CN115304597A - Beta-carboline compounds and application thereof in preparing medicines for treating or preventing tumor diseases - Google Patents

Beta-carboline compounds and application thereof in preparing medicines for treating or preventing tumor diseases Download PDF

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CN115304597A
CN115304597A CN202211008258.7A CN202211008258A CN115304597A CN 115304597 A CN115304597 A CN 115304597A CN 202211008258 A CN202211008258 A CN 202211008258A CN 115304597 A CN115304597 A CN 115304597A
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CN115304597B (en
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王守国
罗木鹏
夏厚军
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Shenzhen Institute of Advanced Technology of CAS
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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 invention relates to beta-carboline compounds and application thereof in preparing medicaments for treating or preventing tumor diseases, belonging to the technical field of pharmacology. The structural formula of the beta-carboline compound in the beta-carboline compound or the pharmaceutically acceptable salt thereof is shown as the formula (I)

Description

Beta-carboline compounds and application thereof in preparing medicines for treating or preventing tumor diseases
Technical Field
The invention belongs to the technical field of pharmacology, and particularly relates to beta-carboline compounds and application thereof in preparing medicines for treating or preventing tumor diseases.
Background
The development direction of anticancer drugs has different angles, and the development of small molecule anticancer drugs still dominates. The search for novel small-molecule antitumor drugs with high selectivity, high efficiency and low toxicity, particularly small molecules with better curative effect on tumor variants with more serious drug resistance, remains a problem to be solved urgently at present.
Beta-carboline is a very important alkaloid, widely exists in nature, beta-carboline alkaloids with various structures and biological activities are separated successively since the first beta-carboline alkaloid is separated in 1841, and medicinal value research on natural products is a hot spot of related field research. In particular, studies have been conducted in recent years to find that many β -carboline alkaloids have significant anti-tumor, anti-Alzheimer, anti-infectious, and anti-Plasmodium activities (Eur.J. Med.chem.2022,229,114057; molecules 2021,26,663, eur.J. Med.chem.2021,224,113688, mini-Rev.Med.chem.2021,21,398, eur.J. Med.chem.2021,216, 113321. However, the natural product has a complex structure and a single source, which limits further research on the pharmaceutical property of the skeleton compound to a certain extent.
The invention provides a method for synthesizing chiral compounds by applying chirality
Figure BDA0003809834990000013
A series of C1-site chiral aminoalkyl substituted beta-carboline compounds with high optical purity and novel structures are constructed by an acid and visible light catalysis concerted catalysis system. And researches find that some compounds show obvious inhibition activity in cell proliferation experiments of human non-small cell lung cancer A549 and PC9, and the inhibition activity of individual compounds is equivalent to that of a positive control medicament cisplatin. In addition, the compound shows obvious inhibitory activity in cell proliferation experiments of human leukemia cells HL60, human leukemia cells K562 and human lymphoma cells Raji.
Disclosure of Invention
In view of the defects in the prior art, the present invention aims to design and provide a β -carboline compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and an application thereof in preparing a medicament for preventing and/or treating various cancers, including but not limited to lung cancer, leukemia, lymphoma and other cancers.
In order to achieve the purpose, the invention adopts the following technical scheme:
on one hand, the invention provides a beta-carboline compound, or an isomer, a solvate or a precursor thereof, or a pharmaceutically acceptable salt thereof, which is characterized in that the structural formula of the beta-carboline compound is shown as the formula (I)
Figure BDA0003809834990000011
Wherein the content of the first and second substances,
R 1 is composed of
Figure BDA0003809834990000012
Preferably, wherein R is 1a Is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, vinyl, ethynyl, alkyloxyacyl, aryloxyoyl, alkylaminoacyl, cyano, carboxyl, alkylacyl, arylacyl, heterocyclyl, aryl, or heteroaryl;
R 2a ，R 3a independently H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkanoyl, cycloalkylacyl, alkyloxyacyl, arylalkyloxyacyl, alkylaminoacyl, arylacyl, or arylalkyl;
R 4a ，R 5a independently H, halogen, cyano, hydroxy, carboxy, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkyloxy, aryl, heteroaryl, alkylamino, alkylacyloxy, arylalkyloxy, arylacyloxy or heterocyclyl;
m, n are independently 0, 1,2 or 3;
x is O, S, CH 2 SO or SO 2 ；
R 2 Is H, alkyloxyformyl, aryloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, aryl, heteroaryl or heterocyclyl;
R 3 is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, aryl or heteroaryl;
R 4 is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkyloxy, arylalkyloxy, halogen, hydroxy, aryl, cyano, carboxy, heteroaryl, alkylacyloxy, aryloyloxy, alkylamino, arylamino, heteroarylamino, or heterocyclyl;
R 5 is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, heterocyclyl, alkylacyl, arylacyl, heteroarylacyl, arylalkyl or heteroarylalkyl.
The beta-carboline compounds, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof, wherein the structural formula of the beta-carboline compounds is shown as the formula (II)
Figure BDA0003809834990000021
Wherein R is 2 Is H or alkyloxyacyl;
R 3 is H or C 1-4 An alkyl group;
R 4 is H, C 1-4 Alkyl, alkyloxy, halogen, hydroxy or aryl;
R 5 is H, C 1-4 Alkyl, arylalkyl or alkanoyl.
The beta-carboline compounds, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof, wherein the structural formula of the beta-carboline compounds is shown as a formula (III)
Figure BDA0003809834990000022
Wherein R is 1a Is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, vinyl, ethynyl, alkyloxyacyl, or aryl;
R 2a ，R 3a independently H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkanoyl, cycloalkylacyl, arylacyl, alkyloxyacyl or arylalkyloxyacyl;
R 4a is H, alkylOxy, hydroxy or halogen;
x is O, S, CH 2 SO or SO 2 ；
m and n are independently 0, 1,2 or 3.
The beta-carboline compounds, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof, wherein the structural formula of the beta-carboline compounds is shown as the formula (IV)
Figure BDA0003809834990000031
Wherein R is 1a Is H, halogen, cyano, C 1-4 Alkyl, alkoxy, aryl, alkylacyloxy or arylalkyloxy;
R 2a ，R 3a independently H, C 1-4 Alkyl, alkanoyl, cycloalkylacyl, arylacyl, alkyloxyacyl or arylalkyloxyacyl; r 4a H, alkoxy, hydroxyl and halogen.
The beta-carboline compounds, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof, comprise any one of the following compounds:
Figure BDA0003809834990000032
Figure BDA0003809834990000041
in one aspect, the invention provides an application of the beta-carboline compounds, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof in preparing medicines for treating or preventing tumor diseases. Comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The application, the tumor diseases comprise lung cancer, leukemia and lymphoma.
The beta-carboline compounds, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof can be applied to the inhibition of the proliferation activity of human non-small cell lung cancer A549 and PC9 cells, human leukemia cells HL60, human leukemia cells K562 and human lymphoma cells Raji.
In another aspect, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition includes any one of the above β -carboline compounds, or an isomer, a solvate, or a precursor thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The dosage form of the pharmaceutical composition comprises solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
Term(s) for
Unless otherwise indicated, the definitions of radicals and terms described in the present description and claims, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present invention as defined in the specification.
The term "alkyl" according to the present invention denotes a straight or branched chain saturated monovalent hydrocarbon radical having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Such alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3 '-dimethylbutyl, 2,2' -dimethylbutyl, 1,1 '-dimethylbutyl, 2,2' -dimethylbutyl, 1,1 '-dimethylbutyl, or 1,1' -dimethylbutyl, and the like; preferably, "C 1-4 Alkyl is understood to mean having 1,2, 3,4A straight or branched chain saturated monovalent hydrocarbon group of carbon atoms. Unless otherwise specified, alkyl groups may be unsubstituted or mono-or polysubstituted, preferably one to four are independently selected from the following: halogen (F, cl, br, I), C 2-8 Alkenyl radical, C 2-8 Block base, -CF 3 、-℃F 3 、-NO 2 CN, -OH, alkoxy, amino, -COOH, C 3-10 Cycloalkyl radical, C 3-10 A heterocycloalkyl group.
The term "aryl" according to the invention means C 6-14 Monocyclic or polycyclic aromatic radicals, preferably C 6-10 A monocyclic or bicyclic aromatic group, or C 10-14 Polycyclic aromatic groups. Specific examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, and biphenyl, among others. Aryl also means C 10-14 Bicyclic and tricyclic carbocycles, wherein one ring is aromatic and the other ring is saturated, partially unsaturated or aromatic, such as dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, and the like. Unless otherwise specified, aryl groups may be unsubstituted or mono-or polysubstituted, preferably one to four are independently selected from the following: halogen (F, cl, br or I), C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Block, alkoxy, amino, -CF 3 、-℃F 3 、-NO 2 、-CN、-OH、-℃℃ 1-8 Alkyl, -COOH, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl.
The term "heteroaryl" as used herein refers to a monocyclic or polycyclic ring system (e.g., bicyclic) containing one to three aromatic rings and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur in the aromatic rings. Heteroaryl also refers to 10-14 membered bicyclic and tricyclic rings, wherein one ring is aromatic and the other ring is saturated, partially unsaturated, or aromatic. Heteroaryl specifically includes, but is not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenylThiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridinyl. Unless otherwise specified, heteroaryl groups may be unsubstituted or mono-or polysubstituted, preferably 1 to 4 or 1 or 2 substituents. The above substituents are independently selected from the following groups: halogen (F, cl, br or I), C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Block, alkoxy, amino, -CF 3 、-℃F 3 、-NO 2 、-CN、-OH、-℃℃ 1-8 Alkyl, -COOH, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl.
The term "heterocyclyl" as used herein means a saturated or partially saturated monovalent monocyclic, fused, spiro or bridged ring containing 1 to 5, preferably 1 to 3 heteroatoms selected from N, O, B and S. In particular, the heterocyclic group may include, but is not limited to: 3-membered rings such as cyclopropyl, aziridinyl; 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 1,3,2-dioxaboropentyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridinyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, such as, but not limited to, a5,5 membered ring, or a5,6 membered bicyclic ring. The nitrogen atom containing ring may be partially unsaturated, i.e. it may contain one or more double bonds, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
The term "C 3-6 Cycloalkyl "means a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.
The term "alkanoyl" refers to "alkyl- (CO) -".
The term "alkyloxyacyl" refers to "alkyl-O- (CO) -".
The term "cycloalkylacyl" refers to "cycloalkyl- (CO) -".
The term "aryloxyacyl" refers to "aryl-O- (CO) -".
The term "arylalkyloxyacyl" refers to "aryl-alkyl-O- (CO) -".
The term "arylacyl" refers to "aryl- (CO) -".
The term "heteroarylacyl" refers to "heteroaryl- (CO) -".
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is predisposed to the disease condition but has not yet been diagnosed as having it;
(ii) Inhibiting the disease or disease state and arresting its development;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "adjuvant" according to the invention means a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or cohesiveness. Typical examples of "pharmaceutically acceptable carriers" suitable for use in the above formulations are sugars, starches, cellulose and its derivatives and like excipients commonly used in pharmaceutical formulations.
The term "pharmaceutically acceptable adjuvants" according to the invention means those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The term "isomer" according to the present invention includes: geometric isomers, enantiomers, diastereomers (e.g., cis-trans isomers, conformers, atropisomers).
The term "solvate" according to the present invention denotes a compound carrying a solvent molecule, which solvate may be a hydrate, for example.
The term "precursor" of the present invention refers to a precursor of the compound which, when administered by a suitable method, undergoes a metabolic or chemical reaction in the patient to convert it to a compound of formula (I), or a salt or solution of a compound of formula (I).
The term "pharmaceutically acceptable salts" according to the present invention refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases. These salts include (but are not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) Salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, or arginine. Other salts include those formed with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium.
The present invention also includes isomers, solvates, precursors of the compounds of formula (I) above, or pharmaceutically acceptable salts thereof, as long as they also have the same or substantially the same function as the compounds of formula (I). The compounds have one or more asymmetric centers. Thus, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.
It will be appreciated by those skilled in the art that, having knowledge of the structure of the compounds of the invention, the compounds of the invention may be obtained commercially or by a variety of methods known in the art using well known starting materials, such as those described with reference to the examples herein. These methods may be included in the present invention.
Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compounds with solid adjuvants, optionally grinding the resulting mixture, if desired with other suitable adjuvants, and processing the mixture into granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweetening or flavoring agents, and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required for the same. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a beta carboline compound with anti-tumor activity or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the beta carboline compound or the pharmaceutically acceptable salt thereof and application of the beta carboline compound or the pharmaceutically acceptable salt thereof in preparation of drugs for preventing and/or treating different cancers. The compound has obvious proliferation inhibiting activity on human non-small cell lung cancer A549 and PC9 cells. The compound shows obvious inhibitory activity in cell proliferation experiments of human leukemia cells HL60, human leukemia cells K562 and human lymphoma cells Raji.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions suggested by the manufacturer. The skilled person can prepare these compounds by similar methods or by combining other methods known to the skilled person. It is also understood that one skilled in the art should be able to prepare other structural compounds not specifically exemplified in a similar manner as described below by using the appropriate starting components and modifying the synthesis parameters as needed. In general, starting components and associated chemicals are available from commercial sources such as Sigma Aldrich, lancaster Synthesis Inc, acros Organics, or synthesized according to sources known to those skilled in the art (see, e.g., advanced Organic Chemistry: reactions, mechanics and Structure, 5 th edition, wiley, 12 months 2000), or prepared as described herein.
