CN104693092A - Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof - Google Patents
Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof Download PDFInfo
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- CN104693092A CN104693092A CN201510083031.2A CN201510083031A CN104693092A CN 104693092 A CN104693092 A CN 104693092A CN 201510083031 A CN201510083031 A CN 201510083031A CN 104693092 A CN104693092 A CN 104693092A
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- chiral
- phosphoric acid
- dissolved
- catalyst
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- -1 3,3-disubstituted oxoindole Chemical class 0.000 title claims description 54
- 238000010189 synthetic method Methods 0.000 title claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 40
- 239000003054 catalyst Substances 0.000 claims abstract description 36
- 229910052751 metal Inorganic materials 0.000 claims abstract description 33
- 239000002184 metal Substances 0.000 claims abstract description 33
- 239000002808 molecular sieve Substances 0.000 claims abstract description 31
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000004440 column chromatography Methods 0.000 claims abstract description 30
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 claims abstract description 16
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 16
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 11
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
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- 239000003426 co-catalyst Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 239000000654 additive Substances 0.000 claims abstract description 3
- 125000004095 oxindolyl group Chemical class N1(C(CC2=CC=CC=C12)=O)* 0.000 claims abstract 10
- GGFAZNCZEXSGIY-UHFFFAOYSA-N 4-diazo-1,3a-dihydroindole-2,3-dione Chemical compound [N-]=[N+]=C1C=CC=C2NC(=O)C(=O)C12 GGFAZNCZEXSGIY-UHFFFAOYSA-N 0.000 claims abstract 7
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- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 2
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 4
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- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical group CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 claims 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229960005081 diclofenamide Drugs 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- ZGZLUDDEYVIROA-UHFFFAOYSA-N gliocladin C Natural products C1=CC=C2C(C34C=C5C(=O)N(C(C(=O)N5C4NC=4C3=CC=CC=4)=O)C)=CNC2=C1 ZGZLUDDEYVIROA-UHFFFAOYSA-N 0.000 description 1
- MRBZKCMQZBKXMZ-UHFFFAOYSA-N gliocladine C Natural products C1=CC=C2C(C34C5=CC=CC=C5NC3N3C(=O)C5(C)SSC3(C4O)C(=O)N5C)=CNC2=C1 MRBZKCMQZBKXMZ-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 150000002503 iridium Chemical class 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940100243 oleanolic acid Drugs 0.000 description 1
- 125000000955 oleanolic acid group Chemical group 0.000 description 1
- 150000002907 osmium Chemical class 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 description 1
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940074386 skatole Drugs 0.000 description 1
- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical compound OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 description 1
- ZEANERNKMXBETI-BJHDJDSNSA-N win-64821 Chemical compound C([C@@H]1NC([C@H]2N([C@@H]3[C@@](C4=CC=CC=C4N3)(C2)[C@@]23[C@@H](N4[C@H](C(N[C@@H](CC=5C=CC=CC=5)C4=O)=O)C2)NC=2C3=CC=CC=2)C1=O)=O)C1=CC=CC=C1 ZEANERNKMXBETI-BJHDJDSNSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及一种具有PTP1B抑制作用的新型的手性3，3-二取代氧化吲哚衍生物的化学合成方法。本发明以重氮靛红、吲哚、芳胺和醛酸酯为原料，以金属催化剂为催化剂，以手性磷酸为共催化剂，以有机溶剂为溶剂，以分子筛为添加剂，在25℃条件下经过一步反应，柱层析提纯即得到产物。本发明具有步骤经济性、原子经济性、非对映选择性和对映选择性高及收率高的优势，且反应条件温和，操作简单安全。本发明合成的具有两个手性中心的光学纯3，3-二取代氧化吲哚衍生物是重要的化工、化学和医药中间体，在医药化工领域具有广泛应用前景。The invention relates to a chemical synthesis method of novel chiral 3, 3-disubstituted oxindole derivatives with PTP1B inhibitory effect. The present invention uses diazo isatin, indole, arylamine and alkyd ester as raw materials, metal catalyst as catalyst, chiral phosphoric acid as co-catalyst, organic solvent as solvent, and Molecular sieve is an additive, and the product can be obtained after one-step reaction at 25°C and purification by column chromatography. The invention has the advantages of step economy, atom economy, high diastereoselectivity and enantioselectivity and high yield, and the reaction conditions are mild, and the operation is simple and safe. The optically pure 3,3-disubstituted oxindole derivative with two chiral centers synthesized by the invention is an important chemical, chemical and pharmaceutical intermediate, and has wide application prospects in the field of pharmaceutical and chemical engineering.
Description
Technical field
The present invention relates to a kind of novel chiral 3,3-bis-and replace oxoindole derivative and synthetic method thereof and application, belong to pharmaceutical intermediate Synthesis and applications field.
Background technology
It is the important skeleton structure unit that a class builds natural product and synthetic drugs that chirality 3,3-bis-replaces oxoindole derivative, all containing this type of skeleton structure in many Structures of Natural Products.Ring tryptamines alkaloid (Cyclotryptamine) extensively also exists 3,3-bis-and replaces Oxoindole skeleton structure.Such as, SP receptor antagonist (the J.Antibiot. that natural compounds (+)-WIN 64821 obtained is a kind of potential neurokinin (NK-1) acceptor and cholecystokinin B (cholecystokinin B) acceptor is separated from aspergillus, 1994,47,411; J.Antibiot., 1994,47,399; J.Antibiot., 1994,47,391).Chaetocin (Chaetocin) not only has well antibacterial and cell growth inhibiting activity, and be a kind of potential istone lysine specific methylation transferring enzyme (HMTs) inhibitor (Nat.Chem.Biol., 2005,1,143).Extensively there is 3,3-bis-in epidithio-dioxypiperazine piperazine (ETP) alkaloid and replace this skeleton of Oxoindole.Such as, leptosin D (leptosin D) has cytotoxin effect (J.Antibiot., 1994,47,1242) to the strain of P-388 lymphocytic leukemia cells.A and B (BionectinsA and B) can be determined than Ou Na and have anti-microbial activity (J.Nat.Prod. to methicillin-resistant staphylococcus aureus (MRSA) and resistance to quinolone streptococcus aureus (QRSA), 2006,69,1816).In addition, 3,3-bis-replaces oxoindole derivative and also can be used for synthesis other antitumor drugs numerous, microbiotic, antifungal drug etc.The discovery that new chirality 3,3-bis-replaces oxoindole derivative provides good basis with the Physiologic Studies synthesizing such important chemical combination, is the new opportunity (Angew.Chem.Int.Ed., 2013,52,2486) that new drug molecule finds.
