CN110684018A - 3-indolyl rhamnoside and preparation method and application thereof - Google Patents
3-indolyl rhamnoside and preparation method and application thereof Download PDFInfo
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- CN110684018A CN110684018A CN201911011059.XA CN201911011059A CN110684018A CN 110684018 A CN110684018 A CN 110684018A CN 201911011059 A CN201911011059 A CN 201911011059A CN 110684018 A CN110684018 A CN 110684018A
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- indolyl
- rhamnoside
- alkynyl
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- -1 3-indolyl rhamnoside Chemical class 0.000 title claims abstract description 45
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229930182470 glycoside Natural products 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000005257 alkyl acyl group Chemical group 0.000 claims abstract description 3
- 125000005103 alkyl silyl group Chemical group 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- 229960001413 acetanilide Drugs 0.000 claims description 14
- FZERHIULMFGESH-UHFFFAOYSA-N methylenecarboxanilide Natural products CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 12
- UYUUAUOYLFIRJG-UHFFFAOYSA-N tris(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 UYUUAUOYLFIRJG-UHFFFAOYSA-N 0.000 claims description 12
- 150000002940 palladium Chemical class 0.000 claims description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 229930182478 glucoside Natural products 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229930182476 C-glycoside Natural products 0.000 description 5
- 150000000700 C-glycosides Chemical class 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- WSNDAYQNZRJGMJ-UHFFFAOYSA-N 2,2,2-trifluoroethanone Chemical compound FC(F)(F)[C]=O WSNDAYQNZRJGMJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 229930182474 N-glycoside Natural products 0.000 description 1
- 108091006269 SLC5A2 Proteins 0.000 description 1
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Steroid Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis and medicines, and particularly discloses 3-indolyl rhamnose carbon glycoside and a preparation method and application thereof. A3-indolyl rhamnoside has a structural formula shown as formula I, wherein R is1Selected from C1-C9 alkylsilyl, R2Selected from the group consisting of alkyl acyl, R3Selected from H, methyl formate or fluoro, R4Selected from H, ethyl, chlorine or methoxy. The synthesis method of the invention efficiently constructs 3-indolyl rhamnose carbon glycoside compounds with various structures by utilizing palladium-catalyzed cyclization reaction, and the reaction method has the advantages of simple operation, higher yield, good substrate universality, high step economy and wide application prospect and practical value.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis and medicines, and particularly relates to 3-indolyl rhamnose carbon glycoside and a preparation method and application thereof.
Background
C-glycoside is a generic term for a class of compounds in which glycosyl groups and glycoside ligands are linked by C-C bonds, and the backbone structure is widely found in natural products and drug molecules with important biological activities. The C-glycoside has better enzyme stability and hydrolysis resistance than O-, N-glycoside with similar structure, which makes the C-glycoside have more excellent physiological metabolism resisting activity.
As a special C-glycoside, the C-indole glycoside has unique structural characteristics and application values, such as: alpha-C-Mannosyltypophan can be generally used as an important component of human protein; the 3-indolyl sugar C-glycoside B has good inhibitory effect on SGLT2 cells, and has potential efficacy of treating stage 2 diabetes (Eur.J.Med.chem.2012,55, 32-38; Eur.J.Med.chem.2018,152, 436-488). Therefore, in recent years, the synthesis of C-indole glycosides has been receiving attention from domestic and foreign organic chemists.
Although the synthesis of C-indole glycoside is rapidly developed, the existing method has limitations, such as complex operation, long steps, harsh reaction conditions and limited substrate practicability. In addition, the existing synthesis means mostly relate to the synthesis of 2-indolyl sugar carbon glycoside, and the high-efficiency synthesis method of 3-indolyl sugar carbon glycoside is rarely reported.
On the other hand, in recent years, researches on constructing 3-substituted indole by using cyclization reaction of o-alkynylaniline catalyzed by transition metal are widely focused by synthetic chemists, but the application of the 3-substituted indole in synthesis of molecules with complex structures such as saccharides and the like is not reported at present. Therefore, the cyclization reaction of the o-alkynyl aniline is efficient, and the economic synthesis of the 3-indolyl sugar carbon glycoside by the steps has important scientific significance.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention mainly aims to provide the 3-indolyl rhamnose carbon glycoside.