Example 1: (R) -N- (1- (9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 1)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000071
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added via syringe and the mixture was heated to argonPrecooling for 1 hour under air atmosphere at-40 ℃ in the dark, followed by reaction under irradiation with 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitoring by TLC until the conversion of the starting material is complete, stirring with silica gel, and column chromatography (petroleum ether: acetone = 3:1) to give compound 1, 43.6mg, white solid, 86% yield, 94% ee, racemic product prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:220-222℃；
1 H NMR(400MHz,DMSO)δ11.62(s,1H),8.48(d,J＝7.8Hz,1H),8.30(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.02(d,J＝5.3Hz,1H),7.61(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.24(t,J＝7.4Hz,1H),5.62(p,J＝7.0Hz,1H),1.89(s,3H),1.48(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO)δ168.9,146.0,140.5,137.2,132.5,128.1,128.0,121.7,120.9,119.4,113.7,112.1,45.9,22.7,20.5；
FTIR(ν max ,cm -1 ):3172,2979,1649,1626,1566,1505,1430,1377,1313,1287,1238,1165,1149,746,737,624,587；
HRMS(ESI-TOF)m/z:calcd for C 15 H 16 N 3 O + [M+H] + ,254.1288；found,254.1285；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.17min,t r (minor)＝4.22min；
[α] D 20 ＝66.1(c＝0.3,CHCl 3 ).
Example 2: (R) -N- (1- (6-phenyl-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 2)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000081
to a 10mL Schlenk reaction tube was added 6-phenyl-9H-pyrido [3,4-b]Indole (2-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 2, 50.7mg,77% yield, 93% ee, racemic product prepared in the same way, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:176-178℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.68(s,1H),8.56(d,J＝1.9Hz,1H),8.49(d,J＝7.8Hz,1H),8.33(d,J＝5.2Hz,1H),8.12(d,J＝5.3Hz,1H),7.87(dd,J＝8.6,1.9Hz,1H),7.78(dt,J＝6.3,1.3Hz,2H),7.69(d,J＝8.5Hz,1H),7.49(t,J＝7.8Hz,2H),7.40–7.30(m,1H),5.63(p,J＝6.9Hz,1H),1.90(s,3H),1.50(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,146.2,140.8,140.0,137.4,133.0,131.8,128.9,128.2,127.2,126.7,126.7,121.6,119.7,113.9,112.5,45.9,22.7,20.5；
FTIR(ν max ,cm -1 ):3220,3177,2988,2906,2384,2347,1650,1558,1493,1375,1239,1062,813,748,700,598；
HRMS(ESI-TOF)m/z:calcd for C 21 H 20 N 3 O + [M+H] + ,330.1601；found,330.1595；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝5.31min,t r (minor)＝7.44min；
[α] D 20 ＝64.9(c＝0.3,CHCl 3 ).
Example 3: (R) -N- (1- (6-methyl-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 3)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000082
to a 10mL Schlenk reaction tube was added 6-methyl-9H-pyrido [3,4-b]Indole (3-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 3, 43.8mg,82% yield, 94% ee, racemic product, prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:177-179℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.45(s,1H),8.44(d,J＝7.8Hz,1H),8.27(d,J＝5.2Hz,1H),7.99(s,1H),7.96(d,J＝5.2Hz,1H),7.50(d,J＝8.3Hz,1H),7.43–7.28(m,1H),5.60(p,J＝7.0Hz,1H),2.47(s,3H),1.89(s,3H),1.48(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.8,145.9,138.8,137.0,132.7,129.6,128.1,127.7,121.1,121.0,113.6,111.8,45.9,22.7,21.0,20.5；
FTIR(ν max ,cm -1 ):3157,2983,2923,2858,2378,1658,1560,1508,1448,1371,1296,1242,1152,1059,793,620,564；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O + [M+H] + ,268.1444；found,268.1441；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝7.14min,t r (minor)＝3.54min；
[α] D 20 ＝41.4(c＝0.3,CHCl 3 ).
Example 4: (R) -N- (1- (8-methyl-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 4)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000091
to a 10mL Schlenk reaction tube was added sequentially 8-methyl-9H-pyrido [3,4-b]Indole (4-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 4, 40.1mg,73% yield, 94% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:230-232℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.26(s,1H),8.51(d,J＝8.0Hz,1H),8.29(d,J＝5.2Hz,1H),8.03(d,J＝7.9Hz,1H),7.99(d,J＝5.2Hz,1H),7.34(d,J＝7.1Hz,1H),7.15(t,J＝7.5Hz,1H),5.78(p,J＝6.9Hz,1H),2.62(s,3H),1.91(s,3H),1.49(d,J＝6.7Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,146.2,139.8,137.3,132.6,128.5,128.4,121.4,120.6,119.6,119.0,113.7,45.8,22.7,20.5,17.2；
FTIR(ν max ,cm -1 ):3380,3270,2919,2382,1653,1542,1433,1372,1288,1232,1029,992,820,765,559；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O + [M+H] + ,268.1444；found,268.1440；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝5.63min,t r (minor)＝3.10min；
[α] D 20 ＝64.4(c＝0.3,CHCl 3 ).
Example 5: (R) -N- (1- (5-methyl-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 5)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000092
to a 10mL Schlenk reaction tube was added 5-methyl-9H-pyrido [3,4-b]Indole (5-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 5, 43.3mg,81% yield, 95% ee, and the racemate was prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:192-194℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.66(s,1H),8.51(d,J＝7.8Hz,1H),8.30(d,J＝5.3Hz,1H),7.97(d,J＝5.5Hz,1H),7.43(d,J＝7.3Hz,2H),7.02(d,J＝6.4Hz,1H),5.74–5.50(m,1H),2.80(s,3H),1.89(s,3H),1.47(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,145.8,140.6,137.3,133.9,132.4,128.1,127.9,120.6,119.7,115.4,109.6,45.9,22.7,20.6,20.2；
FTIR(ν max ,cm -1 ):2974,2828,2382,2148,1701,1648,1541,1500,1473,1457,1238,1089,1048,738,639,540；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O + [M+H] + ,268.1444；found,268.1440；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.35min,t r (minor)＝4.76min；
[α] D 20 ＝55.2(c＝0.3,CHCl 3 ).
Example 6: (R) -N- (1- (4-methyl-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 6)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000101
to a 10mL Schlenk reaction tube was added 4-methyl-9H-pyrido [3,4-b]Indole (6-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 6, 40.6mg,76% yield, 94% ee, racemic product was prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:219-221℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),8.43(d,J＝7.8Hz,1H),8.19(d,J＝7.9Hz,1H),8.10(d,J＝1.0Hz,1H),7.68–7.59(m,1H),7.54(ddd,J＝8.3,7.0,1.2Hz,1H),7.25(ddd,J＝8.0,7.0,1.1Hz,1H),5.59(p,J＝6.9Hz,1H),2.76(d,J＝0.7Hz,3H),1.88(s,3H),1.47(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.8,143.8,140.4,137.6,132.0,127.4,126.6,125.3,123.1,121.4,119.4,111.9,45.6,22.7,20.5,16.8；
FTIR(ν max ,cm -1 ):3298,3155,2920,2879,2384,2337,1653,1459,1273,1108,731,520；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O + [M+H] + ,268.1444；found,268.1440；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.95min,t r (minor)＝3.18min；
[α] D 20 ＝40.3(c＝0.3,CHCl 3 ).
Example 7: (R) -N- (1- (6-methoxy-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 7)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000102
to a 10mL Schlenk reaction tube was added 6-methoxy-9H-pyrido [3,4-b]Indole (7-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 7, 40.8mg,72% yield, 96% ee, racemic product, prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:175-177℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.40(s,1H),8.44(d,J＝7.8Hz,1H),8.26(d,J＝5.3Hz,1H),7.99(d,J＝5.3Hz,1H),7.76(d,J＝2.5Hz,1H),7.52(d,J＝8.9Hz,1H),7.19(dd,J＝8.8,2.5Hz,1H),5.60(p,J＝7.0Hz,1H),3.86(s,3H),1.90(s,3H),1.48(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.8,153.4,146.0,136.6,135.3,133.1,127.8,121.2,118.1,113.7,112.9,103.4,55.6,45.9,22.7,20.4；
FTIR(ν max ,cm -1 ):3228,3179,2925,2850,2384,1641,1558,1500,1437,1377,1287,1290,1210,1157,1024,804,625,557；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O 2 + [M+H] + ,284.1394；found,284.1390；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝4.02min,t r (minor)＝5.55min；
[α] D 20 ＝51.7(c＝0.3,CHCl 3 ).
Example 8: (R) -N- (1- (6-hydroxy-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 8)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000111
to a 10mL Schlenk reaction tube was added 6-hydroxy-9H-pyrido [3,4-b]Indole (8-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 8, 33.9mg,63% yield, 97% ee, and the racemate was prepared in the same manner as the corresponding phosphoric acid catalyst using racemic phosphoric acid.
Mp:259-261℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.28(s,1H),9.17(s,1H),8.46(d,J＝7.8Hz,1H),8.21(d,J＝5.2Hz,1H),7.90(d,J＝5.2Hz,1H),7.48(d,J＝2.3Hz,1H),7.42(d,J＝8.7Hz,1H),7.06(dd,J＝8.7,2.4Hz,1H),5.56(p,J＝6.9Hz,1H),1.88(s,3H),1.45(d,J＝6.9Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,150.9,145.9,136.4,134.6,133.1,127.6,121.6,118.2,113.7,112.6,105.6,45.9,22.7,20.5；
FTIR(ν max ,cm -1 ):2925,2855,2381,1737,1645,1464,1375,1268,1025,820,759,723；
HRMS(ESI-TOF)m/z:calcd for C 15 H 16 N 3 O 2 + [M+H] + ,270.1237；found,270.1233；
HPLC analysis:Chiral NY(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,0.5mL/min,25℃,254nm),t r (major)＝6.77min,t r (minor)＝8.94min；
[α] D 20 ＝9.3(c＝0.3,CHCl 3 ).
Example 9: (R) -N- (1- (8-bromo-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 9)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000112
to a 10mL Schlenk reaction tube was added sequentially 8-bromo-9H-pyrido [3,4-b]Indole (9-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 9, 51.2mg,77% yield, 96% ee, racemic product, prepared in the same manner, using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:221-223℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.45(s,1H),8.58(d,J＝8.1Hz,1H),8.36(d,J＝5.3Hz,1H),8.25(d,J＝7.8Hz,1H),8.05(d,J＝5.2Hz,1H),7.77(d,J＝7.6Hz,1H),7.20(t,J＝7.8Hz,1H),5.92–5.72(m,1H),1.90(s,3H),1.53(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.5,146.9,138.8,138.1,132.9,130.6,128.4,122.9,121.1,120.9,114.1,104.5,45.7,22.6,19.6；
FTIR(ν max ,cm -1 ):3208,3157,2983,2903,2383,2339,1650,1542,1492,1426,1370,1320,1283,1133,835,769,675,600；
HRMS(ESI-TOF)m/z:calcd for C 15 H 15 BrN 3 O + [M+H] + ,332.0393；found,332.0388；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.92min,t r (minor)＝3.27min；
[α] D 20 ＝87.1(c＝0.3,CHCl 3 ).
Example 10: (R) -N- (1- (6-bromo-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 10)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000121
to a 10mL Schlenk reaction tube was added 6-bromo-9H-pyrido [3,4-b]Indole (10-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 10, 51.8mg,78% yield, 90% ee, racemic product prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:188-190℃；
[ 1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),8.47(d,J＝2.0Hz,1H),8.40(d,J＝7.7Hz,1H),8.32(d,J＝5.3Hz,1H),8.06(d,J＝5.2Hz,1H),7.65(dd,J＝8.7,2.0Hz,1H),7.58(d,J＝8.7Hz,1H),5.60(p,J＝7.0Hz,1H),1.89(s,3H),1.49(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.8,146.3,139.1,137.5,132.8,130.4,126.9,124.1,122.8,114.0,113.9,111.2,45.9,22.6,20.2；
FTIR(ν max ,cm -1 ):3218,3165,2979,2850,1653,1556,1495,1375,1275,1239,1070,818,801,610,582；
HRMS(ESI-TOF)m/z:calcd for C 15 H 15 BrN 3 O + [M+H] + ,332.0393；found,332.0390；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝2.95min,t r (minor)＝3.74min；
[α] D 20 ＝43.4(c＝0.3,CHCl 3 ).
Example 11: (R) -N- (1- (7-bromo-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 11)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000122
to a 10mL Schlenk reaction tube was added 7-bromo-9H-pyrido [3,4-b]Indole (11-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 11, 53.2mg,80% yield, 87% ee, racemic product, prepared in the same way, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:245-247℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.46(d,J＝7.8Hz,1H),8.33(d,J＝5.2Hz,1H),8.18(d,J＝8.4Hz,1H),8.03(d,J＝5.3Hz,1H),7.78(d,J＝1.7Hz,1H),7.38(dd,J＝8.4,1.8Hz,1H),5.59(p,J＝6.9Hz,1H),1.88(s,3H),1.48(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,146.3,141.3,137.9,132.7,127.5,123.5,122.4,120.8,120.1,114.6,113.7,45.9,22.6,20.4；
FTIR(ν max ,cm -1 ):3202,2988,2974,2901,2382,2342,1648,1623,1560,1542,1421,1375,1314,1245,1078,1048,841,790,640,583；
HRMS(ESI-TOF)m/z:calcd for C 15 H 15 BrN 3 O + [M+H] + ,332.0393；found,332.0388；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝17.92min,t r (minor)＝21.33min；
[α] D 20 ＝-65.3(c＝0.3,CHCl 3 ).