In view of chirality 3,3-bis-replaces the vital role of oxoindole derivative, develop its simple and practical synthetic method and just there is very important theory significance and economic worth.This skeleton structure is more crowded from space structure, and sterically hindered very large, chirality control method is single, and these all considerably increase the chiral synthesize difficulty of this skeleton.In recent years, organic chemist has developed a series of different route and synthetic method.Such as, Overman seminar, in gliocladin C (Gliocladine C) complete synthesis research, uses Fe catalysis successfully to obtain 3,3-bis-of key first and replaces Oxoindole structure (J.Am.Chem.Soc., 2011,133,6549).Stephenson seminar uses light-sensitive catalyst Ru also to complete the structure (Angew.Chem.Int.Ed., 2011,50,9655) of such important skeleton structure.Zhang Junliang seminar successfully constructs the new chirality of a class 3,3-bis-by the Michael reaction of micromolecule catalyst catalysis and replaces oxoindole derivative (Org.Lett., 2013,15,2266).C-H functionalization/Michael reaction synthesis of chiral 3,3-bis-that Gong Liuzhu seminar has developed a routine Ru and chiral squaric acid amide relay catalysis replaces the novel method (Angew.Chem.Int.Ed., 2014,53,10763) of oxoindole derivative.But these routes and synthetic method much all exist Material synthesis complexity, reactions steps is many, long reaction time, cost are high, productive rate is low, operation and the shortcoming such as aftertreatment is loaded down with trivial details, its practical and economic worth is very restricted.Thus a kind of highly effective is developed and wide such 3,3-bis-method replacing oxoindole derivative of synthesis of universality is the new challenge that modern organic synthesis chemist faces.
Summary of the invention
The object of the invention is openly the chemical synthesis process that a kind of cost is low, yield is high, reaction conditions is gentle, selectivity is good, a kind of novel optical purity 3,3-bis-with two adjacent chiral centres and PTP1B inhibit activities of the simple one-step synthesis of wide application range of substrates, operational safety replaces oxoindole derivative.Replace oxoindole derivative according to the chirality 3,3-bis-of the present invention's synthesis and show good PTP1B restraining effect.
Multi-component reaction has high convergency, atom economy and the efficient ability building complex compound.Two more traditional component reaction, multi-component reaction is close to desirable synthesis mode.Growing in recent years along with Atom economy and step economy concept, multi-component reaction becomes the focus of research day by day, therefore multi-component reaction is applied to pharmaceutical synthesis field and has very wide prospect and numerous potential advantages.For this reason, design diazonium isatin of the present invention, indoles, arylamine, aldehydic acid ester are raw material, metal Lewis acids catalyzer and the syncatalytic Four composition reaction of chiral phosphoric acid catalyzer, one-step synthesis goes out a series ofly to be had 3,3-bis-of PTP1B inhibit activities and high enantioselectivity and replaces oxoindole derivative.Its general formula is as follows:
formula (5);
Wherein:
R
1for alkyl; It comprises benzyl, methyl, ethyl;
R
2for benzyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz);
R
3for hydrogen atom, halogen atom, alkyl, alkoxyl group, nitro; Wherein, described alkyl comprises methyl, ethyl, sec.-propyl; Described alkoxyl group is methoxyl group, oxyethyl group, tert.-butoxy;
R
4for hydrogen atom, halogen atom, alkyl, alkoxyl group; Wherein, described alkyl comprises methyl, ethyl, sec.-propyl; Described alkoxyl group is methoxyl group, oxyethyl group, tert.-butoxy;
Ar is aryl; It comprises phenyl, to bromophenyl, rubigan, 3,4-dichlorophenyls, 3,5-dichlorophenyls, to fluorophenyl, p-methylphenyl.
Chemical reaction mechanism involved in the present invention is shown below: under metal catalytic, diazo decomposition forms metal carbene (I), the zwitter-ion that metal carbene and indoles are formed to (IIa/IIb) by arylamine under chiral phosphoric acid catalysis and the imines (III) that generates of aldehydic acid ester scene catch (Mannich-type trapping), the intermediate compound IV obtained is by follow-up hydrogen migration process (H transferprocess), one step formed have high yield, high cis-selectivity, high enantioselectivity 3,3-bis-replace oxoindole derivative.
The synthesizing new chirality 3 that the present invention proposes, 3-bis-replaces the method for oxoindole derivative, with diazonium isatin, indoles, arylamine and aldehydic acid ester for raw material, with metal catalyst (MLn) for catalyzer, with chiral phosphoric acid (Chiral PPA) for co-catalyst, take organic solvent as solvent, with
molecular sieve
for additive, react, it is characterized in that under 25 DEG C of conditions, the chirality 3,3-bis-namely obtaining having PTP1B inhibit activities through a step Four composition reaction replaces oxoindole derivative; Described synthetic method reaction equation as follows:
Wherein:
R
1for alkyl; It comprises benzyl, methyl, ethyl;
R
2for benzyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz);
R
3for hydrogen atom, halogen atom, alkyl, alkoxyl group, nitro; Wherein, described alkyl comprises methyl, ethyl, sec.-propyl; Described alkoxyl group is methoxyl group, oxyethyl group, tert.-butoxy;
R
4for hydrogen atom, halogen atom, alkyl, alkoxyl group; Wherein, described alkyl comprises methyl, ethyl, sec.-propyl; Described alkoxyl group is methoxyl group, oxyethyl group, tert.-butoxy;
Ar is aryl; It comprises phenyl, to bromophenyl, rubigan, 3,4-dichlorophenyls, 3,5-dichlorophenyls, to fluorophenyl, p-methylphenyl.
In building-up reactions of the present invention, under metal catalytic, diazo decomposition forms metal carbene, the zwitter-ion that metal carbene and indoles are formed to by arylamine under chiral phosphoric acid catalysis and the imines that generates of aldehydic acid ester scene catch, one step formed have high yield, high cis-selectivity, high enantioselectivity 3,3-bis-replace oxoindole derivative.
In the present invention, described diazonium compound comprises diazonium isatin, all kinds of nitrogen replaces diazonium isatin, all kinds of aryl replaces diazonium isatin etc.; Described indoles comprises all kinds of nitrogen substituted indole, all kinds of aryl substituted indoles etc.; Described arylamine comprises without substituted aniline, all kinds of substituted aromatic amines etc.; Described aldehydic acid ester is glyoxylic acid ethyl ester etc.; Described organic solvent comprises methylene dichloride, trichloromethane, toluene, 1,2-ethylene dichloride, dimethylbenzene etc.
In the present invention, described metal catalyst be all can the metallic compound of catalysis diazo decomposition; Such as, described metal catalyst is metal Lewis acids catalyzer, such as metal rhodium class, metallic copper class, palladium metal class, metal Ru class, metal osmium class, metal iridium class, cobalt metal class, metallic iron class, metallic nickel class, metal platinum class etc.
