,1H),7.17–7.13(m,1H),7.07–7.01(m,4H),6.84(t,J＝7.8Hz,2H),6.41(d,J＝8.4Hz,2H),4.02(d,J＝7.2Hz,1H),3.52(ddd,J＝10.2,6.6,4.2Hz,1H),3.20(dd,J＝14.4,4.2Hz,1H),2.52(s,3H),2.27(dd,J＝14.4,9.6Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.6,146.1,138.5,133.8,133.2,129.9,129.2,128.7,128.4,127.9,127.1,126.6,124.3,122.2,120.6,117.9,111.5,103.4,50.4,38.7,32.5,21.9.
HRMS(ESI):m/z calculated forC31H26N2O3S+Na+:529.1562,found:529.1561.
according to the method for synthesizing the compound 1, the corresponding raw materials are adopted to obtain the compounds 2 to 31 shown in the following examples 2 to 31.
EXAMPLE 2 preparation of Compound 2
White solid, 97% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.53(s,1H),7.97(d,J＝8.4Hz,2H),7.41–7.34(m,3H),7.29–7.19(m,4H),7.14(t,J＝7.8Hz,1H),7.06–7.00(m,3H),6.63(d,J＝8.4Hz,2H),6.29(d,J＝7.8Hz,2H),3.99(d,J＝6.6Hz,1H),3.58–3.43(m,1H),3.18(dd,J＝14.4,4.2Hz,1H),2.52(s,3H),2.27(dd,J＝14.4,9.6Hz,1H),2.18(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):172.0,146.1,138.6,136.7,135.4,133.9,133.3,129.9,129.8,129.2,129.0,128.6,127.8,126.6,122.1,120.6,117.9,111.4,103.6,50.5,38.3,32.5,21.9,21.1.
HRMS(ESI):m/z calculated forC32H28N2O3S+Na+:543.1718,found:543.1718.
EXAMPLE 3 preparation of Compound 3
White solid, 96% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.59(s,1H),8.01(d,J＝8.4Hz,2H),7.41–7.35(m,3H),7.30–7.26(m,3H),7.23(d,J＝7.8Hz,1H),7.19–7.12(m,1H),7.04(t,J＝7.2Hz,3H),6.86(d,J＝7.8Hz,1H),6.72(t,J＝7.8Hz,1H),6.37(s,1H),6.21–6.16(1H),4.01(d,J＝6.6Hz,1H),3.59–3.47(m,1H),3.26–3.16(1H),2.49(s,3H),2.29(dd,J＝15.0,10.2Hz,1H),2.00(s,3H)
13C NMR(150MHz,CDCl3)δ(ppm):171.7,146.2,138.6,138.5,138.1,134.1,133.2,130.0,129.9,129.3,129.2,128.9,128.6,128.3,128.0,126.6,125.0,124.4,122.2,120.7,118.0,111.4,103.0,50.3,38.7,32.5,21.9,21.4
HRMS(ESI):m/z calculated forC32H28N2O3S+Na+:543.1718,found:543.1721.
EXAMPLE 4 preparation of Compound 4
White solid, 96% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.58(s,1H),8.02–7.98(m,2H),7.42–7.38(m,3H),7.31–7.26(m,2H),7.24–7.20(m,1H),7.16(ddd,J＝8.4,7.2,1.2Hz,1H),7.08–7.02(m,3H),6.41–6.37(m,2H),6.36–6.31(m,2H),4.02(d,J＝12.9,6.7Hz,1H),3.70(s,3H),3.51(ddd,J＝9.6,6.6,4.2Hz,1H),3.21(dd,J＝14.4,4.2Hz,1H),2.53(s,3H),2.31(dd,J＝14.4,9.6Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.7,158.5,146.0,138.6,133.8,133.3,130.4,129.9,129.8,129.2,129.2,129.0,128.7,126.6,124.3,122.2,120.6,117.9,113.7,111.5,103.7,55.2,50.6,37.8,32.5,21.9.
HRMS(ESI):m/z calculated forC32H28N2O4S+Na+:559.1667,found:559.1668.
EXAMPLE 5 preparation of Compound 5
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.59(s,1H),7.99(d,J＝8.4Hz,2H),7.40–7.35(m,3H),7.28(dd,J＝10.2,3.6Hz,3H),7.22(t,J＝7.2Hz,1H),7.17–7.13(m,1H),7.07–7.02(m,3H),6.67(t,J＝7.8Hz,1H),6.62–6.58(m,1H),6.32(d,J＝1.8Hz,1H),5.84(d,J＝7.2Hz,1H),4.01(d,J＝6.6Hz,1H),3.62(s,3H),3.52(ddd,J＝10.6,6.6,4.2Hz,1H),3.23(dd,J＝14.4,4.2Hz,1H),2.50(s,3H),2.33(dd,J＝14.4,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.6,159.6,146.1,140.2,138.6,134.1,133.2,130.0,129.4,129.2,129.1,128.7,126.7,124.4,122.2,120.7,119.6,118.0,114.6,112.2,111.5,102.9,55.1,50.2,38.7,32.5,22.0.
