CN114456217A - Synthetic method of glycal compound - Google Patents
Synthetic method of glycal compound Download PDFInfo
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- CN114456217A CN114456217A CN202210195192.0A CN202210195192A CN114456217A CN 114456217 A CN114456217 A CN 114456217A CN 202210195192 A CN202210195192 A CN 202210195192A CN 114456217 A CN114456217 A CN 114456217A
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- -1 glycal compound Chemical class 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 235000000346 sugar Nutrition 0.000 claims abstract description 15
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 10
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003017 phosphorus Chemical class 0.000 claims abstract description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- KIZFHUJKFSNWKO-UHFFFAOYSA-M calcium monohydroxide Chemical compound [Ca]O KIZFHUJKFSNWKO-UHFFFAOYSA-M 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- UNYOJUYSNFGNDV-UHFFFAOYSA-M magnesium monohydroxide Chemical compound [Mg]O UNYOJUYSNFGNDV-UHFFFAOYSA-M 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 6
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 abstract description 3
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 150000003003 phosphines Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical class OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 13
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- NYWRBDSLXCKNAJ-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoyl bromide Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(Br)=O NYWRBDSLXCKNAJ-SQOUGZDYSA-N 0.000 description 1
- GKHCBYYBLTXYEV-HENWMNBSSA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-6-phenylmethoxyoxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OCC1=CC=CC=C1 GKHCBYYBLTXYEV-HENWMNBSSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- YTNVHUSMDIAWLT-UHFFFAOYSA-N 91374-23-1 Chemical compound CCCN(CCC)CCC1=CC=CC([N+]([O-])=O)=C1C YTNVHUSMDIAWLT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- RXVWSYJTUUKTEA-UHFFFAOYSA-N D-maltotriose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 RXVWSYJTUUKTEA-UHFFFAOYSA-N 0.000 description 1
- 229910007568 Zn—Ag Inorganic materials 0.000 description 1
- UAOKXEHOENRFMP-ZJIFWQFVSA-N [(2r,3r,4s,5r)-2,3,4,5-tetraacetyloxy-6-oxohexyl] acetate Chemical compound CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C=O UAOKXEHOENRFMP-ZJIFWQFVSA-N 0.000 description 1
- LLPWGHLVUPBSLP-UTUOFQBUSA-N [(2r,3s,4r)-3,4-diacetyloxy-3,4-dihydro-2h-pyran-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O LLPWGHLVUPBSLP-UTUOFQBUSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- VQPFDLRNOCQMSN-UHFFFAOYSA-N bromosilane Chemical compound Br[SiH3] VQPFDLRNOCQMSN-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940075397 calomel Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RXVWSYJTUUKTEA-CGQAXDJHSA-N maltotriose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 RXVWSYJTUUKTEA-CGQAXDJHSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
-
- 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
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- 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
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
A synthesis method of a glycal compound comprises the steps of taking acyl-protected, silyl-protected or alkoxy-protected sugar and triaryl or trialkyl phosphine as raw materials, adding an organic solvent at room temperature for full dissolution, reacting at 20-60 ℃ for 2-36 hours to obtain a phosphorus salt intermediate compound, hydrolyzing under an alkaline condition, extracting after the reaction is finished, collecting an organic phase, re-dissolving the organic phase in toluene, diethyl ether or methyl tert-butyl ether after the solvent is dried, filtering to remove insoluble substances, and separating by silica gel column chromatography after the solvent is dried to obtain the target glycal compound. The invention realizes the reduction elimination reaction by taking trisubstituted phosphine as an oxidant to obtain the glycal compound, and in addition, when deuterated sodium hydroxide and deuterated water are selected as alkaline conditions, the corresponding 1-D-glycal compound can be obtained.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a glycal compound.