In the present invention, the described chiral phosphoric acid as co-catalyst is S type, its structure such as formula shown in (A), wherein, R is that triphenyl is silica-based, 9-phenanthryl, phenyl, 3,4,5-trifluorophenyl, 3,5-difluorophenyl, 3,5-bis-(trifluoromethyl) phenyl, 3,5-dichlorophenyl, 2,4,6-triisopropyl phenyl, p-methylphenyl, p-methoxyphenyl or 4-xenyl;
formula (A).
Synthesis of chiral 3,3-bis-of the present invention replaces the process of oxoindole derivative, comprises and is dissolved in organic solvent by arylamine, aldehydic acid ester, metal Lewis acids catalyzer and chiral phosphoric acid catalyzer under 25 DEG C of conditions; Then the mixture of the benzazolyl compounds dissolved in organic solvent, diazonium compound is added drop-wise in reaction system at 25 DEG C in 1h, after dropwising, except desolventizing, obtains crude product; Be ethyl acetate by crude product volume ratio: sherwood oil=1: the solution of 30 ~ 1: 10 carries out column chromatography, the chirality 3,3-bis-that obtains of high yield, high cis-selectivity and high enantioselectivity replaces oxoindole derivative.
In the inventive method, the mol ratio of raw material and catalyzer is indoles: diazonium isatin: arylamine: aldehydic acid ester: metal catalyst: chiral phosphoric acid=1.1: (1.0-1.1): (1.1-1.2): (1.1-1.2): (0.01-0.02): (0.05-0.10);
the add-on of molecular sieve with diazonium isatin for benchmark is for 100mg/mmol; The add-on of described organic solvent with diazonium isatin for benchmark is for 1ml/mmol.
In the inventive method, the method for crude product separation and purification is by ethyl acetate: sherwood oil volume ratio be 1: 30 ~ 1: 10 moving phase carry out column chromatography.
In a specific embodiment, novel chiral 3, the 3-bis-of the present invention synthetic method that replaces oxoindole derivative is as follows: by arylamine (0.33mmol, 1.1eq), aldehydic acid ester (0.36mmol, 1.2eq),
molecular sieve (300mg), metal Lewis acids catalyzer (0.006mmol) and chiral phosphoric acid catalyzer (0.015mmol) are dissolved in (1.5ml) in organic solvent under 25 DEG C of conditions; Then, diazonium compound (the 0.30mmol in organic solvent (1.5ml) will be dissolved in, 1.0eq) with benzazolyl compounds (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.
The invention allows for a kind of prepare by above-mentioned synthetic method 3,3-bis-replace oxoindole derivative, its structure is such as formula shown in (5).It is important chemical industry, chemistry and medicine intermediate that the optical purity 3,3-bis-with two chiral centres of the present invention's synthesis replaces oxoindole derivative.
The invention allows for a kind of newly 3,3-bis-replace oxoindole derivative, its structure such as formula shown in (5),
formula (5);
Wherein:
R
1for alkyl; It comprises benzyl, methyl, ethyl;
R
2for benzyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz);
R
3for hydrogen atom, halogen atom, alkyl, alkoxyl group, nitro; Wherein, described alkyl comprises methyl, ethyl, sec.-propyl; Described alkoxyl group is methoxyl group, oxyethyl group, tert.-butoxy;
R
4for hydrogen atom, halogen atom, alkyl, alkoxyl group; Wherein, described alkyl comprises methyl, ethyl, sec.-propyl; Described alkoxyl group is methoxyl group, oxyethyl group, tert.-butoxy;
Ar is aryl; It comprises phenyl, to bromophenyl, rubigan, 3,4-dichlorophenyls, 3,5-dichlorophenyls, to fluorophenyl, p-methylphenyl.
Preferably, R
1for benzyl, methyl; R
2for benzyl, tertbutyloxycarbonyl; R
3for hydrogen atom, halogen atom; R
4for hydrogen atom, halogen atom; Ar is phenyl, to bromophenyl.
More preferably, R
1for benzyl; R
2for tertbutyloxycarbonyl; R
3for hydrogen atom; R
4for hydrogen atom; Ar is to bromophenyl.
Further, R
1for benzyl, methyl; R
2for benzyl, tertbutyloxycarbonyl; R
3for hydrogen atom, halogen atom, methyl, methoxyl group, nitro; R
4for hydrogen atom, halogen atom, methyl; Ar be phenyl, to bromophenyl, rubigan, 3,4-dichlorophenyls, 3,5-dichlorophenyls, to fluorophenyl, p-methylphenyl.
The invention allows for a kind of described chirality 3,3-bis-and replace the application of oxoindole derivative in the suppression medicine of preparation obesity specific target gene-PTP 1B.
Reaction mechanism involved in the present invention is: under metal catalytic, diazo decomposition forms metal carbene, the zwitter-ion that metal carbene and indoles are formed to by arylamine under chiral phosphoric acid catalysis and the imines that generates of aldehydic acid ester scene catch, one step formed have high yield, high cis-selectivity, high enantioselectivity 3,3-bis-replace oxoindole derivative.Beneficial effect of the present invention comprises: build the novel chiral 3,3-bis-with two adjacent chiral centres by a step multi-component reaction and replace oxoindole derivative, its reaction conditions is gentle, yield is high, selectivity good, substrate applicability is wide, operational safety is simple.The chirality 3,3-bis-of synthesis replaces oxoindole derivative originally has important application in bioprotein and enzyme research aspect, has economic serviceability very by force.The present invention has step economy, Atom economy, cis-selectivity and the advantage that enantioselectivity is high and yield is high, and reaction conditions is gentle, safety simple to operate.It is important chemical industry, chemistry and medicine intermediate that the novel optical pure 3,3-bis-of what the present invention obtained have two chiral centres replaces oxoindole derivative, very extensive in field of medicine and chemical technology application, therefore has great application prospect.
Accompanying drawing explanation
Figure 1 shows that for embodiment 25,3,3-bis-steric configurations replacing oxoindole derivative that the present invention prepares are defined as (2S, 3S) by single crystal diffraction.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.
Embodiment 1:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the chiral phosphoric acid catalyzer (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and the silica-based replacement of triphenyl is dissolved in (1.5m1) in methylene dichloride under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in methylene dichloride (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 86% to 72%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.51-7.49(m，1H)，7.45-7.41(m，2H)，7.27-7.22(m，4H)，7.20-7.14(m，3H)，7.12-7.08(m，1H)，7.05(s，1H)，7.03-6.99(m，3H)，6.78-6.75(m，3H)，5.38(d，J＝10.6Hz，1H)，5.17(s，2H)，4.69(d，J＝10.3Hz，1H)，3.77-3.70(m，2H)，1.60(s，9H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，170.94，149.28，146.18，140.69，137.01，136.94，129.46，129.28，128.74，128.49，127.67，127.21，126.69，126.58，125.87，124.41，122.08，121.41，119.85，119.21，115.38，114.83，111.05，109.92，84.49，62.44，60.93，54.71，50.20，28.10，13.29；HRMS(ESI)calcd for C
38H
37N
3NaO
5[M+Na]
+＝638.2631，found 638.2644.
