CN109293657A - A kind of α-carboline ketone compounds and its preparation method and application - Google Patents
A kind of α-carboline ketone compounds and its preparation method and application Download PDFInfo
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Abstract
The present invention provides compound shown in formula I or pharmaceutically acceptable salts: where R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、‑(CH2)aR6, the substituted or non-substituted phenyl is separately by one or more selected from alkoxy, C1~C6Alkyl, nitro, halogen substituent group replaced；R2Selected from C1~C6Alkyl ,-(CH2)bR3；R3Selected from-OR4, substituted or non-substituted phenyl, the substituted or non-substituted phenyl separately by it is one or more selected from halogen, alkoxy substituent groups replaced；R4Selected from benzyl, R5、R6Selected from phenyl；A=2；B=1,2.The present invention also provides the preparation method of above compound and purposes.The experimental results showed that the present invention successfully synthesizes a kind of α-carboline ketone compounds, and the preparation method of the compounds of this invention is easy, reaction is mild, high income, and has anti-tumor activity, has a vast market application prospect.
Description
Technical field
The invention belongs to chemical medicines, and in particular to a kind of α-carboline ketone compounds and preparation method thereof and answer
With.
Background technique
Tumour refers to body under the effect of the various tumorigenesis factors, and the cell of local organization loses at the genetic level gives birth to it
Long normal regulation leads to clonal abnormality hyperplasia and the neoformation that is formed.In the world, tumour suffers from higher hair
Sick rate and lethality.According to statistics, in global 7,000,000,000 populations, ten thousand people about more than 1000 suffer from tumour every year, because of tumor mortality person
Up to millions of.It can be seen that the prevention and treatment of tumour have become the public health problem of society's great attention.
In recent decades, the mankind are that treatment tumour has paid unremitting effort, and the treatment of tumour at present mainly has operation, changes
Treatment, radiotherapy, cellular immunotherapy are learned, the use in conjunction of several method can increase the survival rate of patient.Tumour cell
Transfer is that treating cancer suffers from a problem that, however it is limited for its therapeutic effect with radiotherapy to perform the operation between organ,
Therefore chemotherapy, i.e. drug therapy are mainly taken.Many chemotherapeutic agents have been reported, these tumour medicines are roughly divided into
Several classes below: using 5 FU 5 fluorouracil as the antitumor antimetabolite of representative, using doxorubicin hydrochloride as the antitumor antibiotics of representative,
Using vincaleukoblastinum and taxol as the anti-tumor drug derived from plant of representative, using cis-platinum as anti-tumor platinum complex compound of representative etc..
Benzazole compounds are more important heterocycle derivative alkaloids, and majority has significant physiological activity, domestic
A large number of studies show that, indoles or class indole structure have antitumaous effect, and the indoles anticancer compound having been reported includes length outside
Spring bases, epiphysin, Indomethacin, indigo red and other indoles substances in the brassicaceous vegetable.People at present
The research of indoles series antineoplastic medicament is had made great progress, but there are still many defects in clinical application, such as damage
Human normal cell is serious, the immune function of body, weight cell is inhibited to be also easy to produce drug resistance etc..Therefore high curative effect, low is synthesized
The anti-tumor drug of toxicity is still research hotspot.
Summary of the invention
The object of the present invention is to provide a kind of α-carboline ketone compounds and its preparation method and application.
The present invention provides compound shown in formula I or pharmaceutically acceptable salts:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, described to take
Generation or unsubstituted phenyl are separately selected from alkoxy, C by one or more1~C6The substituent group institute of alkyl, nitro, halogen
Replace；
R2Selected from C1~C6Alkyl ,-(CH2)bR3；
R3Selected from-OR4, substituted or non-substituted phenyl, the substituted or non-substituted phenyl is separately one or more
Selected from halogen, alkoxy substituent group replaced；
R4Selected from benzyl, R5、R6Selected from phenyl；
A=2；B=1,2.
Further, the type I compound has structure shown in formula II:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, described to take
Generation or unsubstituted phenyl are separately selected from alkoxy, C by one or more1~C6The substituent group institute of alkyl, nitro, halogen
Replace；
R2Selected from C1~C6Alkyl ,-(CH2)bR3；
R3Selected from-OR4, substituted or non-substituted phenyl, the substituted or non-substituted phenyl is separately one or more
Selected from halogen, alkoxy substituent group replaced；
R4Selected from benzyl, R5、R6Selected from phenyl；
A=2；B=1,2.
