CN116120386A - Synthesis method of 2,3, 4-trihydroxy nitrogen glycoside compounds - Google Patents
Synthesis method of 2,3, 4-trihydroxy nitrogen glycoside compounds Download PDFInfo
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- -1 nitrogen glycoside compounds Chemical class 0.000 title claims abstract description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 29
- 229930182470 glycoside Natural products 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000003446 ligand Substances 0.000 claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 235000000346 sugar Nutrition 0.000 claims abstract description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 4
- KZKQFFFEMJUSJN-UHFFFAOYSA-N [N].CN1CCOCC1 Chemical compound [N].CN1CCOCC1 KZKQFFFEMJUSJN-UHFFFAOYSA-N 0.000 claims abstract 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 229930182478 glucoside Natural products 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 230000008034 disappearance Effects 0.000 claims description 4
- 239000005467 galactogogue Substances 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- DXOKBYGKGLTZMX-UHFFFAOYSA-N oxoosmium;potassium Chemical compound [K].[Os]=O DXOKBYGKGLTZMX-UHFFFAOYSA-N 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- MOBKGIYZCYKWHZ-UHFFFAOYSA-N osmium;potassium;dihydrate Chemical compound O.O.[K].[Os] MOBKGIYZCYKWHZ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000007254 oxidation reaction Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 4
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- IGNNHTRPEUSRDR-UHFFFAOYSA-N [N]=O.CN1CCOCC1.[N] Chemical group [N]=O.CN1CCOCC1.[N] IGNNHTRPEUSRDR-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229930189065 blasticidin Natural products 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000002464 Galactosidases Human genes 0.000 description 1
- 108010093031 Galactosidases Proteins 0.000 description 1
- 102000007390 Glycogen Phosphorylase Human genes 0.000 description 1
- 108010046163 Glycogen Phosphorylase Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000813090 Rhizoctonia solani Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960001169 brivudine Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 229910000487 osmium oxide Inorganic materials 0.000 description 1
- JIWAALDUIFCBLV-UHFFFAOYSA-N oxoosmium Chemical compound [Os]=O JIWAALDUIFCBLV-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003336 secondary aromatic amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
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Abstract
The invention provides a method for synthesizing 2,3, 4-trihydroxy nitrogen glycoside compounds, which comprises the steps of adding a palladium catalyst, phosphine ligand and galacto-allyl sugar into an organic solvent and amine, stirring at room temperature for reaction, detecting the reaction progress by TLC, adding potassium osmium dihydrate and nitrogen methylmorpholine oxynitride (50% aqueous solution) into a reaction solution after the galacto-allyl sugar completely disappears, stirring at room temperature for reaction, detecting the reaction progress by TLC, stopping the reaction after the reaction product completely disappears, and obtaining 2,3, 4-trihydroxy nitrogen glycoside, wherein the structural formula of the amine is R 1 ‑NH‑R 2 Which is provided withR in (B) 1 Including alkyl, hydrogen; r is R 2 Including any one of alkyl, phenyl, substituted phenyl, five-membered or six-membered heterocyclic groups. The invention adopts a two-step one-pot reaction, has high efficiency and simple post-treatment.
Description
Technical Field
The invention mainly relates to a method for synthesizing 2,3, 4-trihydroxy nitrogen glycoside compounds, and belongs to the technical field of organic synthesis.
Background
Azosides are an important component of carbohydrates and are widely found in nature and in clinical medicine. Among the most well known nitrogen glycosides are nucleotides, which can not only be an important component of DNA/RNA. As clinical drugs for tumor treatment such as capecitabine and fludarabine, antiviral treatment such as brivudine and immunomodulation. Azoglycoside blasticidin is used as an important natural antibiotic in the field of pesticides such as blasticidin for controlling rice blast and diseases caused by rhizoctonia solani. Another common class of nitrogen glycosides are glycopeptides and glycoproteins, which typically function as enzymes, hormones, and antibodies in biological systems. Many other nitrogen glycosides are found in natural products and drug molecules and exhibit a variety of biological activities, such as glycogen phosphorylase inhibitors and galactosidase inhibitors. However, in the research of nitrogen glucoside at present, most of amine substrates are limited to amide, sulfonamide and heterocyclic amine, but few of aromatic amine and aliphatic amine nitrogen glucoside are researched, so that the development of the 2,3, 4-trihydroxy nitrogen glucoside compound with high efficiency for synthesizing the aromatic amine and aliphatic amine as substrates is significant.
