CN103012507A - Synthetic method of 3-deoxidized-D-sweet dew-2-octulosonic ammonium salt - Google Patents
Synthetic method of 3-deoxidized-D-sweet dew-2-octulosonic ammonium salt Download PDFInfo
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Abstract
The invention relates to a synthetic method of 3-deoxidized-D-sweet dew-2-octulosonic ammonium salt. The synthetic method comprises the following steps: using D-sweet dew as a raw material and performing the reaction on D-sweet dew and 2,2-dimethoxy propane; protecting hydroxy at 2 and 3 positions and 5 and 6 positions by isopropylidene to obtain an intermediate in a formula I; performing the reaction on a product in the formula I and 2-dimethoxy phosphoroso-2-dimethyl tertiary butyl silica ethyl acetate in a formula II to obtain an intermediate in a formula III; removing a silicyl oxide protecting group in a product in the formula III to form intramolecular hemiketal so as to obtain an intermediate in a formula IV; performing the deprotection, saponification and ammonium salt formation reaction on a product in the formula IV to obtain the final product 3-deoxidized-D-sweet dew-2-octulosonic ammonium salt. The method has the advantages of low price of the raw material, easiness for obtaining the raw material, mild reaction condition, simplicity and convenience for operation, high safety, high route total yield, simplicity for purification treatment on the final product and stable quality of the final product, and thus, the synthetic method disclosed by the invention enables the total cost to be greatly reduced and is suitable for the requirements on large-scale industrial production.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the synthetic method of a kind of 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Background technology
3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid is one of necessary moiety of lipopolysaccharides in the gram-negative bacteria cell wall.The derivative that carries out the structural modification gained take 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid as parent has good restraining effect to Gram-negative bacteria; Simultaneously, 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid also can be used as antigen, is applied in some antibiotic (such as anti-meningitis) vaccine.The chemical structural formula of 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid is as follows:
The source of at present, 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid mainly contains enzymic synthesis and two kinds of approach of chemosynthesis.
The enzymic synthesis method has the characteristics of reaction conditions gentleness, but because the enzyme reaction small scale, and relevant enzyme can't the commercialization purchase, the separation and purification cost is very high again, so the range of application of enzymic synthesis method is narrower.
In existing report, adopt the method for short synthetic route chemosynthesis 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid to mainly contain following several:
Method 1: with 2,3:4,5-two-O-isopropylidene-D-R is raw material, under the effect of stoichiometry indium metal, with 2-brooethyl ethyl propenoate generation nucleophilic addition, obtain 2,3-, two deoxidations-2-methylene radical-5,6:7,8-two-O-isopropylidene-D-sweet dew octose acetoacetic ester and 2,3-two deoxidations-2-methylene radical-5,6:7,8-two-O-isopropylidene-D-grape octose acetoacetic ester; Wherein 2,3-two deoxidations-2-methylene radical-5,6:7,8-two-O-isopropylidene-D-sweet dew octose acetoacetic ester generates 3-deoxidation-5,6:7,8-two-O-isopropylidene-D-sweet dew-methyln-hexyl ketone saccharic acid ethyl ester through ozonization; Finally by deprotection, hydrolysis ester group, ammonium salt, the total recovery with 20% obtain target product 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt (Journal of Organic Chemistry, 1994,59,3714-3715).The method needs to use the plurality of heavy metal indium in building-up process, not only expensive, and environmental pollution is serious; And the stereoselectivity of the first step nucleophilic addition is poor, and is required 2,3-two deoxidations-2-methylene radical-5, and 6:7,8-two-O-isopropylidene-D-sweet dew octose acetoacetic ester only can obtain with 40% yield.
Method 2: with 2,3,4,5,6-, five-O-ethanoyl sweet dew alditol and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy methyl acetate ester couples together by the Horner-Emmons reaction, obtains intermediate 3-deoxidation-2-O-dimethyl tertiary butyl silica-based-4,5,6,7,8-, five-O-ethanoyl-D-sweet dew-2-octene saccharic acid ethyl ester; This intermediate deprotection base under the catalysis of alkali obtains 3-deoxidation-D-sweet dew-γ-(2-octene saccharic acid) lactone; 3-deoxidation-D-sweet dew-γ-(2-octene saccharic acid) lactone is through lactone open loop, ammonium salt, finally obtain target product 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt (Bulletin ofthe Chemical Society of Japan, 1988,61,3356-3358).This method has the easy characteristics of operation, but the method employed starting raw material-2,3,4,5,6-five-O-ethanoyl sweet dew alditol-must could make from D-MANNOSE through polystep reaction, and the total recovery of whole piece route is not high.