Background
Glycal compounds (Glycals) are a very important sugar chemical intermediate and are widely applied toN-a glycoside,O-a glycoside,C-a glycoside,SGlycosides, oligosaccharides and some natural products. In view of the glycalThe important function of the compound in the synthesis is played, and synthetic chemists are dedicated to developing a synthetic method which is environment-friendly, efficient, practical, cheap and simple and can be used for industrial production for a long time. At present, the related synthetic methods are reported very much, but basically, the methods are obtained by taking unstable 1-halogeno sugar as a raw material and reducing and eliminating the unstable 1-halogeno sugar by various metal reagents, such as (Cp)2TiCl)2、Al-Hg、Zn-Ag、Li-NH3And reduction of Cr (II) salt and cobalt metal. In addition, electrochemical reduction methods have been reported, but they have not been widely used because they require expensive electrodes and separate electrolytic cells. Since the glycal compound is reported by Ferrier and the like for the first time in 1913, the synthesis process is continuously optimized and updated, but the new methods are not substantially improved and still cannot replace the traditional Ferrier-Zach glycal synthesis method, namely, the glycal (glycal) is synthesized by taking bromoglucose as a raw material and reacting at the temperature of-20-0 ℃ in a zinc powder-acetic acid systemSitz. Ber. Kgl. Preuss. Akad. Wiss., 1913, 16, 311-317.). Several common methods of synthesizing glycals are as follows.
1.1 Ferrier-Zach reduction Synthesis of glycal
Although the Ferrier-Zach reduction method has been widely used and has been optimized and improved in recent years, these methods often require very harsh conditions, such as inert gas environment, nearly 10 equivalents of zinc metal, and low temperature condition (-20 to-10)oC) And the like. Later developed Zn/CuSO4、Zn/NaH2PO4Systems such as Zn/beta-CD and Zn/NH4Cl, although the operability of the experiment is improved and the yield of the reaction is also improved, the conditions that far excessive zinc powder is used as a reducing agent and an inert gas environment is required are still needed (Methods Carbohydr. Chem.1963, 2, 405–408; J. Carbohydr. Chem., 1996, 15, 955-964; Carbohydr. Res.2010, 345, 168–171; RSC Adv., 2014, 4, 46662-46665; Carbohydr. Res., 2016, 431, 42-46; Chin. J. Chem.2011, 29, 1434-1440; Green Chem.2009, 11, 1124–1127)。
In summary, this kind of process uses pentaacetyl sugar as starting material, firstly converts into corresponding 1-bromo sugar, then converts into glycal compound, these steps can be completed in a reactor, without separating the intermediate, however, this process has low yield, is easy to break other glycosidic bond, produces more by-product, is not easy to purify, has large amount of zinc powder, is complex to operate, has large danger, so this process is not suitable for commercial production of glycal.
1.2 reduction of Ti (III) to obtain glycal
Schwantz et al, 1995, reported the use of (Cp)2TiC1)2Reducing bromo sugar, removing 2-OAcetyl and 1-Br gave the glycal. The method firstly uses bromosilane and acetylated sugar to react at low temperature to generate brominated sugar, then the obtained brominated acetylated sugar is dissolved in THF under the protection of inert gas, and is slowly added into (Cp) dropwise2TiCl)2In the THF solution of (1), after about 15 minutes, the color of the reaction liquid turned from green to red, confirming the end of the reaction: (Tetrahedron Lett., 1996, 37, 4357-4360; J. Org. Chem., 1995, 60, 7055-7057; J. Org. Chem. 1999, 64, 3987-3995; Tetrahedron Lett., 1999, 40, 6087-6090; Tetrahedron Lett.,2000, 418645-. The reaction route is as follows:
schwartz et al subsequently extended the process further to other halo sugar compounds such as chloro sugars, bromo furanoses and the like. Although (Cp) may be modified by the participation of Mn metal2TiCl)2The use equivalent of (A) is reduced to 30%, while a large amount, particularly expensive, of highly toxic (Cp) is still used2TiCl)2Metal complexes, complicated operation and difficult separation, so that the process is also suitable for use in the preparation of a catalystCan not be applied to industrial production.
1.3 electrochemical Synthesis method
The electrochemical synthesis method is reported by professor Maran and Vianello for the first time in 1989, and is further developed by rondini and Daniel Little et al, however, the methods often need expensive calomel electrode, complex bipolar separation electrolytic cell and strong acid condition, so the problems of expensive electrode, complex operation and equipment corrosion still need to be overcome when the method is applied to industrialization (the method is applied to industrializationTetrahedron Lett., 2001, 42, 7371–7374)。
In conclusion, the glycal compounds play a very important role in organic synthesis, although the synthesis of glycal is interesting to a large number of scholars, the synthesis methods are continuously updated and perfected, but all the methods have fatal defects (such as expensive reagents, high risk, high toxicity, difficult separation and purification and the like) which bring serious difficulties to the industrial production of glycal. Therefore, facing the increasing market demand for glycal compounds, a synthetic method which is environment-friendly, low in cost and simple in separation must be sought.