HRMS(ESI):m/z calculated forC32H28N2O4S+Na+:559.1667,found:559.1666.
EXAMPLE 6 preparation of Compound 6
White solid, 95% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.58(s,1H),8.02(d,J＝7.8Hz,2H),7.39(d,J＝9.0Hz,3H),7.29-7.25(m,3H),7.24-7.21(m,1H),7.19-7.11(m,1H),7.05(t,J＝7.8Hz,3H),6.33(d,J＝2.4Hz,1H),6.26(d,J＝8.4Hz,1H),5.83-5.73(1H),3.98(d,J＝6.6Hz,1H),3.75(s,3H),3.59(s,3H),3.55(tt,J＝10.8,3.6Hz,1H),3.24(dd,J＝15.0,4.2Hz,1H),2.50(s,3H),2.34(dd,J＝14.4,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.8,148.7,147.9,145.9,138.4,134.4,133.3,131.2,129.9,129.8,129.3,129.2,128.6,126.7,124.3,122.2,120.7,119.6,117.9,111.9,111.5,111.0,103.1,55.8,55.7,50.1,38.1,32.5,21.9.
HRMS(ESI):m/z calculated forC33H30N2O5S+Na+:589.1773,found:589.1770.
EXAMPLE 7 preparation of Compound 7
White solid, 95% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.63(s,1H),8.00–7.97(m,2H),7.71–7.67(m,2H),7.45–7.41(m,3H),7.32–7.26(m,3H),7.23–7.17(m,2H),7.09–7.05(m,1H),7.00(d,J＝7.2Hz,2H),6.57–6.54(m,2H),4.14(d,J＝6.6Hz,1H),3.60(ddd,J＝10.2,6.6,4.8Hz,1H),3.24(dd,J＝15.0,4.8Hz,1H),2.59(s,3H),2.23(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.1,146.8,146.2,137.6,133.6,133.3,130.2,130.2,129.3,129.0,128.9,128.7,127.0,123.9,123.6,122.6,121.0,117.6,111.8,102.0,49.9,38.2,32.6,21.9.
HRMS(ESI):m/z calculated forC31H25N3O5+Na+:574.1413,found:574.1413.
EXAMPLE 8 preparation of Compound 8
White solid, 97% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.58(s,1H),8.00–7.97(m,2H),7.42–7.38(m,3H),7.30–7.26(m,2H),7.23(dd,J＝8.4,6.0Hz,2H),7.19–7.15(m,1H),7.07–7.01(m,3H),6.55–6.50(m,2H),6.40–6.35(m,2H),4.03(d,J＝6.6Hz,1H),3.56–3.50(m,1H),3.20(dd,J＝15.0,4.2Hz,1H),2.53(s,3H),2.26(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.5,162.5,160.9,146.3,138.2,134.3,133.8,133.3,130.0,129.9,129.5,129.3,129.1,128.8,126.8,124.2,122.4,120.8,117.8,115.3,115.2,111.6,103.2,50.3,37.9,32.5,21.9.
HRMS(ESI):m/z calculated forC31H25FN2O3+Na+:547.1468,found:547.1467.
EXAMPLE 9 preparation of Compound 9
White solid, 94% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.57(s,1H),7.96(dd,J＝15.0,8.4Hz,2H),7.40(d,J＝8.4Hz,3H),7.28(t,J＝7.2Hz,2H),7.23(dd,J＝8.4,6.0Hz,2H),7.20-7.14(m,1H),7.08-6.99(m,3H),6.83-6.79(m,2H),6.35(d,J＝9.0Hz,2H),4.01(d,J＝6.0Hz,1H),3.53(qd,J＝5.4,4.2Hz,1H),3.21(dd,J＝15.0,4.8Hz,1H),2.54(s,3H),2.26(dd,J＝14.4,10.2Hz,1H)
13C NMR(150MHz,CDCl3)δ(ppm):171.5,146.4,138.2,137.2,133.9,133.4,132.9,130.1,129.3,129.3,129.2,128.9,128.6,126.9,124.2,122.5,120.9,117.9,111.7,103.0,50.3,38.0,32.6,22.0.
HRMS(ESI):m/z calculated forC31H25ClN2O3+Na+:563.1172,found:563.1170.
EXAMPLE 10 preparation of Compound 10
White solid, 97% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.56(s,1H),7.97–7.93(m,2H),7.41–7.37(m,3H),7.29–7.25(m,2H),7.24–7.20(m,2H),7.19–7.14(m,1H),7.06–7.00(m,3H),6.97–6.93(m,2H),6.29–6.26(m,2H),3.99(d,J＝6.6Hz 1H),3.52(ddd,J＝10.2,6.6,4.2Hz,1H),3.20(dd,J＝15.0,4.2Hz,1H),2.54(s,3H),2.25(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.4,146.4,138.2,137.6,133.8,133.3,131.5,130.0,129.6,129.2,129.1,128.8,126.8,124.1,122.4,121.0,120.8,117.8,111.6,102.9,50.1,38.0,32.6,22.0.
HRMS(ESI):m/z calculated forC31H25BrN2O3+Na+:607.0667,found:607.0667.