Method 3: it is silica-based-1 first D-MANNOSE to be modified into the starting raw material 3-O-dimethyl tertiary butyl through Multi-step conversion, 2:4,5-two-O-isopropylidene-PEARLITOL 25C; With carbodiimide reagent that the 3-O-dimethyl tertiary butyl is silica-based-1,2:4, the hydroxyl oxygen in 5-two-O-isopropylidene-PEARLITOL 25C changes into aldehyde, and it is silica-based-2 to obtain the intermediate 4-O-dimethyl tertiary butyl, 3:5,6-two-O-isopropylidene-D-MANNOSE; This intermediate and 3-triphenyl phosphorus-1, the Wittig reaction occurs in 4-dioxy spiral shell [4.5]-2-decanone, and it is silica-based-2 to make (E)-1-deoxidation-4-O-dimethyl tertiary butyl, 3:5,6-two-O-isopropylidene-1-[2-(Asia-3-oxo-Isosorbide-5-Nitrae-dioxy spiral shell [4.5] decyl)]-PEARLITOL 25C; Under acidic conditions, (E)-1-deoxidation-4-O-dimethyl tertiary butyl silica-based-2,3:5,6-two-O-isopropylidene-1-[2-(Asia-3-oxo-1,4-dioxy spiral shell [4.5] decyl)]-PEARLITOL 25C deprotection base, obtain (E)-1-deoxidation-1-[2-(Asia-3-oxo-Isosorbide-5-Nitrae-dioxy spiral shell [4.5] decyl)]-PEARLITOL 25C; Be hydrolyzed at last ester group, ammonium salt, obtain target compound 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt (Tetrahedron Letters, 1988,29,4877-4880; Tetrahedron, 1991,47,5625-5636).Similar with method 3, although method 4 easy handlings, the employed starting raw material 3-O-dimethyl tertiary butyl is silica-based-1, and 2:4,5-two-O-isopropylidene-PEARLITOL 25C also must could be obtained by the conversion of D-MANNOSE through complexity.
Method 4: from 2,3:5,6-two-O-isopropylidene-D-MANNOSE sets out, and prolongs 2 carbochains with 3,3-diethyl mercaptopropionic acid ethyl ester generation nucleophilic addition; The 2-position ketone carbonyl that dissociates again obtains intermediate 4,5:7,8-two-O-isopropylidene-D-glycerine-α-D-gala-2-pyrans octulosonic acid; This intermediate obtains 3-deoxidation-4 by the Barton-McCombie deoxidation reaction, 5:7,8-two-O-isopropylidene-α-D-gala-2-pyrans octulosonic acid methyl esters; 3-deoxidation-4; 5:7; 8-two-O-isopropylidene-α-D-gala-2-pyrans octulosonic acid methyl esters is through taking off isopropylidene protection, hydrolysis ester group, ammonium salt; finally obtain target product 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt (Tetrahedron:Asymmetry; 2000; 11,319-335).The Barton-McCombie deoxidation reaction that the method adopts need to use the tributyltin hydride of explosive Diisopropyl azodicarboxylate and high toxicity, high pollution.