Disclosure of Invention
The invention aims to provide a method for synthesizing the glycal compound, which has the advantages of high reaction yield, simple and convenient operation, easily obtained raw materials and larger market demand.
The synthesis method of the glycal compound comprises the steps of taking acyl-protected, silyl-protected or alkoxy-protected sugar (I) and triaryl or trialkyl phosphine as raw materials, adding an organic solvent to fully dissolve at room temperature, reacting for 2-36 hours at 20-60 ℃ to obtain a phosphorus salt intermediate compound (II), hydrolyzing under an alkaline condition, extracting after the reaction is finished, collecting an organic phase, re-dissolving the solvent in toluene, diethyl ether or methyl tert-butyl ether after the solvent is dried, filtering to remove insoluble substances, and separating by silica gel column chromatography after the solvent is dried to obtain a target glycal compound (III);
wherein R in the formulas (I), (II) and (III) is Ar and CH3、(CH2)nCH3、C(CH3)3、(CH2)nAr、O(CH2)nCH3、OC(CH3)3、O(CH2)nAny one of Ar; r1～R10Each independently is H, D, (CH)2)nR′、O(CH2)nR′、OCOR′、OSiR′3、(CH2)nO(CH2)mR′、COOR′、C(CH3)3Ar, F, Cl, Br, I, O-glycyl, wherein R' is H, CH3、(CH2)n(CH=CH)mCH3、(CH2)n(CH=CH)mAr、C(CH3)3Ar and O-glycyl; n and m are values of 0 to 10. The reaction is represented by the following formula:
the organic solvent is C1-C4 halohydrocarbon or any one of acetonitrile, tetrahydrofuran, benzene, toluene, DMF and dioxane.
The mass of the organic solvent is 10-50 times of that of the sugar (I) protected by acyl, silyl or alkoxy.
The alkaline conditions are as follows: NaOH, KOH, LiOH, CaOH, MgOH, K2CO3、Na2CO3One or more of DABCO, DBU, triethylamine, potassium tert-butoxide, sodium tert-butoxide and sodium ethoxide in water.
Compared with the prior art, the invention has the beneficial effects that: 1. provides a strategy for synthesizing glycal without participation of precious metals and other highly toxic reagents; 2. the reduction elimination reaction of the hydrolysis of the phosphorus salt is realized for the first time; 3. the synthesis of the deuterated glycal compound is realized for the first time; 4. the method has the advantages of high yield, simple and convenient operation and wide substrate applicability, and solves the problem of synthesizing the glycal compound in the prior art; 5. the invention has the advantages of simple and easily obtained raw materials and wide reaction application range.
Detailed Description
EXAMPLE 1 preparation of 3, 5-di-O-benzoylfuranose
Representative implementation procedure: 1-acetoxy-2, 3, 5-tribenzoyloxy-1-D-ribofuranose compound I-1 (0.925 g, 2 mmol) and 10 ml of dichloromethane were sequentially added to a reaction flask at room temperature, and the mixture was reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-1 after the reaction is finished, adding the reaction liquid into a sodium hydroxide aqueous solution, and hydrolyzing for 30 minutes at room temperature; adding 10 ml of water, extracting with ethyl acetate, collecting an organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating to remove ethyl acetate solvent, and separating and purifying by silica gel column chromatography to obtain 3, 5-di-O-benzoyl furanose III-10.5514 g, 85% total reaction yield.
Colorless oil, yield (85%);1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.7 Hz, 2H), 6.21 (d, J = 5.8 Hz, 1H), 5.92 (d, 1H), 5.87 (d, J = 4.2 Hz, 1H), 5.23 (s, 1H), 4.42 (td, 2H), 3.41 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 166.46 (C), 133.25 (2C), 132.29 (2CH), 130.01 (C), 129.90 (C), 129.81 (4CH), 128.52 (3CH), 128.49 (CH), 128.46 (CH), 109.57 (CH), 83.72 (CH), 65.93 (CH), 54.41 (CH2)。
EXAMPLE 2 preparation of 2-methyl-3, 5-di-O-benzylfuranose
Representative procedure 1-O-methyl-2, 3, 5-tribenzyl-2-C-methyl-alpha-D-ribofuranose I-2 (0.897 g, 2 mmol) and 10 ml of methylene chloride were sequentially added to a reaction flask at room temperature, and the mixture was reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-2 after the reaction is finished, adding the reaction liquid into a sodium hydroxide aqueous solution, and hydrolyzing for 30 minutes at room temperature; adding 10 ml of water, extracting with ethyl acetate, collecting an organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; the ethyl acetate solvent is removed by evaporation, and then the 3, 5-dibenzyl-2-C-methyl-alpha-D-ribofuranose III-20.552 g is obtained by silica gel column chromatography separation and purification, with the total reaction yield of 89%.