EXAMPLE 11 preparation of Compound 11
White solid, 98% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.64(s,1H),7.99(d,J＝8.4Hz,2H),7.41–7.37(m,3H),7.29(t,J＝7.2Hz,2H),7.26–7.22(m,2H),7.20–7.15(m,1H),7.09–6.99(m,4H),6.78(t,J＝7.8Hz,1H),6.55(d,J＝1.8Hz,1H),6.30(d,J＝7.8Hz,1H),4.04(d,J＝6.6Hz,1H),3.59–3.54(m,1H),3.24(dd,J＝15.0,4.2Hz,1H),2.49(s,3H),2.29(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.2,146.4,140.8,138.1,134.5,133.9,133.2,130.2,129.7,129.2,129.0,128.8,128.3,127.6,126.8,126.1,124.2,122.4,120.8,117.8,111.6,102.0,49.9,38.4,32.5,22.0.
HRMS(ESI):m/z calculated forC31H25ClN2O3+Na+:563.1172,found:563.1171.
EXAMPLE 12 preparation of Compound 12
White solid, 97% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.63(s,1H),8.04-7.94(d,J＝7.8Hz,2H),7.40(t,J＝7.8Hz,3H),7.30(t,J＝7.8Hz,2H),7.25-7.15(m,4H),7.11-6.96(m,3H),6.79-6.77(m,1H),6.66(t,J＝7.8Hz,1H),6.24(d,J＝7.8Hz,1H),4.01(d,J＝6.6Hz,1H),3.57(qd,J＝5.4,4.2Hz,1H),3.24(dd,J＝14.8,4.2Hz,1H),2.49(s,3H),2.27(dd,J＝15.0,10.2Hz,1H)
13C NMR(150MHz,CDCl3)δ(ppm):171.2,146.3,141.0,138.0,133.9,133.2,131.4,130.5,130.2,129.9,129.2,129.0,128.8,128.6,126.8,126.3,124.2,122.6,122.4,120.8,117.8,111.6,102.0,49.9,38.3,32.5,22.1.
HRMS(ESI):m/z calculated forC31H25BrN2O3+Na+:607.0667,found:607.0666.
EXAMPLE 13 preparation of Compound 13
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.59(s,1H),7.98(d,J＝8.4Hz,2H),7.48-7.35(4H),7.32-7.15(m,5H),7.08(t,J＝7.2Hz,1H),7.01(d,J＝7.2Hz,2H),6.35(d,J＝6.6Hz,1H),5.76(d,J＝6.6Hz,1H),4.82(d,J＝6.6Hz,1H),3.58(d,J＝5.4Hz,1H),3.14(dd,J＝14.4,4.8Hz,1H),2.54(s,3H),2.32(q,J＝7.8Hz,1H)
13C NMR(150MHz,CDCl3)δ(ppm):171.2,146.4,138.1,135.5,134.5,133.7,133.3,133.2,130.1,129.8,129.6,129.3,129.1,128.8,127.3,126.8,126.7,124.2,122.6,120.9,118.6,111.5,102.4,50.1,34.2,32.7,22.0.
HRMS(ESI):m/z calculated forC31H24Cl2N2O3+H+:575.0963,found:575.0968.
EXAMPLE 14 preparation of Compound 14
1. Preparation of substrate indole electron-deficient olefin
At 60 ℃, 50mL of methanol, 11.7g of indole (100mmol) and 9.9g of p-toluenesulfonyl azide (50mmol) are sequentially added into a 100mL flask, the reaction is carried out for 4 hours, the TLC method is used for monitoring the reaction until the reaction is completed, solid is separated out, the filtration and the vacuum drying are carried out, and the compound a, 13.0g of pink solid product and 90% yield are obtained.
At room temperature, 50mL of dichloromethane, 5.0g of compound a (17.5mmol) and 2-naphthalene benzaldehyde (52.5mmol) are sequentially added into a 100mL flask, 3.5mL of titanium tetrachloride (35.0mmol) is added to promote the reaction to occur for 8 hours, the reaction is monitored by a TLC method until the reaction is complete, a solid is separated out, a solid product is obtained by filtration, and vacuum drying is carried out, so that the substrate 14a of the compound 14 is obtained, 6.3g of yellow powder is obtained, and the yield is 81%.
2. Preparation of Compound 14 of the present invention
Under argon, the substrate 14a (0.1mmol), (0.15mmol, 31.0mg) potassium phosphate, carbene catalyst 3a (0.005mmol, 2.4mg), 1mL tetrahydrofuran and α -chloroaldehyde (0.25mmol) were added sequentially to the reaction tube, the tube was sealed and stirred at 60 ℃, the reaction was monitored by TLC method, after completion of the reaction, the reaction solvent was removed under reduced pressure, and the residue was subjected to silica gel column with petroleum ether: eluting with 35:1 ethyl acetate, collecting eluent with Rf of 0.4-0.5, and eluting with PE, EA, 6:1, the solvent was removed to obtain compound 14 shown below.