Few nitrogen glycosides have been reported to be synthesized by reacting 1-halo, 1-amino and 1-cyano sugars. The method often has the product of the nitrogen glycoside with the protecting group, and further deprotection is needed to obtain polyhydroxy nitrogen glycoside for biological activity research. In addition, the method has the limitations of low stereoselectivity, complex structure of the required raw materials, large catalyst consumption and the like in synthesis.
Disclosure of Invention
Aiming at the technical problems, the invention develops a high-regioselectivity and stereoselectivity nitrogen glycosylation and oxidation reaction tandem one-pot method for synthesizing the 2,3, 4-trihydroxy nitrogen glycoside compound by adopting high-activity 3, 4-carbonate galacto-glycal and palladium catalyst and osmium oxide.
The synthesis method of the 2,3, 4-trihydroxy nitrogen glycoside compounds comprises the following steps:
firstly, adding a catalyst, a ligand and galacto-glycal into an organic solvent and amine, stirring at room temperature for reaction, and detecting the reaction progress by TLC;
secondly, adding an oxidant and an additive into the reaction liquid after the complete disappearance of the galactoalkene sugar, stirring at room temperature for reaction, detecting the reaction progress by TLC, and stopping the reaction after the complete disappearance of the reaction product in the last step to obtain the 2,3, 4-trihydroxy nitrogen glucoside, wherein the reaction formula is as follows:
the R is 1 Including any one of silicon-based, alkyl, benzyl, phenyl, triphenylmethyl, benzoate; r is R 2 -NH-R 3 Wherein R is 2 Including hydrogen, alkyl, alkoxy; r is R 3 Including any one of phenyl, substituted phenyl, five-membered or six-membered heterocyclic groups;
the general glycyl nitrogen glycoside compound is unstable and difficult to separate and purify, and the invention adopts a one-pot method to continuously react, and intermediate products are directly subjected to a second-step reaction without separation and purification, so that the 2,3, 4-trihydroxy nitrogen glycoside compound is successfully obtained.
The five-membered or six-membered heterocyclic group comprises any one of pyridyl, pyrazinyl, imidazolyl, thienyl, thiazolyl and quinolinyl.
The first-step reaction ligand comprises Xantphos and PPh 3 DPPB, DPPF, t-Buxphos.
The first-step reaction palladium catalyst comprises Pd (PPh 3 ) 4 、Pd(acac) 2 、Pd 2 (dba) 3 、Pd 2 (dba) 3 ·CHCl 3 Any one of the following.
The molar ratio of the palladium catalyst, the phosphine ligand, the galacto-glycal and the amine in the first step is (0.01-0.05): 1 (0.5-2).
The second step reaction oxidation reaction oxidant comprises potassium osmium oxide and potassium osmium oxide dihydrate.
The second-step reaction oxidation reaction additive is nitrogen methyl morpholine nitrogen oxide (50% aqueous solution).
The addition amount of the oxidizing agent in the second-step reaction oxidation reaction is 0.05-0.1 time of the molar amount of the galactagogue, and the addition amount of the additive is 1-1.5 times of the molar amount of the galactagogue.
The solvent comprises any one of tetrahydrofuran, dichloromethane, toluene and chloroform.
The structural formula of the 2,3, 4-trihydroxy nitrogen glycoside compound prepared by the method is as follows:
wherein the preferred structural formula includes the following:
any one of the following.
The key steps are that the palladium catalytic nitrogen glycosylation reaction in the first step is not purified and the second osmium oxidation dihydroxylation reaction is directly carried out, so that the high-product and the high-purity target product can be obtained. If the first step and the second step are used for purification step by step, one-pot operation is not performed, the intermediate is unstable and easy to decompose, and the yield and the purity of the product are greatly reduced.
Drawings
FIG. 1 is a hydrogen spectrum of the compound described in example 1.
FIG. 2 is a carbon spectrum of the compound described in example 1.
Detailed Description
The experimental reagents used in this embodiment are as follows:
bis (acetylacetonate) palladium (Beijing carboline technologies Co., ltd.), petroleum ether (boiling range 60-90, tianjin Co., ltd.), ethyl acetate (analytically pure, tianjin Co., miou chemical reagent Co., ltd.), anhydrous sodium sulfate (analytically pure, national drug group chemical reagent Co., ltd.), deuterated acetone (deuterium atom content 99.8%, TMS content 0.03% V/V,10 x 0.5 mL/box, switzerland ARMAR Co., ltd.), deuterated chloroform (deuterium atom content 99.8%, TMS content 0.03% V/V,10 x 0.5 mL/box, switzerland ARMAR Co.); nuclear magnetic resonance tube (5 mm 100/pk 2ST500-8, norell Co., U.S.A.).
