CN106946968A - A kind of synthetic method of different Astragaloside IV - Google Patents
A kind of synthetic method of different Astragaloside IV Download PDFInfo
- Publication number
- CN106946968A CN106946968A CN201710188497.8A CN201710188497A CN106946968A CN 106946968 A CN106946968 A CN 106946968A CN 201710188497 A CN201710188497 A CN 201710188497A CN 106946968 A CN106946968 A CN 106946968A
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- China
- Prior art keywords
- compound
- solvent
- room temperature
- synthetic method
- astragaloside
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- QMNWISYXSJWHRY-YLNUDOOFSA-N astragaloside IV Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)CO4)O)C4(C)C)[C@H]4[C@@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)C[C@H]3[C@]2(C)C[C@@H]1O QMNWISYXSJWHRY-YLNUDOOFSA-N 0.000 title claims abstract description 31
- QMNWISYXSJWHRY-BCBPIKMJSA-N astragaloside IV Natural products CC(C)(O)[C@@H]1CC[C@@](C)(O1)[C@H]2[C@@H](O)C[C@@]3(C)[C@@H]4C[C@H](O[C@@H]5O[C@H](CO)[C@H](O)[C@@H](O)[C@H]5O)[C@H]6C(C)(C)[C@H](CC[C@@]67C[C@@]47CC[C@]23C)O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O QMNWISYXSJWHRY-BCBPIKMJSA-N 0.000 title claims abstract description 31
- PFKIBRPYVNVMRU-UHFFFAOYSA-N cyclosieversioside F Natural products CC(C)(O)C1COC(C)(C1)C2C(O)CC3(C)C4CC(OC5OC(CO)C(O)C(O)C5O)C6C(C)(C)C(CCC67CC47CCC23C)OC8OCC(O)C(O)C8O PFKIBRPYVNVMRU-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 230000004224 protection Effects 0.000 claims abstract description 28
- WENNXORDXYGDTP-UOUCMYEWSA-N cycloastragenol Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O)C4(C)C)[C@H]4[C@@H](O)C[C@H]3[C@]2(C)C[C@@H]1O WENNXORDXYGDTP-UOUCMYEWSA-N 0.000 claims abstract description 23
- WENNXORDXYGDTP-UHFFFAOYSA-N cyclosiversigenin Natural products O1C(C(C)(O)C)CCC1(C)C1C2(C)CCC34CC4(CCC(O)C4(C)C)C4C(O)CC3C2(C)CC1O WENNXORDXYGDTP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
- 238000006206 glycosylation reaction Methods 0.000 claims abstract description 13
- 229940126214 compound 3 Drugs 0.000 claims abstract description 12
- -1 glycosides compound Chemical class 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 25
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 13
- 229940125898 compound 5 Drugs 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- 239000000348 glycosyl donor Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 9
- 150000002460 imidazoles Chemical class 0.000 claims description 9
- 239000002808 molecular sieve Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000004756 silanes Chemical class 0.000 claims description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940126142 compound 16 Drugs 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims 4
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 229940029575 guanosine Drugs 0.000 claims 2
- 230000000536 complexating effect Effects 0.000 claims 1
- 239000012279 sodium borohydride Substances 0.000 claims 1
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 239000009636 Huang Qi Substances 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000007787 solid Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 6
- 229930182470 glycoside Natural products 0.000 abstract description 3
- 238000009509 drug development Methods 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- SMDOOINVMJSDPS-UHFFFAOYSA-N Astragaloside Natural products C1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)OC2C(C(OC3C(C(O)C(O)C(CO)O3)O)C(O)C(CO)O2)O)=C1 SMDOOINVMJSDPS-UHFFFAOYSA-N 0.000 description 8
- QMNWISYXSJWHRY-XWJCTJPOSA-N astragaloside Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)CO4)O)C4(C)C)C4[C@@H](O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)CC3[C@]2(C)C[C@@H]1O QMNWISYXSJWHRY-XWJCTJPOSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000386 donor Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000005554 pickling Methods 0.000 description 2
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
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- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
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- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
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- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 150000004676 glycans Chemical class 0.000 description 1
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- 150000002367 halogens Chemical class 0.000 description 1
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- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
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- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
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Abstract
The invention discloses a kind of synthetic method of different Astragaloside IV, comprise the following steps：By 3 hydroxyls of cycloastragenol with protection group R1Protection, 6 and 16 hydroxyls are with protection group R2Compound 3 is obtained after protection, compound 3 is subjected to glycosylation reaction, afterwards 3 protection group R of removing1Proceed occur glycosylation reaction; obtain compound 8; all protection group removings, obtain different Astragaloside IV 1, and the present invention is efficient, the different Astragaloside IV synthetic method of highly-solid selectively; research and application for different Astragaloside IV provide enough raw materials; synthesis for different Radix Astragali glycosides compound provides reference, fills up the blank of prior art, activity mechanism research and its process of drug development of Astrageloside compound will be promoted significantly.