Example 12: (R) -N- (1- (6-chloro-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 12)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000131
to a 10mL Schlenk reaction tube was added 6-chloro-9H-pyrido [3,4-b]Indole (12-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetoalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 12, 50.0mg,87% yield, 86% ee, racemic product, which was prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:202-204℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.78(s,1H),8.47(d,J＝7.7Hz,1H),8.33(dd,J＝10.2,3.7Hz,2H),8.06(d,J＝5.2Hz,1H),7.63(d,J＝8.7Hz,1H),7.54(dd,J＝8.6,2.1Hz,1H),5.60(p,J＝7.0Hz,1H),1.89(s,3H),1.48(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,146.5,138.9,137.5,133.1,128.0,127.1,123.6,122.2,121.2,114.0,113.7,45.9,22.6,20.4；
FTIR(ν max ,cm -1 ):3397,3279,2905,2371,2287,2134,1648,1387,1256,1140,1021,985,782,576；
HRMS(ESI-TOF)m/z:calcd for C 15 H 15 ClN 3 O + [M+H] + ,288.0898；found,288.0894；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝14.24min,t r (minor)＝12.17min；
[α] D 20 ＝48.7(c＝0.3,CHCl 3 ).
Example 13: (R) -N- (1- (6-fluoro-9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 13)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000141
to a 10mL Schlenk reaction tube was added 6-fluoro-9H-pyrido [3,4-b]Indole (13-1, 0.20mmol), 1,3-dioxoisoindolin-2-ylacetylalanine (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 13, 45.5mg,84% yield, 91% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp 206-208℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),8.39(d,J＝7.8Hz,1H),8.30(d,J＝5.3Hz,1H),8.14–7.92(m,2H),7.62(dd,J＝8.9,4.4Hz,1H),7.40(td,J＝9.3,2.6Hz,1H),5.60(p,J＝7.0Hz,1H),1.90(s,3H),1.49(d,J＝6.8Hz,3H).
13 C NMR(101MHz,DMSO-d 6 )δ168.8,156.5(d,J 1 ＝235.3Hz),146.4,137.0,136.9,133.4,127.6(d,J 4 ＝4.0Hz)121.2(d,J 3 ＝10.1Hz),116.1(J 2 ＝25.2Hz),113.8,113.1(J 3 ＝9.1Hz),106.8(J 2 ＝24.2Hz),45.9,22.6,20.2.
19 F NMR(376MHz,DMSO)δ-123.87；
FTIR(ν max ,cm -1 ):3218,3175,3102,3037,2838,2357,1655,1580,1505,1283,1159,816,620；HRMS(ESI-TOF)m/z:calcd for C 15 H 15 FN 3 O + [M+H] + ,272.1194；found,272.1190；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.22min,t r (minor)＝3.28min；
[α] D 20 ＝59.7(c＝0.3,CHCl 3 ).
Example 14: (R) -N- (1- (6-methoxy-9H-pyrido [3,4-b ] indol-1-yl) -2-phenylethyl) acetamide (Compound 14)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000142
to a 10mL Schlenk reaction tube was added 6-methoxy-9H-pyrido [3,4-b]Indole (7-1, 0.20mmol), 1,3-dioxoisoindol-2-ylacetoalaninate (14-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (lambda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone =)3:1) to give compound 14, 59.7mg,83% yield, 92% percent by weight ee, the racemic product was prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:189-191℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.40(s,1H),8.55(d,J＝8.4Hz,1H),8.28(d,J＝5.3Hz,1H),8.00(d,J＝5.3Hz,1H),7.75(d,J＝2.5Hz,1H),7.52(d,J＝8.8Hz,1H),7.26(d,J＝7.4Hz,2H),7.19(dt,J＝8.9,6.4Hz,3H),7.12(t,J＝7.2Hz,1H),5.77(td,J＝8.5,5.7Hz,1H),3.85(s,3H),3.19(qd,J＝13.7,7.3Hz,2H),1.79(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,153.3,145.1,138.5,136.7,135.4,133.6,129.4,127.8,126.0,121.1,118.2,113.8,112.9,103.4,55.6,51.2,38.8,22.5.；
FTIR(ν max ,cm -1 ):3211,3177,3032,2991,2382,1655,1575,1498,1377,1290,1210,1171,1031,813,731,620；
HRMS(ESI-TOF)m/z:calcd for C 22 H 22 N 3 O 2 +[M+H] + ,360.1707；found,360.1701；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝8.84min,t r (minor)＝10.74min；
[α] D 20 ＝40.1(c＝0.3,CHCl 3 ).
Example 15: (R) -N- (1- (6-hydroxy-9H-pyrido [3,4-b ] indol-1-yl) -2-phenylethyl) acetamide (Compound 15)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000151
to a 10mL Schlenk reaction tube was added 6-hydroxy-9H-pyrido [3,4-b]Indole (8-1, 0.20mmol), 1,3-dioxoisoindol-2-ylacetoalaninate (14-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, and ultra-dry THF was added via syringe(4.0 mL) and precooled in the refrigerator under argon atmosphere at-40 ℃ for 1 hour in the dark, followed by reaction under irradiation with 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until conversion of the starting material is complete, stirred on silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 15, 60.1mg,87% yield, 82% ee, racemic product prepared in the same manner, the corresponding phosphoric acid catalyst using racemic phosphoric acid.
Mp:251-252℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.23(s,1H),9.12(s,1H),8.51(d,J＝8.5Hz,1H),8.24(d,J＝5.2Hz,1H),7.90(d,J＝5.2Hz,1H),7.48(d,J＝2.4Hz,1H),7.43(d,J＝8.7Hz,1H),7.26(d,J＝7.0Hz,2H),7.20(t,J＝7.5Hz,2H),7.12(t,J＝7.1Hz,1H),7.06(dd,J＝8.7,2.4Hz,1H),5.76(td,J＝8.7,5.8Hz,1H),3.29–3.09(m,2H),1.79(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,150.9,144.9,138.5,136.5,134.6,133.6,129.5,127.9,127.7,126.1,121.5,118.2,113.8,112.6,105.5,51.2,22.6；
FTIR(ν max ,cm -1 ):3385,3289,2382,1984,1650,1570,1495,1379,1239,1208,1024,992,820,648,582；
HRMS(ESI-TOF)m/z:calcd for C 21 H 20 N 3 O 2 + [M+H] + ,346.1550；found,346.1545；
HPLC analysis:Chiral NQ(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,0.5mL/min,25℃,254nm),t r (major)＝27.47min,t r (minor)＝9.96min；
[α] D 20 ＝14.8(c＝0.3,CHCl 3 ).
Example 16: (R) -N- (1- (6-bromo-9H-pyrido [3,4-b ] indol-1-yl) -2-phenylethyl) acetamide (compound 16)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000152
to a 10mL Schlenk reaction tube was added 6-bromo-9H-pyrido [3,4-b]Indole (1)0-1,0.20mmol), 1,3-dioxyisoindol-2-yl-acetyl-phenylalanine ester (14-2,0.30mmol), ir [ dF (CF (F) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 16, 60.1mg,87% yield, 82% ee, racemic product prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:212-214℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.78(s,1H),8.58(d,J＝8.3Hz,1H),8.53–8.42(m,1H),8.35(d,J＝5.3Hz,1H),8.07(d,J＝5.2Hz,1H),7.74–7.61(m,1H),7.57(d,J＝8.7Hz,1H),7.25(d,J＝7.5Hz,2H),7.19(t,J＝7.4Hz,2H),7.11(t,J＝7.2Hz,1H),5.78(q,J＝8.0Hz,1H),3.19(q,J＝8.3Hz,2H),1.78(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,145.5,139.2,138.3,137.7,133.4,130.5,129.4,127.9,127.0,126.1,124.3,122.7,114.1,111.2,51.2,39.6,22.5.；
FTIR(ν max ,cm -1 ):3165,3035,2984,2387,1651,1539,1488,1273,1232,1072,823,804,741,698,603；
HRMS(ESI-TOF)m/z:calcd for C 21 H 19 BrN 3 O + [M+H] + ,408.0706；found,408.0702；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝5.59min,t r (minor)＝7.34min；
[α] D 20 ＝32.7(c＝0.3,CHCl 3 ).
Example 17: (R) -N- (1- (7-bromo-9H-pyrido [3,4-b ] indol-1-yl) -2-phenylethyl) acetamide (Compound 17)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000161
to a 10mL Schlenk reaction tube was added 7-bromo-9H-pyrido [3,4-b]Indole (11-1, 0.20mmol), 1,3-dioxoisoindol-2-ylacetoalaninate (14-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 17, 63.7mg,78% yield, 88% ee, racemic product, prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:245-247℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.61(d,J＝8.3Hz,1H),8.36(d,J＝4.9Hz,1H),8.18(d,J＝8.3Hz,1H),8.04(d,J＝5.2Hz,1H),7.77(s,1H),7.37(d,J＝8.1Hz,1H),7.32–7.15(m,4H),7.11(d,J＝7.2Hz,1H),5.77(q,J＝7.7Hz,1H),3.19(q,J＝7.7Hz,2H),1.79(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,145.4,141.3,138.3,138.0,133.2,129.4,127.9,127.5,126.1,123.6,122.3,120.9,120.0,114.6,113.9,51.2,22.5；
FTIR(ν max ,cm -1 ):3223,3166,3022,2853,2359,1648,1624,1588,1541,1495,1312,1232,1048,920,845,794,716,574；
HRMS(ESI-TOF)m/z:calcd for C 21 H 19 BrN 3 O + [M+H] + ,408.0706；found,408.0704；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝5.48min,t r (minor)＝7.41min；
[α] D 20 ＝15.0(c＝0.3,CHCl 3 ).
Example 18 (R) -N- (2-phenyl-1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) carboxamide (Compound 18)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000162
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindol-2-ylcarboxylanilide ester (18-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 18, 49.2mg,78% yield, 50% ee, racemic product prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:217-219℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),8.80(d,J＝8.5Hz,1H),8.33(d,J＝5.2Hz,1H),8.22(d,J＝8.0Hz,1H),8.04(d,J＝5.2Hz,1H),8.00(s,1H),7.62(d,J＝8.3Hz,1H),7.55(t,J＝7.6Hz,1H),7.29–7.16(m,5H),7.12(t,J＝7.0Hz,1H),5.92(td,J＝8.7,5.7Hz,1H),3.19(qd,J＝13.7,7.2Hz,2H)； 1
3 C NMR(101MHz,DMSO-d 6 )δ160.7,144.3,140.6,138.0,137.4,132.9,129.5,128.2,128.1,127.9,126.2,121.7,120.8,119.4,113.9,112.0,49.8；
FTIR(ν max ,cm -1 ):3165,2986,2872,2359,1655,1544,1505,482,1454,1375,1237,1050,823,779,731,700,571；
HRMS(ESI-TOF)m/z:calcd for C 20 H 18 N 3 O + [M+H] + ,316.1444；found,316.1441；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝85:15,0.5mL/min,25℃,254nm),t r (major)＝10.19min,t r (minor)＝15.67min；
[α] D 20 ＝7.5(c＝0.3,CHCl 3 ).
Example 19: (R) -N- (1- (9H-pyrido [3,4-b ] indol-1-yl) propyl) acetamide (Compound 19)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000171
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindolin-2-yl 2-acetamidobutyrate (19-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 19, 43.3mg,81% yield, 90% ee, racemic product, prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:218-220℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.64(s,1H),8.40(d,J＝8.2Hz,1H),8.31(d,J＝5.2Hz,1H),8.21(d,J＝7.8Hz,1H),8.00(d,J＝5.2Hz,1H),7.61(d,J＝8.2Hz,1H),7.58–7.48(m,1H),7.23(t,J＝7.4Hz,1H),5.49(q,J＝7.5Hz,1H),1.99–1.78(m,2H),1.90(s,3H),0.86(t,J＝7.3Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,145.5,140.5,137.3,133.1,128.1,127.8,121.7,120.9,119.3,113.5,112.0,51.3,27.5,22.6,10.5；
FTIR(ν max ,cm -1 ):3649,3175,2993,2899,2357,2345,1655,1539,1503,1459,1314,1239,1058,874,738,564；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O + [M+H] + ,268.1444；found,268.1441；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝2.76min,t r (minor)＝3.81min；
[α] D 20 ＝-41.7(c＝0.3,CHCl 3 ).