The experimental apparatus used in this embodiment is as follows:
ZXZM type rotary vane vacuum pump (Shanghai, tanshi vacuum equipment Co., ltd.), DZF-6020 type vacuum drying oven (Shanghai, new Miao medical equipment manufacturing Co., ltd.), SHBTHA circulating water type multipurpose vacuum pump (Shanghai, yukang science and teaching equipment Co., ltd.), CL-4 type flat magnetic stirrer (Zheng, great wall, industrial and trade Co., ltd.), EYELASBT100 rotary evaporator (Shanghai, ailang instruments Co., ltd.), FA2104B analytical balance (Shanghai, yuan Ping technology instruments Co., ltd.), DFT01S heat-collecting constant temperature heating magnetic stirrer (Ying, hua instruments Co., ltd.), GZX-9240MBE digital display blast drying oven (Shanghai, bo, ultranshi 400MHz Plus Nuclear, germany), API 4000LC-MS/MS mass spectrometer (Bruker Dalton)
Example 1
Taking 3, 4-O-carbonate galacto-enase and O-nitroaniline as examples for experimental condition optimization, the experimental conditions are specifically as follows:
note that: all experiments were carried out using 0.1mmol galactose with 0.15mmol o-nitroaniline, 5mol% palladium catalyst, 10mol% monodentate phosphorus ligand (or 5mol% bidentate phosphorus ligand) in 2.5mL solvent at 25℃in Schlenk tubes, unless otherwise specified; isolation yield; the regioselectivity and the stereoselectivity are measured by nuclear magnetic hydrogen spectrum to be more than 99 percent.
The technical scheme of the invention screens and optimizes the reaction conditions. The oxidation conditions were first determined and screening was performed with Xantphos as ligand and DCM as solvent, and found that Pd (acac) was used 2 When the catalyst is used, the yield of the glycosylation reaction is highest. Next, ligands were screened under the determination of the optimal catalyst precursor, and it was found that the yield was up to 85% when DPPB was used as the ligand. Finally, the solvent is screened, and the optimized result shows that the reaction effect is best under the condition that THF is used as the solvent, and the yield can reach 88%. Meanwhile, we also conducted a blank experiment, and found that the reaction was difficult to carry out without adding a ligand. We have also tried for the second oxidation conditions not for the combined oxidation system, experimental results show that K 2 OsO 4 ·2H 2 The highest combined yield of O/NMO can reach 89%.
The reaction condition screening experiment shows that the optimal reaction condition of the obtained 2,3, 4-trihydroxy nitrogen glucoside compound is Pd (acac) 2 As catalyst, DPPB as ligand, THF as solvent, and oxidation conditions K were used 2 OsO 4 ·2H 2 The combined reaction of O/NMO is best.