Description
Technical field
The invention belongs to the field of chemical synthesis, a kind of preparation method of different Astragaloside IV is more particularly related to.
Background technology
The Radix Astragali is first of tonic, to belong to pulse family Astragalus.Recently as modern separation and the development of identification technology,
A large amount of triterpenoid saponins, flavone compound and polysaccharide constituents have been isolated from the Radix Astragali.The biological biochemistry experiment table in later stage
The medicinal efficacy of the bright Radix Astragali is mainly showed by astragaloside.Recent studies suggest that, astragaloside is in immunological regulation, drop
Sugar, improves insulin resistance activity, antitumor, to cardiovascular system regulation and antiviral, all table in terms of antioxidation activity
Reveal extremely gratifying prospect in medicine, and in numerous astragalosides, with the activity of Astragaloside IV and different Astragaloside IV most
It is good.
Promote people to study it to deepen continuously although astragaloside is widely applied prospect, currently used for active testing
Astragaloside be generally that from the Radix Astragali obtained by separation and Extraction, because contained saponin(e species is various in the Radix Astragali, and structure is similar, and this gives
Separating-purifying brings very big difficulty.Also some astragalosides are secondary saponin(e, and the content in the Radix Astragali is very low, to be obtained enough
Amount is even more difficult so that active testing is used, and this has turned into the deep bottleneck of restriction astragaloside activity research, up to the present
Almost report is studied in the chemical synthesis not on astragaloside.
Content of the different Astragaloside IV in the Radix Astragali is especially few, and its molecular structural formula is as follows：
Its saponin fraction is cycloastragenol, and due to 3 of cycloastragenol (compound 1), 6,16 and 25 contain 4
The hydroxyl of inertia OH, particularly 25 is that tert-hydroxyl activity is low, and glycosylation reaction is difficult, and 4 inertia OH it is mutual before it is anti-
Activity is answered to be difficult to differentiate between, selective glycosylation which part hydroxyl is increasingly difficult.
The hydroxyl protection reaction of cycloastragenol carries out difficulty and product is complicated and changeable, has document report, in excessive acetylation
Under reagent effect, 60 DEG C, up to the full acetylated cycloastragenol under the reaction time of 50 days, being only capable of obtaining 56% yield.Contracting
Short reaction time or reduction reaction temperature cause reaction product sufficiently complex, are that random 1 or 2 hydroxyl in 4 hydroxyls is protected
The cycloastragenol of shield.Different Astragaloside IV synthesis is difficult as can be seen here, and so far there are no both at home and abroad successfully reports.
Bibliography：a)Mamedova,R.P.；Agzamova,M.A.；Isaev,M.I.Chem.Nat.Compd.2001,
37,533-536.b)Isaev,I.M.；Iskenderov,D.A.；Isaev,M.I.Chem.Nat.Compd.2009,45,381-
384.c)Isaev,I.M.；Iskenderov,D.A.；Isaev,M.I.Chem.Nat.Compd.2010,46,407-411.d)
Procopiou,P.A.；Baugh,S.P.D.；Flack,S.S.；Inglis,G.G.J.Org.Chem.1998,63,2342-
2347.
The content of the invention
The present invention provides a kind of synthetic method of different Astragaloside IV, and energy is efficient, the different Astragaloside IV of synthesis of high selectivity, is
The research and application of different Astragaloside IV provide enough raw materials, and the synthesis for different Radix Astragali glycosides compound provides reference.
What the present invention was realized by following steps：
A kind of synthetic method of different Astragaloside IV, comprises the following steps：
(1) 3 hydroxyls of cycloastragenol are protected with protection group R1, obtains compound 2；
(2) 6 of compound 2 and 16 hydroxyls are protected with protection group R2, obtains compound 3；
(3) glycosylation reaction is occurred into for compound 3 and glycosyl donor compound 4, obtains compound 5；
(4) 3 protection group R1 of compound 5 are removed, obtains compound 6；
(5) glycosylation reaction is occurred into for compound 6 and glycosyl donor compound 7, obtains compound 8；
(6) all protection groups of compound 8 are removed, obtains different Astragaloside IV；
Wherein, the R1Selected from substituted or non-substituted C1-C9 alkane silicon substrates；The R2Selected from substituted or non-substituted C2-C6
Alkanoyl；The R3Or R4It is independently selected from C1-C6 aroyls；X is selected from substituted or non-substituted alkynes benzoyloxy.