Yellow oil, yield (89%);1H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.32 (m, 10H), 6.28 (s, 1H), 4.64 – 4.56 (m, 4H), 4.49 (d, J = 12.3 Hz, 2H), 3.56 (dd, J = 9.9, 6.4 Hz, 1H), 3.40 (dd, J = 9.9, 6.3 Hz, 1H), 1.72 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 144.29 (s, CH), 138.35 (d, J = 53.8 Hz, C), 133.84 (d, J = 19.4 Hz, C), 128.48 (d, J = 5.2 Hz, 4CH), 127.91 (s, 2CH), 127.82 (s, 2CH), 127.67 (s, 2CH), 109.91 (s, CH), 85.90 (s, CH), 84.48 (s, CH), 73.55 (s, CH2), 70.31 (s, CH2), 69.72 (s, CH2), 9.04 (s, CH3)。
example 3: 3,4, 6-tris-OPreparation of (E) -acetyl-D-glucal
The representative implementation process is that the reaction bottles are sequentially added at room temperatureβD-glucose pentaacetate Compound I-3 (0.781 g, 2 mmol) and 10 ml of dichloromethane were reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-3 after the reaction is finished, adding the reaction liquid into a sodium hydroxide aqueous solution, and hydrolyzing for 30 minutes at room temperature; adding 10 mlExtracting with ethyl acetate, collecting organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating the ethyl acetate solvent, and then separating and purifying by silica gel column chromatography to obtain the 3,4, 6-tris-O-acetyl-D-glucal III-30.4574 g, total reaction yield 84%.
Yellow oil, yield (84%);1H NMR (400 MHz, Chloroform-d) δ 6.45 (d, J = 6.1 Hz, 1H), 5.34 – 5.30 (m, 1H), 5.21 (dd, J = 7.5, 5.8 Hz, 1H), 4.83 (dd, J = 6.1, 3.2 Hz, 1H), 4.38 (dd, J = 12.0, 5.7 Hz, 1H), 4.26 – 4.21 (m, 1H), 4.18 (dd, J = 12.0, 3.0 Hz, 1H), 2.08 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H); 13C NMR (101 MHz, Chloroform-d) δ 170.70 (C), 170.52 (C), 169.69 (C), 145.75 (CH), 99.11 (CH), 74.07 (CH), 67.55 (CH), 67.31 (CH), 61.49 (CH2), 21.10 (CH3), 20.90 (CH3), 20.83 (CH3).
example 4: 3,4, 6-tris-OPreparation of (E) -acetyl-D-galactosaccharide
The representative implementation process is that the reaction bottles are sequentially added at room temperatureβ-D-galactose pentaacetate Compound I-4 (0.781 g, 2 mmol) and 10 ml dichloromethane were reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-4 after the reaction is finished, adding the reaction liquid into a sodium hydroxide aqueous solution, and hydrolyzing for 30 minutes at room temperature; adding 10 ml of water, extracting with ethyl acetate, collecting an organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating to remove ethyl acetate solvent, and separating and purifying by silica gel column chromatography to obtain 3,4, 6-trivaloneO-acetyl-D-galactosaccharide III-40.4574 g, total reaction yield 86%.