Under the condition of the route, the invention adopts the technical route of preparing 2,3, 4-hydroxy-1-azoose by taking 3, 4-O-carbonate galacto-glycal as raw material:
palladium bis (acetylacetonate) (Pd (acac) 2 3.0mg,0.01 mmol), 1, 4-bis (diphenylphosphine) butane (DPPB, 4.3mg,0.01 mmol) and 3, 4-O-carbonate galacto-enase 1 (0.1 mmol) were added 2.5mL of tetrahydrofuran and O-nitroaniline (0.15 mmol). Stirring at 25deg.C, detecting reaction progress by TLC, adding when alkene sugar completely disappearsAdding nitrogen methyl morpholine nitrogen oxide (NMO, 50% aqueous solution) and potassium osmium sulfonate dihydrate, stirring at 25deg.C, detecting reaction progress by TLC, terminating reaction after the reaction product completely disappears, extracting and collecting organic phase, vacuum distilling to remove solvent to obtain crude product, and performing column chromatography with petroleum ether/ethyl acetate solution as mobile phase to obtain 2,3, 4-hydroxy-1-o-nitrophenylaminoglycoside (total yield is 89%)
Example 2
Palladium bis (acetylacetonate) (Pd (acac) 2 3.0mg,0.01 mmol), 1, 4-bis (diphenylphosphine) butane (DPPB, 4.3mg,0.01 mmol) and 3, 4-O-carbonate galacto-enase 1 (0.1 mmol) were added 2.5mL of tetrahydrofuran and m-nitroaniline (0.15 mmol). Stirring at 25 ℃, detecting the reaction progress by TLC, adding nitrogen methyl morpholine nitrogen oxide (NMO, 50% aqueous solution) and potassium osmium sulfate dihydrate after alkene sugar materials completely disappear, stirring at 25 ℃, stopping the reaction after the reaction products completely disappear in the last step, extracting and collecting an organic phase, distilling under reduced pressure to remove a solvent to obtain a crude product, and then carrying out column chromatography by using petroleum ether/ethyl acetate solution as a mobile phase to obtain 2,3, 4-hydroxy-1-m-nitroaniline glucoside (total yield is 85%)
Example 3
Palladium bis (acetylacetonate) (Pd (acac) 2 3.0mg,0.01 mmol), 1, 4-bis (diphenylphosphine) butane (DPPB, 4.3mg,0.01 mmol) and 3, 4-O-carbonate galacto-enase 1 (0.1 mmol) were added 2.5mL of tetrahydrofuran and p-nitroaniline (0.15 mmol). Stirring at 25 ℃, detecting the reaction progress by TLC, adding nitrogen methyl morpholine nitrogen oxide (NMO, 50% aqueous solution) and potassium osmium sulfate dihydrate after alkene sugar materials completely disappear, stirring at 25 ℃, stopping the reaction after the reaction products completely disappear in the last step, extracting and collecting an organic phase, distilling under reduced pressure to remove a solvent to obtain a crude product, and then carrying out column chromatography by adopting petroleum ether/ethyl acetate solution as a mobile phase to obtain 2,3, 4-hydroxy-1-p-nitroaniline glucoside (total yield is 79%)
Substrate range
Anilines: preparation procedure reference is made to the best protocol in example 1
Aromatic heterocycles: preparation procedure reference is made to the best protocol in example 1
Secondary aromatic amines: preparation procedure reference is made to the best protocol in example 1
Fatty amines: the preparation procedure is as in example 1, with reference to the optimal protocol:
based on different sugar donors (substitution R 1 Group) substrate range for preparing nitrogen glycosides: the preparation procedure was as described for the best mode in example 1.
Spectral data
(2R,3R,4R,5R,6R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-((2-nitrophenyl)amino)tetrah ydro-2H-pyran-3,4,5-triol
1 H NMR(400MHz,Chloroform-d)δ8.32(d,J＝7.8Hz,1H),8.20(dd,J＝8.6,1.6Hz,1H),7.68-7.62(m,4H),7.45–7.37(m,2H),7.37–7.29(m,3H),7.26(brs,2H),7.19(t,J＝7.5Hz,2H),7.09(dd,J＝8.7,1.2Hz,1H),6.83(ddd,J＝8.4,7.0,1.3Hz,1H),5.05(dd,J＝8.9,7.8Hz,1H),4.21(t,J＝3.5Hz,1H),4.14–4.02(m,3H),3.96(d,J＝4.2Hz,2H),3.54(s,1H),2.76(s,2H),1.03(s,9H).
13 C NMR(100MHz,Chloroform-d)δ143.9,136.3,135.9,135.7,133.9,132.8,132.3,130.1,130.0,127.9,127.8,126.6,118.1,116.1,81.4,72.4,71.3,71.0,68.3,65.1,26.9,19.2.
(2R,3R,4R,5R,6R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-((3-nitrophenyl)amino)tetrah ydro-2H-pyran-3,4,5-triol
1 H NMR(400 MHz,acetone-d 6 )δ7.77-7.68(m,4H),7.66-7.65(m,1H),7.54-7.47(m,1H),7.45-7.28(m,8H),7.25-7.22(m,1H),6.36(d,J＝8.1 Hz,1H),5.02-4.98(m,1H),4.38(d,J＝3.2 Hz,1H),4.24-4.20(m,1H),4.15-4.06(m,3H),3.98-3.83(m,4H),1.02(s,9H).
13 C NMR(100 MHz,acetone-d 6 )δ150.0,149.5,136.3,136.3,134.2,134.0,130.6,130.5,130.4,128.5,128.4,120.5,112.7,108.4,82.8,74.5,72.6,71.0,68.8,64.9,27.0,19.6.