The X is
In above-mentioned steps (1), the method for the protection comprises the following steps：At room temperature, that cycloastragenol is dissolved in into first is molten
In agent, halogenated silanes and imidazoles are added, reaction temperature is slowly increased to stir after room temperature until TLC tracking display cycloastragenols
Reaction is complete；First solvent be dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene,
In benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether
One or more, the mol ratio of the cycloastragenol, halogenated silanes and imidazoles is 1:1:1~1:5:10, preferably 1:2:3~
1:4:6, concentration of the cycloastragenol in the first solvent is 0.1~1mol/L, preferably 0.45~0.5mol/L, the halogen
It is TBSCl, TESCl, TBDMSCl, TBDPSCl, DIPSCl, DPSCl or TIPDSCl for silane.
In above-mentioned steps (2), the method for the protection comprises the following steps：Less than 0 DEG C, compound 2 is dissolved in second molten
In agent, pivaloyl chloride is added, reaction temperature is slowly increased to be heated to 50 DEG C after room temperature, continues to stir until TLC tracking
Display compound 2 reacts complete, and second solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, first
One in benzene, benzene, dioxane, pyridine, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether
Plant or a variety of；The compound 2 and the mol ratio of pivaloyl chloride are 1:2~1:20, preferably 1:2~1:10；The compound 2
Concentration in the second solvent is 0.1~1mol/L, preferably 0.108~0.5mol/L.
In above-mentioned steps (3), the glycosylation reaction comprises the following steps：Under inert gas shielding, by the He of compound 3
Glycosyl donor compound 4 is dissolved in the 3rd solvent, and adds drier, is stirred at room temperature 0.5~2 hour and is added catalysis
Agent, continues to be stirred at room temperature until TLC tracking displays compound 2 reacts complete；3rd solvent is dichloromethane, chlorine
Imitative, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, second
One or more in acetoacetic ester, acetone, methanol, ethanol, DMSO or ether, the catalyst is aurous complex compound, excellent
Elect PPh as3AuNTf2Or PPh3AuOTf；The mol ratio of the compound 3, glycosyl donor compound 4 and the catalyst is 1:
1:0.1~1:5:0.8, preferably 1:1:0.1~1:2:0.5；Concentration of the compound 3 in the 3rd solvent be 0.001~
1mol/L, preferably 0.006~0.05mol/L；The drier is molecular sieve, is preferablyMolecular sieve or picklingMolecular sieve, more preferably 4A molecular sieves.
In above-mentioned steps (4), the protection group R1The method of removing comprises the following steps：At room temperature, compound 5 is dissolved in
In 4th solvent, camphorsulfonic acid is added, stirring reacts complete until TLC tracking displays compound 5；4th solvent is two
Chloromethanes, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran,
One or more in triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether, the compound 5 and camphorsulfonic acid
Mol ratio 1:1~1:10, preferably 1:1~1:4；Concentration of the compound 5 in the 4th solvent is 0.001~1mol/
L, preferably 0.001~0.004mol/L.
In above-mentioned steps (5), the glycosylation reaction comprises the following steps：Compound 6 and glycosyl donor compound 7 is molten
In the 5th solvent, and drier is added, be stirred at room temperature 0.5~2 hour and add catalyst, continue to be stirred at room temperature
Until TLC tracking displays compound 6 reacts complete, the 5th solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloros
Ethane, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, second
One or more in alcohol, DMSO or ether；The mol ratio of the compound 6, glycosyl donor compound 7 and the catalyst is
1:1:0.1~1:5:0.8, preferably 1:1:0.1~1:2.5:1；Concentration of the compound 6 in the 5th solvent is 0.001
~1mol/L, preferably 0.001~0.003mol/L；The catalyst is aurous complex compound, preferably PPh3AuNTf2Or
PPh3AuOTf；The drier is molecular sieve, is preferablyMolecular sieve or picklingMolecular sieve, more preferably 4A point
Son sieve.
In above-mentioned steps (6), the reaction of the protection group removing comprises the following steps：Compound 8 is dissolved in the 6th solvent
In, reducing agent is added, is stirred at room temperature until TLC tracking displays compound 8 reacts complete；The reducing agent is hydroboration
Sodium, lithium aluminium hydride reduction, borine；8th solvent be dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene,
In benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether
One or more, preferably methanol.
It is preferred that, the either step in above-mentioned steps (1)~(6) is carried out under the conditions of inert gas shielding, described lazy
Property gas be selected from nitrogen, argon gas or helium.
In step (1), work as cycloastragenol, the mol ratio of TBSCl and imidazoles is 1:20:When 20, what is obtained is cycloastragenol 3
The compound of the whole protection of position and 6 hydroxyls, works as cycloastragenol, and the mol ratio of TBSCl and imidazoles is 1:2:When 2, other reactions
Parameter is identical, and reaction yield only has 40%.
The solution have the advantages that：The present invention is efficient, the different Astragaloside IV synthetic method of highly-solid selectively, is different
The research and application of Astragaloside IV provide enough raw materials, and the synthesis for different Radix Astragali glycosides compound provides reference, fills up existing
The blank of technology, activity mechanism research and its process of drug development of Astrageloside compound will be promoted significantly.