The invention also aims to provide a preparation method of the 3-indolyl rhamnose glucoside.
The invention further aims to provide the application of the 3-indolyl rhamnoside in preparing the medicament for treating secondary diabetes.
The purpose of the invention is realized by the following scheme:
a3-indolyl rhamnoside has a structural formula shown in formula I:
wherein R is1Selected from C1-C9 alkylsilyl, R2Selected from the group consisting of alkyl acyl, R3Selected from H, methyl formate or fluoro, R4Selected from H, ethyl, chlorine or methoxy.
Preferably, R1Is Triisopropylsilyl (TIPS), R2Is Trifluoroacetyl (TFA).
A method for preparing the 3-indolyl rhamnoside comprises the following specific steps:
uniformly mixing 1-iodorhamnosene, o-alkynyl aniline, palladium salt, phosphine ligand, solvent and alkali, stirring for reaction, and purifying after the reaction is finished to obtain the 3-indolyl rhamnoside.
Wherein said R1、R2、R3、R4In accordance with formula I above.
The molar ratio of the 1-iodorhamnosene to the o-alkynyl aniline is 1:1-1.5: 1.
The palladium salt is at least one of tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium and bis (triphenylphosphine) palladium dichloride, and is preferably tetrakis (triphenylphosphine) palladium.
The molar ratio of the added palladium salt to the o-alkynyl acetanilide is 0.05:1-0.2:1, and preferably 0.1: 1.
The phosphine ligand is at least one of tri (4-methoxyphenyl) phosphine and triphenylphosphine.
The molar ratio of the added amount of the phosphine ligand to the palladium salt is 1:1-3: 1.
The solvent is at least one of 1, 4-dioxane, tetrahydrofuran, toluene, acetonitrile and N, N-dimethylformamide; tetrahydrofuran is preferred.
The dosage of the solvent satisfies that the concentration of the o-alkynyl aniline is 0.01-0.5 mol/L.
The alkali is at least one of potassium carbonate, sodium carbonate, cesium carbonate and silver carbonate, and preferably potassium carbonate.
The molar ratio of the base to the ortho-alkynylaniline is 2:1 to 5:1, preferably 2: 1.
The stirring reaction is carried out for 4-15h at the temperature of 80-140 ℃; stopping the reaction until the reaction of the o-alkynyl acetanilide is completed by Thin Layer Chromatography (TLC). The temperature of the stirring reaction is preferably 90 to 110 ℃.
The purification is to filter the reaction liquid, and separate and purify the crude product obtained after reduced pressure distillation by column chromatography to obtain the 3-indolyl rhamnose glucoside. Preferably, the column chromatography separation and purification uses a mixed solvent of petroleum ether and ethyl acetate as an eluent, and the volume ratio is 200:1-30: 1.
The preparation method is preferably carried out under the protection of inert gas and nitrogen; preferably nitrogen.
The application of the 3-indolyl rhamnoside in preparing medicine for treating secondary diabetes is provided.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the synthesis method of the invention efficiently constructs 3-indolyl rhamnose carbon glycoside compounds with various structures by utilizing palladium-catalyzed cyclization reaction, and the reaction method has the advantages of simple operation, higher yield, good substrate universality, high step economy and wide application prospect and practical value.
Drawings
FIG. 1 is a hydrogen spectrum of the product obtained in example 1.
FIG. 2 is a carbon spectrum of the product obtained in example 1.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
The 1-iodorhamnosene and 2-alkynylacetanilide used in the examples were synthesized by reference to Org.Lett.2016,18, 1836-1839; J.Org.chem.2010,75,3412-3419) and other reagents were commercially available without specific reference.
Example 1
Adding 0.12mmol of 1-iodorhamnose 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2a,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3a with the yield of 81%.