Embodiment 2:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.33mmol, 1.1eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in toluene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in toluene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is that 25 DEG C are added drop-wise in reaction system in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 86% to 80%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.51-7.49(m，1H)，7.45-7.41(m，2H)，7.27-7.22(m，4H)，7.20-7.14(m，3H)，7.12-7.08(m，1H)，7.05(s，1H)，7.03-6.99(m，3H)，6.78-6.75(m，3H)，5.38(d，J＝10.6Hz，1H)，5.17(s，2H)，4.69(d，J＝10.3Hz，1H)，3.77-3.70(m，2H)，1.60(s，9H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，170.94，149.28，146.18，140.69，137.01，136.94，129.46，129.28，128.74，128.49，127.67，127.21，126.69，126.58，125.87，124.41，122.08，121.41，119.85，119.21，115.38，114.83，111.05，109.92，84.49，62.44，60.93，54.71，50.20，28.10，13.29；HRMS(ESI)calcd for C
38H
37N
3NaO
5[M+Na]
+＝638.2631，found 638.2644.
Embodiment 3:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
molecular sieve (300mg), rhodium acetate (0.006mmol) and 3,5-difluorophenyl substituted chiral phosphoric acid catalyst (0.015mmol) are dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 92% to 75%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.51-7.49(m，1H)，7.45-7.41(m，2H)，7.27-7.22(m，4H)，7.20-7.14(m，3H)，7.12-7.08(m，1H)，7.05(s，1H)，7.03-6.99(m，3H)，6.78-6.75(m，3H)，5.38(d，J＝10.6Hz，1H)，5.17(s，2H)，4.69(d，J＝10.3Hz，1H)，3.77-3.70(m，2H)，1.60(s，9H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，170.94，149.28，146.18，140.69，137.01，136.94，129.46，129.28，128.74，128.49，127.67，127.21，126.69，126.58，125.87，124.41，122.08，121.41，119.85，119.21，115.38，114.83，111.05，109.92，84.49，62.44，60.93，54.71，50.20，28.10，13.29；HRMS(ESI)calcd for C
38H
37N
3NaO
5[M+Na]
+＝638.2631，found 638.2644.
Embodiment 4:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
molecular sieve (300mg), rhodium acetate (0.006mmol) and 9-phenanthryl substituted chiral phosphoric acid catalyst (0.015mmol) are dissolved in (1.5ml) in 1,2-ethylene dichloride under 25 DEG C of conditions; Then, to 1 be dissolved in, N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in 2-ethylene dichloride (1.5ml), 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 66% to 74%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.51-7.49(m，1H)，7.45-7.41(m，2H)，7.27-7.22(m，4H)，7.20-7.14(m，3H)，7.12-7.08(m，1H)，7.05(s，1H)，7.03-6.99(m，3H)，6.78-6.75(m，3H)，5.38(d，J＝10.6Hz，1H)，5.17(s，2H)，4.69(d，J＝10.3Hz，1H)，3.77-3.70(m，2H)，1.60(s，9H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，170.94，149.28，146.18，140.69，137.01，136.94，129.46，129.28，128.74，128.49，127.67，127.21，126.69，126.58，125.87，124.41，122.08，121.41，119.85，119.21，115.38，114.83，111.05，109.92，84.49，62.44，60.93，54.71，50.20，28.10，13.29；HRMS(ESI)calcd for C
38H
37N
3NaO
5[M+Na]
+＝638.2631，found 638.2644.
Embodiment 5:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
molecular sieve (300mg), palladium (0.006mmol) and p-methoxyphenyl substituted chiral phosphoric acid catalyst (0.015mmol) are dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 73% to 59%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.51-7.49(m，1H)，7.45-7.41(m，2H)，7.27-7.22(m，4H)，7.20-7.14(m，3H)，7.12-7.08(m，1H)，7.05(s，1H)，7.03-6.99(m，3H)，6.78-6.75(m，3H)，5.38(d，J＝10.6Hz，1H)，5.17(s，2H)，4.69(d，J＝10.3Hz，1H)，3.77-3.70(m，2H)，1.60(s，9H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，170.94，149.28，146.18，140.69，137.01，136.94，129.46，129.28，128.74，128.49，127.67，127.21，126.69，126.58，125.87，124.41，122.08，121.41，119.85，119.21，115.38，114.83，111.05，109.92，84.49，62.44，60.93，54.71，50.20，28.10，13.29；HRMS(ESI)calcd for C
38H
37N
3NaO
5[M+Na]
+＝638.2631，found 638.2644.
Embodiment 6:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.1eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), cyclooctadiene network rhodium chloride (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.3mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 73% to 57%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.51-7.49(m，1H)，7.45-7.41(m，2H)，7.27-7.22(m，4H)，7.20-7.14(m，3H)，7.12-7.08(m，1H)，7.05(s，1H)，7.03-6.99(m，3H)，6.78-6.75(m，3H)，5.38(d，J＝10.6Hz，1H)，5.17(s，2H)，4.69(d，J＝10.3Hz，1H)，3.77-3.70(m，2H)，1.60(s，9H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，170.94，149.28，146.18，140.69，137.01，136.94，129.46，129.28，128.74，128.49，127.67，127.21，126.69，126.58，125.87，124.41，122.08，121.41，119.85，119.21，115.38，114.83，111.05，109.92，84.49，62.44，60.93，54.71，50.20，28.10，13.29；HRMS(ESI)calcd for C
38H
37N
3NaO
5[M+Na]
+＝638.2631，found 638.2644.
Embodiment 7:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 97% to 94%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.49-7.38(m，3H)，7.26-7.16(m，7H)，7.12-7.07(m，1H)，7.00(t，J＝6.9Hz，4H)，6.66-6.57(m，2H)，5.33-5.25(m，1H)，5.16(s，2H)，4.81(d，J＝9.7Hz，1H)，3.78-3.70(m，2H)，1.60(s，9H)，0.67(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.97，170.54，149.22，145.20，140.61，136.99，136.85，132.06，129.58，128.79，128.24，127.77，127.11，126.81，126.45，125.77，124.52，122.19，121.20，119.95，116.31，115.44，111.02，110.94，109.99，84.64，62.41，61.13，54.48，50.19，28.12，13.34；HRMS(ESI)calcd forC
38H
36BrN
3NaO
5[M+Na]
+＝716.1736，found 716.1682.