Example 20: (R) -N- (1- (9H-pyrido [3,4-b ] indol-1-yl) butyl) acetamide (Compound 20)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000172
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindolin-2-yl 2-acetylaminovalerate (20-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 20, 41.1mg,73% yield, 87% ee, racemic product, prepared in the same way, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:182-184℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),8.40(d,J＝8.2Hz,1H),8.30(d,J＝5.2Hz,1H),8.20(d,J＝7.9Hz,1H),8.00(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.23(t,J＝7.4Hz,1H),5.55(q,J＝7.5Hz,1H),1.92–1.78(m,2H),1.88,(s,3H),1.46–1.31(m,1H),1.30–1.16(m,1H),0.85(t,J＝7.4Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,145.7,140.5,137.4,133.0,128.0,127.8,121.6,120.9,119.3,113.5,112.0,49.9,36.6,22.6,18.9,13.9；
FTIR(ν max ,cm -1 ):3654,3228,3160,2988,2911,2382,2342,1701,1650,1638,1544,1505,1457,1398,1237,1075,1053,874,738,622；
HRMS(ESI-TOF)m/z:calcd for C 17 H 20 N 3 O + [M+H] + ,282.1601；found,282.1598；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝4.03min,t r (minor)＝3.00min；
Example 21: (R) -N- (1- (9H-pyrido [3,4-b ] indol-1-yl) pentyl) acetamide (Compound 21)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000181
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindolin-2-yl 2-acetamidohexanoate (21-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 21, 50.2mg,85% yield, 97% ee, racemic product, prepared in the same way, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:183-185℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.59(s,1H),8.39(d,J＝8.2Hz,1H),8.30(d,J＝5.2Hz,1H),8.21(d,J＝7.8Hz,1H),7.99(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.54(ddd,J＝8.2,7.0,1.2Hz,1H),7.23(ddd,J＝8.0,7.0,1.0Hz,1H),5.61–5.45(m,1H),1.90–1.83(m,2H),1.88(s,3H),1.38–1.12(m,4H),0.80(t,J＝7.0Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,145.7,140.5,137.4,133.0,128.0,127.8,121.6,FTIR(ν max ,cm -1 ):3218,3090,2930,2879,2392,2323,1652,1627,1554,1505,1432,1370,1321,1243,1071,821,738,626,577；
HRMS(ESI-TOF)m/z:calcd for C 18 H 22 N 3 O + [M+H] + ,296.1757；found,296.1754；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.72min,t r (minor)＝2.88min；
[α] D 20 ＝53.3(c＝0.3,CHCl 3 ).
Example 22: (R) -N- (1- (9H-pyrido [3,4-b ] indol-1-yl) heptyl) acetamide (Compound 22)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000182
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindolin-2-yl 2-acetamidooctanoate (22-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 22, 51.7mg,80% yield, 89% ee, racemic product was prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:136-138℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.59(s,1H),8.39(d,J＝8.2Hz,1H),8.30(d,J＝5.2Hz,1H),8.20(d,J＝7.9Hz,1H),7.99(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.23(t,J＝7.4Hz,1H),5.53(q,J＝7.5Hz,1H),1.92–1.81(m,2H),1.88(s,3H),1.43–1.28(m,1H),1.28–1.11(m,7H),0.79(t,J＝6.7Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,145.7,140.5,137.3,133.0,128.0,127.8,121.6,120.9,119.2,113.4,112.0,50.1,34.4,31.2,28.6,25.5,22.6,22.0,13.9；
FTIR(ν max ,cm -1 ):3223,3012,2920,2855,2384,2325,2180,2141,1972,1718,1650,1561,1459,1377,1239,1055,818,733,627,569；
HRMS(ESI-TOF)m/z:calcd for C 20 H 26 N 3 O + [M+H] + ,324.2070；found,324.2067；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.71min,t r (minor)＝2.53min；
[α] D 20 ＝46.4(c＝0.3,CHCl 3 ).
Example 23: (R) -N- (3-methyl-1- (9H-pyridinyl [3,4-b ] indol-1-yl) butyl) acetamide (Compound 23)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000191
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl acetyl leucine ester (23-2, 0.30mmol), ir [ dF (CF (R)) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 23, 43.7mg,74% yield, 72% ee, and the racemate was prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:199-201℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.49(s,1H),8.41(d,J＝8.3Hz,1H),8.30(d,J＝5.2Hz,1H),8.20(d,J＝7.9Hz,1H),7.99(d,J＝5.2Hz,1H),7.64(d,J＝8.2Hz,1H),7.54(ddd,J＝8.2,7.0,1.2Hz,1H),7.29–7.16(m,1H),5.58(td,J＝8.5,6.2Hz,1H),1.90–1.83(m,1H),1.86(s,3H),1.81–1.68(m,1H),1.58(hept,J＝6.6Hz,1H),0.90(dd,J＝6.6,2.8Hz,6H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,146.0,140.5,137.5,133.0,128.1,128.0,121.6,120.9,119.3,113.5,112.1,48.5,42.8,24.6,23.0,22.6,22.3；
FTIR(ν max ,cm -1 ):3218,3175,2981,2923,2382,1648,1560,1542,1504,1428,1375,1320,1242,1128,1055,823,742,705,654,601,566；
HRMS(ESI-TOF)m/z:calcd for C 18 H 22 N 3 O + [M+H] + ,296.1757；found,296.1754；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝4.19min,t r (minor)＝3.14min；
[α] D 20 ＝51.1(c＝0.3,CHCl 3 ).
Example 24: (R) -N- (2-cyclohexyl-1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 24)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000201
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisooctanol-2-yl 2-acetamide-3-cyclohexylpropionate (24-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), replacing argon 3 times, adding extra dry THF (4.0 mL) with syringe and under argon atmosphere, precooling for 1 hour at-40 ℃ in the dark, then reacting for 72 hours under 3W blue light (lambda =455-465 nm) irradiation, monitoring by TLC until the conversion of the starting material is complete, stirring with silica gel, column chromatography (petroleum ether: acetone = 3:1) to give compound 24, 56.3mg,84% yield, 78% ee, racemic product prepared according to the same method, the corresponding phosphoric acid catalyst used is racemic phosphoric acid.
Mp:218-220℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.45(s,1H),8.40(d,J＝8.3Hz,1H),8.29(d,J＝5.2Hz,1H),8.20(d,J＝7.9Hz,1H),7.99(d,J＝5.2Hz,1H),7.63(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.23(t,J＝7.4Hz,1H),5.60(td,J＝8.7,6.1Hz,1H),1.87–1.77(m,2H),1.85(s,3H),1.73(dd,J＝13.4,6.1Hz,2H),1.67–1.51(m,3H),1.31(d,J＝12.6Hz,1H),1.10(d,J＝7.7Hz,3H),0.93(q,J＝10.6Hz,2H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,146.1,140.5,137.4,132.9,128.0,128.0,121.6,120.9,119.3,113.5,112.1,47.8,41.4,33.9,33.2,32.4,26.1,25.8,25.7,22.6；
FTIR(ν max ,cm -1 ):3205,2971,2923,2364,2342,1783,1750,1647,1541,1500,1487,1420,1248,1056,880,735,670,569；
HRMS(ESI-TOF)m/z:calcd for C 21 H 26 N 3 O + [M+H] + ,336.2070；found,336.2065；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.98min,t r (minor)＝2.95min；
[α] D 20 ＝20.8(c＝0.3,CHCl 3 ).
Example 25: (R) -N- (3-phenyl-1- (9H-pyridine [3,4-b ] indol-1-yl) propyl) acetamide (Compound 25)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000202
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-4-phenylbutyrate (25-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon for 1 hour at-40 deg.C in the dark, followed by reaction for 72 hours under 3W blue light (λ =455-465 nm) irradiationTLC was monitored until complete conversion of the starting material, silica gel was sampled and column chromatographed (petroleum ether: acetone = 3:1) to give compound 25, 48.8mg,71% yield, 91% ee, racemic product was prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:184-186℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),8.54(d,J＝8.3Hz,1H),8.32(d,J＝5.2Hz,1H),8.22(d,J＝7.8Hz,1H),8.02(d,J＝5.2Hz,1H),7.63(d,J＝8.2Hz,1H),7.55(ddd,J＝8.2,7.0,1.2Hz,1H),7.29–7.18(m,3H),7.18–7.08(m,3H),5.62(td,J＝8.0,6.0Hz,1H),2.71(ddd,J＝13.6,10.8,5.6Hz,1H),2.56(ddd,J＝13.7,10.9,5.7Hz,1H),2.26–2.09(m,2H),1.92(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.2,145.2,141.7,140.5,137.4,133.0,128.3,128.1,128.0,125.7,121.7,120.9,119.3,113.6,112.0,50.1,36.1,31.9,22.6；
FTIR(ν max ,cm -1 ):3216,3165,2965,2905,2887,2380,2325,2308,2138,1922,1845,1653,1558,15441,1507,1473,1458,1372,1323,1235,1074,737,624；
HRMS(ESI-TOF)m/z:calcd for C 22 H 22 N 3 O + [M+H] + ,344.1757；found,344.1753；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝8.78min,t r (minor)＝7.50min；
[α] D 20 ＝58.0(c＝0.3,CHCl 3 ).
Example 26: (R) -N- (1- (9H-pyridine [3,4-b ] indol-1-yl) -but-3-yn-1-yl) acetamide (Compound 26)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000211
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamidopenta-4-ynoate(26-2，0.30mmol)、Ir[dF(CF 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 26, 45.5mg,82% yield, 96% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:151-153℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.64(s,1H),8.53(d,J＝7.9Hz,1H),8.34(d,J＝5.2Hz,1H),8.22(d,J＝7.9Hz,1H),8.05(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.59–7.45(m,1H),7.24(t,J＝7.4Hz,1H),5.70(q,J＝7.3Hz,1H),2.93–2.77(m,2H),2.67(d,J＝2.6Hz,1H),1.89(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.3,143.3,140.6,137.4,133.3,128.2,128.1,121.7,120.8,119.4,114.0,112.1,81.4,72.5,49.2,23.5,22.6；
FTIR(ν max ,cm -1 ):3332,3305,3225,2974,2908,2384,1750,1699,1648,1508,1241,1070,840,731,685,657,600,554；
HRMS(ESI-TOF)m/z:calcd for C 17 H 16 N 3 O + [M+H] + ,278.1288；found,278.1285；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝11.18min,t r (minor)＝15.21min；
[α] D 20 ＝58.3(c＝0.3,CHCl 3 ).
Example 27: (R) -N- (1- (9H-pyridine [3,4-b ] indol-1-yl) -but-3-en-1-yl) acetamide (Compound 27)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000212
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamidopenta-4-enoate (27-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 27, 40.2mg,72% yield, 94% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:157-159℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.61(s,1H),8.43(d,J＝8.3Hz,1H),8.31(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.01(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.24(t,J＝7.5Hz,1H),5.78(ddt,J＝17.1,10.9,6.9Hz,1H),5.63(q,J＝7.5Hz,1H),5.01(dd,J＝17.2,2.1Hz,1H),4.93(dd,J＝10.3,2.2Hz,1H),2.65(dp,J＝14.0,7.3Hz,2H),1.88(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,144.8,140.5,137.3,134.8,133.0,128.1,127.9,121.6,120.9,119.3,117.3,113.6,112.0,49.6,38.5,22.6；
FTIR(ν max ,cm -1 ):3223,2964,2848,2357,2163,1994,1650,1544,1459,1237,1120,808,741,582；
HRMS(ESI-TOF)m/z:calcd for C 17 H 18 N 3 O + [M+H] + ,280.1444；found,280.1441；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝8.10min,t r (minor)＝11.80min；
[α] D 20 ＝37.1(c＝0.3,CHCl 3 ).
Example 28: (R) -N- (3- (methylthio) -1- (9H-pyridine [3,4-b ] indol-1-yl) propyl) acetamide (Compound 28)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000221
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxo-isoindolin-2-yl-acetyl-methionine (28-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 28, 40.7mg,68% yield, 90% ee, racemic product prepared in the same way, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:198-200℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.57(s,1H),8.49(d,J＝8.2Hz,1H),8.31(d,J＝5.2Hz,1H),8.22(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.63(d,J＝8.1Hz,1H),7.55(t,J＝7.6Hz,1H),7.24(t,J＝7.4Hz,1H),5.62(q,J＝7.4Hz,1H),2.54-2.41(m,2H),2.16(tp,J＝16.4,5.7Hz,2H),2.00(s,3H),1.89(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.2,144.7,140.5,137.3,133.0,128.2,128.0,121.7,120.9,119.4,113.7,112.1,49.5,34.0,29.9,22.6,14.7；
FTIR(ν max ,cm -1 ):3223,3181,3100,3025,2950,2911,2854,2360,2165,2010,1771,1717,1650,1541,1425,1238,821,730,624,556；
HRMS(ESI-TOF)m/z:calcd for C 17 H 20 N 3 OS + [M+H] + ,314.1322；found,314.1317；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝21.48min,t r (minor)＝18.41min；
[α] D 20 ＝25.2(c＝0.3,CHCl 3 ).
Example 29: (R) -N- (2- (benzylsulfanyl) -1- (9H-pyrido [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 29)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000222
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisoindol-2-yl N-acetyl-S-benzylcysteine ester (29-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 29, 51.8mg,69% yield, 98% ee, and the racemate was prepared in the same manner as the corresponding phosphoric acid catalyst using racemic phosphoric acid.