The hydrogen spectrum and the carbon spectrum of the product 3a obtained in this example are shown in fig. 1 and fig. 2, respectively, and the structural characterization data thereof are as follows:
1H NMR(400MHz,CDCl3)δ8.20(s,1H),7.81(d,J＝7.7Hz,1H),7.71–7.68(m,2H),7.38–7.30(m,4H),7.19–7.11(m,2H),5.01(dd,J＝5.1,1.2Hz,1H),4.47(q,J＝7.1Hz,1H),4.18(dd,J＝3.1,2.1Hz,1H),4.00(d,J＝1.5Hz,1H),1.54(d,J＝7.1Hz,3H),1.10(d,J＝4.6Hz,21H),1.02(s,21H)；13C NMR(101MHz,CDCl3)δ146.11,135.68,135.51,132.59,128.85,128.45,128.13,127.80,122.51,120.43,120.35,110.83,110.68,100.66,75.42,73.13,67.42,18.24,18.21,18.19,18.14,17.73,16.30,12.57,12.45,12.31；[α]D 23＝+12.8(c＝0.68,CHCl3)；HRMS(ESI)m/z calcd for C38H60NO3Si2[M+H]+:634.4106；Found:634.4120.
example 2
Adding 0.12mmol of 1-iodorhamnose alkene 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2b,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3b, wherein the yield is 84%.
The structural characterization data for product 3b obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.71–7.68(m,2H),7.60(s,1H),7.36(t,J＝7.4Hz,2H),7.30(d,J＝7.3Hz,1H),7.22(d,J＝8.2Hz,1H),7.00(dd,J＝8.2,1.0Hz,1H),5.01(dd,J＝5.2,1.2Hz,1H),4.47(q,J＝7.1Hz,1H),4.19(dd,J＝3.1,2.1Hz,1H),4.00(d,J＝1.6Hz,1H),2.43(s,3H),1.53(d,J＝7.1Hz,3H),1.11(d,J＝4.7Hz,21H),1.03(s,21H)；13C NMR(101MHz,CDCl3)δ146.28,135.65,133.85,132.70,129.59,129.11,128.42,127.96,127.66,124.12,120.03,110.49,110.30,100.61,75.40,73.07,67.40,21.49,18.25,18.23,18.19,18.14,17.72,16.34,12.58,12.45；[α]D 23＝+8.8(c＝0.75,CHCl3)；HRMS(ESI)m/z calcd for C39H62NO3Si2[M+H]+:648.4263；Found:648.4271.
example 3
Adding 0.12mmol of 1-iodorhamnose alkene 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2c,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3c, wherein the yield is 83%.
The structural characterization data for product 3c obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.51(s,1H),7.90(dd,J＝8.5,1.4Hz,1H),7.69(d,J＝7.0Hz,2H),7.39–7.32(m,4H),5.06–5.02(m,1H),4.48(q,J＝7.0Hz,1H),4.22–4.18(m,1H),4.01(d,J＝1.4Hz,1H),3.91(s,3H),1.55(d,J＝7.1Hz,3H),1.10(d,J＝4.9Hz,21H),1.03(s,21H)；13C NMR(101MHz,CDCl3)δ168.17,145.58,138.07,136.94,132.03,128.53,128.30,128.18,128.16,124.07,123.34,122.49,111.86,110.45,101.08,75.56,72.96,67.20,51.75,18.20,18.18,18.17,18.11,17.71,16.28,12.55,12.40,12.31；[α]D 23＝+8.1(c＝0.68,CHCl3)；HRMS(ESI)m/z calcd for C40H62NO5Si2[M+H]+:692.4161；Found:692.4171.
example 4
Adding 0.12mmol of 1-iodorhamnose alkene 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2d,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3d with the yield of 75%.