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.61(s,1H),8.04–8.02(m,2H),7.69–7.64(m,1H),7.43–7.40(m,2H),7.40–7.36(m,3H),7.32–7.26(m,5H),7.25–7.21(m,1H),7.16–7.12(m,1H),7.06(d,J＝3.6Hz,1H),7.04–7.00(m,3H),6.48(d,J＝8.4Hz,1H),4.22(d,1H),3.63–3.60(m,1H),3.23(dd,J＝15.0,4.2Hz,1H),2.57(s,3H),2.33(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.7,146.2,138.5,136.1,134.2,133.3,132.5,130.1,130.0,129.3,128.7,128.3,127.8,127.6,127.1,127.0,126.7,126.1,126.0,125.8,124.4,122.3,120.7,118.0,111.5,102.9,50.3,38.9,32.6,22.0.
HRMS(ESI):m/z calculated forC35H28N2O3S+Na+:579.1718,found:579.1718.
EXAMPLE 15 preparation of Compound 15
White solid, 92% yield, >19:1d.r, 97% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.55(s,1H),7.98–7.94(m,2H),7.39(d,J＝8.4Hz,1H),7.34–7.27(m,5H),7.25–7.22(m,1H),7.19–7.15(m,1H),7.14–7.10(m,2H),7.09–7.05(m,1H),6.91–6.89(m,1H),6.60(dd,J＝5.4,3.6Hz,1H),6.16–6.10(m,1H),4.33(d,J＝6.0Hz,1H),3.47(ddd,J＝10.2,6.0,4.2Hz,1H),3.29(dd,J＝14.4,4.2Hz,1H),2.52(dd,J＝14.4,9.0Hz,1H),2.47(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):171.1,146.1,142.1,138.4,134.1,133.2,129.8,129.3,128.8,126.8,126.7,125.1,124.3,123.9,122.3,120.8,117.9,111.5,103.5,51.0,33.2,32.5,21.9.
HRMS(ESI):m/z calculated forC29H24N2O3S2+Na+:535.1126,found:535.1127.
EXAMPLE 16 preparation of Compound 16
White solid, 94% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.62(s,1H),8.35–8.33(m,1H),8.16–8.13(m,1H),7.99–7.96(m,2H),7.42–7.39(m,3H),7.31–7.27(m,2H),7.24–7.22(m,2H),7.19–7.16(m,1H),7.07–7.04(m,1H),7.01(d,J＝7.2Hz,2H),6.61(dd,J＝7.8,4.8Hz,1H),6.34–6.30(m,1H),4.06(d,J＝6.6Hz,1H),3.58(ddd,J＝10.2,6.6,4.8Hz,1H),3.23(dd,J＝15.0,4.2Hz,1H),2.53(s,3H),2.22(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.2,149.7,148.5,146.5,137.7,134.9,134.4,133.7,133.3,130.1,129.2,129.0,128.9,127.0,124.0,123.4,122.6,121.0,117.7,111.6,102.1,50.0,35.8,32.6,22.0.
HRMS(ESI):m/z calculated forC30H25N3O3S+Na+:530.1514,found:530.1517.
EXAMPLE 17 preparation of Compound 17
White solid, 93% yield, >19:1d.r, > 96% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.42(s,1H),7.84–7.81(m,2H),7.45–7.40(m,2H),7.30–7.28(m,2H),7.28–7.25(m,1H),7.24–7.20(m,6H),7.16–7.13(m,1H),7.06–7.03(m,4H),3.80(d,J＝5.4Hz,1H),3.38(dd,J＝14.4,3.6Hz,1H),3.11(ddd,J＝10.8,5.4,3.6Hz,1H),2.94(dd,J＝14.4,10.8Hz,1H),2.12(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):170.7,145.8,138.1,134.7,133.3,131.7,130.8,129.6,129.3,128.9,128.5,128.2,126.9,123.6,122.7,122.4,120.9,118.1,111.7,100.4,85.9,85.3,50.4,33.2,24.6,21.7.
HRMS(ESI):m/z calculated forC33H26N2O3S+Na+:553.1562,found:553.1564.
EXAMPLE 18 preparation of Compound 18
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.30(s,1H),7.81(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,1H),7.31–7.25(m,5H),7.22–7.17(m,2H),7.15–7.08(m,3H),3.25(dd,J＝14.4,5.4Hz,1H),3.09(dt,J＝10.2,5.4Hz,1H),2.80–2.74(m,1H),2.62(dd,J＝14.4,9.6Hz,1H),2.42(s,3H),1.51–1.43(m,1H),1.06–0.96(m,2H),0.60(t,J＝7.2Hz,3H),0.32(tt,J＝16.2,8.4Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.8,145.9,138.8,134.1,133.5,129.7,129.6,129.0,128.7,128.7,126.6,125.3,122.2,120.6,118.4,111.5,105.9,50.5,33.2,32.7,31.7,21.8,20.1,14.1.
HRMS(ESI):m/z calculated forC28H28N2O3S+Na+:495.1718,found:495.1718.