Embodiment 8:
By p-Chlorobenzoic acid amide (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the mixture of N-tertbutyloxycarbonyl diazonium isatin (0.30mmol, 1.0eq) in dimethylbenzene (1.5ml) and N-benzylindole (0.33mmol, 1.1eq) will be dissolved in 25 DEG C.Be added drop-wise in 1h in reaction system, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 97% to 70%, dr value.
1H NMR(400MHz，CDCl3)δ7.99(d，J＝8.1Hz，1H)，7.49-7.38(m，3H)，7.26-7.16(m，7H)，7.12-7.07(m，1H)，7.00(t，J＝6.9Hz，4H)，6.66-6.57(m，2H)，5.33-5.25(m，1H)，5.16(s，2H)，4.81(d，J＝9.7Hz，1H)，3.78-3.70(m，2H)，1.60(s，9H)，0.67(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.93，170.60，149.20，144.73，140.61，136.97，136.84，129.54，129.14，128.76，128.25，127.74，127.05，126.77，126.45，125.77，124.47，123.87，122.16，121.25，119.91，115.90，115.41，110.91，109.94，84.61，62.53，61.08，54.54，50.18，28.09，13.29；HRMS(ESI)calcd forC
38H
36BrN
3NaO
5[M+Na]
+＝672.2241，found 672.2198.
Embodiment 9:
By open-chain crown ether (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 49% to 58%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.2Hz，1H)，7.54-7.40(m，3H)，7.29-7.14(m，6H)，7.12-7.07(m，1H)，7.06-6.95(m，6H)，6.68(d，J＝8.4Hz，2H)，5.36(d，J＝10.9Hz，1H)，5.17(s，2H)，4.48(d，J＝10.5Hz，1H)，3.77-3.67(m，2H)，2.22(s，3H)，1.59(s，9H)，0.62(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.87，171.15，149.32，143.88，140.77，137.07，136.96，129.78，129.43，128.74，128.58，128.57，127.66，127.20，126.68，126.66，125.94，124.35，122.07，121.60，119.82，115.38，115.21，111.07，109.90，84.43，62.89，60.85，54.95，50.19，28.11，20.50，13.28；HRMS(ESI)calcd for C
39H
39N
3NaO
5[M+Na]
+＝652.2787，found 652.2831.
Embodiment 10:
By para-fluoroaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 78% to 71%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.53-7.50(m，2H)，7.46-7.41(m，1H)，7.29-7.18(m，5H)，7.13-7.09(m，1H)，7.05-7.01(m，3H)，6.98(s，1H)，6.88-6.83(m，2H)，6.71-6.68(m，2H)，5.31(d，J＝10.8Hz，1H)，5.22-5.13(m，2H)，4.44(d，J＝10.7Hz，1H)，3.77-3.70(m，2H)，1.59(s，9H)，0.62(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.90，171.02，156.94(d，
1J
C-F＝237.2Hz)，149.25，142.50(d，
4J
C-F＝2.1Hz)，140.75，137.02，136.97，129.50，128.76，128.45，127.72，126.98，126.71，126.59，125.89，124.38，122.15，121.64，119.88，116.43(d，
3J
C-F＝7.6Hz)，115.71(d，
2J
C-F＝22.4Hz)，115.42，110.90，109.92，84.53，63.36，60.98，55.09，50.17，28.10，13.26；HRMS(ESI)calcd for C
38H
36FN
3NaO
5[M+Na]
+＝656.2537，found 656.2568.
Embodiment 11:
By 3,4-DCA (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 98% to 86%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.0Hz，1H)，7.46-7.40(m，2H)，7.35(d，J＝8.0Hz，1H)，7.26-7.18(m，5H)，7.16(d，J＝8.7Hz，1H)，7.12-7.08(m，1H)，7.04-7.00(m，3H)，6.98(s，1H)，6.80(d，J＝2.7Hz，1H)，6.56(dd，J＝8.8，2.8Hz，1H)，5.22(d，J＝10.2Hz，1H)，5.20-5.12(s，2H)，5.00(d，J＝9.4Hz，1H)，3.81-3.71(m，2H)，1.61(s，9H)，0.70(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ175.01，170.18，149.17，145.63，140.52，137.01，136.69，132.91，130.77，129.67，128.80，128.05，127.84，127.07，126.91，126.34，125.68，124.62，122.26，121.73，120.96，120.04，115.72，115.48，114.07，110.83，110.03，84.75，62.19，61.30，54.15，50.21，28.12，13.38；HRMS(ESI)calcd for C
38H
35Cl
2N
3NaO
5[M+Na]
+＝706.1851，found 706.1829.
Embodiment 12:
By 3,5-dichlorphenamide bulk powder (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 95% to 88%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(d，J＝8.1Hz，1H)，7.45-7.40(m，2H)，7.30-7.18(m，6H)，7.13-7.09(m，1H)，7.04-6.98(m，4H)，6.72(t，J＝1.6Hz，1H)，6.59(d，J＝1.7Hz，2H)，5.19-5.14(m，4H)，3.85-3.70(m，2H)，1.62(s，9H)，0.73(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.97，169.94，149.15，147.74，140.44，136.96，136.65，135.59，129.68，128.80，128.00，127.86，127.06，126.91，126.26，125.63，124.66，122.26，120.76，120.07，118.80，115.48，112.44，110.77，110.03，84.78，61.81，61.37，53.83，50.23，28.11，13.39；HRMS(ESI)calcd for C
38H
35Cl
2N
3NaO
5[M+Na]
+＝706.1851，found 706.1879.
Embodiment 13:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with the bromo-N-benzylindole of 5-(0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 89% to 87%, dr value.
1H NMR(400MHz，CDCl
3)δ7.97(d，J＝8.1Hz，1H)，7.59(s，1H)，7.47-7.42(m，2H)，7.24-7.21(m，6H)，7.19-7.16(m，1H)，7.03(d，J＝8.7Hz，1H)，6.97-6.95(m，3H)，6.61(d，J＝8.8Hz，2H)，5.25(d，J＝7.3Hz，1H)，5.12(s，2H)，4.72(d，J＝9.6Hz，1H)，3.80-3.71(m，2H)，1.62(s，9H)，0.68(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.91，170.42，149.00，145.06，140.56，136.32，135.66，132.09，129.79，129.34，128.88，128.01，127.97，126.70，126.62，125.64，125.20，124.59，123.96，116.44，115.56，113.50，111.46，111.23，110.64，84.90，62.38，61.20，54.41，50.40，28.11，13.34；HRMS(ESI)calcd for C
38H
35Br
2N
3NaO
5[M+Na]
+＝794.0841，found794.0803.
Embodiment 14:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with 5-methoxyl group-N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 57% to 79%, dr value.