The structural characterization data for product 3d obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.69–7.65(m,3H),7.35(t,J＝7.4Hz,2H),7.29(d,J＝7.3Hz,1H),7.10(s,1H),6.96(d,J＝8.1Hz,1H),5.01(dd,J＝5.1,1.1Hz,1H),4.45(q,J＝7.0Hz,1H),4.21–4.16(m,1H),3.99(d,J＝1.5Hz,1H),2.44(s,3H),1.52(d,J＝7.1Hz,3H),1.09(d,J＝4.6Hz,21H),1.02(s,21H)；13C NMR(101MHz,CDCl3)δ146.27,135.95,134.96,132.78,132.36,128.39,128.01,127.58,126.74,122.11,120.06,110.71,110.59,100.44,75.37,73.14,67.46,21.73,18.23,18.20,18.18,18.14,17.72,16.28,12.57,12.46；[α]D 23＝+2.9(c＝0.62,CHCl3)；HRMS(ESI)m/z calcd for C39H62NO3Si2[M+H]+:648.4263；Found:648.4269.
example 5
Adding 0.12mmol of 1-iodorhamnose 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2e,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3e with the yield of 82%.
The structural characterization data for product 3e obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.80(d,J＝7.7Hz,1H),7.60(d,J＝8.1Hz,2H),7.31(d,J＝7.8Hz,1H),7.19(d,J＝8.0Hz,2H),7.17–7.09(m,2H),4.99(d,J＝5.1Hz,1H),4.47(q,J＝7.0Hz,1H),4.20–4.16(m,1H),4.00(d,J＝1.4Hz,1H),2.67(q,J＝7.6Hz,2H),1.54(d,J＝7.1Hz,3H),1.25(t,J＝7.6Hz,3H),1.10(d,J＝4.7Hz,21H),1.02(s,21H)；13C NMR(101MHz,CDCl3)δ146.23,143.97,135.89,135.42,129.95,128.90,128.09,127.96,122.31,120.36,120.26,110.58,110.47,100.55,75.38,73.17,67.45,28.69,18.23,18.21,18.18,18.14,17.72,16.30,15.45,12.58,12.46；[α]D 23＝+2.4(c＝0.75,CHCl3)；HRMS(ESI)m/z calcd for C40H64NO3Si2[M+H]+:662.4419；Found:662.4422.
example 6
Adding 0.12mmol of 1-iodorhamnose alkene 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2f,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3f, wherein the yield is 86%.
The structural characterization data for product 3f obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.60(d,J＝7.9Hz,3H),7.19(dd,J＝7.9,5.5Hz,3H),6.99(d,J＝8.2Hz,1H),4.99(d,J＝4.3Hz,1H),4.47(q,J＝7.0Hz,1H),4.21–4.15(m,1H),4.00(d,J＝1.3Hz,1H),2.66(q,J＝7.6Hz,2H),2.43(s,3H),1.54(d,J＝7.1Hz,3H),1.25(t,J＝7.6Hz,3H),1.11(d,J＝4.6Hz,21H),1.03(s,21H)；13C NMR(101MHz,CDCl3)δ146.37,143.82,135.87,133.74,130.02,129.50,129.15,127.96,127.92,123.90,119.93,110.24,110.07,100.51,75.37,73.07,67.40,28.70,21.51,18.27,18.24,18.20,18.16,16.36,15.50,12.58,12.45；[α]D 23＝+5.3(c＝0.46,CHCl3)；HRMS(ESI)m/z calcdfor C41H66NO3Si2[M+H]+:676.4575；Found:676.4596.
example 7
Adding 0.12mmol of 1-iodorhamnose alkene 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2g,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain 3g of rhamnose indoside with the yield of 79%.
The structural characterization data for 3g of product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.50(s,1H),7.88(dd,J＝8.5,1.6Hz,1H),7.58(d,J＝8.1Hz,2H),7.28(d,J＝8.5Hz,1H),7.18(d,J＝8.1Hz,2H),5.03(dd,J＝5.2,1.3Hz,1H),4.48(q,J＝7.0Hz,1H),4.19(dt,J＝5.0,1.8Hz,1H),4.01(d,J＝1.6Hz,1H),3.91(s,3H),2.66(q,J＝7.6Hz,2H),1.55(d,J＝7.1Hz,3H),1.25(t,J＝7.6Hz,3H),1.10(d,J＝4.9Hz,21H),1.03(s,21H)；13C NMR(101MHz,CDCl3)δ168.25,145.67,144.40,138.02,137.18,129.31,128.34,128.10,128.05,123.90,123.19,122.35,111.38,110.41,100.97,75.54,72.92,67.19,51.74,28.70,18.19,18.13,16.30,15.41,12.54,12.41；[α]D 23＝+10.5(c＝0.76,CHCl3)；HRMS(ESI)m/z calcd for C42H65NO5Si2Na[M+Na]+:742.4294；Found:742.4278.