Yellow oil, yield (86%);1H NMR (400 MHz, Chloroform-d) δ 6.46 (d, J = 6.2 Hz, 1H), 5.55 (s, 1H), 5.43 (d, J = 4.3 Hz, 1H), 4.73 (d, J = 5.3 Hz, 1H), 4.33 – 4.29 (m, 1H), 4.28 – 4.18 (m, 1H), 2.13 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H); 13C NMR (101 MHz, Chloroform-d) δ 170.72 (C), 170.45 (C), 170.30 (C), 145.57 (CH), 98.99 (CH), 72.95 (CH), 64.04 (CH), 63.90 (CH), 62.07 (CH2), 20.96 (CH3), 20.91 (CH3), 20.81 (CH3)。
example 5: 3,4, 6-tris-OPreparation of (deuterated) benzyl-D-hexenose
Representative procedure 1-acetyl-2, 3,4, 6-tetra-substituted benzene was sequentially added to the reaction flask at room temperatureO-benzyl-D-glucopyranose Compound I-5 (1.165 g, 2 mmol) and 10 ml dichloromethane were reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-5 after the reaction is finished, adding potassium tert-butoxide (0.4937 g, 4.4 mmol) into the reaction liquid, and hydrolyzing for 15 minutes at room temperature; 0.1 ml of heavy water was added, and the methylene chloride solvent was distilled off. Extracting with ethyl acetate, collecting organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating to remove ethyl acetate solvent, and separating and purifying by silica gel column chromatography to obtain 3,4, 6-trivaloneO-benzyl-D-hexenose III-50.7181 g, total reaction yield 86%.
The mixture is colorless and oily,1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.21 (m, 1H), 4.85 (dd, J = 15.3, 6.7 Hz, 1H), 4.66 – 4.52 (m, 5H), 4.21 (dd, J = 5.9, 2.2 Hz, 1H), 4.06 (dd, J = 7.1, 3.9 Hz, 1H), 3.90 – 3.74 (m, 3H). 13C NMR (101 MHz, Chloroform-d) δ 144.83 (CD), 138.45 (C), 138.28 (C), 138.09 (C), 128.52 (3CH), 128.51 (2CH), 128.49 (2CH), 128.02 (2CH), 127.90 (2CH), 127.84 (2CH), 127.76 (2CH), 99.85 (CH), 76.84 (CH), 75.81 (CH), 74.50 (CH), 73.86 (CH2), 73.61 (CH2), 70.56 (CH2), 68.62 (CH2)。
example 6 preparation of hexaacetyl-D-cellobiose
Representative procedure D- (+) -Cellobiose Octaacetate Compound I-6 (1.3572 g, 2 mmol) and 10 ml of dichloromethane were added sequentially to a reaction flask at room temperature, and reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-6 after the reaction is finished, adding the reaction liquid into a sodium hydroxide aqueous solution, and hydrolyzing for 30 minutes at room temperature; adding 10 ml of water, extracting with ethyl acetate, collecting an organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; the ethyl acetate solvent was evaporated and then separated and purified by silica gel column chromatography to obtain hexaacetyl-D-cellobiose III-60.9865 g with a total reaction yield of 88%.
Yellow oil;1H NMR (400 MHz, Chloroform-d) δ 6.40 (d, J = 6.0 Hz, 1H), 5.41 ( 1H), 5.18 (t, J = 9.4 Hz, 1H), 5.08 (t, J = 9.6 Hz, 1H), 4.97 (t, J = 8.7 Hz, 1H), 4.82 (dd, J = 6.0, 3.2 Hz, 1H), 4.68 (d, J = 7.9 Hz, 1H), 4.44 (d, J = 11.3 Hz, 1H), 4.31 (dd, J = 12.3, 4.4 Hz, 1H), 4.21 – 4.11 (m, 2H), 4.05 (d, J = 12.3 Hz, 1H), 3.98 (t, 1H), 3.67 (d, 1H), 2.13 – 1.98 (m, 18H). 13C NMR (101 MHz, Chloroform-d) δ 170.79 (C), 170.56 (C), 170.41 (C), 170.08 (C), 169.44 (C), 169.33 (C), 145.56 (CH), 100.67 (CH), 99.19 (CH), 74.79 (CH), 74.46 (CH), 72.86 (CH), 72.13 (CH), 71.48 (CH), 68.73 (CH), 68.17 (CH), 61.91 (CH2), 61.89 (CH2), 29.83 (CH3), 21.12 (CH3), 20.98 (CH3), 20.81 (CH3), 20.70 (CH3), 20.68 (CH3)。
example 7 preparation of nonaacetyl-D-maltotrione
Representative procedure D-maltotriose compound I-7 (966 mg, 1 mmol) and 10 ml of methylene chloride were successively added to a reaction flask at room temperature, and reacted at room temperature for 6 hours. Tracking the reaction progress by TLC, obtaining an intermediate II-7 after the reaction is finished, adding the reaction liquid into a sodium hydroxide aqueous solution, and hydrolyzing for 30 minutes at room temperature; adding 10 ml of water, extracting with ethyl acetate, collecting an organic phase, washing with saturated saline solution, and drying with anhydrous sodium sulfate; the ethyl acetate solvent was evaporated and then separated and purified by silica gel column chromatography to give nonaacetyl-D-maltotrione III-7725 mg, with a total reaction yield of 85%.