1H NMR(400MHz，CDCl
3)δ7.97(d，J＝8.1Hz，1H)，7.46-7.40(m，2H)，7.28-7.19(m，6H)，7.07-6.99(m，4H)，6.74(dd，J＝8.9，2.4Hz，1H)，6.64-6.60(m，3H)，5.19(d，J＝10.2Hz，1H)，5.14(s，2H)，4.98(d，J＝9.5Hz，1H)，3.85-3.73(m，2H)，3.64(s，3H)，1.61(s，9H)，0.75(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ175.14，170.37，154.01，149.13，145.13，140.59，136.86，132.07，129.53，128.77，128.55，127.74，127.28，126.77，126.69，125.84，124.58，116.10，115.26，112.46，110.89，110.68，110.26，102.44，84.68，62.42，61.16，55.60，54.00，50.41，28.09，13.42；HRMS(ESI)calcd for C
39H
38BrN
3NaO
6[M+Na]
+＝746.1842，found 746.1806.
Embodiment 15:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with 5-nitro-N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 90% to 49%, dr value.
1H NMR(400MHz，CDCl
3)δ8.37(s，1H)，8.04-7.99(m，2H)，7.51-7.43(m，2H)，7.30-7.22(m，7H)，7.18(s，1H)，7.02-7.00(m，2H)，6.63(d，J＝8.9Hz，2H)，5.24-5.21(m，3H)，4.82(d，J＝9.5Hz，1H)，3.81-3.75(m，2H)，1.63(s，9H)，0.71(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.79，170.02，148.78，144.84，141.94，140.57，139.64，135.48，132.15，131.15，130.12，129.06，128.32，126.78，126.22，125.64，125.41，124.73，118.62，117.86，116.36，115.75，113.93，111.37，110.00，85.18，62.60，61.30，54.10，50.75，28.05，13.40；HRMS(ESI)calcd for C
38H
35BrN
4NaO
7[M+Na]
+＝761.1587，found 761.1601.
Embodiment 16:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with the bromo-N-benzylindole of 6-(0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 96% to 86%, dr value.
1H NMR(400MHz，CDCl
3)δ7.98(d，J＝8.0Hz，1H)，7.46-7.42(m，2H)，7.35-7.20(m，8H)，7.12(dd，J＝8.7，1.6Hz，1H)，7.01-6.99(m，2H)，6.94(s，1H)，6.61(d，J＝8.8Hz，2H)，5.25-5.23(m，1H)，5.12(s，2H)，4.68(d，J＝9.8Hz，1H)，3.79-3.73(m，2H)，1.60(s，9H)，0.68(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.76，170.41，149.08，145.04，140.62，137.85，136.22，132.07，129.74，128.91，128.83，127.99，126.72，126.63，125.68，125.31，124.55，123.29，122.67，116.42，116.01，115.52，112.85，111.34，111.25，84.80，62.36，61.18，54.48，50.23，28.08，13.37；HRMS(ESI)calcd for C
38H
35Br
2N
3NaO
5[M+Na]
+＝794.0841，found 794.0805.
Embodiment 17:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with 7-methyl-N-benzyl indoles (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 82% to 76%, dr value.
1H NMR(400MHz，CDCl
3)δ7.98(d，J＝8.1Hz，1H)，7.44-7.39(m，2H)，7.24-7.17(m，7H)，6.95(s，1H)，6.89-6.80(m，4H)，6.60(d，J＝8.7Hz，2H)，5.43(s，2H)，5.26(d，J＝10.1Hz，1H)，4.93(d，J＝9.4Hz，1H)，3.83-3.73(m，2H)，2.44(s，3H)，1.61(s，9H)，0.76(t，J＝7.1Hz，3H)；
13CNMR(100MHz，CDCl
3)δ175.01，170.44，149.23，145.16，140.50，139.02，135.80，132.06，130.25，129.54，128.88，127.48，127.34，125.70，125.46，125.18，124.59，121.29，120.25，118.88，116.14，115.42，110.99，110.88，84.64，62.40，61.19，54.20，52.43，28.13，19.62，13.46；HRMS(ESI)calcdfor C
39H
38BrN
3NaO
5[M+Na]
+＝730.1893，found 730.1897.
Embodiment 18:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the 5-fluoro-N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 86% to 77%, dr value.
1H NMR(400MHz，CDCl
3)δ7.99(dd，J＝9.0，4.6Hz，1H)，7.41(d，J＝8.1Hz，1H)，7.26-7.20(m，7H)，7.15-7.10(m，2H)，7.05-7.00(m，3H)，6.98(s，1H)，6.64-6.60(m，2H)，5.27(d，J＝10.4Hz，1H)，5.18(s，2H)，4.73(d，J＝10.0Hz，1H)，3.81-3.73(m，2H)，1.59(s，9H)，0.68(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.57，170.43，159.72(d，
1J
C-F＝244.3Hz)，149.17，145.02，137.03，136.69，136.64(d，
4J
C-F＝2.3Hz)，132.09，128.94(d，
3J
C-F＝8.1Hz)，128.82，128.09，127.83，126.82，126.25，122.34，121.04，120.10，116.76(d，
3J
C-F＝7.8Hz)，116.38，116.17(d，
2J
C-F＝22.8Hz)，113.39(d，
2J
C-F＝24.9Hz)，111.25，110.35，110.08，84.84，62.26，61.25，54.80，50.24，28.08，13.33；HRMS(ESI)calcd for C
38H
35FBrN
3NaO
5[M+Na]
+＝734.1642，found 734.1660.
Embodiment 19:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, 5-methyl-N-tertbutyloxycarbonyl diazonium isatin (the 0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 96% to 87%, dr value.
1H NMR(400MHz，CDCl
3)δ7.85(d，J＝8.2Hz，1H)，7.30-7.18(m，9H)，7.10(t，J＝7.5Hz，1H)，7.03-6.97(m，4H)，6.61(d，J＝8.8Hz，2H)，5.22(d，J＝10.2Hz，1H)，5.18(s，2H)，4.96(d，J＝9.3Hz，1H)，3.79-3.73(m，2H)，2.34(s，3H)，1.60(s，9H)，0.72(t，J＝7.1Hz，3H)；
13C NMR(101MHz，CDCl
3)δ175.21，170.37，149.24，145.16，138.12，136.92，136.78，134.15，132.04，130.04，128.77，128.08，127.74，127.14，126.87，126.41，126.13，122.10，120.95，119.90，116.04，115.15，111.15，110.77，109.92，84.45，62.44，61.07，54.15，50.20，28.11，21.21，13.36；HRMS(ESI)calcdfor C
39H
38BrN
3NaO
5[M+Na]
+＝730.1893，found 730.1929.
Embodiment 20
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the 6-fluoro-N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 91% to 87%, dr value.