Further, the R2Selected from benzyl.
Further, the aryl is selected from phenyl, naphthalene, thiophene, pyridine.
Further, the compound is selected from one of following structural formula:
The present invention also provides a kind of method for preparing aforesaid compound, it the following steps are included:
(1) indoles electron deficient olefins, alpha-chloro aldehyde, potassium phosphate and catalyst are taken, is dissolved in tetrahydrofuran and reacting；Wherein,
Indoles electron deficient olefins substrate, alpha-chloro aldehyde, potassium phosphate and catalyst molar ratio be 0.1:0.25:0.15:0.005；
(2) depressurized after fully reacting, remove reaction dissolvent, eluent is collected in elution, remove solvent to get；
Synthetic route is as follows:
Wherein, R2Selected from C1~C6Alkyl ,-(CH2)bR3；R3Selected from-OR4, substituted or non-substituted phenyl, the substitution or non-
Substituted-phenyl is separately replaced one or more substituent groups for being selected from halogen, alkoxy；R4Selected from benzyl；B=1,
2；NHC 3a is catalyst, and structural formula isTHF is in tetrahydrofuran；
Preferably, it in step (1), reacts under the conditions of argon gas, 60 DEG C are stirred to react 8h；
And/or in step (1), is monitored and reacted with TLC method；
And/or in step (2), elution uses silicagel column, and the petroleum ether and ethyl acetate that eluent is volume ratio 35:1 are mixed
Close solution；
And/or in step (2), it is 0.4-0.5 that the condition for collecting eluent, which is Rf, and solvent is the petroleum of volume ratio 6:1
Ether and ethyl acetate mixture.
Further, the indoles electron deficient olefins preparation method the following steps are included:
A. indoles and p-toluene sulfonyt azide are taken, is dissolved in methanol and reacting, solid is precipitated after fully reacting, is filtered, vacuum
It is dry, obtain compound a；Wherein, the molar ratio of indoles and p-toluene sulfonyt azide is 100:50；
B. compound a, substituted benzaldehyde and titanium tetrachloride are taken, is dissolved in methylene chloride and reacting, be precipitated after fully reacting
Solid, filtering, vacuum drying to get；Wherein the molar ratio of compound a, substituted benzaldehyde and titanium tetrachloride is 17.5:
52.5:35；
Synthetic route is as follows:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, described to take
Generation or unsubstituted phenyl are separately selected from alkoxy, C by one or more1~C6The substituent group institute of alkyl, nitro, halogen
Replace；R5、R6Selected from phenyl；A=2；
Preferably, reaction is to react 4h at 60 DEG C in step a；
And/or in step a, is monitored and reacted with TLC method；
And/or in step b, react to react 4~16h at room temperature；
And/or in step b, is monitored and reacted with TLC method.
The present invention also provides the purposes of aforesaid compound or its pharmaceutically acceptable salt in the preparation of antitumor drugs.
Further, the tumour is colon cancer, breast cancer, prostate cancer, melanoma.
The present invention also provides a kind of drugs, it is with compound above-mentioned or its pharmaceutically acceptable salt, in addition medicine
The preparation that acceptable auxiliary material or complementary ingredient are prepared on.
The experimental results showed that the present invention is successfully prepared a kind of α-carboline ketone compounds, and the system of the compounds of this invention
Preparation Method is easy, reaction is mild, high income, and has anti-tumor activity, has a vast market application prospect.
About the definition of the invention using term: unless otherwise indicated, group or term herein provide initial
Definition is suitable for group or term of entire description；For the term being not specifically defined herein, it should according to open
Content and context, their meaning can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix (Ca~Cb) alkyl
Show any alkyl containing " a " to " b " a carbon atom.Thus, for example, (C1~C6) alkyl refers to comprising 1~6 carbon atom
Alkyl.
The C1~C6Alkyl refers to C1、C2、C3、C4、C5、C6Alkyl, i.e., with 1~6 carbon atom linear chain or branched chain
Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, sec-butyl, amyl, hexyl etc..
The alkoxy, which refers to, connects alkyl substituent on oxygen atom, such as methoxyl group, ethyoxyl, propoxyl group, butoxy
Deng.
The halogen refers to fluorine atom, bromine atom, chlorine atom, iodine atom.