(2R,3R,4R,5R,6R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-((4-nitrophenyl)amino)tetrah ydro-2H-pyran-3,4,5-triol
1 H NMR(400 MHz,acetone-d 6 )δ8.02-8.00(m,2H),7.75-7.70(m,4H),7.46-7.30(m,6H),6.99-6.89(m,3H),5.00(dd,J＝8.9,7.6 Hz,1H),4.44(s,1H),4.26-4.02(m,4H),3.97-3.83(m,4H),1.04(s,9H).
13 C NMR(100 MHz,acetone-d 6 )δ154.4,139.3,136.4,134.2,130.6,128.5,128.4,126.4,113.6,82.3,74.8,72.6,71.1,68.6,64.9,27.1,19.7。
Claims (10)
1. The synthesis method of the 2,3, 4-trihydroxy nitrogen glycoside compounds is characterized by comprising the following steps:
firstly, adding a palladium catalyst, a phosphine ligand and galacto-glycal into an organic solvent and amine, stirring at room temperature for reaction, and detecting the reaction progress by TLC;
secondly, adding an oxidant and an additive into the reaction liquid after the complete disappearance of the galactoalkene sugar, stirring at room temperature for reaction, detecting the reaction progress by TLC, and stopping the reaction after the complete disappearance of the reaction product in the last step to obtain the 2,3, 4-trihydroxy nitrogen glucoside, wherein the reaction formula is as follows:
the R is 1 Any one selected from silicon base, alkyl, benzyl, phenyl, triphenylmethyl and benzoate; r is R 2 Selected from hydrogen, alkyl, alkoxy; r is R 3 Selected from any one of phenyl, substituted phenyl, five-membered or six-membered heterocyclic groups.
2. The method for synthesizing 2,3, 4-trihydroxy nitrogen glycoside compounds according to claim 1, wherein the five-membered or six-membered heterocyclic group includes any one of pyridyl, pyrazinyl, imidazolyl, thienyl, thiazolyl and quinolinyl.
3. The method for synthesizing 2,3, 4-trihydroxy azaglycoside compounds according to claim 1, wherein the first-step ligands include Xantphos and PPh 3 DPPB, DPPF, t-Buxphos.
4. The method for synthesizing 2,3, 4-trihydroxy azaglycoside compounds according to claim 1, wherein the method comprises the steps ofThe palladium catalyst in the first step reaction comprises Pd (PPh) 3 ) 4 、Pd(acac) 2 、Pd 2 (dba) 3 、Pd 2 (dba) 3 ·CHCl 3 Any one of the following.
5. The method for synthesizing 2,3, 4-trihydroxy nitrogen glycoside compounds according to claim 1, wherein the molar ratio of palladium catalyst, phosphine ligand, galacto-glycal and amine in the first step is (0.01-0.05): 1 (0.5-2).
6. The method for synthesizing 2,3, 4-trihydroxy-nitrogen-glycoside compounds according to claim 1, wherein the organic solvent is selected from any one of tetrahydrofuran, dichloromethane, toluene and chloroform.
7. The method for synthesizing 2,3, 4-trihydroxy azaglycoside compounds according to claim 1, wherein the oxidizing agent in the second reaction step comprises potassium osmium oxide or potassium osmium oxide dihydrate.
8. The method for synthesizing 2,3, 4-trihydroxy nitrogen glycoside compounds according to claim 1, wherein the additive in the second step is nitrogen methyl morpholine oxynitride, wherein the nitrogen methyl morpholine oxynitride is 30-50% aqueous solution.
9. The method for synthesizing 2,3, 4-trihydroxy nitrogen glycoside compounds according to claim 1, wherein the addition amount of the oxidizing agent in the second step is 0.05-0.1 times of the molar amount of the galactagogue, and the addition amount of the additive is 1-1.5 times of the molar amount of the galactagogue.
10. The 2,3, 4-trihydroxy nitrogen glycoside compound prepared by the method of any one of claims 1 to 9, wherein the compound has the structural formula:
the R is 1 Any one selected from silicon base, alkyl, benzyl, phenyl, triphenylmethyl and benzoate; r is R 2 Selected from hydrogen, alkyl, alkoxy; r is R 3 Any one selected from phenyl, substituted phenyl, five-membered or six-membered heterocyclic groups; wherein the preferred structural formula includes the following: />
Any one of the following.
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