1H NMR(400MHz，CDCl
3)δ7.79(dd，J＝10.2，2.4Hz，1H)，7.47-7.42(m，2H)，7.27-7.20(m，6H)，7.15-7.11(m，1H)，7.06-7.01(m，3H)，6.96(s，1H)，6.92(td，J＝8.6，2.5Hz，1H)，6.64-6.60(m，2H)，5.28(d，J＝10.5Hz，1H)，5.18(s，2H)，4.65(d，J＝10.1Hz，1H)，3.79-3.72(m，2H)，1.59(s，9H)，0.67(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.68，170.60，163.27(d，
1J
C-F＝246.4Hz)，148.94，145.05，141.90(d，
3J
C-F＝12.5Hz)，137.03，136.75，132.08，128.80，128.18，127.81，127.00(d，
3J
C-F＝9.5Hz)，126.80，126.33，122.42(d，
4J
C-F＝2.8Hz)，122.30，121.20，120.04，116.45，111.16(d，
2J
C-F＝23.0Hz)，110.64，110.02，104.22(d，
2J
C-F＝29.6Hz)，85.11，62.33，61.19，54.43，50.21，28.04，13.32；HRMS(ESI)calcd for C
38H
35FBrN
3NaO
5[M+Na]
+＝734.1642.found 734.1636.
Embodiment 21:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the 6-chlorine N-tertbutyloxycarbonyl diazonium isatin (0.3mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 82% to 78%, dr value.
1H NMR(400MHz，CDCl
3)δ8.08(d，J＝1.9Hz，1H)，7.49-7.42(m，2H)，7.27-7.20(m，7H)，7.13(t，J＝7.3Hz，1H)，7.07-7.00(m，3H)，6.94(s，1H)，6.62(d，J＝8.8Hz，2H)，5.30(d，J＝10.6Hz，1H)，5.17(s，2H)，4.60(d，J＝10.0Hz，1H)，3.78-3.73(m，2H)，1.59(s，9H)，0.66(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.38，170.58，148.98，145.05，141.63，137.06，136.74，135.40，132.08，128.81，128.19，127.83，126.80，126.76，126.30，125.36，124.54，122.35，121.27，120.09，116.51，116.18，111.36，110.33，110.05，85.15，62.22，61.23，54.63，50.21，28.04，13.30；HRMS(ESI)calcd for C
38H
35ClBrN
3NaO
5[M+Na]
+＝750.1346，found 750.1332.
Embodiment 22:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-tertbutyloxycarbonyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-skatole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 70% to 73%, dr value.
1H NMR(400MHz，CDCl
3)δ7.98(d，J＝8.2Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.45-7.41(m，1H)，7.35(d，J＝8.1Hz，1H)，7.28-7.14(m，5H)，7.02-6.99(m，1H)，6.94(s，1H)，6.67-6.64(m，2H)，5.30(d，J＝10.5，1H)，4.86(d，J＝10.2Hz，1H)，3.83-3.72(m，2H)，3.65(s，3H)，1.59(s，9H)，0.70(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ174.96，170.52，149.19，145.17，140.54，137.40，132.04，129.53，128.87，127.25，126.15，125.77，124.49，121.96，121.03，119.68，116.34，115.38，111.00，110.21，109.41，84.59，62.33，61.06，54.37，32.90，28.09，13.33；HRMS(ESI)calcd forC
40H
34BrN
3NaO
3[M+Na]
+＝706.1681，found 706.1689.
Embodiment 23:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-benzyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with N-benzylindole (0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 87% to 83%, dr value.
1H NMR(400MHz，CDCl
3)δ7.48(d，J＝7.1Hz，2H)，7.29-7.16(m，11H)，7.12-6.95(m，6H)，6.80(d，J＝7.8Hz，1H)，6.63(d，J＝8.8Hz，2H)，5.40(d，J＝10.3Hz，1H)，5.19(s，2H)，5.03(d，J＝15.6Hz，1H)，4.89-4.81(m，2H)，3.78-3.71(m，2H)，0.63(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ176.94，171.11，145.38，143.72，137.13，137.06，135.49，132.05，129.22，128.75，128.70，128.04，128.01，127.69，127.61，127.58，126.74，126.53，126.28，122.59，122.13，121.50，119.74，116.08，110.84，110.74，109.92，109.59，61.58，60.95，54.38，50.14，44.29，13.37；HRMS(ESI)calcd for C
32H
32BrN
3NaO
5[M+Na]
+＝640.1423，found 640.1413.
Embodiment 24:
By para-bromoaniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-benzyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with the bromo-N-benzylindole of 6-(0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 94% to 90%, dr value.
1H NMR(400MHz，CDCl
3)δ7.45(d，J＝7.4Hz，1H)，7.39-7.36(m，2H)，7.29-7.25(m，8H)，7.22-7.16(m，3H)，7.10-7.06(m，2H)，7.02-7.00(m，3H)，6.81(d，J＝7.8Hz，1H)，6.62(d，J＝8.7Hz，2H)，5.35(d，J＝10.5Hz，1H)，5.15(s，2H)，5.02(d，J＝15.6Hz，1H)，4.81(d，J＝15.6Hz，1H)，4.75(d，J＝9.8Hz，1H)，3.80-3.73(m，2H)，0.65(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ176.72，170.96，145.23，143.70，137.97，136.43，135.34，132.08，129.42，128.89，128.74，128.62，127.93，127.69，127.53，126.65，126.18，125.41，123.07，122.95，122.66，116.17，115.96，112.82，111.29，110.97，109.72，61.57，61.03，54.34，50.17，44.28，13.44；HRMS(ESI)calcd forC
40H
34BrN
3NaO
3[M+Na]
+＝706.1681，found 706.1688.
Embodiment 25:
By aniline (0.33mmol, 1.1eq), glyoxylic acid ethyl ester (0.36mmol, 1.2eq),
the silica-based substituted chiral phosphoric acid catalyst (0.015mmol) of molecular sieve (300mg), rhodium acetate (0.006mmol) and triphenyl is dissolved in (1.5ml) in dimethylbenzene under 25 DEG C of conditions; Then, the N-benzyl diazonium isatin (0.30mmol in dimethylbenzene (1.5ml) will be dissolved in, 1.0eq) with the bromo-N-benzylindole of 5-(0.33mmol, mixture 1.1eq) is added drop-wise in reaction system in 25 DEG C in 1h, after dropwising, vacuum rotary steam, except desolventizing, obtains crude product.Crude product is carried out column chromatography (ethyl acetate: sherwood oil=1: 30 ~ 1: 10) obtain straight product.Productive rate is that to be greater than 95: 5, ee value be 95% to 87%, dr value.