Embodiment
According to following embodiments, the present invention may be better understood, however, as it will be easily appreciated by one skilled in the art that real
Apply the content described by example and be merely to illustrate the present invention, without should be also without limitation on sheet described in detail in claims
Invention.
The sugar 4 and 7 of Bz protections is synthesized according to this area conventional method：
Compound 4-1 synthetic method is as follows：
In nitrogen protection, hydroxyl exposed full Bz glucose (100mg, 0.17mmol) in different head position is dissolved in dry dichloro
In methane (4mL), then the adjacent alkynyl benzoic acid (37.4mg, 0.2mmol) of addition into system, DMAP (28.1mg, 0.23mmol),
EDCI (43.9mg, 0.23mmol), DIPEA (74 μ L), be stirred overnight at room temperature until TLC tracking displays raw material reaction completely,
Reaction system is extracted with dichloromethane, and washed successively with 1mol/l HCl, saturated sodium bicarbonate, saturation NaCl, anhydrous slufuric acid
Sodium is dried, suction filtration, and be concentrated under reduced pressure crude product, and then column chromatography obtains compound as white solid 4-1 (121mg, 93%)：1H NMR
(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3) δ 8.07 (d, J=7.5Hz, 2H), 7.92-7.87 (m, 6H), 7.44-
7.28 (m, 17H), 6.94 (d, J=3.3Hz, 1H), 6.38 (dd, J=9.6,9.9Hz, 1H), 5.94 (dd, J=9.9,
10.2Hz, 1H), 5.76 (dd, J=3.3,9.9Hz, 1H), 4.80-4.66 (m, 2H), 4.54 (dd, J=3.3,6.0Hz, 1H),
1.56 (m, 1H), 0.84 (d, J=6.6Hz, 4H)
Compound 7-1 synthetic method is as follows：
Similar to synthesis compound 4-1, compound as white solid 7-1 is obtained from the exposed full Bz xyloses of different head position hydroxyl
(612mg, 89%)：[α]D 25=0.02 (c 1.0, CHCl3)；1H NMR(400MHz,CDCl3)δ8.04-7.98(m,6H),
7.90 (dd, J=1.2,8.0Hz, 1H), 7.58-7.51 (m, 3H), 7.49-7.42 (m, 2H), 7.38-7.30 (m, 6H), 7.21
(td, J=1.6,7.6Hz, 1H), 6.42 (d, J=7.6Hz, 1H), 5.81 (t, J=5.2Hz, 1H), 5.58 (dd, J=4.0,
5.2Hz, 1H), 5.36-5.32 (m, 1H), 4.63 (dd, J=3.6,12.8Hz, 1H), 4.06 (dd, J=4.8,12.4Hz,
1H),1.54-1.47(m,1H),0.90-0.84(m,4H)；13C NMR(100MHz,CDCl3)δ164.9,164.4,164.3,
163.3,133.7,132.8,129.9,129.7,129.4,129.3,128.5,128.3,127.8(2C),126.3,124.7,
99.7,91.4,73.6,67.8,67.6,67.2,60.9,8.2,-0.0；HRMS(ESI-TOF)m/z:[M+H]+calcd for
C38H31O9631.1968；found 631.1966.
Embodiment 1
The synthesis of different Astragaloside IV,
The synthesis of the cycloastragenol derivative 2 of (1) 3 hydroxyl protection,
Under nitrogen protection, cycloastragenol (400mg, 0.82mmol) is dissolved in dry DMF and adds TBSCl into system again
(489mg, 3.3mmol), imidazoles (333mg, 4.9mmol) is stirred at room temperature until TLC tracking displays raw material reaction is complete, incited somebody to action
Reaction system is extracted with ethyl acetate, and is washed successively with 1mol/l HCl, saturated sodium bicarbonate, saturation NaCl, anhydrous sodium sulfate
Dry, suction filtration, be concentrated under reduced pressure crude product, and then column chromatography obtains compound as white solid 2 (76.8%)：[α]D 25=30.5 (c
=1, CHCl3)；1H NMR(400MHz,CDCl3) δ 4.67 (dd, J=7.6,14.4Hz, 1H), 3.72 (dd, J=6.0,