Yellow oil;1H NMR (400 MHz, Chloroform-d) δ 6.43 (d, J = 6.1 Hz, 1H), 5.45 – 5.40 (m, 1H), 5.39 – 5.31 (m, 3H), 5.20 – 5.16 (m, 1H), 5.05 (t, J = 9.9 Hz, 1H), 4.84 (dd, J = 10.5, 4.0 Hz, 1H), 4.79 (dd, J = 6.1, 3.3 Hz, 1H), 4.68 (dd, J = 10.3, 4.0 Hz, 1H), 4.48 (dd, J = 12.3, 2.1 Hz, 1H), 4.37 (d, J= 4.5 Hz, 2H), 4.30 – 4.25 (m, 1H), 4.23 (dd, J = 12.5, 3.4 Hz, 1H), 4.17 (dd, J = 12.3, 3.4 Hz, 1H), 4.06 – 4.02 (m, 1H), 4.01 (d, J = 2.0 Hz, 1H), 3.99 (d, J = 9.7 Hz, 1H), 3.96 – 3.90 (m, 2H), 2.13 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.74 (C), 170.64 (2C), 170.56 (C), 170.52 (2C), 169.97 (C), 169.85 (C), 169.56 (C), 145.78 (CH), 98.67 (CH), 95.79 (CH), 95.76 (CH), 74.16 (CH), 72.80 (CH), 72.61 (CH), 72.02 (CH), 70.99 (CH), 70.12 (CH), 69.89 (CH), 69.44 (CH), 68.76 (CH), 68.56 (CH), 68.01 (CH), 62.46 (CH2), 62.10 (CH2), 61.46 (CH2), 21.19 (CH3), 21.03 (CH3), 20.92 (2CH3), 20.77 (CH3), 20.69 (3CH3), 20.60 (CH3)。
Claims (4)
1. a method for synthesizing a glycal compound is characterized in that: the method comprises the steps of taking acyl-protected, silyl-protected or alkoxy-protected saccharide (I) and triaryl or trialkyl phosphine as raw materials, adding an organic solvent to fully dissolve at room temperature, reacting at 20-60 ℃ for 2-36 hours to obtain a phosphorus salt intermediate compound (II), hydrolyzing under an alkaline condition, extracting after the reaction is finished, collecting an organic phase, dissolving the solvent in toluene, diethyl ether or methyl tert-butyl ether again after spin drying, filtering to remove insoluble substances, and separating by silica gel column chromatography after spin drying the solvent to obtain a target glycal compound (III);
wherein R in the formulas (I), (II) and (III) is Ar and CH3、(CH2)nCH3、C(CH3)3、(CH2)nAr、O(CH2)nCH3、OC(CH3)3、O(CH2)nAny one of Ar; r1～R10Each independently is H, D, (CH)2)nR′、O(CH2)nR′、OCOR′、OSiR′3、(CH2)nO(CH2)mR′、COOR′、C(CH3)3Ar, F, Cl, Br, I, O-glycyl, wherein R' is H, CH3、(CH2)n(CH=CH)mCH3、(CH2)n(CH=CH)mAr、C(CH3)3Ar and O-glycyl; n and m are values of 0 to 10.
2. The method of claim 1, wherein the method comprises the steps of: the organic solvent is C1-C4 halohydrocarbon or any one of acetonitrile, tetrahydrofuran, benzene, toluene, DMF and dioxane.
3. The method of claim 1, wherein the method comprises the steps of: the mass of the organic solvent is 10-50 times of that of the sugar protected by acyl, silyl or alkoxy.
4. The method of claim 1, wherein the method comprises the steps of: the alkaline conditions are as follows: selected from NaOH, KOH, LiOH, CaOH, MgOH, K2CO3、Na2CO3One or more of DABCO, DBU, triethylamine, potassium tert-butoxide, sodium methoxide and sodium ethoxide in water.
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