Term " pharmaceutically acceptable salt " refers to above compound or its stereoisomer, with inorganic and/or organic acid
The acid and/or basic salt formed with alkali also includes amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be to be directly obtained in being finally separating and purify of compound.It is also possible to by by above compound or it is vertical
Body isomers is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be in the solution
It forms precipitating and is collected with filter method, or recycle obtain after the solvent evaporates, or be freeze-dried after reacting in an aqueous medium
It is made.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, can be commercially available by market.
The synthesis general formula of substrate indoles electron deficient olefins is as follows:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, described to take
Generation or unsubstituted phenyl are separately selected from alkoxy, C by one or more1~C6The substituent group institute of alkyl, nitro, halogen
Replace；R5、R6Selected from phenyl；A=2.
The synthesis general formula of the compounds of this invention is as follows:
Wherein, R2Selected from C1~C6Alkyl ,-(CH2)bR3；R3Selected from-OR4, substituted or non-substituted phenyl, the substitution or non-
Substituted-phenyl is separately replaced one or more substituent groups for being selected from halogen, alkoxy；R4Selected from benzyl；B=1,
2；NHC 3a is catalyst, and structural formula isTHF is in tetrahydrofuran.
The preparation of 1 compound 1 of embodiment
1, the preparation of substrate indoles electron deficient olefins
At 60 DEG C, 50mL methanol is sequentially added in 100mL flask, 11.7g indoles (100mmol) and 9.9g are to toluene sulphur
Acyl azide (50mmol) reacts 4 hours, and with TLC method monitoring reaction to fully reacting, solid is precipitated, filters, vacuum drying, i.e.,
Obtain compound a, pink solid product 13.0g, yield 90%.
At room temperature, 50mL methylene chloride, 5.0g compound a (17.5mmol) and benzene first are sequentially added in 100mL flask
Aldehyde (52.5mmol) adds 3.5mL titanium tetrachloride (35.0mmol) and promotes reaction, react 8 hours, monitored with TLC method
Solid is precipitated to fully reacting in reaction, the solid was filtered product, is dried in vacuo to get the substrate 1a of compound 1, yellow powder is arrived
Last 4.9g, yield 71%.
2, the preparation of the compounds of this invention 1
Under the conditions of argon gas, sequentially added substrate 1a (0.1mmol) toward reaction tube, (0.15mmol, 31.0mg) phosphoric acid
Potassium, carbone catalyst 3a (0.005mmol, 2.4mg), 1mL tetrahydrofuran and alpha-chloro aldehyde (0.25mmol), tube sealing is at 60 DEG C
Stirring is monitored with TLC method and is reacted, after complete reaction, reaction dissolvent is removed under reduced pressure, silicagel column petroleum ether on residue: second
Acetoacetic ester=35:1 elution, collects the eluent that Rf is 0.4-0.5, and solvent PE:EA=6:1 removes solvent to get as follows
Shown compound 1.
Compound 1 be white solid, 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 synthesis compound 1 method, using corresponding raw material, obtain compound 2 shown in following examples 2~31~
31。
The preparation of 2 compound 2 of embodiment
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.
The preparation of 3 compound 3 of embodiment
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.
The preparation of 4 compound 4 of embodiment
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.
The preparation of 5 compound 5 of embodiment
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.
The preparation of 6 compound 6 of embodiment
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.
The preparation of 7 compound 7 of embodiment
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.
The preparation of 8 compound 8 of embodiment
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.
The preparation of 9 compound 9 of embodiment
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.
The preparation of 10 compound 10 of embodiment
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.
The preparation of 11 compound 11 of embodiment
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.
The preparation of 12 compound 12 of embodiment
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.
The preparation of 13 compound 13 of embodiment
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.
The preparation of 14 compound 14 of embodiment
1, the preparation of substrate indoles electron deficient olefins
At 60 DEG C, 50mL methanol is sequentially added in 100mL flask, 11.7g indoles (100mmol) and 9.9g are to toluene sulphur
Acyl azide (50mmol) reacts 4 hours, and with TLC method monitoring reaction to fully reacting, solid is precipitated, filters, vacuum drying, i.e.,
Obtain compound a, pink solid product 13.0g, yield 90%.
At room temperature, 50mL methylene chloride, 5.0g compound a (17.5mmol) and 2- naphthalene are sequentially added in 100mL flask
Benzaldehyde (52.5mmol) adds 3.5mL titanium tetrachloride (35.0mmol) and promotes reaction, reacts 8 hours, with TLC method
Solid is precipitated to fully reacting in monitoring reaction, the solid was filtered product, is dried in vacuo to get the substrate 14a of compound 14 is arrived,
Yellow powder 6.3g, yield 81%.