Mp:152-154℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.70(s,1H),8.50(d,J＝8.1Hz,1H),8.34(d,J＝5.2Hz,1H),8.23(d,J＝7.9Hz,1H),8.06(d,J＝5.2Hz,1H),7.65(d,J＝8.2Hz,1H),7.56(ddd,J＝8.2,7.0,1.2Hz,1H),7.30–7.12(m,6H),5.84–5.72(m,1H),3.65(q,J＝13.0Hz,2H),3.07–2.90(m,2H),1.89(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.2,143.8,140.6,138.5,137.4,133.7,128.9,128.3,128.2,128.1,126.7,121.7,120.8,119.4,114.0,112.1,49.7,38.9,35.2,34.7,22.6；
FTIR(ν max ,cm -1 ):3212,2970,2897,2365,2340,1651,1542,1457,1385,1230,1087,828,743,703,619,570；
HRMS(ESI-TOF)m/z:calcd for C 22 H 22 N 3 OS + [M+H] + ,376.1478；found,376.1473；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝42.83min,t r (minor)＝49.85min；
[α] D 20 ＝29.0(c＝0.3,CHCl 3 ).
Example 30: (R) -4-acetamide-4- (9H-pyridine [3,4-b ] indol-1-yl) butyric acid ethyl ester (Compound 30)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000231
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1- (1,3-dioxoisooctanol-2-yl) 5-ethylacetoglutamate (30-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 30, 50.2mg,74% yield, 88% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:142-144℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.59(s,1H),8.47(d,J＝8.2Hz,1H),8.31(d,J＝5.2Hz,1H),8.22(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.63(d,J＝8.2Hz,1H),7.59–7.48(m,1H),7.24(t,J＝7.5Hz,1H),5.58(q,J＝7.3Hz,1H),3.95(qq,J＝6.8,3.7Hz,2H),2.44–2.23(m,2H),2.23–2.05(m,2H),1.90(s,3H),1.09(t,J＝7.1Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ172.4,169.2,144.5,140.5,137.4,133.0,128.2,128.0,121.7,120.9,119.4,113.8,112.0,59.8,49.3,30.4,29.4,22.6,14.0；
FTIR(ν max ,cm -1 ):3351,3199,2983,2905,2359,2337,2161,1723,1648,1541,1500,1450,1398,1244,1055,741,670,593；
HRMS(ESI-TOF)m/z:calcd for C 19 H 22 N 3 O 3 + [M+H] + ,340.1656；found,340.1651；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝80:20,1.0mL/min,25℃,254nm),t r (major)＝3.30min,t r (minor)＝8.34min；
[α] D 20 ＝-43.0(c＝0.3,CHCl 3 ).
Example 31: (R) -N- (2-phenyl-1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 31)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000232
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindol-2-ylacetoalaninate (14-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 31, 52.7mg,80% yield, 89% ee, racemic product, prepared in the same way, using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:158-160℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.58(s,1H),8.54(d,J＝8.4Hz,1H),8.33(d,J＝5.2Hz,1H),8.20(d,J＝7.9Hz,1H),8.02(d,J＝5.2Hz,1H),7.61(d,J＝8.2Hz,1H),7.54(t,J＝7.5Hz,1H),7.37–7.15(m,5H),7.11(t,J＝7.2Hz,1H),5.81(q,J＝7.8Hz,1H),3.16(d,J＝13.5Hz,2H),1.79(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,145.0,140.5,138.4,137.3,133.0,129.4,128.1,128.0,127.8,126.0,121.6,120.8,119.3,113.7,112.0,51.2,22.5；
FTIR(ν max ,cm -1 ):3215,3178,3025,2991,2825,2361,2341,1649,15556,15041,1429,1375,1320,1241,1065,741,705,656,602,566；
HRMS(ESI-TOF)m/z:calcd for C 21 H 20 N 3 O + [M+H] + ,330.1601；found,330.1595；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝5.94min,t r (minor)＝8.82min；
[α] D 20 ＝63.2(c＝0.3,CHCl 3 ).
Example 32: (R) -N- (2- (4-bromophenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 32)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000241
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (4-bromophenyl) propionate (32-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 32, 54.7mg,67% yield, 87% ee, racemic product, prepared in the same way, using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:190-192℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.63(s,1H),8.56(d,J＝8.4Hz,1H),8.33(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.55(ddd,J＝8.2,6.9,1.2Hz,1H),7.45–7.34(m,2H),7.24(dq,J＝7.8,1.7Hz,3H),5.80(td,J＝8.7,5.6Hz,1H),3.20(dd,J＝13.7,5.7Hz,1H),3.12(dd,J＝13.7,8.9Hz,1H),1.79(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,144.7,140.5,137.9,137.3,132.9,131.7,130.7,128.1,128.0,121.7,120.8,119.3,119.3,113.8,112.0,50.9,39.0,22.5；
FTIR(ν max ,cm -1 ):3172,2978,2938,2359,2338,1793,1748,1717,1688,1648,1557,1542,1507,1456,1431,1374,1318,1238,1071,1012,880,735,647,562；
HRMS(ESI-TOF)m/z:calcd for C 21 H 19 BrN 3 O + [M+H] + ,408.0706；found,408.0702；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝7.19min,t r (minor)＝6.00min；
[α] D 20 ＝80.3(c＝0.3,CHCl 3 ).
Example 33: (R) -N- (2- (4-fluorophenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 33)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000251
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (4-fluorophenyl) propionate (33-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 33, 61.8mg,89% yield, 87% ee, racemic product, prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:184-186℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.69(s,1H),8.62(d,J＝8.4Hz,1H),8.33(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.02(d,J＝5.2Hz,1H),7.62(dt,J＝8.2,1.0Hz,1H),7.54(ddd,J＝8.2,7.0,1.2Hz,1H),7.36–7.27(m,2H),7.23(ddd,J＝7.9,7.0,1.1Hz,1H),7.08–6.97(m,2H),5.77(td,J＝8.5,6.0Hz,1H),3.26–3.08(m,2H),1.80(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,144.9,140.5,137.3,134.6,132.9,131.3,131.2,128.1,128.0,121.6,120.8,119.3,114.6,114.4,113.7,112.0,51.5,38.7,22.5；
FTIR(ν max ,cm -1 ):3218,2974,2911,2366,2335,1754,1701,1650,1556,1505,1457,1396,1237,1072,818,738,670,533；
HRMS(ESI-TOF)m/z:calcd for C 21 H 19 FN 3 O + [M+H] + ,348.1507；found,348.1503；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,0.5mL/min,25℃,254nm),t r (major)＝9.78min,t r (minor)＝18.49min；
[α] D 20 ＝67.4(c＝0.3,CHCl 3 ).
Example 34: (R) -N- (2- (4-chlorophenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 34)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000252
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisooctanol-2-yl 2-acetamide-3- (4-chlorophenyl) propionate (34-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon for 1 hour at-40 deg.C in the dark, followed by reaction for 72 hours under 3W blue light (λ =455-465 nm) irradiationTLC was monitored until conversion of starting material was complete, silica gel was stirred and column chromatography (petroleum ether: acetone = 3:1) gave compound 34, 52.4mg,72% yield, 89% ee, racemic product was prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:191-193℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.65(s,1H),8.59(d,J＝8.4Hz,1H),8.33(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.02(d,J＝5.2Hz,1H),7.63(d,J＝8.2Hz,1H),7.54(ddd,J＝8.2,6.9,1.2Hz,1H),7.35–7.19(m,5H),5.82(td,J＝8.7,5.6Hz,1H),3.29–3.08(m,2H),1.80(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,144.7,140.5,137.5,137.3,133.0,131.3,130.8,128.2,128.0,127.8,121.7,120.8,119.3,113.8,112.0,51.0,39.0,22.5；
FTIR(ν max ,cm -1 ):3218,3172,2988,2923,2357,1655,1563,1499,1319,1241,1094,1036,1019,738,576；
HRMS(ESI-TOF)m/z:calcd for C 21 H 19 ClN 3 O + [M+H] + ,364.1211；found,364.1207；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝5.08min,t r (minor)＝9.81min；
[α] D 20 ＝82.3(c＝0.3,CHCl 3 ).
Example 35: (R) -N- (1- (9H-pyridine [3,4-b ] indol-1-yl) -2- (p-tolyl) ethyl) acetamide (Compound 35)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000261
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisooctanol-2-yl 2-acetamide-3- (p-tolyl) propionate (35-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP(0.02 mmol), argon was replaced 3 times, ultra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred on silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 35, 50.1mg,73% yield, 90% ee, racemic product, prepared in the same way using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:166-168℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.58(s,1H),8.52(d,J＝8.3Hz,1H),8.33(d,J＝5.2Hz,1H),8.20(d,J＝7.8Hz,1H),8.01(d,J＝5.2Hz,1H),7.62(dt,J＝8.3,1.0Hz,1H),7.54(ddd,J＝8.3,7.0,1.2Hz,1H),7.23(ddd,J＝8.0,7.0,1.0Hz,1H),7.15(d,J＝7.9Hz,2H),7.00(d,J＝7.8Hz,2H),5.78(td,J＝8.5,5.9Hz,1H),3.25–3.08(m,2H),2.20(s,3H),1.80(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,145.1,140.5,137.3,135.3,134.9,133.1,129.3,128.5,128.1,128.0,121.6,120.8,119.3,113.7,112.0,51.3,39.1,22.5,20.6；
FTIR(ν max ,cm -1 ):3218,3179,2981,2904,2381,2340,1859,1771,1749,1698,1653,1647,1576,1541,1521,1507,1457,1398,1320,1235,883,748,705,670,518；
HRMS(ESI-TOF)m/z:calcd for C 22 H 22 N 3 O + [M+H] + ,344.1757；found,344.1753；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝6.25min,t r (minor)＝11.25min；
[α] D 20 ＝67.2(c＝0.3,CHCl 3 ).
Example 36: (R) - (2- ([ 1,1' -biphenyl ] -4-yl) -1- (9H-pyridinyl [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 36)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000262
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 3- ([ 1,1' -biphenyl]-4-yl) -2-acetaminopropionate (36-2,0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), replacing argon 3 times, adding extra dry THF (4.0 mL) with syringe and pre-cooling in the dark at-40 ℃ for 1 hour under argon atmosphere, then reacting under 3W blue light (. Lamda. =455-465 nm) irradiation for 72 hours, monitoring by TLC until the conversion of the starting material is complete, stirring with silica gel, column chromatography (petroleum ether: acetone = 3:1) to give compound 36, 58.4mg,72% yield, 88% ee, racemic product prepared according to the same method, the corresponding phosphoric acid catalyst used is racemic phosphoric acid.
Mp:180-182℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.64(s,1H),8.61(d,J＝8.4Hz,1H),8.35(d,J＝5.2Hz,1H),8.22(d,J＝7.9Hz,1H),8.04(d,J＝5.2Hz,1H),7.67–7.58(m,3H),7.58–7.49(m,3H),7.42(dd,J＝8.4,6.9Hz,2H),7.40–7.35(m,2H),7.35–7.28(m,1H),7.24(ddd,J＝8.0,7.0,1.1Hz,1H),5.86(td,J＝8.6,5.7Hz,1H),3.25(qd,J＝13.8,7.3Hz,2H),1.82(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,145.0,140.5,140.0,137.8,137.8,137.3,133.0,130.0,128.8,128.1,128.0,127.2,126.5,126.1,121.6,120.8,119.3,113.8,112.0,51.2,39.2,22.6；
FTIR(ν max ,cm -1 ):3218,3179,2975,2925,2364,2340,1772,1748,1648,1455,1419,1398,1375,1318,1240,1055,744,690,669,570；
HRMS(ESI-TOF)m/z:calcd for C 27 H 24 N 3 O + [M+H] + ,406.1914；found,406.1909；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝12.07min,t r (minor)＝32.76min；
[α] D 20 ＝61.9r(c＝0.3,CHCl 3 ).
Example 37: (R) - (2- (4-methoxyphenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 37)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000271
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (4-methoxyphenyl) propionate (37-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), replacing argon 3 times, adding extra dry THF (4.0 mL) with syringe and under argon atmosphere, precooling for 1 hour at-40 ℃ in the dark, then reacting for 72 hours under 3W blue light (lambda =455-465 nm) irradiation, monitoring by TLC until the conversion of the starting material is complete, stirring with silica gel, column chromatography (petroleum ether: acetone = 3:1) to give compound 37, 63.3mg,88% yield, 91% ee, racemic product prepared according to the same method, the corresponding phosphoric acid catalyst used is racemic phosphoric acid.
Mp:188-190℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.59(s,1H),8.52(d,J＝8.4Hz,1H),8.33(d,J＝5.2Hz,1H),8.21(d,J＝7.8Hz,1H),8.01(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.54(ddd,J＝8.2,6.9,1.2Hz,1H),7.23(ddd,J＝8.0,6.9,1.1Hz,1H),7.20–7.13(m,2H),6.81–6.70(m,2H),5.81–5.70(m,1H),3.67(s,3H),3.25–3.02(m,2H),1.80(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,157.6,145.1,140.5,137.3,133.0,130.4,130.3,128.1,127.9,121.6,120.8,119.3,113.7,113.3,112.0,54.9,51.5,38.7,22.5；
FTIR(ν max ,cm -1 ):3216,3175,2985,2920,2901,2359,2341,1748,1701,1650,1637,1558,1505,1462,1432,1378,1319,1183,1083,880,814,775,738,668,629,557；
HRMS(ESI-TOF)m/z:calcd for C 22 H 22 N 3 O 2 + [M+H] + ,360.1707；found,360.1701；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝13.62min,t r (minor)＝11.06min；
[α] D 20 ＝69.6(c＝0.3,CHCl 3 ).