Method 5: with 2,3:5,6-two-O-isopropylidene-D-MANNOSE is raw material, first with (E)-2,3-two deoxidations-4,5:7,8-two-O-isopropylidene-D-sweet dew-2-octene saccharic acid ethyl ester carry out the Wittig reaction; Dihydroxylation reaction occurs in the new two keys that make up under the condition of perosmic anhydride/N-methyl-N-morpholine oxide, introduce two hydroxyls; The two hydroxyls that then will introduce are protected with sulfoxide, obtain 4,5:7,8-two-O-isopropylidene-ring-2,3-sulfurous acid-D-sweet dew octose acid; 4,5:7,8-two-O-isopropylidene-ring-2,3-sulfurous acid-D-sweet dew octose acid removes sulfurous gas under the assistance of alkali, use simultaneously two hydroxyls of trimethyl silicon based protection, obtain intermediate (Z)-3-deoxidation-2,6-two-O-trimethyl silicon based-4,5:7,8-two-O-isopropylidene-D-sweet dew-2-octene saccharic acid ethyl ester; This intermediate is desiliconization Ji Guan ring under acidic conditions, obtains 3-deoxidation-4,5:7,8-two-O-isopropylidene-D-sweet dew-2-pyrans octulosonic acid ethyl ester; Finally by deprotection, saponification, ammonium salt, obtain target product 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt (Tetrahedron Letters, 2004,45,4545 – 4548).The reaction that this method adopts is comparatively easy, but dihydroxylation reaction wherein must use the very large perosmic anhydride of toxicity, can cause very big pollution to environment.
In sum, still have at present that the route total recovery is not high, environmental pollution serious, the high in cost of production problem in the synthetic technology for 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt (KDO).
Summary of the invention
For existing deficiency in the preparation process that overcomes 3-deoxidation of the prior art-D-sweet dew-methyln-hexyl ketone saccharic acid, the invention provides that a kind of reaction conditions is gentle, the route total recovery is high, raw material cheaply is easy to get, be suitable for the synthetic method of the 3-deoxidation of industrial applications-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Solving the problems of the technologies described above the technical scheme that adopts is may further comprise the steps:
(1) gets D-MANNOSE and be dissolved in N, in the dinethylformamide, add 2,2-dimethoxypropane, stirring and evenly mixing, organic acid, mineral acid or ion exchange resin as the katalysis of catalyzer under 0～50 ℃ the reaction 2～24 hours, D-MANNOSE and 2,2-dimethoxypropane, catalyzer, N, the mol ratio of dinethylformamide is 1:2～20:0.05～0.5:3～65, purifying obtains formula I intermediate, and reaction equation is:
(2) under nitrogen protection; getting 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the non-protonic solvent; add highly basic; stirring at room 0.5～2 hour adds formula I intermediate, and 50～150 ℃ were reacted 1～24 hour; the mol ratio of formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate, highly basic, non-protonic solvent is 1:1～4:1～4:17～105; purifying obtains formula II intermediate, and reaction equation is:
(3) formula II intermediate is dissolved in polar solvent, adds fluorine-containing deprotecting regent, and-20～50 ℃ were reacted 1～24 hour; the mol ratio of formula II intermediate and fluorine-containing deprotecting regent, polar solvent is 1:1～4:20～110; purifying obtains the formula III intermediate, and reaction equation is:
(4) the formula III intermediate is water-soluble, 0～90 ℃ was reacted 0.5～3 hour under the katalysis of acetic acid or ion exchange resin, formula III intermediate and acetic acid, the mol ratio of water is 1:34～140:13～55 or formula III intermediate and ion exchange resin, the mol ratio of water is 1:0.1～0.5:200～400, concentrating under reduced pressure except anhydrate and acetic acid or remove by filter ion exchange resin after concentrating under reduced pressure except anhydrating, the gained material is water-soluble, add sodium hydroxide, it is 10～14 that potassium hydroxide or lithium hydroxide are adjusted pH, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate is 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying, obtain 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, reaction equation is:
Above-mentioned organic acid is tosic acid or camphorsulfonic acid;
Above-mentioned mineral acid is the vitriol oil or concentrated hydrochloric acid;
Above-mentioned non-protonic solvent is toluene, benzene, DMF, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), methylene dichloride or 1,2-ethylene dichloride;
Above-mentioned highly basic is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, LHMDS, sodium hexamethyldisilazide or potassium hexamethyldisilazide;
Above-mentioned polar solvent is tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride or 1,2-ethylene dichloride;
Above-mentioned fluorine-containing deprotecting regent is tetrabutyl ammonium fluoride, Neutral ammonium fluoride, Potassium monofluoride or hydrofluoric acid pyridine.