EXAMPLE 19 preparation of Compound 19
White solid, 94% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.54(s,1H),7.95–7.92(m,2H),7.40–7.38(m,1H),7.32–7.25(m,5H),7.22–7.14(m,4H),7.10–7.03(m,1H),3.36(dd,J＝14.4,4.8Hz,1H),3.13(ddd,J＝10.2,6.6,4.8Hz,1H),2.86(dd,J＝6.6,3.0Hz,1H),2.66(dd,J＝14.4,10.2Hz,1H),2.42(s,3H),2.06–1.96(m,1H),1.56(s,3H),0.84(d,J＝6.6Hz,2H).
13C NMR(150MHz,CDCl3)δ(ppm):173.0,146.0,138.9,133.8,133.5,131.4,129.6,129.3,128.9,128.8,126.6,126.1,121.9,120.5,119.3,111.3,100.0,49.4,37.6,32.5,27.1,23.2,21.9,15.5.
HRMS(ESI):m/z calculated forC28H28N2O3S+Na+:495.1718,found:495.1718.
EXAMPLE 20 preparation of Compound 20
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.27(s,1H),7.83–7.79(m,2H),7.40–7.37(m,1H),7.30–7.27(m,3H),7.27–7.23(m,2H),7.21–7.17(m,2H),7.13–7.07(m,3H),3.21(dd,J＝14.4,5.4Hz,1H),3.07(dt,J＝10.2,5.4Hz,1H),2.79(ddd,J＝12.6,4.8,3.0Hz,1H),2.61(dd,J＝14.4,9.6Hz,1H),2.41(s,3H),1.45–1.34(m,1H),1.27–1.19(m,1H),0.85(d,J＝6.6Hz,3H),0.51(d,J＝6.6Hz,3H),0.20(t,J＝12.6Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.7,145.9,138.6,134.2,133.5,129.8,129.6,129.1,128.7,128.6,126.7,125.3,122.2,120.6,118.4,111.6,106.8,50.8,40.4,32.7,29.8,25.3,24.1,21.8,21.4.
HRMS(ESI):m/z calculated forC29H30N2O3S+Na+:509.1875,found:509.1877.
EXAMPLE 21 preparation of Compound 21
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.30(s,1H),7.83–7.80(m,2H),7.41–7.38(m,1H),7.31–7.25(m,5H),7.21–7.17(m,2H),7.14–7.09(m,3H),3.25(dd,J＝14.4,5.4Hz,1H),3.10(dt,J＝9.6,5.4Hz,1H),2.75(ddd,J＝11.4,5.4,3.6Hz,1H),2.63(dd,J＝14.4,9.6Hz,1H),2.42(s,3H),1.49(tt,J＝12.6,4.2Hz,1H),1.07–0.96(m,5H),0.92–0.83(m,1H),0.77(t,J＝7.2Hz,3H),0.39–0.26(m,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.8,145.8,138.8,134.1,133.5,129.7,129.3,129.0,128.8,128.7,126.6,125.3,122.1,120.6,118.5,111.5,105.9,50.6,32.7,32.0,31.9,30.9,26.6,22.5,21.9,14.3.
HRMS(ESI):m/z calculated forC30H32N2O3S+Na+:523.2031,found:523.2034.
EXAMPLE 22 preparation of Compound 22
White solid, 92% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.30(s,1H),7.83–7.79(m,2H),7.40–7.38(m,1H),7.31–7.25(m,5H),7.21–7.17(m,2H),7.14–7.08(m,3H),3.25(dd,J＝14.4,5.2Hz,1H),3.10(tt,J＝9.9,4.8Hz,1H),2.75(ddd,J＝11.1,5.2,3.7Hz,1H),2.63(dd,J＝14.4,9.6Hz,1H),2.41(s,3H),1.54–1.47(m,1H),1.21–1.13(m,2H),1.05–0.96(m,5H),0.88–0.84(m,1H),0.82(t,J＝7.8Hz,3H),0.48–0.23(m,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.8,145.8,138.8,134.2,133.5,129.7,129.3,129.0,128.7,126.6,125.3,122.1,120.6,118.5,111.5,105.8,50.5,32.7,31.9,31.7,30.9,29.5,26.9,22.9,21.9,14.2.
HRMS(ESI):m/z calculated forC31H34N2O3S+Na+:537.2188,found:537.2187.
EXAMPLE 23 preparation of Compound 23
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.49(s,1H),7.91(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,1H),7.32–7.25(m,5H),7.21–7.15(m,4H),7.09(dd,J＝7.8,7.2Hz,1H),3.33(dd,J＝14.4,5.4Hz,1H),3.15(dt,J＝9.6,5.4Hz,1H),3.08(dd,J＝6.6,3.6Hz,1H),2.69(dd,J＝14.4,9.6Hz,1H),2.41(s,3H),1.92–1.78(m,1H),1.66–1.58(m,1H),1.37–1.20(m,3H),1.18–1.05(m,2H),0.99–0.88(m,1H),0.64–0.52(m,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.9,146.0,139.0,133.6,133.5,131.3,129.5,129.3,129.0,128.7,126.6,126.0,121.9,120.5,118.9,111.4,101.5,50.3,40.0,34.4,32.8,31.8,25.7,24.1,23.8,21.8.