1H NMR(400MHz，CDCl
3)δ7.69(s，1H)，7.49(d，J＝7.3Hz，1H)，7.30-7.24(m，6H)，7.21-7.17(m，6H)，7.12-7.08(m，2H)，7.05-6.99(m，3H)，6.80-6.76(m，4H)，5.42(d，J＝10.7Hz，1H)，5.17(s，2H)，5.04(d，J＝15.8Hz，1H)，4.82(d，J＝15.8Hz，1H)，4.67(d，J＝10.0Hz，1H)，3.79-3.71(m，2H)，0.64(t，J＝7.1Hz，3H)；
13C NMR(100MHz，CDCl
3)δ176.82，171.34，146.17，143.87，136.68，135.74，135.39，129.45，129.38，129.33，128.82，128.80，128.31，127.83，127.64，127.53，127.30，126.56，126.28，125.07，124.34，122.60，119.19，114.73，113.28，111.36，110.73，109.74，61.67，60.85，54.53，50.37，44.30，13.37；HRMS(ESI)calcd for C
40H
33Br
2N
3NaO
3[M+Na]
+＝784.0786，found 784.0790.
Replacing oxoindole derivative with 3,3-bis-of preparation in embodiment 25 is that example determines the absolute configuration of this compounds by single crystal diffraction.As shown in Figure 1, detected result shows, the steric configuration that 3,3-bis-replaces oxoindole derivative is defined as (2S, 3S) by single crystal diffraction.
Application Example: PTP1B inhibit activities is tested
Screening model:
Title: PTP1B
Another name: PTPN1
English full name: protein tyrosine phosphatase 1B
Chinese full name: Protein-tyrosine-phosphatase PTP1B
Brief introduction: PTP1B is first certified protein-tyrosine-phosphatase (protein tyrosine phosphatase); the experiment on mice of being rejected by PTP1B is shown; PTP1B by the dephosphorization acidylate to insulin receptor, and then plays very important effect in adjustment insulin sensitivity and fat metabolic process.Thus, optionally, highly active PTP1B inhibitor has important value in the treatment of diabetes and obesity.
Screening method:
Protocol id：25
Protocol name：PTP 1B activity assay，absorbance
Instrument: VERSAmax (Molecular Devices, USA).
Material: PTP 1B, this laboratory applications escherichia expression system obtains gst fusion protein.
Substrate, pNPP.
Process: adopt photoabsorption detection method, detect enzymic activity in 96 holes or 384 hole flat bottom clear microwell plates.Substrate pNPP is hydrolyzed through PTP1B the free product obtained has very strong photoabsorption at 405nm place.By the change of microplate reader monitoring 405nm place optical absorption intensity, calculate initial velocity of reaction.The control compound adopted in experiment is Oleanolic Acid.
Sample preparation: sample DMSO dissolves, cryopreservation, the concentration of DMSO in final system controls within the scope not affecting detection of active.
Data processing and result illustrate: under primary dcreening operation selects single concentration conditions, such as 20 μ g/ml, test the activity of sample.For showing active sample under certain condition, such as inhibiting rate %Inhibition is greater than 50, test agents amount dependence, i.e. IC
50/ EC
50value, by sample activity, sample concentration is carried out Nonlinear Quasi and obtained, calculating software used is GraphpadPrism 4, the model that matching uses is Sigmoidaldose-response (varible slope), for most of inhibitor screening model, bottom matched curve and top is set as 0 and 100.Generally, each sample all arranges multiple hole (n >=2) in testing, represents in the result with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE).Generally, each test all has the compound reported as reference.All data are all accomplished credible as far as possible within the scope of the Knowledge Capability of this area, accurately, correctly.Detected result is as shown in table 1 below.
Table 1
Experimental result shows, the present invention 3,3-bis-replaces oxoindole derivative and has significant PTP1B inhibition, is applicable to the suppression medicine preparing obesity specific target gene-PTP 1B.
The present invention is described in further detail, and protection content of the present invention is not limited to above detected result.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.
Claims (10)
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Cited By (9)
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| CN105801466A (en) * | 2016-04-26 | 2016-07-27 | 华东师范大学 | Beta-alkoxy-beta-quaternary carbon center-alpha-amino acid derivative and synthetic method and application thereof |
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| CN109776384A (en) * | 2019-02-03 | 2019-05-21 | 华东师范大学 | 3-Aryl-3'-aminobisquaternary carbon bisoxidole compound and its synthetic method and application |
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| CN105801466B (en) * | 2016-04-26 | 2018-12-14 | 华东师范大学 | A kind of β-alkoxy-β-quaternary carbon center-alpha-amino acid derivatives and its synthetic method and application |
| CN105801466A (en) * | 2016-04-26 | 2016-07-27 | 华东师范大学 | Beta-alkoxy-beta-quaternary carbon center-alpha-amino acid derivative and synthetic method and application thereof |
| CN107056676B (en) * | 2017-03-31 | 2020-04-07 | 上海工程技术大学 | Method for preparing chiral 3- (aminomethyl) -3-fluoro-2-indolone |
| CN107056676A (en) * | 2017-03-31 | 2017-08-18 | 上海工程技术大学 | One kind prepares chirality 3（Amine methyl）The method of the indolone of 3 fluorine 2 |
| CN108383771A (en) * | 2018-01-08 | 2018-08-10 | 华东师范大学 | Chiral 3,3- bis- replaces 1-isoindolinone derivative and its synthetic method and application |
| CN108409746A (en) * | 2018-05-15 | 2018-08-17 | 中山大学 | A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure |
| CN108409746B (en) * | 2018-05-15 | 2021-08-24 | 中山大学 | A kind of chiral oxospirocyclic indole compound containing pyrrole or indoloazepine structure and its racemate and preparation method |
| CN109438324A (en) * | 2018-11-19 | 2019-03-08 | 广西中医药大学 | A kind of chiral preparation method of α, β-amino acid analogs derived from trifluoromethyl indole |
| CN109503507A (en) * | 2018-12-24 | 2019-03-22 | 华东师范大学 | A kind of 4- quaternary carbon -4H- [1,3] benzoxazine derivative and its synthetic method |
| CN109776384A (en) * | 2019-02-03 | 2019-05-21 | 华东师范大学 | 3-Aryl-3'-aminobisquaternary carbon bisoxidole compound and its synthetic method and application |
| CN109776384B (en) * | 2019-02-03 | 2022-01-07 | 华东师范大学 | 3-aryl-3' -amino di-quaternary carbon bis-oxoindole compound and synthesis method and application thereof |
| CN112939844A (en) * | 2019-12-10 | 2021-06-11 | 华东师范大学 | Polysubstituted tetrahydrocarbazole and derivative thereof, and synthetic method and application thereof |
| CN113200905A (en) * | 2021-03-31 | 2021-08-03 | 中山大学 | Chiral indolone derivative and synthesis method thereof |
| CN113200905B (en) * | 2021-03-31 | 2022-12-27 | 中山大学 | Chiral indolone derivative and synthesis method thereof |
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