D-MANNOSE is dissolved in N in the above-mentioned steps (1), in the dinethylformamide, add 2,2-dimethoxypropane, mixing, organic acid, mineral acid or ion exchange resin as the katalysis of catalyzer under 0～50 ℃ the reaction 2～24 hours, the preferred molar ratio of D-MANNOSE and 2,2-dimethoxypropane, catalyzer, DMF is 1:3.5～10:0.1～0.2:7～15, purifying obtains formula I intermediate.
D-MANNOSE is dissolved in N in the above-mentioned steps (1), in the dinethylformamide, add 2,2-dimethoxypropane, mixing, organic acid, mineral acid or ion exchange resin as the katalysis of catalyzer under 0～50 ℃ the reaction 2～24 hours, the optimum mole ratio of D-MANNOSE and 2,2-dimethoxypropane, catalyzer, DMF is 1:4:0.15:10, purifying obtains formula I intermediate.
Above-mentioned steps (2) is under nitrogen protection; getting 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the non-protonic solvent; add highly basic; stirring at room 0.5～2 hour; adding formula I intermediate, 50～150 ℃ were reacted 1～24 hour, and the preferred molar ratio of formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate, highly basic, non-protonic solvent is 1:1.2～2:1.2～2:20～35; purifying obtains formula II intermediate.
2-dimethoxy phosphoroso-described in the step (2)-2-dimethyl tertiary butyl siloxy ethyl acetate is prepared by following methods:
A) the D-diethyl tartrate is dissolved in the methyl alcohol, adds sodium periodate, the mol ratio of D-diethyl tartrate and sodium periodate, methyl alcohol is 1:2:49, reflux 1 hour, and purifying obtains Compound I;
B) Compound I is dissolved in toluene, adds dimethylphosphite, the mol ratio of Compound I and dimethylphosphite, toluene is 1:1:9.5, heating reflux reaction 3 hours, and concentrating under reduced pressure is removed toluene, obtains Compound I I;
C) Compound I I and imidazoles, TERT-BUTYL DIMETHYL CHLORO SILANE are dissolved in anhydrous N, in the dinethylformamide, Compound I I and imidazoles, TERT-BUTYL DIMETHYL CHLORO SILANE, N, the mol ratio of dinethylformamide is 1:1.3:1.3:13, stirring at room 15 hours, purifying gets 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate.
Above-mentioned steps (3) Chinese style II intermediate is dissolved in polar solvent; add fluorine-containing deprotecting regent;-20～50 ℃ were reacted 1～24 hour; the preferred molar ratio of formula II intermediate and fluorine-containing deprotecting regent, polar solvent is 1:1.5～2:25～60; remove silicon ether protecting group; purifying obtains the formula III intermediate.
The formula III intermediate is water-soluble in the above-mentioned steps (4), 0～90 ℃ was reacted 0.5～3 hour under the catalysis of acetic acid, formula III intermediate and acetic acid, the preferred molar ratio of water is 1:45～80:20～30, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, add sodium hydroxide, it is 10～14 that potassium hydroxide or lithium hydroxide are adjusted pH, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate was 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Water-soluble 0～90 ℃ of reaction 0.5～3 hour under the catalysis of ion exchange resin of formula III intermediate in the above-mentioned steps (4), formula III intermediate and ion exchange resin, the preferred molar ratio of water is 1:0.3～0.4:300～380, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, add sodium hydroxide, it is 12～14 that potassium hydroxide or lithium hydroxide are adjusted the pH value, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate is 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Above-mentioned steps (2) is under nitrogen protection, getting 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the non-protonic solvent, add highly basic, stirring at room 0.5～2 hour, adding formula I intermediate, 50～150 ℃ were reacted 1～24 hour, and the optimum mole ratio of formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate, highly basic, non-protonic solvent is 1:1.5:1.5:20, purifying obtains formula II intermediate; The formula III intermediate is water-soluble in the above-mentioned steps (4), 0～90 ℃ was reacted 0.5～3 hour under the catalysis of acetic acid, formula III intermediate and acetic acid, the optimum mole ratio of water is 1:50:20, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, add sodium hydroxide, it is 10～14 that potassium hydroxide or lithium hydroxide are adjusted pH, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate was 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Above-mentioned ion exchange resin is Hydrogen ion exchange resin, Dowex50WX2 Hydrogen ion exchange resin or the Amberlite IR120 Hydrogen ion exchange resin that can adopt LG-DOW to produce.