2, the preparation of the compounds of this invention 14
Under the conditions of argon gas, sequentially added substrate 14a (0.1mmol) toward reaction tube, (0.15mmol, 31.0mg) phosphoric acid
Potassium, carbone catalyst 3a (0.005mmol, 2.4mg), 1mL tetrahydrofuran and alpha-chloro aldehyde (0.25mmol), tube sealing is at 60 DEG C
Stirring is monitored with TLC method and is reacted, after complete reaction, reaction dissolvent is removed under reduced pressure, silicagel column petroleum ether on residue: second
Acetoacetic ester=35:1 elution, collects the eluent that Rf is 0.4-0.5, and solvent PE:EA=6:1 removes solvent to get as follows
Shown compound 14.
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.
The preparation of 15 compound 15 of embodiment
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.
The preparation of 16 compound 16 of embodiment
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.
The preparation of 17 compound 17 of embodiment
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.
The preparation of 18 compound 18 of embodiment
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.
The preparation of 19 compound 19 of embodiment
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.
The preparation of 20 compound 20 of embodiment
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.
The preparation of 21 compound 21 of embodiment
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.
The preparation of 22 compound 22 of embodiment
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.
The preparation of 23 compound 23 of embodiment
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.
The preparation of 24 compound 24 of embodiment
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.
The preparation of 25 compound 25 of embodiment
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.
The preparation of 26 compound 26 of embodiment
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.
The preparation of 27 compound 27 of embodiment
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.
The preparation of 28 compound 28 of embodiment
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.
The preparation of 29 compound 29 of embodiment
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.
The preparation of 30 compound 30 of embodiment
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.
The preparation of 31 compound 31 of embodiment
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.
Illustrate beneficial effects of the present invention below by way of the mode of test example.
The antitumor research of test example 1
1, cell strain is tested
Tumor cell line (colon cancer cell HCT116, human breast cancer cell MDA-MB231, human breast cancer cell MB468,
Prostate gland cancer cell PC3, B16 mouse melanoma cell line, mouse melanin tumor cell A375) by Sichuan University's biological therapy
National Key Laboratory provides, and the above tumour cell freezes in biological therapy National Key Laboratory of Sichuan University.
2, test method
The preparation and processing of 2.1 cells
6 kinds of tumour cells are incubated at the RPMI-1640 culture solution containing 10% inactivation newborn calf serum, 37 DEG C, 5%
80% cell fusion is grown in CO2 incubator, is digested with 0.1% trypsin solution, single cell suspension is made, and adjusts cell concentration
It is 5 × 104A/mL is uniformly inoculated in 96 hole microtest plates, every group of 3 multiple holes, 100 holes μ L/, set 37 DEG C of saturated humidities,
5%CO2In incubator after culture for 24 hours, the culture solution containing equivalent is added in Normal group；The test medicine of concentration gradient is added
(100,50,25,12.5,6.25 μ g/mL), each concentration set 3 multiple holes, test parallel 2 times.For 24 hours to drug and cytosis
Afterwards, 10 μ L MTT solution (5mg/mL) are added in every hole, continue every hole after cultivating 4h and 100 μ L DMSO are added, oscillation mixes, makes to tie
Brilliant object sufficiently dissolves, its absorbance value (A value) is surveyed at microplate reader 490nm wavelength, and each concentration group takes its average value.
The measurement of 2.2 Cytostatic to tumor cell rates
Cell proliferation inhibition rate is calculated according to the following formula: cell proliferation inhibition rate (%)=(1- test group A value/control group
A value) × 100%.All experimental datas are for statistical analysis using SPSS 13.0.Experimental result acquires IC using Probit50
Value.
3, test result
It is as shown in the table for test result.
The inhibition situation that the different compounds of table 1 grow subject cell
The experimental results showed that the compounds of this invention has antitumous effect.Wherein, the antitumous effect of compound 14 is most
It is good.
In conclusion the present invention successfully synthesizes a kind of α-carboline ketone compounds, and the preparation side of the compounds of this invention
Method is easy, reaction is mild, high income, and has anti-tumor activity, has a vast market application prospect.
Claims (10)
1. compound shown in formula I or pharmaceutically acceptable salt:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, it is described substitution or
Unsubstituted phenyl is separately selected from alkoxy, C by one or more1~C6Alkyl, nitro, halogen substituent group replaced；
R2Selected from C1~C6Alkyl ,-(CH2)bR3；
R3Selected from-OR4, substituted or non-substituted phenyl, the substituted or non-substituted phenyl is separately selected from by one or more
Halogen, alkoxy substituent group replaced；
R4Selected from benzyl, R5、R6Selected from phenyl；
A=2；B=1,2.