HRMS(ESI):m/z calculated forC30H30N2O3S+Na+:521.1875,found:521.1875.
EXAMPLE 24 preparation of Compound 24
White solid, 93% yield, >19:1d.r, 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.53(d,J＝13.2Hz,1H),7.94(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,1H),7.32-7.27(m,4H),7.26(d,J＝6.0Hz,1H),7.22-7.15(m,4H),7.09(t,J＝6.6Hz,1H),3.36(dd,J＝14.4,4.8Hz,1H),3.10(qd,J＝5.5,4.2Hz,1H),2.82(q,J＝3.0Hz,1H),2.66(dd,J＝14.4,9.6Hz,1H),2.42(s,3H),1.62-1.56(m,2H),1.54-1.48(m,1H),1.40(d,J＝13.2Hz,1H),1.18-1.00(m,2H),0.93-0.85(m,2H),0.67(qt,J＝12.6,4.2Hz,1H),0.55(d,J＝12.6Hz,1H),0.08-0.01(m,1H)
13C NMR(150MHz,CDCl3)δ(ppm):173.1,146.0,138.9,133.7,133.5,131.2,129.5,129.3,128.9,128.8,126.6,126.0,121.9,120.5,119.4,111.3,101.3,49.1,37.5,37.1,32.9,32.6,26.8,26.0,25.7,25.6,21.8.
HRMS(ESI):m/z calculated forC31H32N2O3S+Na+:535.2031,found:535.2033.
EXAMPLE 25 preparation of Compound 25
White solid, 93% yield, >19:1d.r, 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.36(s,1H),7.81(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.29–7.25(m,2H),7.23–7.17(m,6H),7.16–7.10(m,4H),6.85–6.81(m,2H),3.27(dd,J＝14.4,5.4Hz,1H),3.16(dt,J＝10.2,5.4Hz,1H),2.90–2.85(m,1H),2.65(dd,J＝14.4,9.6Hz,1H),2.32–2.26(m,2H),2.25(s,3H),1.89–1.80(m,1H),0.78–0.65(m,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.5,146.1,141.5,138.6,133.9,133.6,129.9,129.8,129.0,128.8,128.6,128.3,128.2,126.7,126.0,125.2,122.3,120.7,118.5,111.6,105.2,50.4,33.2,32.8,32.7,31.9,21.8.
HRMS(ESI):m/z calculated forC33H30N2O3S+Na+:557.1875,found:557.1875.
EXAMPLE 26 preparation of Compound 26
White solid, 91% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.58(s,1H),7.98–7.94(m,2H),7.42–7.39(m,1H),7.38–7.33(m,3H),7.20–7.16(m,1H),7.08(ddd,J＝7.8,5.4,1.8Hz,1H),7.03–6.98(m,1H),6.83–6.79(m,2H),6.51–6.47(m,2H),4.21(d,J＝6.6Hz,1H),3.09(dd,J＝13.8,6.6Hz,1H),2.49(s,3H),1.64–1.58(m,1H),1.43–1.36(m,2H),1.07(ddd,J＝14.4,12.0,7.2Hz,1H),0.86–0.82(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):172.0,146.0,138.7,133.9,133.3,130.3,129.9,129.2,128.3,127.6,127.0,124.5,122.2,120.7,117.9,111.5,103.2,48.9,39.7,29.2,21.9,20.4,14.1.
HRMS(ESI):m/z calculated forC27H26N2O3S+Na+:481.1562,found:481.1559.
EXAMPLE 27 preparation of Compound 27
White solid, 91% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.58(s,1H),7.95(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,1H),7.35(dd,J＝8.4,2.4Hz,3H),7.20–7.16(m,1H),7.10–7.06(m,1H),7.00(t,J＝7.2Hz,1H),6.81(t,J＝7.8Hz,2H),6.50–6.47(m,2H),4.22(d,J＝6.6Hz,1H),3.07(dd,J＝13.8,6.6Hz,1H),2.49(s,3H),1.62(tt,J＝10.2,5.4Hz,1H),1.39–1.32(m,2H),1.29–1.19(m,2H),1.08(dt,J＝21.6,7.8Hz,1H),0.83(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):172.0,146.0,138.6,133.9,133.3,130.3,129.9,129.2,128.3,127.7,127.0,124.5,122.2,120.7,117.9,111.5,103.2,49.2,39.6,29.4,26.7,22.7,21.9,14.0.
HRMS(ESI):m/z calculated forC28H28N2O3S+Na+:495.1718,found:495.1716.
EXAMPLE 28 preparation of Compound 28
White solid, 91% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.60(s,1H),7.98–7.95(m,2H),7.41(d,J＝8.4Hz,1H),7.37–7.34(m,3H),7.20–7.16(m,1H),7.11–7.07(m,1H),7.03–7.00(m,1H),6.84–6.80(m,2H),6.50(d,J＝8.4,2H),4.22(d,J＝6.6Hz,1H),3.08(dd,J＝13.8,6.6Hz,1H),2.50(s,3H),1.67–1.59(m,2H),1.40–1.35(m,2H),1.26–1.23(m,2H),1.11–1.05(m,1H),0.90–0.87(m,1H),0.84(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):172.0,146.0,138.6,133.9,133.3,130.3,129.9,129.2,128.3,127.6,127.0,124.5,122.1,120.7,117.9,111.5,103.1,49.2,39.6,31.8,26.9,26.8,22.5,21.9,14.1.