example 8
Adding 0.12mmol of 1-iodorhamnose 1a,0.1mmol of o-alkynyl trifluoroacetylaniline for 2h,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside for 3h, wherein the yield is 78%.
The structural characterization data for product 3h obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.60–7.56(m,3H),7.14(d,J＝8.2Hz,1H),6.96(d,J＝8.2Hz,1H),6.85(d,J＝8.7Hz,2H),5.03–4.98(m,1H),4.46(q,J＝7.0Hz,1H),4.22–4.18(m,1H),4.00(d,J＝1.5Hz,1H),3.80(s,3H),2.43(s,3H),1.53(d,J＝7.1Hz,3H),1.10(d,J＝4.6Hz,21H),1.04(s,21H)；13C NMR(101MHz,CDCl3)δ159.23,146.43,135.66,133.71,129.43,129.20,129.17,125.29,123.72,119.77,113.89,110.26,109.56,100.48,75.40,73.06,67.40,55.25,21.53,18.27,18.24,18.22,18.18,16.43,12.58,12.47；[α]D 23＝+3.5(c＝0.65,CHCl3)；HRMS(ESI)m/z calcd for C40H64NO4Si2[M+H]+:678.4368；Found:678.4386.
example 9
Adding 0.12mmol of 1-iodorhamnose alkene 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2i,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), stopping the reaction, filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3i with the yield of 80%.
The structural characterization data for product 3i obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.52(s,1H),7.82(dd,J＝8.5,1.5Hz,1H),7.50(d,J＝8.7Hz,2H),7.17(d,J＝8.5Hz,1H),6.76(d,J＝8.7Hz,2H),5.09–5.07(m,1H),4.46(q,J＝7.0Hz,1H),4.22(dd,J＝3.1,2.1Hz,1H),4.00(d,J＝1.4Hz,1H),3.91(s,3H),3.77(s,3H),1.53(d,J＝7.1Hz,3H),1.08(d,J＝4.8Hz,21H),1.04(s,21H)；13C NMR(101MHz,CDCl3)δ168.28,159.55,145.69,138.04,137.01,129.36,128.35,124.43,123.69,122.86,122.23,113.94,110.69,110.52,101.03,75.64,72.89,67.16,55.20,51.77,18.20,18.15,16.40,12.52,12.42；[α]D 23＝+0.56(c＝0.92,CHCl3)；HRMS(ESI)m/zcalcd for C41H64NO6Si2[M+H]+:722.4267；Found:722.4287.
example 10
Adding 0.12mmol of 1-iodorhamnose 1a,0.1mmol of o-alkynyl trifluoroacetylaniline 2j,0.01mmol of tetrakis (triphenylphosphine) palladium, 0.02mmol of tris (4-methoxyphenyl) phosphine and 0.2mmol of potassium carbonate into a clean reaction vessel, adding 1.5mL of tetrahydrofuran, reacting for 6h under the protection of nitrogen at 100 ℃ until the o-alkynyl acetanilide is completely reacted by TLC (thin layer chromatography), filtering the reaction solution, carrying out reduced pressure distillation on the crude product, and separating and purifying by column chromatography (eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 90: 1) to obtain rhamnose indoside 3j with the yield of 81%.