8.0Hz, 1H), 3.51 (td, J=3.6,9.6Hz, 1H), 3.25 (dd, J=4.8,10.0Hz, 1H), 2.59 (dd, J=10.4,
21.6Hz, 1H), 2.31 (d, J=8.0Hz, 1H), 2.00-1.92 (m, 4H), 1.76 (dd, J=4.0,12.0Hz, 1H), 1.25
(s,3H),1.21(s,3H),1.17(s,3H),1.13(s,3H),1.11(s,3H),1.09(s,3H),0.91(s,3H),0.89
(s, 3H), 0.85 (s, 9H), 0.47 (d, J=4.0Hz, 1H), 0.31 (d, J=4.4Hz, 1H), 0.00 (s, 3H), -0.005
(s,3H)；13C NMR(100MHz,CDCl3)δ87.1,81.4,78.8,73.4,71.8,68.9,57.5,53.7,46.9,
46.5,46.0,45.0,42.1,37.7,34.4,33.0,32.1,31.4,30.8,29.4,28.6,27.9,27.7,26.4,
25.9(2C),25.8,21.4,20.5,20.0,18.1,15.8；HRMS(ESI)calcd for C36H65O5Si[M+H]+
605.4596,found 605.4599；
(2) 3, the synthesis of the cycloastragenol derivative 3 of 6 and 16 hydroxyl protections,
Under nitrogen protection, 0 degrees celsius, compound 2 (300mg, 0.5mmol) is dissolved in dry pyridine (2ml)
In, then into system add PivCl (50 μ L, 4.96mmol), be slowly increased to be heated to 50 degree after room temperature, stirring until TLC with
Track show raw material reaction completely, reaction system is extracted with ethyl acetate, and successively with 1mol/l HCl, saturated sodium bicarbonate,
Saturation NaCl is washed, anhydrous sodium sulfate drying, suction filtration, and be concentrated under reduced pressure crude product, and then column chromatography obtains compound as white solid 3
(94.9%)：[α]D 25=72.9 (c=1, CHCl3)；1H NMR(400MHz,CDCl3)δ5.31-5.26(m,1H),4.74-
4.69 (m, 1H), 3.74 (t, J=7.2Hz, 1H), 3.24 (dd, J=4.8,10.0Hz, 1H), 2.37 (d, J=8.0Hz, 1H),
2.08-2.00(m,2H),1.36(s,3H),1.31(s,3H),1.18(s,3H),1.16(s,9H),1.13(s,9H),1.07
(s, 3H), 0.96 (s, 3H), 0.85 (s, 12H), 0.80 (s, 3H), 0.54 (d, J=4.8Hz, 1H), 0.21 (d, J=4.8Hz,
1H)；13C NMR(100MHz,CDCl3)δ178.2,177.7,85.5,83.3,78.5,75.7,71.2,69.7,57.5,49.2,
46.7,46.2,45.1,43.0,41.9,38.6,38.2,32.5,31.9,31.4,27.8,27.4,27.3,27.2,27.1
(2C),26.6,26.2,26.0,25.9,25.4,24.5,20.7,19.8,19.6,18.1,15.4；HRMS(ESI)calcd
for C64H81O7Si[M+H]+773.5746,found 773.5743；
The synthesis of (3) 25 glycosylation products 5,
Under nitrogen protection, compound 3 and glucose alkynes ester donor 4-1 are dissolved in dry dichloromethane, and added
4A molecular sieves, being stirred at room temperature half an hour adds catalyst Ph3PAuNTf2(0.2eq), continues to be stirred at room temperature directly
To TLC tracking displays raw material reaction completely, be concentrated under reduced pressure crude product, and then column chromatography obtains compound as white solid 5
(91.6%)：[α]D 25=40.3 (c=1, CHCl3)；1H NMR(400MHz,CDCl3)δ8.02-7.96(m,4H),7.91(dd,
J=1.2,8.0Hz, 2H), 7.86 (dd, J=1.2,8.4Hz, 2H), 7.54-7.48 (m, 4H), 7.43-7.34 (m, 7H),
7.31 (t, J=8.0Hz, 1H), 5.90 (t, J=9.6Hz, 1H), 5.53 (dd, J=9.2,10.0Hz, 1H), 5.48 (dd, J=
7.6,9.2Hz, 1H), 5.35 (d, J=8.0Hz, 1H), 5.23-5.18 (m, 1H), 4.76 (dd, J=6.8,14.4Hz, 1H),
4.60 (dd, J=2.8,12.0Hz, 1H), 4.44 (dd, J=7.2,12.0Hz, 1H), 4.13-4.08 (m, 1H), 3.72 (dd, J
=4.8,8.4Hz, 1H), 3.20 (m, 1H), 2.42 (d, J=7.6Hz, 1H), 2.14-2.06 (m, 2H), 1.37 (s, 3H),
1.33(s,3H),1.18(s,9H),1.17(s,9H),1.16(s,3H),1.13(s,3H),0.98(s,3H),0.86(s,
12H), 0.80 (s, 3H), 0.56 (d, J=4.8Hz, 1H), 0.27 (d, J=4.8Hz, 1H)；13C NMR(100MHz,CDCl3)δ
178.0,177.7,165.9,165.8,165.4,164.9,134.2,134.1,133.5,133.2,133.1(2C),129.8