The synthetic method of 3-deoxidation of the present invention-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is by take D-MANNOSE as raw material; with 2; the reaction of 2-Propanal dimethyl acetal; with its 2; 3 and 5; 6 hydroxyls are protected with isopropylidene, obtain formula I intermediate, formula I and formula II2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy acetic acid ethyl reaction; obtain the formula III intermediate; after formula III removes silicon ether protecting group, form hemiketal in the molecule, obtain formula IV intermediate; formula IV is through deprotection; saponification; become the ammonium salt reaction; obtain final product 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, the method raw material cheaply is easy to get, and reaction conditions is gentle; easy and simple to handle; safe, the route total recovery is high, and the purification process of its final product is simple; steady quality; therefore, synthetic method of the present invention makes total cost obtain greatly reducing, and is fit to the demand of large-scale industrial production.
Description of drawings
Fig. 1 is the proton nmr spectra of commercially available 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Fig. 2 is the proton nmr spectra of the prepared 3-deoxidation of embodiment 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment
Below in conjunction with embodiment technical scheme of the present invention is described further, but the present invention is not limited only to following embodiment.
Embodiment 1
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
(1) gets D-MANNOSE 10g and be dissolved in 42.7mLN, in the dinethylformamide, add 27.3mL2, the 2-Propanal dimethyl acetal, stirring and evenly mixing adds the 1.43g tosic acid in solution, 25 ℃ were reacted 12 hours under the katalysis of tosic acid, D-MANNOSE and 2, the 2-Propanal dimethyl acetal, tosic acid, the mol ratio of DMF is 1:4:0.15:10, stops to stir, be further purified, detailed process is: add the 3g sodium bicarbonate in reaction solution, the cancellation reaction is filtered, filtrate is removed N by the oil pump decompression, dinethylformamide adds the dilution of 500mL ethyl acetate, washes with water 2 times, saturated common salt water washing 1 time, by anhydrous magnesium sulfate drying, filter, use re-crystallizing in ethyl acetate after filtrate is concentrated, obtain white solid formula I intermediate 12.86g, productive rate 89%.Adopt Tyke, Beijing X-6 of Instr Ltd. type micro melting point apparatus, the German Bruker AVANCE400 of company NMR spectrometer with superconducting magnet, the German Bruker maXis of company electron spray(ES) flight time tandom mass spectrometer that it is carried out fusing point, proton nmr spectra, high resolution mass spectrum analysis, the result is: fusing point: 126-127 ℃;
1H NMR (400MHz, CDCl
3) δ (ppm): 1.33,1.38,1.46,1.54 (4s, 12H), (3.15 m, 1H), 4.07,4.09 (d, 2H, J=5.1Hz), 4.11-4.20 (t, 1H, J=3.6Hz), 4.40-4.42 (m, 1H), 4.61-4.63 (m, 1H), 4.80-4.83 (t, 1H, J=3.6Hz), 5.38,5.50 (d, 1H, J=3.6Hz); ESI-HRMS theoretical value: C
12H
20O
6Na[(M+Na)
+] 283.1158, measured value: 283.1150.Reaction equation is:
(2) under nitrogen protection; 19.35g2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the 120mL toluene; add 4.74g trimethyl carbinol lithium; stirring at room 1 hour; add 12.86g formula I intermediate; be heated to 100 ℃ of reactions 10 hours; formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate; trimethyl carbinol lithium; the mol ratio of toluene is 1:1.2:1.2:23; question response liquid is cooled to room temperature; be further purified, detailed process is: add the dilution of 500mL ethyl acetate in reaction solution, wash with water 2 times; saturated common salt water washing 1 time; by anhydrous magnesium sulfate drying, to filter, filtrate is concentrated; resistates separates through column chromatography, and eluent is V