The structural characterization data of product 3j obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.80(d,J＝7.5Hz,1H),7.57(d,J＝8.5Hz,2H),7.29(d,J＝8.5Hz,2H),7.26(d,J＝8.4Hz,1H),7.19–7.11(m,2H),5.01(dd,J＝5.1,1.1Hz,1H),4.46(q,J＝7.0Hz,1H),4.19(dd,J＝3.1,2.1Hz,1H),4.00(d,J＝1.4Hz,1H),1.53(d,J＝7.1Hz,3H),1.09(d,J＝4.4Hz,21H),1.03(s,21H)；13C NMR(101MHz,CDCl3)δ145.89,135.61,134.39,133.71,131.07,129.36,128.70,128.67,122.80,120.52,120.42,111.27,110.79,100.92,75.51,73.02,67.30,18.21,18.18,18.18,18.13,17.72,16.32,12.56,12.46；[α]D 23＝+9.6(c＝0.52,CHCl3)；HRMS(ESI)m/z calcd for C38H59ClNO3Si2[M+H]+:668.3717；Found:668.3726.
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A3-indolyl rhamnoside is characterized by a structural formula shown in formula I:
wherein R is1Selected from C1-C9 alkylsilyl, R2Selected from the group consisting of alkyl acyl, R3Selected from H, methyl formate, fluoro, R4Selected from H, ethyl, chlorine, methoxy.
2. The 3-indolyl rhamnoside according to claim 1, characterized in that:
the R is1Is triisopropylsilyl, R2Is trifluoroacetyl.
3. A method for preparing the 3-indolyl rhamnose glycoside of claim 1 or 2, characterized by the following specific steps:
uniformly mixing 1-iodorhamnosene, o-alkynyl aniline, palladium salt, phosphine ligand, solvent and alkali, stirring for reaction, and purifying after the reaction is finished to obtain the 3-indolyl rhamnoside.
4. The method of 3-indolyl rhamnoside according to claim 3, characterized in that:
the molar ratio of the 1-iodorhamnosene to the o-alkynyl aniline is 1:1-1.5: 1.
5. The method of 3-indolyl rhamnoside according to claim 3, characterized in that:
the palladium salt is at least one of tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium and bis (triphenylphosphine) palladium dichloride;
the molar ratio of the added amount of the palladium salt to the o-alkynyl acetanilide is 0.05:1-0.2: 1;
the phosphine ligand is at least one of tri (4-methoxyphenyl) phosphine and triphenylphosphine;
the molar ratio of the added amount of the phosphine ligand to the palladium salt is 1:1-3: 1.
6. The method of 3-indolyl rhamnoside according to claim 3, characterized in that:
the molar ratio of the added amount of the palladium salt to the o-alkynyl acetanilide is 0.1: 1.
7. The method of 3-indolyl rhamnoside according to claim 3, characterized in that:
the solvent is at least one of 1, 4-dioxane, tetrahydrofuran, toluene, acetonitrile and N, N-dimethylformamide;
the dosage of the solvent meets the requirement that the concentration of the o-alkynyl aniline is 0.01-0.5 mol/L;
the alkali is at least one of potassium carbonate, sodium carbonate, cesium carbonate and silver carbonate;
the molar ratio of the added amount of the alkali to the o-alkynyl aniline is 1:1-3: 1.
8. The method of 3-indolyl rhamnoside according to claim 3, characterized in that:
the stirring reaction is carried out for 4-15h at the temperature of 80-140 ℃.
9. The method of 3-indolyl rhamnoside according to claim 3, characterized in that:
the purification is to filter the reaction liquid, and separate and purify the crude product obtained after reduced pressure distillation by column chromatography to obtain the 3-indolyl rhamnose glucoside.
10. The use of 3-indolyl rhamnoside according to claim 1 or 2 for the preparation of a medicament for the treatment of secondary diabetes.
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| BATTISTUZZI GIANFRANCOA,ET AL.: "The aminopalladation/reductive elimination domino reaction in the construction of functionalized indole rings", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| MUKHERJEE DEBARAJ,ET AL.: "A rapid stereoselective C-glycosidation of indoles and pyrrole via indium trichloride promoted reactions of glycosyl halides", 《TETRAHEDRON LETTERS》 * |
| SANDRO CACCHI,ET AL.: "Synthesis and Functionalization of Indoles Through Palladium-catalyzedReactions", 《CHEMICAL REVIEWS》 * |
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