(2C),129.7(2C),129.6,129.3,129.2,129.0,128.8,128.4,128.3(2C),96.2,86.0,84.1,
80.1,78.3,76.1,73.1,72.1(2C),70.5,69.8,63.9,57.8,49.1,46.8,46.3,45.2,43.2,
41.9,38.6,38.5,38.2,32.6,32.1,31.2,30.5,27.8,27.4,27.2(2C),25.9,25.5,24.0,
21.7,20.6,19.7,19.6,18.1,15.4,-3.9,-4.9；HRMS(ESI)calcd for C80H107O16Si[M+H]+
1351.73229,found 1351.73310；
The synthesis of (4) 3 exposed products 6 of hydroxyl,
Under nitrogen protection, compound 5 (20mg, 0.03mmol) is dissolved in dry methanol (2.0mL), at room temperature
Camphorsulfonic acid (26mg, 0.11mmol) is added, stirring is complete until TLC tracking displays raw material reaction, and be concentrated under reduced pressure crude product, so
Column chromatography obtains compound as white solid 6 (82.9%) afterwards：[α]D 25=20.5 (c=1, CHCl3)；1H NMR(400MHz,
CDCl3) δ 8.00-7.96 (m, 4H), 7.91 (dd, J=1.2,8.0Hz, 2H), 7.85 (dd, J=1.2,8.0Hz, 2H),
7.54-7.49 (m, 3H), 7.45-7.33 (m, 7H), 7.31-7.27 (m, 2H), 5.91 (t, J=9.6Hz, 1H), 5.54 (t, J
=10.1Hz, 1H), 5.48 (dd, J=8.0,9.6Hz, 1H), 5.27 (d, J=8.0Hz, 1H), 5.23-5.18 (m, 1H),
4.78-4.73 (m, 1H), 4.59 (dd, J=3.2,12.0Hz, 1H), 4.44 (dd, J=7.2,11.6Hz, 1H), 4.14-4.08
(m, 1H), 3.72 (dd, J=4.8,8.4Hz, 1H), 3.24 (dd, J=4.8,11.6Hz, 1H), 2.43 (d, J=8.0Hz,
1H), 2.16 (dd, J=7.6,13.6Hz, 1H), 2.05-2.01 (m, 1H), 1.36 (s, 3H), 1.33 (s, 3H), 1.18 (s,
12H), 1.17 (s, 9H), 1.11 (s, 3H), 1.00 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.56 (d, J=4.8Hz,
1H), 0.30 (d, J=4.4Hz, 1H)；13C NMR(100MHz,CDCl3)δ178.1,177.7,166.0,165.8,165.4,
164.9,133.5,133.2(2C),133.1,129.8(2C),129.7(2C),129.6(2C),128.9,128.8,128.4,
128.3(2C),96.2,86.0,84.1,80.1,77.9,76.1,73.1,72.1,72.0,70.4,69.9,63.9,57.8,
49.2,46.8,46.3,45.4,43.7,41.3,38.6,38.5,38.3,32.3(2C),31.3,30.0,28.0,27.3,
27.2,27.1,26.9,26.1,25.9,25.6,23.8,22.0,20.8,19.8,19.7,15.0；HRMS(ESI)calcd
for C74H93O16[M+H]+1237.64581,found 1237.64675；
(5) 3, the synthesis of 25 glycosylation products 8,
Under nitrogen protection, compound 6 and xylose alkynes ester donor 7 are dissolved in dry dichloromethane, and add 4A points
Son sieve, being stirred at room temperature half an hour adds catalyst Ph3PAuNTf2(0.2eq), continues to be stirred at room temperature until TLC
Completely, be concentrated under reduced pressure tracking display raw material reaction crude product, and then column chromatography obtains compound as white solid 8 (83.2%)：
[α]D 25=25.2 (c=0.3, CHCl3)；1H NMR(400MHz,CDCl3) δ 8.02-7.94 (m, 10H), 7.92 (dd, J=
1.2,8.0Hz, 2H), 7.86 (dd, J=1.2,8.0Hz, 2H), 7.55-7.43 (m, 7H), 7.41-7.27 (m, 14H), 5.91
(t, J=10.0Hz, 1H), 5.80 (t, J=8.0Hz, 1H), 5.52-5.42 (m, 3H), 5.32-5.27 (m, 2H), 5.23-
5.18 (m, 1H), 4.80 (d, J=6.4Hz, 1H), 4.65-4.58 (m, 2H), 4.42-4.33 (m, 2H), 4.14-4.09 (m,
1H), 3.73 (dd, J=4.8,8.4Hz, 1H), 3.62 (dd, J=7.6,12.0Hz, 1H), 3.15 (dd, J=4.4,11.2Hz,
1H), 2.44 (d, J=7.6Hz, 1H), 2.13-2.03 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H), 1.19 (s, 3H), 1.17
(s, 9H), 1.13 (s, 3H), 1.08 (s, 9H), 0.97 (s, 3H), 0.78 (s, 3H), 0.64 (s, 3H), 0.52 (d, J=
4.8Hz, 1H), 0.26 (d, J=4.8Hz, 1H)；13C NMR(100MHz,CDCl3)δ178.0,177.5,166.0,165.9,
165.6(2C),165.4,165.1,164.9,133.6,133.4,133.3,133.2(2C),133.1,129.9,129.8,
129.7(2C),129.6(2C),129.4,129.2,129.1,128.9,128.8,128.5,128.4(2C),128.3(2C),