2. compound shown according to claim 1 or pharmaceutically acceptable salt, it is characterised in that: the type I compound has
Structure shown in formula II:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, it is described substitution or
Unsubstituted phenyl is separately selected from alkoxy, C by one or more1~C6Alkyl, nitro, halogen substituent group replaced；
R2Selected from C1~C6Alkyl ,-(CH2)bR3；
R3Selected from-OR4, substituted or non-substituted phenyl, the substituted or non-substituted phenyl is separately selected from by one or more
Halogen, alkoxy substituent group replaced；
R4Selected from benzyl, R5、R6Selected from phenyl；
A=2；B=1,2.
3. compound according to claim 1 or claim 2, it is characterised in that: the R2Selected from benzyl.
4. compound according to claim 1 or claim 2, it is characterised in that: the aryl is selected from phenyl, naphthalene, thiophene, pyridine.
5. compound according to claim 1 or claim 2, it is characterised in that: the compound is selected from one of following structural formula:
6. a kind of method for preparing compound described in Claims 1 to 5 any one, it is characterised in that: it the following steps are included:
(1) indoles electron deficient olefins, alpha-chloro aldehyde, potassium phosphate and catalyst are taken, is dissolved in tetrahydrofuran and reacting；Wherein, indoles
Electron deficient olefins substrate, alpha-chloro aldehyde, potassium phosphate and catalyst molar ratio be 0.1:0.25:0.15:0.005；
(2) depressurized after fully reacting, remove reaction dissolvent, eluent is collected in elution, remove solvent to get；
Synthetic route is as follows:
Wherein, R2Selected from C1~C6Alkyl ,-(CH2)bR3；R3Selected from-OR4, substituted or non-substituted phenyl, it is described substituted or non-substituted
Phenyl is separately replaced one or more substituent groups for being selected from halogen, alkoxy；R4Selected from benzyl；B=1,2；NHC
3a is catalyst, and structural formula isTHF is in tetrahydrofuran；
Preferably, it in step (1), reacts under the conditions of argon gas, 60 DEG C are stirred to react 8h；
And/or in step (1), is monitored and reacted with TLC method；
And/or in step (2), elution uses silicagel column, and the petroleum ether and ethyl acetate mixing that eluent is volume ratio 35:1 are molten
Liquid；
And/or in step (2), it is 0.4-0.5 that the condition for collecting eluent, which is Rf, petroleum ether that solvent is volume ratio 6:1 and
Ethyl acetate mixture.
7. according to the method described in claim 6, it is characterized by: the preparation method of the indoles electron deficient olefins includes following
Step:
A. indoles and p-toluene sulfonyt azide are taken, is dissolved in methanol and reacting, solid is precipitated after fully reacting, is filtered, vacuum drying,
Obtain compound a；Wherein, the molar ratio of indoles and p-toluene sulfonyt azide is 100:50；
B. compound a, substituted benzaldehyde and titanium tetrachloride are taken, is dissolved in methylene chloride and reacting, solid is precipitated after fully reacting,
Filtering, vacuum drying to get；Wherein the molar ratio of compound a, substituted benzaldehyde and titanium tetrachloride is 17.5:52.5:35；
Synthetic route is as follows:
Wherein, R1Selected from C1~C10Alkyl, substituted or non-substituted aryl, naphthenic base ,-C ≡ C-R5、-(CH2)aR6, it is described substitution or
Unsubstituted phenyl is separately selected from alkoxy, C by one or more1~C6Alkyl, nitro, halogen substituent group replaced；
R5、R6Selected from phenyl；A=2；
Preferably, reaction is to react 4h at 60 DEG C in step a；
And/or in step a, is monitored and reacted with TLC method；
And/or in step b, react to react 4~16h at room temperature；
And/or in step b, is monitored and reacted with TLC method.
8. compound described in Claims 1 to 5 any one or its pharmaceutically acceptable salt are in the preparation of antitumor drugs
Purposes.
9. purposes according to claim 8, it is characterised in that: the tumour is colon cancer, breast cancer, prostate cancer, black
Melanoma.
10. a kind of drug, it is characterised in that: it be with compound described in Claims 1 to 5 any one or its pharmaceutically may be used
The salt of receiving, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
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