Example 38: (R) - (2- (4-benzyloxyphenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 38)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000281
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (4-benzyloxyphenyl) propionate (38-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 38, 66.2mg,76% yield, 92% ee, racemic product, prepared in the same way, using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:176-178℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.60(s,1H),8.53(d,J＝8.3Hz,1H),8.33(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.02(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.59–7.48(m,1H),7.43–7.33(m,4H),7.33–7.27(m,1H),7.24(t,J＝7.2Hz,1H),7.19(d,J＝8.7Hz,2H),6.85(d,J＝8.6Hz,2H),5.76(td,J＝8.5,5.8Hz,1H),5.00(s,2H),3.13(qd,J＝13.8,7.3Hz,2H),1.80(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,156.7,145.1,140.5,137.3,137.2,133.0,130.6,130.4,128.4,128.1,127.9,127.7,127.7,121.6,120.8,119.3,114.2,113.7,112.0,69.1,51.4,38.8,22.6；
FTIR(ν max ,cm -1 ):3217,3180,2987,2392,2340,1739,1716,1659,1648,1542,1508,1487,1378,1241,1058,1044,737,669,571；
HRMS(ESI-TOF)m/z:calcd for C 28 H 26 N 3 O 2 + [M+H] + ,436.2020；found,436.2014；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝21.50min,t r (minor)＝17.15min；
[α] D 20 ＝44.3(c＝0.3,CHCl 3 ).
Example 39: (R) - (2- (4-tert-butoxyphenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 39)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000282
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisooctanol-2-yl 2-acetamide-3- (4-tert-butoxyphenyl) propionate (39-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under irradiation of 3W blue light (. Lamda. =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 39, 76.2mg,95% yield, 88% ee, racemic product prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:186-188℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.51(s,1H),8.54(d,J＝8.3Hz,1H),8.33(d,J＝5.2Hz,1H),8.18(d,J＝7.9Hz,1H),8.00(d,J＝5.3Hz,1H),7.66–7.40(m,2H),7.21(t,J＝7.4Hz,1H),7.09(d,J＝8.0Hz,2H),6.74(d,J＝7.9Hz,2H),5.76(q,J＝7.7Hz,1H),3.21–2.98(m,2H),1.80(s,3H),1.14(s,9H)；
13 C NMR(101MHz,DMSO-d 6 )δ168.9,153.1,145.0,140.5,137.2,133.0,129.8,129.0,128.0,123.6,123.2,121.6,120.7,119.2,113.6,112.0,77.5,51.4,34.5,28.4,22.5；
FTIR(ν max ,cm -1 ):3216,3118,2974,2908,2376,2342,1774,1752,1648,1581,1544,1508,1482,1385,1244,1070,900,820,738,666,559；
HRMS(ESI-TOF)m/z:calcd for C 25 H 28 N 3 O 2 + [M+H] + ,402.2176；found,402.2171；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝3.85min,t r (minor)＝14.07min；
[α] D 20 ＝47.8(c＝0.3,CHCl 3 ).
Example 40: phenyl (R) -4- (2-acetylamino-2- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetate (Compound 40)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000291
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (4-acetoxyphenyl) propionate (40-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 40, 53.4mg,69% yield, 88% ee, racemic product was prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:204-206℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.62(s,1H),8.57(d,J＝8.4Hz,1H),8.33(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.02(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.40–7.12(m,3H),6.97(d,J＝8.0Hz,2H),5.81(td,J＝8.6,5.6Hz,1H),3.20(qd,J＝14.0,7.2Hz,2H),2.22(s,3H),1.80(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,169.1,148.8,145.0,140.5,137.3,135.9,133.0,130.3,128.1,128.0,121.6,121.1,120.8,119.3,113.7,112.0,51.2,38.9,22.5,20.8；
FTIR(ν max ,cm -1 ):3216,3177,2983,2928,2382,2335,1760,1647,1558,1542,1500,1457,1431,1374,1228,1071,914,822,738,668,623,570；
HRMS(ESI-TOF)m/z:calcd for C 23 H 22 N 3 O 3 + [M+H] + ,388.1656；found,388.1649；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝13.54min,t r (minor)＝17.76min；
[α] D 20 ＝44.0(c＝0.3,CHCl 3 ).
Example 41: (R) - (2- (4-cyanophenyl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 41)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000292
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisooctanol-2-yl 2-acetamide-3- (4-cyanophenyl) propionate (41-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (λ =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography(Petroleum ether: acetone = 3:1) to give compound 41, 56.7mg,80% yield, 87% ee, racemic product prepared according to the same method, corresponding phosphoric acid catalyst using racemic phosphoric acid.
Mp:206-208℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.66(s,1H),8.62(d,J＝8.5Hz,1H),8.34(d,J＝5.1Hz,1H),8.22(d,J＝7.9Hz,1H),8.04(d,J＝5.2Hz,1H),7.71(d,J＝8.0Hz,2H),7.62(d,J＝8.2Hz,1H),7.59–7.52(m,1H),7.50(d,J＝8.0Hz,2H),7.31–7.17(m,1H),5.86(td,J＝8.8,5.5Hz,1H),3.32–3.18(m,2H),1.79(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.1,144.6,144.4,140.5,137.4,132.9,131.7,130.6,128.2,128.1,121.7,120.8,119.4,119.0,113.9,112.0,109.0,50.7,39.7,22.5；
FTIR(ν max ,cm -1 ):3230,3177,2979,2942,2383,2338,2226,1748,1715,1698,1658,1648,1558,1537,1455,1430,1377,1318,1238,1059,884,818,738,625,554；
HRMS(ESI-TOF)m/z:calcd for C 22 H 19 N 4 O + [M+H] + ,355.1553；found,355.1549；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝15.93min,t r (minor)＝25.88min；
[α] D 20 ＝106.9(c＝0.3,CHCl 3 ).
Example 42: (R) -N- (2- (naphthalen-2-yl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide ((Compound 42)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000301
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (naphthalen-2-yl) propionate (42-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere at-40 ℃ for 1 hour in the dark, followed by reaction under 3W blue light (. Lamda. =455-465 nm) irradiation for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred on silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 42, 50.8mg,67% yield, 90% ee, racemic product, prepared in the same manner using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:210-212℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.66(s,1H),8.61(d,J＝8.4Hz,1H),8.35(d,J＝5.3Hz,1H),8.21(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.78(td,J＝11.9,9.0Hz,4H),7.62(d,J＝8.2Hz,1H),7.54(ddd,J＝8.2,7.0,1.2Hz,1H),7.50–7.36(m,3H),7.29–7.17(m,1H),5.95(td,J＝8.6,5.8Hz,1H),3.42(dd,J＝13.7,5.8Hz,1H),3.34(dd,J＝13.7,5.8Hz,1H),1.78(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.0,145.0,140.5,137.4,136.2,133.0,132.9,131.7,128.2,128.1,128.0,127.6,127.4,127.3,127.1,125.9,125.3,121.6,120.8,119.3,113.8,112.0,51.2,22.5；
FTIR(ν max ,cm -1 ):3546,3526,3503,2987,2971,2901,2891,2780,2741,1749,1715,1698,1647,1558,1542,1522,1507,1458,1397,1055,737,669；
HRMS(ESI-TOF)m/z:calcd for C 25 H 22 N 3 O + [M+H] + ,380.1757；found,380.1753；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝18.30min,t r (minor)＝22.18min；
[α] D 20 ＝–15.0(c＝0.3,CHCl 3 ).
Example 43, (R) -N- (2- (naphthalen-1-yl) -1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide ((Compound 43)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000302
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl 2-acetamide-3- (naphthalen-1-yl) propionate (43-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 43, 52.4mg,69% yield, 88% ee, racemic product was prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:220-222℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.41(s,1H),8.57(d,J＝8.0Hz,1H),8.36(d,J＝5.2Hz,1H),8.26(d,J＝8.1Hz,1H),8.19(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.85(d,J＝7.9Hz,1H),7.69(d,J＝7.6Hz,1H),7.57(d,J＝8.1Hz,1H),7.49(dt,J＝14.2,7.0Hz,3H),7.38–7.25(m,2H),7.22(t,J＝7.4Hz,1H),5.95(q,J＝7.4Hz,1H),3.91–3.64(m,2H),1.81(s,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.3,144.4,140.5,137.4,134.4,133.3,133.3,132.0,128.4,128.2,128.1,127.2,126.7,126.0,125.4,125.2,124.0,121.6,120.8,119.3,113.9,112.1,51.0,35.8,22.5；
FTIR(ν max ,cm -1 ):3221,3179,2981,2908,2382,2337,1698,1648,1542,1506,1474,1373,1319,1234,1089,874,749,664,561；
HRMS(ESI-TOF)m/z:calcd for C 25 H 22 N 3 O + [M+H] + ,380.1757；found,380.1753；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝12.48min,t r (minor)＝18.67min；
[α] D 20 ＝15.7(c＝0.3,CHCl 3 ).
Example 44: (R) -N- (1- (9H-pyridinyl [3,4-b ] indol-1-yl) ethyl) benzamide ((compound 44)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000311
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindol-2-ylbenzoylalanine (44-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and reacted under irradiation with 3W blue light (. Lamda. =455-465 nm) at 25 ℃ under argon atmosphere for 48 hours, monitored by TLC until the conversion of the starting material was complete, stirred on silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 44, 37.8mg,60% yield, 34% ee, and the racemic product was prepared in the same manner, using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:168-170℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.70(s,1H),8.94(d,J＝7.4Hz,1H),8.30(d,J＝5.3Hz,1H),8.23(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.98–7.86(m,2H),7.64(d,J＝8.2Hz,1H),7.54(q,J＝7.4Hz,2H),7.47(t,J＝7.4Hz,2H),7.25(t,J＝7.5Hz,1H),5.82(p,J＝6.9Hz,1H),1.64(d,J＝6.9Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ165.8,146.2,140.5,137.3,131.3,128.3,128.1,128.0,127.5,123.0,121.7,120.9,119.4,113.8,112.1,47.0,20.2；
FTIR(ν max ,cm -1 ):3312,3199,3061,2918,2382,1752,1631,1522,1389,1307,1091,1050,716,646,537；
HRMS(ESI-TOF)m/z:calcd for C 20 H 18 N 3 O + [M+H] + ,316.1444；found,316.1441；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝7.85min,t r (minor)＝13.33min.
Example 45: (R) -tert-butyl (1- (9H-pyridinyl [3,4-b ] indol-1-yl) carbamic acid ethyl ester) (compound 45)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000312
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisoindol-2-yl (tert-butyloxycarbonyl) alanine ester (45-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and reacted under irradiation of 3W blue light (. Lamda. =455-465 nm) at 25 ℃ under argon atmosphere for 48 hours, TLC monitored until the conversion of the starting material was complete, silica gel stirred, column chromatography (petroleum ether: acetone = 3:1) gave 45, 40.5mg,65% yield, 7% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:133-135℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.58(s,1H),8.27(d,J＝5.2Hz,1H),8.22(d,J＝7.9Hz,1H),8.00(d,J＝5.3Hz,1H),7.61(d,J＝8.2Hz,1H),7.55(t,J＝7.6Hz,1H),7.23(q,J＝7.3Hz,1H),5.30(p,J＝6.9Hz,1H),1.46(d,J＝6.8Hz,3H),1.36(s,9H)；
13 C NMR(101MHz,DMSO-d 6 )δ169.3,146.4,140.5,137.2,132.6,128.1,128.0,121.7,120.9,119.4,113.7,112.0,78.0,47.8,28.2,20.7；
FTIR(ν max ,cm -1 ):2971,2905,2359,1698,1544,1505,1459,1398,1165,1070,879,716,545；
HRMS(ESI-TOF)m/z:calcd for C 18 H 22 N 3 O 2 + [M+H] + ,312.1707；found,312.1702；
HPLC analysis:Chiral INC(2)(150x4.6mm,3μm,hexane/i-PrOH＝99:1,0.5mL/min,25℃,254nm),t r (major)＝6.90min,t r (minor)＝7.95min.
Example 46: (R) -benzyl (1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) carbamate (Compound 46)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000321
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindol-2-yl ((benzyloxy) carbonyl) alanine ester (46-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and reacted under irradiation with 3W blue light (. Lamda. =455-465 nm) at 25 ℃ under argon atmosphere for 48 hours, monitored by TLC until the conversion of the starting material was complete, stirred on silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 46, 56.8mg,82% yield, 26% ee, and the racemic product was prepared in the same manner, using racemic phosphoric acid as the corresponding phosphoric acid catalyst.
Mp:155-157℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.61(s,1H),8.29(d,J＝5.1Hz,1H),8.22(d,J＝7.8Hz,1H),8.01(d,J＝5.2Hz,1H),7.76(d,J＝7.7Hz,1H),7.62(d,J＝8.2Hz,1H),7.55(t,J＝7.6Hz,1H),7.44–7.18(m,6H),5.38(q,J＝7.1Hz,1H),5.12–4.89(m,2H),1.50(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ155.6,146.1,140.5,137.3,137.2,132.3,128.3,128.1,128.0,127.7,127.6,121.7,120.8,119.3,113.7,112.0,65.3,48.3,20.5；
FTIR(ν max ,cm -1 ):3121,2991,2895,2381,1701,1544,1505,1455,1288,1057,1014,733,568；
HRMS(ESI-TOF)m/z:calcd for C 21 H 20 N 3 O 2 + [M+H] + ,346.1550；found,346.1546；
HPLC analysis:Chiral NX(2)(150x4.6mm,3μm,hexane/i-PrOH＝95:5,1.0mL/min,25℃,254nm),t r (major)＝16.89min,t r (minor)＝15.26min.