102.6,96.2,88.6,86.1,84.2,80.2,76.1,73.1,72.1(2C),71.2,71.0,70.4,69.6,69.3,
63.9,61.7,57.8,49.2,46.8,46.3,45.2,42.9,41.4,38.5,38.3,32.5,31.8,31.1,28.6,
27.4,27.2,27.1,26.6,26.2,25.9,25.6,24.0,21.9,20.7,19.7,19.6,15.6；HRMS(ESI)
calcd for C100H116O23N[M+NH4]+1699.79666,found 1699.79904；
(6) synthesis of different Astragaloside IV,
Protected in nitrogen under conditions of 0 degree Celsius, compound 13 (70mg, 0.042mmol) be dissolved in dry THF,
Li-Al hydrogen (25mg, 0.67mmol) is slowly added into system, then is slowly increased to be stirred at room temperature until TLC tracking display raw materials are anti-
Should be complete, be concentrated under reduced pressure crude product, and then column chromatography obtains the different Astragaloside IV (yield of compound as white solid：75.6%)：：
[α]D 25=7.9 (c=0.25, CH3OH)；1H NMR(400MHz,C5D5N) δ 5.08 (d, J=7.6Hz, 1H), 4.93 (d, J=
7.2Hz, 1H), 4.45 (dd, J=3.6,11.6Hz, 1H), 4.40 (dd, J=4.8,11.2Hz, 1H), 4.32 (dd, J=4.8,
11.6Hz,1H),4.25-4.15(m,4H),4.09-4.00(m,3H),3.92-3.88(m,2H),3.81-3.72(m,2H),
3.64-3.61 (m, 1H), 2.85 (dd, J=11.6,19.6Hz, 1H), 2.48 (d, J=7.6Hz, 1H), 2.00 (s, 3H),
1.67 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H), 0.94 (s, 3H), 0.56 (d, J=
3.2Hz, 1H), 0.28 (d, J=4.0Hz, 1H)；13C NMR(100MHz,C5D5N)δ107.4,98.6,88.4,87.0,81.8,
78.3,77.8,75.4,75.0,73.3,71.1,71.0,67.7,66.8,62.5,57.9,53.8,46.6,45.9,45.8,
45.0,42.5,38.4,34.8,33.2,32.2,30.3,30.1,29.3,28.7,27.6,26.0,25.7,25.4,22.8,
21.3,20.7,19.8,16.4；HRMS(ESI)calcd for C41H68O14Na[M+Na]+807.4501,found
807.4498。
Comparative example 1：In step (3) or (5), alkynes ester donor is replaced to carry out glycosylation reaction with tri- chloroacetimidate donor
When reaction system it is very miscellaneous, product is few, illustrate alkynes ester donor synthesize different Astragaloside IV when have more superiority.
Comparative example 2：In step (1), the mol ratio of the cycloastragenol, halogenated silanes and imidazoles is 1:20:When 20, other
Response parameter is identical, reacts for 3, the product that 6 hydroxyls are protected simultaneously.
Comparative example 3：In step (1), work as cycloastragenol, the mol ratio of TBSCl and imidazoles is 1:2:When 2, other reaction ginsengs
Number is identical, and reaction yield only has 40%.
Comparative example 4：In step (2), when the concentration of compound 2 is 0.001mol/L, other response parameters are identical, compound
2 only 6 hydroxyls are protected.
Claims (8)
1. a kind of synthetic method of different Astragaloside IV, it is characterised in that comprise the following steps：
(1) 3 hydroxyls of cycloastragenol are protected with protection group R1, obtains compound 2；
(2) 6 of compound 2 and 16 hydroxyls are protected with protection group R2, obtains compound 3；
(3) glycosylation reaction is occurred into for compound 3 and glycosyl donor compound 4, obtains compound 5；
(4) 3 protection group R1 of compound 5 are removed, obtains compound 6；
(5) glycosylation reaction is occurred into for compound 6 and glycosyl donor compound 7, obtains compound 8；
(6) all protection groups of compound 8 are removed, obtains different Astragaloside IV.