HRMS(ESI):m/z calculated forC29H30N2O3S+Na+:509.1875,found:509.1875.
EXAMPLE 29 preparation of Compound 29
White solid, 92% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.56(s,1H),7.94(d,J＝9.0Hz,2H),7.43–7.38(m,1H),7.38–7.26(m,8H),7.21–7.14(m,1H),7.12–7.05(m,1H),6.98(t,J＝4.8Hz,1H),6.78(dd,J＝10.8,4.8Hz,2H),6.41(d,J＝8.4,2H),4.50(d,J＝12.0Hz,1H),4.42–4.37(m,1H),4.15(dd,J＝6.6,2.4Hz,1H),3.55(ddd,J＝9.6,6.6,4.8Hz,1H),3.49(ddd,J＝9.6,7.2,4.8Hz,1H),3.46–3.39(m,1H),2.49(s,3H),1.96–1.84(m,1H),1.41(ddd,J＝14.4,12.0,6.8Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):172.0,146.0,138.8,138.4,133.9,133.4,130.1,129.9,129.2,128.6,128.4,128.0,127.8,127.7,127.0,124.5,122.2,120.7,118.1,111.5,103.2,73.1,67.3,45.6,39.9,27.8,21.9
HRMS(ESI):m/z calculated forC33H30N2O4S+Na+:573.1824,found:573.1824.
EXAMPLE 30 preparation of Compound 30
White solid, 93% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.56(s,1H),7.99(d,J＝8.4Hz,2H),7.38(d,J＝8.4Hz,3H),7.29–7.24(m,1H),7.18–7.13(m,1H),7.04(ddd,J＝7.2,6.0,3.0Hz,2H),6.94(d,J＝8.4Hz,2H),6.88–6.79(m,4H),6.45(d,J＝7.8Hz,2H),4.04(d,J＝6.6Hz,1H),3.79(s,3H),3.50–3.44(m,1H),3.13(dd,J＝15.0,4.2Hz,1H),2.52(s,3H),2.24(dd,J＝15.0,10.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.7,158.3,146.1,138.6,133.9,133.3,130.4,130.2,129.9,129.3,128.4,128.0,127.1,124.3,122.2,120.7,118.0,114.1,111.5,103.5,55.4,50.6,38.6,31.7,21.9.
HRMS(ESI):m/z calculated forC32H28N2O4S+Na+:559.1667,found:559.1666.
EXAMPLE 31 preparation of Compound 31
White solid, 97% yield, >19:1d.r, > 99% ee,
1H NMR(600MHz,CDCl3)δ(ppm):9.57(s,1H),7.98(d,J＝9.0Hz,2H),7.41-7.36(m,3H),7.30(d,J＝6.0Hz,1H),7.20(d,J＝4.8Hz,2H),7.17(t,J＝7.8Hz,1H),7.09-7.03(m,2H),7.00(s,1H),6.94-6.89(m,1H),6.86(t,J＝7.8Hz,2H),6.41(d,J＝6.6Hz,2H),4.01(d,J＝6.6Hz,1H),3.48(qd,J＝5.4,3.6Hz,1H),3.14(dd,J＝14.4,4.8Hz,1H),2.53(s,3H),2.27(dd,J＝14.4,9.6Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):171.3,146.2,140.6,138.3,134.4,133.7,133.3,130.0,129.9,129.8,129.4,129.3,128.5,127.9,127.4,127.3,126.9,124.3,122.3,120.7,118.0,111.5,103.2,50.2,38.9,32.5,22.0.
HRMS(ESI):m/z calculated forC31H25ClN2O3S+Na+:563.1172,found:563.1174.
the advantageous effects of the present invention are described below by way of test examples.
Test example 1 antitumor study
1. Test cell lines
The tumor cell strains (colon cancer cell HCT116, human breast cancer cell MDA-MB231, human breast cancer cell MB468, prostate cancer cell PC3, mouse melanoma cell B16 and mouse melanoma cell A375) are provided by the national center of biotherapy of Sichuan university, and the tumor cells are all frozen and stored in the national center of biotherapy of Sichuan university.
2. Test method
2.1 preparation and treatment of cells
Culturing 6 kinds of tumor cells in RPMI-1640 culture medium containing 10% inactivated newborn calf serum, culturing at 37 deg.C in 5% CO2 culture box until 80% cells are fused, digesting with 0.1% pancreatin solution to obtain single cell suspension, adjusting cell concentration to 5 × 104Uniformly inoculating the cells/mL into 96-well microplate, placing 3 multiple wells per group, 100 μ L/well, placing at 37 deg.C saturated humidity and 5% CO2After culturing in an incubator for 24h, adding culture solution with the same amount into a normal control group; a concentration gradient of test drug (100, 50, 25, 12.5, 6.25. mu.g/mL) was added, 3 replicates per concentration and experiments were performed in 2 replicates. After the drug and the cells act for 24 hours, 10 mu L of MTT solution (5mg/mL) is added into each hole, after the culture is continued for 4 hours, 100 mu L of DMSO is added into each hole, the mixture is shaken and uniformly mixed to ensure that the crystal is fully dissolved, the absorbance value (A value) is measured at the 490nm wavelength of an enzyme-labeling instrument, and the average value of each concentration group is taken.