Example 47: (R) -N- (1- (9H-pyridinyl [3,4-b ] indol-1-yl) ethyl) carboxamide (Compound 47)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000322
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl formylalanine ester (47-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and reacted under irradiation with 3W blue light (. Lamda. =455-465 nm) at 25 ℃ under argon atmosphere for 48 hours, TLC monitored until the conversion of the starting material was complete, silica gel stirred, column chromatography (petroleum ether: acetone = 3:1) gave 47, 38.7mg,81% yield, 52% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:148-150℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.71(s,1H),8.77(d,J＝7.9Hz,1H),8.31(d,J＝5.2Hz,1H),8.23(d,J＝7.9Hz,1H),8.09(s,1H),8.04(d,J＝5.2Hz,1H),7.61(d,J＝8.2Hz,1H),7.55(t,J＝7.5Hz,1H),7.24(t,J＝7.4Hz,1H),5.69(p,J＝6.9Hz,1H),1.48(d,J＝6.7Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 )δ160.7,145.3,140.6,137.3,132.3,128.2,128.1,121.7,120.9,119.4,113.9,112.1,44.7,20.9；
FTIR(ν max ,cm -1 ):2990,2896,2359,1754,1672,1587,1543,1505,1459,1243,1052,730,619,571；
HRMS(ESI-TOF)m/z:calcd for C 14 H 14 N 3 O + [M+H] + ,240.1131；found,240.1128；
HPLC analysis:Chiral NY(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,0.5mL/min,25℃,254nm),t r (major)＝6.77min,t r (minor)＝8.94min；
[α] D 20 ＝52.8(c＝0.3,CHCl 3 ).
Example 48: (R) -N- (2-methyl-1- (9H-pyridine [3,4-b ] indol-1-yl) propyl) acetamide (Compound 48)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000331
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindole-2-acetylvaline ester (48-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), replacing argon 3 times, adding extra dry THF (4.0 mL) with syringe and pre-cooling in the dark at-40 ℃ for 1 hour under argon atmosphere, then reacting under 3W blue light (. Lamda. =455-465 nm) irradiation for 72 hours, monitoring by TLC until the conversion of the starting material is complete, stirring with silica gel, column chromatography (petroleum ether: acetone = 3:1) to give compound 48, 22.5mg,40% yield, 19 ee, racemic product prepared according to the same method, the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp:205-207℃；
1 H NMR(400MHz,DMSO)δ11.69(s,1H),8.34(d,J＝8.9Hz,1H),8.31(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.00(d,J＝5.2Hz,1H),7.61(d,J＝8.2Hz,1H),7.54(t,J＝7.6Hz,1H),7.23(t,J＝7.4Hz,1H),5.38(t,J＝8.6Hz,1H),2.24(h,J＝6.8Hz,1H),1.88(s,3H),0.98(d,J＝6.6Hz,3H),0.76(d,J＝6.6Hz,3H)；
13 C NMR(101MHz,DMSO)δ168.9,145.4,140.5,137.3,133.6,128.0,127.6,121.6,120.8,119.2,113.3,111.9,55.0,32.5,22.6,19.4,19.0；
FTIR(ν max ,cm -1 ):3527,3447,3386,3118,2987,2898,2883,2381,2340,1748,1716,1697,1647,1566,1541,1507,1457,1338,1085,878,736,636,518；
HRMS(ESI-TOF)m/z:calcd for C 17 H 20 N 3 O + [M+H] + ,282.1601；found,282.1597；
HPLC analysis:Chiral ND(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝2.65min,t r (minor)＝4.30min.
Example 49: (R) -N- (2-methoxy-1- (9H-pyridine [3,4-b ] indol-1-yl) ethyl) acetamide (Compound 49)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000332
to a 10mL Schlenk reaction tube was added sequentially 9H-pyrido [3,4-b]Indole (1-1, 0.20mmol), 1,3-dioxoisoindol-2-yl N-acetyl-O-methylserine ester (49-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 49, 31.7mg,68% yield, 68% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:178-180℃；
1 H NMR(400MHz,DMSO)δ11.63(s,1H),8.45(d,J＝8.0Hz,1H),8.31(d,J＝5.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.03(d,J＝5.2Hz,1H),7.62(d,J＝8.2Hz,1H),7.55(t,J＝7.6Hz,1H), 13 C NMR(101MHz,DMSO)δ169.2,143.1,140.5,137.4,133.6,128.1,128.0,121.7,120.8,119.3,113.8,112.0,73.5,58.3,49.8,22.6；
FTIR(ν max ,cm -1 ):3221,3118,3100,3025,2990,2913,2854,2370,2175,2023,1987,1651,1559,1505,1431,1375,1320,1238,870,818,738,556；
HRMS(ESI-TOF)m/z:calcd for C 16 H 18 N 3 O 2 + [M+H] + ,284.1394；found,284.1390；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝5.00min,t r (minor)＝7.09min.
Example 50: (R) -1- (1-Acetamidoethyl) -9H-pyridine [3,4-b ] indole-3-carboxylic acid ethyl ester (Compound 50)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000341
to a 10mL Schlenk reaction tube was added sequentially 9H-pyridine [3,4-b]Indole-3-carboxylic acid methyl ester (50-1, 0.20mmol), 1,3-dioxoisoindol-2-ylacetoalaninate (1-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, extra dry THF (4.0 mL) was added with a syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 50, 45.5mg,73% yield, 38% ee, racemic product prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp:242-244℃；
1 H NMR(400MHz,DMSO)δ11.97(s,1H),8.84(s,1H),8.51(d,J＝7.3Hz,1H),8.37(d,J＝7.9Hz,1H),7.68(d,J＝8.2Hz,1H),7.64–7.49(m,1H),7.30(t,J＝7.5Hz,1H),5.60(p,J＝6.9Hz,1H),3.92(s,3H),1.89(s,3H),1.54(d,J＝6.8Hz,3H)；
13 C NMR(101MHz,DMSO)δ169.1,166.0,146.2,140.8,135.9,134.4,128.6,127.9,122.0,121.2,120.3,116.8,112.4,52.0,46.3,22.6,19.6；
FTIR(ν max ,cm -1 ):3354,3143,2991,2905,2382,2342,1720,1643,1508,1437,1350,1250,1067,978,741,601；
HRMS(ESI-TOF)m/z:calcd for C 17 H 18 N 3 O 3 [M+H] + ,312.1343；found,312.1340；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝8.86min,t r (minor)＝3.12min；
Example 51: (R) -N- (1- (7-bromo-9H-pyridine [3,4-b ] indol-1-yl) -3-methylbutyl) acetamide (Compound 51)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000342
to a 10mL Schlenk reaction tube was added in sequence 7-bromo-9H-pyridine [3,4-b]Indole (11-1, 0.20mmol), 1,3-dioxyisooctanol-2-yl acetyl leucine (23-2, 0.30mmol), ir [ dF (CF (F)) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 51, 62.1mg,83% yield, 59% ee, racemic product prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp 234-236℃；
1 H NMR(400MHz,DMSO)δ11.65(s,1H),8.45(d,J＝8.2Hz,1H),8.33(d,J＝5.2Hz,1H),8.16(d,J＝8.4Hz,1H),8.01(d,J＝5.2Hz,1H),7.80(d,J＝1.8Hz,1H),7.37(dd,J＝8.4,1.8Hz,1H),5.55(td,J＝8.5,6.4Hz,1H),1.88–1.81(m,1H),1.85(s,3H),1.73(dq,J＝13.5,6.9Hz,1H),1.55(dp,J＝13.3,6.6Hz,1H),0.89(dd,J＝6.6,3.6Hz,6H)；
13 C NMR(101MHz,DMSO)δ169.1,146.3,141.4,138.1,133.2,127.5,123.5,122.3,120.8,120.1,114.7,113.6,48.4,42.8,24.6,22.9,22.5,22.4；
FTIR(ν max ,cm -1 ):3385,3274,2384,1643,1548,1488,1421,1372,1312,1234,1025,998,782,582；HRMS(ESI-TOF)m/z:calcd for C 18 H 21 BrN 3 O[M+H] + ,374.0863；found,374.0860；
HPLC analysis:Chiral MX(2)(150x4.6mm,3μm,hexane/i-PrOH＝90:10,1.0mL/min,25℃,254nm),t r (major)＝3.16min,t r (minor)＝2.57min；
Example 52: (R) -N- (1- (6-bromo-9H-pyridine [3,4-b ] indol-1-yl) -2-phenethyl) carboxamide (Compound 52)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000351
to a 10mL Schlenk reaction tube was added 6-bromo-9H-pyridine [3,4-b]Indole (10-1, 0.20mmol), 1,3-dioxoisoindol-2-ylacetoalaninate (18-2, 0.30mmol), ir [ dF (CF) 3 )ppy) 2 (dtbpy)]PF 6 (0.002 mmol) and (R) -STRIP (0.02 mmol), argon was replaced 3 times, ultra-dry THF (4.0 mL) was added via syringe and pre-cooled under argon atmosphere in the dark at-40 ℃ for 1 hour, followed by reaction under 3W blue light (. Lamda =455-465 nm) for 72 hours, monitored by TLC until the conversion of the starting material was complete, stirred with silica gel, and separated by column chromatography (petroleum ether: acetone = 3:1) to give compound 52, 62.1mg,83% yield, 59% ee, racemic product prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
1 H NMR(400MHz,DMSO)δ11.88(s,1H),8.80(d,J＝8.5Hz,1H),8.57–8.43(m,1H),8.36(d,J＝5.3Hz,1H),8.09(d,J＝5.2Hz,1H),8.01(s,1H),7.72–7.61(m,1H),7.58(d,J＝8.8Hz,1H),7.28–7.02(m,5H),5.91(q,J＝7.8Hz,1H),3.19(qd,J＝13.7,7.2Hz,2H)； 1
3 C NMR(101MHz,DMSO)δ160.8,144.8,139.2,137.9,137.8,133.3,130.7,129.5,127.9,127.2,126.2,124.4,122.8,114.3,114.1,111.3,49.8.
Example 53: (R) -1- (6-bromo-9H-pyridine [3,4-b ] indol-1-yl) -2-phenylethane-1-amine (Compound 53)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000352
to a 10mL Schlenk reaction tube was added (R) -N- (1- (6-bromo-9H-pyridine [3,4-b)]Indol-1-yl) -2-phenethyl) acetamide (16, 0.30mmol), methanol (3 mL) and 12N concentrated hydrochloric acid (2 mL) react at 80 ℃ overnight, after the raw materials are completely converted, the solvent is decompressed and added with saturated NaHCO 3 The solution was made basic, extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, stirred on silica gel and separated by column chromatography (DCM: meOH = 20).
1 H NMR(400MHz,CDCl 3 )δ10.43(s,1H),8.37(d,J＝5.3Hz,1H),8.22(d,J＝1.8Hz,1H),7.78(d,J＝5.3Hz,1H),7.61(dd,J＝8.6,2.0Hz,1H),7.38(d,J＝8.6Hz,1H),7.35–7.17(m,5H),4.84(dd,J＝10.1,4.1Hz,1H),3.51–3.27(m,1H),2.98(dd,J＝13.3,9.4Hz,1H),2.46(s,2H).
HRMS(ESI-TOF)m/z:calcd for C 19 H 17 BrN 3 + [M+H] + ,366.0600；found,366.0602.
Example 54: tert-butyl (R) - (1- (6-bromo-9H-pyridine [3,4-b ] indol-1-yl) -2-phenylethyl) carbamate (compound 54)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000361
to a 10mL Schlenk reaction tube were added in sequence (R) -1- (6-bromo-9H-pyridine [3,4-b ] indol-1-yl) -2-phenylethane-1-amine (53, 0.3mmol), THF (3 mL), 1N NaOH solution (0.6 mL) at 25 ℃ for 5 hours, after complete conversion of the starting material, ethyl acetate and water were added, the mixture was separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, silica gel stirred, and column chromatography (petroleum ether: acetone = 6:1) gave 54, 116.0mg,83% yield, racemic product was prepared in the same manner, and racemic phosphoric acid was used as the corresponding phosphoric acid catalyst.
Mp,247-249℃；
1 H NMR(400MHz,DMSO-d 6 )δ11.77(s,1H),8.49(s,1H),8.39–8.20(m,1H),8.06(d,J＝5.3Hz,1H),7.66(d,J＝8.7Hz,1H),7.58(d,J＝8.8Hz,1H),7.35–7.07(m,6H),5.59–5.21(m,1H),3.25–2.96(m,2H),1.28(s,9H)；
13 C NMR(101MHz,DMSO-d 6 )δ155.2,145.7,139.1,138.2,137.6,133.2,130.5,129.4,127.8,127.0,126.1,124.3,122.7,114.0,111.2,77.9,53.2,28.1；
FTIR(ν max ,cm -1 ):3180,2984,2903,2389,2342,1673,1542,1475,1271,1161,1053,742,694,605,556；
HRMS(ESI-TOF)m/z:calcd forC 24 H 25 BrN 3 O 2 + [M+H] + ,466.1125；found,466.1128；
[α] D 20 ＝24.8(c＝0.3,CHCl 3 ).