Wherein, the R1Selected from substituted or non-substituted C1-C9 alkane silicon substrates；The R2Selected from substituted or non-substituted C2-C6 alkane acyls
Base；The R3Or R4It is independently selected from C1-C6 aroyls；X is selected from substituted or non-substituted alkynes benzoyloxy.
2. the synthetic method of a kind of different Astragaloside IV according to claim 1, it is characterised in that in step (1), described to protect
The method of shield comprises the following steps：At room temperature, cycloastragenol is dissolved in the first solvent, adds halogenated silanes and imidazoles, will
Reaction temperature is slowly increased to stir after room temperature until the reaction of TLC tracking displays cycloastragenol is complete；First solvent is dichloro
Methane, dichloroethanes, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, four
One or more in hydrogen furans, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether, the halogenated silanes is
TBSCl, TESCl, TBDMSCl, TBDPSCl, DIPSCl, DPSCl or TIPDSCl.The cycloastragenol, halogenated silanes and imidazoles
Mol ratio be 1:1:3~1:5:10；Concentration of the cycloastragenol in the first solvent is 0.1~1mol/L.
3. the synthetic method of a kind of different Astragaloside IV according to claim 1, it is characterised in that in step (2), described to protect
The method of shield comprises the following steps：Less than 0 DEG C, compound 2 is dissolved in the second solvent, pivaloyl chloride is added, by reaction temperature
Degree is slowly increased to be heated to 50 DEG C after room temperature, and continuation stirring reacts complete until TLC tracking displays compound 2, and described second
Solvent be dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene, benzene, dioxane, pyridine, tetrahydrofuran,
One or more in triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether；The compound 2 and pivaloyl chloride
Mol ratio be 1:2~1:20；Concentration of the compound 2 in the second solvent is 0.1~1mol/L.
4. the synthetic method of a kind of different Astragaloside IV according to claim 1, it is characterised in that in step (3), the sugar
Reaction of guanosine comprises the following steps：Under inert gas shielding, compound 3 and glycosyl donor compound 4 are dissolved in the 3rd solvent
In, and add drier, be stirred at room temperature 0.5~2 hour and add catalyst, continue to be stirred at room temperature until TLC with
Track shows that compound 2 reacts complete；3rd solvent be dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF,
Toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or second
One or more in ether, the mol ratio of compound 3, glycosyl donor compound 4 and the catalyst is 1:1:0.1~1:5:
0.8；Concentration of the compound 3 in the 3rd solvent is 0.001~1mol/L；The catalyst is selected from aurous complexing
Thing；The drier is selected from molecular sieve.
5. the synthetic method of a kind of different Astragaloside IV according to claim 1, it is characterised in that in step (4), described to protect
Protect base R1The method of removing comprises the following steps：At room temperature, compound 5 is dissolved in the 4th solvent, adds camphorsulfonic acid, stirred
Mix until TLC tracking displays compound 5 reacts complete；4th solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2- bis-
Chloroethanes, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, second
The mol ratio 1 of one or more in alcohol, DMSO or ether, the compound 5 and camphorsulfonic acid:1~1:10；The compound
5 concentration in the 4th solvent is 0.001~1mol/L.
6. the synthetic method of a kind of different Astragaloside IV according to claim 1, it is characterised in that in step (5), the sugar
Reaction of guanosine comprises the following steps：Compound 6 and glycosyl donor compound 7 are dissolved in the 5th solvent, and add drier,
Stirring adds catalyst in 0.5~2 hour at room temperature, continues to be stirred at room temperature until TLC tracking displays compound 6 has been reacted
Entirely, the 5th solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene, benzene, dioxane, pyrrole
One or more in pyridine, glacial acetic acid, tetrahydrofuran, triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether；Institute
The mol ratio for stating compound 6, glycosyl donor compound 7 and the catalyst is 1:1:0.1~1:5:0.8；The compound 6 exists
Concentration in 5th solvent is 0.001~1mol/L；The catalyst is selected from aurous complex compound；The drier, which is selected from, to be divided
Son sieve.
7. the synthetic method of a kind of different Astragaloside IV according to claim 1, it is characterised in that in step (6), described to protect
The reaction of shield base removing comprises the following steps：Compound 8 is dissolved in the 6th solvent, reducing agent is added, stirs straight at room temperature
React complete to TLC tracking displays compound 8；The reducing agent is sodium borohydride, lithium aluminium hydride reduction, borine；8th solvent
For dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, DMF, toluene, benzene, dioxane, pyridine, glacial acetic acid, tetrahydrochysene furan
Mutter, the one or more in triethylamine, ethyl acetate, acetone, methanol, ethanol, DMSO or ether.
8. the synthetic method of different Astragaloside IV according to claim 1, it is characterised in that any in step (1)~(6)
Step is carried out under the conditions of inert gas shielding.
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