2.2 measurement of tumor cell proliferation inhibition Rate
The cell proliferation inhibition rate was calculated according to the following formula: the cell growth inhibition ratio (%) × 100% (1-test group a value/control group a value). All experimental data were statistically analyzed using SPSS 13.0. Experimental results adopt Probit to obtain IC50The value is obtained.
3. Test results
The test results are shown in the table.
TABLE 1 inhibition of growth of test cells by different compounds
Experimental results show that the compound has an anti-tumor effect. Among them, compound 14 had the best antitumor effect.
In conclusion, the alpha-carboline compound is successfully synthesized, and the compound has the advantages of simple and convenient preparation method, mild reaction, high yield, antitumor activity and wide market application prospect.
Claims (13)
1. A compound or pharmaceutically acceptable salt of formula II:
wherein R is1Is selected from C1～C10Alkyl, substituted or unsubstituted phenyl, naphthyl, thiophene, pyridine, -C ≡ C-R5、-(CH2)aR6The substituent groups on the substituted or unsubstituted phenyl are respectively and independently selected from one or more methoxy, C1～C6Alkyl, nitro, halogen;
R2is selected from C1～C6Alkyl, - (CH)2)bR3；
R3Is selected from-OR4Substituted or unsubstituted phenyl, wherein the substituent on the substituted or unsubstituted phenyl is independently selected from one or more halogen and methoxy;
R4selected from benzyl, R5、R6Is selected from phenyl;
a＝2；b＝1，2；
formula IThe compounds of formula I are not
2. The compound or pharmaceutically acceptable salt according to claim 1, wherein: the R is2Selected from benzyl.
3. The compound or pharmaceutically acceptable salt according to claim 1, wherein: the compound is selected from one of the following structural formulas:
4. the following compounds or pharmaceutically acceptable salts:
5. a process for preparing a compound according to any one of claims 1 to 4, characterized in that: it comprises the following steps:
(1) dissolving indole electron-deficient olefin, alpha-chloroaldehyde, potassium phosphate and a catalyst in tetrahydrofuran for reaction; wherein the molar ratio of the indole electron-deficient olefin substrate, the alpha-chloroaldehyde, the potassium phosphate and the catalyst is 0.1:0.25:0.15: 0.005;
(2) decompressing after the reaction is completed, removing the reaction solvent, eluting, collecting the eluent, and removing the solvent to obtain the product;
the synthetic route is as follows:
wherein R is1、R2The method according to any one of claims 1 to 4; NHC 3a is catalyst with the structural formula
THF is tetrahydrofuran.
6. The method of claim 5, wherein: in the step (1), the reaction is carried out for 8 hours at 60 ℃ under the argon condition;
and/or, in step (1), monitoring the reaction by TLC;
and/or, in the step (2), a silica gel column is used for elution, and the eluent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 35: 1;
and/or in the step (2), the conditions for collecting the eluent are that Rf is 0.4-0.5, and the developing agent is a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 6: 1.
7. The method of claim 5, wherein: the preparation method of the indole electron-deficient olefin comprises the following steps:
a. dissolving indole and p-toluenesulfonyl azide in methanol for reaction, separating out a solid after the reaction is completed, filtering, and drying in vacuum to obtain a compound a; wherein the mol ratio of indole to p-toluenesulfonyl azide is 100: 50;
b. dissolving a compound a, substituted benzaldehyde and titanium tetrachloride in dichloromethane for reaction, precipitating a solid after the reaction is completed, filtering, and drying in vacuum to obtain the compound a; wherein the molar ratio of the compound a to the substituted benzaldehyde to the titanium tetrachloride is 17.5:52.5: 35;
the synthetic route is as follows:
wherein R is1As claimed in any one of claims 1 to 4As set forth in one aspect.
8. The method of claim 7, wherein: the reaction in the step a is carried out for 4 hours at the temperature of 60 ℃;
and/or, in step a, the reaction is monitored by TLC method;
and/or in the step b, the reaction is carried out at room temperature for 4-16 h;
and/or, in step b, the reaction is monitored by TLC.
9. Use of a compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor medicament.
10. Use according to claim 9, characterized in that: the tumor is colon cancer, breast cancer, prostatic cancer, and melanoma.
11. A medicament, characterized by: the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, and pharmaceutically acceptable auxiliary materials or auxiliary components.
12. The application of the following compounds or pharmaceutically acceptable salts thereof in preparing antitumor drugs:
13. use according to claim 12, characterized in that: the tumor is colon cancer, breast cancer, prostatic cancer, and melanoma.
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