Example 55: iodinated tert-butyl (R) -6-bromo-1- (1- (tert-butoxycarbonyl) amino) -2-phenylethyl) -2-methyl-9H-pyridine [3,4-b ] indole (Compound 55)
The synthesis route and the specific synthesis steps are as follows:
Figure BDA0003809834990000362
under argon atmosphere, tert-butyl (R) - (1- (6-bromo-9H-pyridine [3,4-b ] indol-1-yl) -2-phenylethyl) carbamate (54, 0.25mmol), dried acetonitrile (2.5 mL), methyl iodide (0.15 mL) were added sequentially to a 10mL Schlenk reaction tube, reacted at 80 ℃ for 24 hours, and after the conversion of the starting material was completed, the solvent was removed under reduced pressure to obtain 55, 150.6mg,99% yield of the compound, and the racemic product was prepared in the same manner, and the corresponding phosphoric acid catalyst used was racemic phosphoric acid.
Mp,268-270℃；
1 H NMR(400MHz,DMSO-d 6 )δ12.53(s,1H),8.82(s,1H),8.75(d,J＝6.5Hz,1H),8.63(d,J＝6.6Hz,1H),8.10–7.90(m,1H),7.84(d,J＝8.9Hz,1H),7.22(d,J＝12.7Hz,5H),5.69(s,1H),4.36(s,3H),3.43(d,J＝7.8Hz,2H),1.23(s,9H)；
HRMS(ESI-TOF)m/z:calcd for C 25 H 27 BrN 3 O 2 + [M-I] + ,480.1281；found,480.1284；
[α] D 20 ＝27.3(c＝0.3,CHCl 3 ).
Example 56: human non-small cell lung cancer A549 and PC9 cell proliferation inhibition experiment
1. Brief introduction of experimental principles:
MTT is a yellow compound, is a dye which accepts hydrogen ions, can act on a respiratory chain in mitochondria of living cells, and a tetrazolium ring is cracked under the action of succinate dehydrogenase and cytochrome C to generate blue formazan (formazan) crystals. Since succinate dehydrogenase disappears from dead cells and MTT cannot be reduced, the amount of formazan crystals produced is only proportional to the number of viable cells. After the formazan crystals generated by reduction are dissolved by DMSO, the OD value of the optical density of the solution can be measured at 570nm by using an enzyme-labeling instrument to reflect the number of living cells. Experimental methods the main references: eur J Med chem.2020,206,112677.
2. Experimental materials and instruments:
human non-small cell lung cancer cell lines A549 and PC9 were purchased from ATCC (USA).
96-well plates were purchased from Corning (USA).
RPMI-1640 medium was purchased from cytvia (USA).
FBS was purchased from Transgen (Beijing, china).
Penicilin-streptomycin was purchased from Biyunyan (Jiangsu, china).
1640 complete medium: RPMI1640 medium +10% FBS +1% Penicilin-streptomycin.
MTT (98%, reagent grade) was purchased from Biyunyun (Jiangsu, china).
3. The experimental method comprises the following steps:
first day, 8000A 549 or PC9 cells per well in 96-well plate, 100. Mu.L 1640 complete medium was added, 37 ℃,5% CO 2 The culture was carried out overnight in an incubator.
The next day, drug gradient dilution: drug concentrations were diluted to 100. Mu.M, 50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M and 3.125. Mu.M with 1640 complete medium gradient.
PC9 and a549 cells were plated 24 hours later and treated with a drug. The original culture medium in the 96-well plate is removed by suction, a newly prepared culture medium containing the drugs is added, 100ul of the culture medium is added into each well, and more than three wells are prepared for each drug concentration. Followed by placing in a 37 ℃ cell culture chamber (containing 5% CO) 2 ) And culturing for 48 hours.
On day four, 10. Mu. LMTT solution (5 mg/mL) was added per well, at 37 ℃,5% CO, protected from light 2 The culture was carried out in an incubator for 4 hours. After 4 hours, the MTT solution in the 96-well plate is sucked up by using a 1mL syringe, then 100 mul of DMSO is added to dissolve the purple formazan crystals, and the mixture is shaken on a shaking table at a low speed for 10min so that the crystals are fully dissolved. The absorbance of each well was measured at OD570 nm using an enzyme linked immunosorbent assay.
4. And (3) data analysis:
cell viability was calculated according to the following formula:
cell viability = (OD drug group-OD blank)/(OD control-OD blank) X100%
OD blank is cell-free medium group
OD control group is tumor cell drug-free group
OD drug group is tumor cell drug group
5. The experimental results are as follows:
under the experimental condition, the tested compound has certain inhibitory activity on the proliferation of human non-small cell lung cancer cell lines A549 and PC 9. Half Inhibitory Concentration (IC) of Compound 49 in PC9 50 ) Is similar to the positive control drug cisplatin. The following table lists the IC of the test compounds after treatment of A549 and PC9 50 The specific results are shown in table 1 below.
TABLE 1 IC of test Compounds after treatment of A549 and PC9 50 Results
Figure BDA0003809834990000371
Figure BDA0003809834990000381
Example 57: cell proliferation inhibition experiment of human leukemia cell HL60, human leukemia cell K562 and human lymphoma cell Raji with Compound 18
1. Brief introduction of experimental principles:
the Cell Counting Kit-8 (CCK-8 for short) reagent can be used for simple and accurate Cell proliferation and toxicity analysis. The basic principle is as follows: the reagent contains WST-8 [ chemical name: 2- (2-Methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2,4-disulfonic acid benzene) -2H-tetrazole monosodium salt ] which is reduced by dehydrogenases in cells to a yellow Formazan product (Formazan dye) with high water solubility under the action of the electron carrier 1-Methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced was proportional to the number of living cells.
2. Experimental materials and instruments:
human leukemia cell HL60, human leukemia cell K562 and human lymphoma cell Raji; the cell lines are all frozen and passaged in the laboratory.
96-well plates were purchased from Corning (USA).
DMEM medium was purchased from Thermo Fisher Scientific.
FBS was purchased from Transgen (Beijing, china).
Other materials:
full-wavelength multifunctional microplate reader: the model is as follows: varioskan Flash manufacturer: thermo scientific
Culture solution: DMEM Medium +10% FBS + Dual antibody
3. Experimental methods
Sample preparation: after 10mM in DMSO (Merck), 1000M solution or homogeneous suspension was prepared by adding PBS (-) and then diluted with DMSO-containing PBS (-). The final concentration of the sample was 100, 10, 1, 0.1, 0.01, 0.001M. CCK-8 method. 96 well plates were added 100L of cell suspension at a concentration of 3X 104/mL per well, incubated at 37 ℃ and 5% CO 2 In the incubator. 24h later, the sample solution was added at 10L/well in duplicate wells at 37 ℃ with 5% CO 2 The reaction is carried out for 72 hours. Adding 10L of CCK-8 solution into each hole, placing in an incubator, acting for 2.5h, and measuring 450nm OD value with a full-wavelength multifunctional microplate reader.
4. The experimental results are as follows:
under the experimental conditions, the tested compound has certain inhibitory activity on the proliferation of human leukemia cell HL60, human leukemia cell K562 and human lymphoma cell Raji. Table 2 below lists the IC of the test compounds after treatment of human leukemia cells HL60, human leukemia cells K562 and human lymphoma cells Raji 50 。
TABLE 2 IC after treatment of HL60, K562 and Raji cells with test Compounds 50
Test compounds HL60 IC 50 (μM) K562 IC 50 (μM) RajiIC 50 (μM)
Compound 18 25.47 30.34 53.25

Claims (10)

1. The beta-carboline compounds or the pharmaceutically acceptable salts thereof are characterized in that the structural formula of the beta-carboline compounds is shown as the formula (I)
Figure FDA0003809834980000011
Wherein the content of the first and second substances,
R 1 is composed of
Figure FDA0003809834980000012
Preferably, wherein R is 1a Is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, vinyl, ethynyl, alkyloxyacyl, aryloxyoyl, alkylaminoacyl, cyano, carboxyl, alkylacyl, arylacyl, heterocyclyl, aryl, or heteroaryl;
R 2a ，R 3a independently H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkanoyl, cycloalkylacyl, alkyloxyacyl, arylalkyloxyacyl, alkylaminoacyl, arylacyl, or arylalkyl;
R 4a ，R 5a independently H, halogen, cyano, hydroxy, carboxy, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkyloxy, aryl, heteroaryl, alkylamino, alkylacyloxy, arylalkyloxy, arylacyloxy or heterocyclyl;
m, n are independently 0, 1,2 or 3;
x is O, S, CH 2 SO or SO 2 ；
R 2 Is H, alkyloxyformyl, aryloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, aryl, heteroaryl or heterocyclyl;
R 3 is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, aryl or heteroaryl;
R 4 is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkyloxy, arylalkyloxy, halogen, hydroxy, aryl, cyano, carboxy, heteroaryl, alkylacyloxy, aryloyloxy, alkylamino, arylamino, heteroarylamino, or heterocyclyl;
R 5 is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, heterocyclyl, alkylacyl, arylacyl, heteroarylacyl, arylalkyl or heteroarylalkyl.
2. The beta-carboline compounds or pharmaceutically acceptable salts thereof according to claim 1, wherein the structural formula of the beta-carboline compounds is shown as formula (II)
Figure FDA0003809834980000013
Wherein R is 2 Is H or alkyloxyacyl;
R 3 is H or C 1-4 An alkyl group;
R 4 is H, C 1-4 Alkyl, alkyloxy, halogen, hydroxy or aryl;
R 5 is H, C 1-4 Alkyl, arylalkyl or alkanoyl.
3. The beta-carboline compounds or pharmaceutically acceptable salts thereof according to claim 1, wherein the structural formula of the beta-carboline compounds is shown as formula (III)
Figure FDA0003809834980000021
Wherein R is 1a Is H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, vinyl, ethynyl, alkyloxyacyl, or aryl;
R 2a ，R 3a independently H, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, alkanoyl, cycloalkylacyl, arylacyl, alkyloxyacyl or arylalkyloxyacyl;
R 4a is H, alkyloxy, hydroxy or halogen;
x is O, S, CH 2 SO or SO 2 ；
m and n are independently 0, 1,2 or 3.
4. The beta-carboline compounds or pharmaceutically acceptable salts thereof according to claim 1, wherein the structural formula of the beta-carboline compounds is shown as formula (IV)
Figure FDA0003809834980000022
Wherein R is 1a Is H, halogen, cyano, C 1-4 Alkyl, alkoxy, aryl, alkylacyloxy or arylalkyloxy;
R 2a ，R 3a independently H, C 1-4 Alkyl, alkanoyl, cycloalkylacyl, arylacyl, alkyloxyacyl or arylalkyloxyacyl;
R 4a h, alkoxy, hydroxyl and halogen.
5. The beta-carboline compounds or pharmaceutically acceptable salts thereof according to claim 1, wherein the beta-carboline compounds comprise any one of the following compounds:
Figure FDA0003809834980000031
Figure FDA0003809834980000041
6. the use of a β -carboline compound, or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, in the manufacture of a medicament for the treatment or prevention of a neoplastic disease.
7. Use according to claim 6, characterized in that said neoplastic diseases comprise lung cancer, leukemia and lymphoma.
8. The use of a class of β -carboline compounds according to any one of claims 1-5, or isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof, for inhibiting the proliferative activity of human non-small cell lung cancer a549 and PC9 cells, human leukemia cells HL60, human leukemia cells K562 and human lymphoma cells Raji.
9. A pharmaceutical composition comprising a β -carboline compound, or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, and a pharmaceutically acceptable excipient.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is in the form of solid, semi-solid, liquid or gaseous formulation, such as tablet, pill, capsule, powder, granule, paste, emulsion, suspension, suppository, injection, inhalant, gel, microsphere and aerosol.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014057436A2 (en) * 2012-10-10 2014-04-17 Adamed Sp. Z O.O. Anticancer conjugate
CN104177377A (en) * 2013-05-20 2014-12-03 新疆华世丹药物研究有限责任公司 3-Position diamine beta-carboline alkali compound, and preparation method, medicinal composition and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014057436A2 (en) * 2012-10-10 2014-04-17 Adamed Sp. Z O.O. Anticancer conjugate
CN104177377A (en) * 2013-05-20 2014-12-03 新疆华世丹药物研究有限责任公司 3-Position diamine beta-carboline alkali compound, and preparation method, medicinal composition and use thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AHMED KAMAL ET AL.: "An efficient one-pot decarboxylative aromatization of tetrahydro-β-carbolines by using N -chlorosuccinimide: total synthesis of norharmane, harmane and eudistomins" *
JAMES MCNULTY ET AL.: "Diastereoselective Pictet-Spengler reactions of L-(Boc)phenylalaninal and L-(Boc)prolinal: biomimetic syntheses of eudistomin T and (-)-woodinine" *
KOBAYASHI, JUNICHI ET AL.: "Eudistomidins B, C, and D: novel antileukemic alkaloids from the Okinawan marine tunicate Eudistoma glaucus" *
MU-PENG LUO ET AL.: "Photocatalytic enantioselective Minisci reaction of β-carbolines and application to natural product synthesis" *
PU YONG ZHANG ET AL.: "First total synthesis of eudistalbin A" *
RHYS FINLAYSON ET AL.: "Establishment of the absolute configuration of the bioactive marine alkaloid eudistomin X by stereospecific synthesis" *
RINEHART, KENNETH L. ET AL.: "Eudistomins A-Q, β-carbolines from the antiviral Caribbean tunicate Eudistoma olivaceum" *

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