Sherwood oil/ V
Ethyl acetate=8:1 gets colorless oil formula II intermediate 20.1g, (E)-Shi II with (Z)-mol ratio=5:1 of Shi II, productive rate 88%.Adopt the German Bruker AVANCE400 of company NMR spectrometer with superconducting magnet, the German Bruker maXis of company electron spray(ES) flight time tandom mass spectrometer that it is carried out proton nmr spectra, high resolution mass spectrum analysis, the result is: (E)-and Shi II intermediate:
1H NMR (400MHz, CDCl
3) δ (ppm) :-0.11 (s, 6H), 0.78 (s, 9H), (1.15-1.34 m, 15H), 3.18 (d, 1H, J=6.7Hz), 3.80-4.48 (m, 5H), (4.47 d, 1H, J=7.6Hz), (5.32 d, 1H, J=7.3Hz), (5.55 d, 1H, J=7.1Hz); ESI-HRMS theoretical value: C
23H
42O
8SiNa[(M+Na)
+] 483.2390, measured value: 483.2369.(Z)-Shi II intermediate:
1H NMR (400MHz, CDCl
3) δ (ppm) :-0.11 (s, 6H), 0.75 (s, 9H), 1.05-1.32 (m, 15H), (3.20 d, 1H, J=6.7Hz), 3.79-4.25 (m, 6H), 5.07 (t, 1H, J=7.7Hz), 6.01 (d, 1H, J=8.6Hz); ESI-HRMS theoretical value: C
23H
42O
8SiNa[(M+Na)
+] 483.2390, measured value: 483.2363.Reaction equation is:
Above-mentioned 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate can adopt the following steps preparation:
A) the 17mLD-diethyl tartrate is dissolved in the 200mL methyl alcohol, stirring at room adds the 42.78g sodium periodate, and the mol ratio of D-diethyl tartrate and sodium periodate, methyl alcohol is 1:2:49, reflux 1 hour, be further purified, that is: be cooled to room temperature, add anhydrous magnesium sulfate 80g, stirred 15 minutes, filter, filtrate is concentrated, obtains colorless oil Compound I 23.9g.Reaction equation is:
B) above-mentioned Compound I 23.9g is dissolved in the 200mL toluene, add the 18.3mL dimethylphosphite, the mol ratio of compound and dimethylphosphite, toluene is 1:1:9.5, heating reflux reaction 3 hours, be further purified, that is: be cooled to room temperature, toluene is removed in decompression, obtains white solid Compound I I41.2g.Reaction equation is:
C) with above-mentioned Compound I I41.2g and 17.2g imidazoles, 38.1g TERT-BUTYL DIMETHYL CHLORO SILANE is dissolved in the anhydrous N of 194mL, in the dinethylformamide, Compound I I and imidazoles, TERT-BUTYL DIMETHYL CHLORO SILANE, N, the mol ratio of dinethylformamide is 1:1.3:1.3:13, stirring at room 15 hours, be further purified processing, that is: will react by the oil pump decompression and remove DMF, add the dilution of 500mL ether, wash with water 2 times, anhydrous magnesium sulfate drying is passed through in saturated common salt water washing 1 time, filter, filtrate is concentrated, and resistates separates through column chromatography, eluent: V
Sherwood oil/ V
Ethyl acetate=1:1 gets colorless oil 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate 55g.Adopt the German Bruker AVANCE400 of company NMR spectrometer with superconducting magnet, the German Bruker maXis of company electron spray(ES) flight time tandom mass spectrometer that it is carried out proton nmr spectra, high resolution mass spectrum analysis, the result is:
1H NMR (400MHz, CDCl
3) δ (ppm) :-0.0082 (s, 6H), 0.81 (s, 9H), 1.19 (t, 3H, J=7.2Hz), 3.72 (q, 6H, J=10.7Hz), 4.16 (q, 2H, J=6.7Hz), 4.50 (d, 1H, J=18.6Hz); ESI-HRMS theoretical value: C
12H
27O
6PSiNa[(M+Na)
+] 349.1212, measured value: 349.1203.Reaction equation:
(3) modus ponens II intermediate 20.1g is dissolved in the 90mL tetrahydrofuran (THF), adds the 17g tetrabutyl ammonium fluoride, and 26 ℃ were reacted 4 hours; the mol ratio of formula II intermediate and tetrabutyl ammonium fluoride, tetrahydrofuran (THF) is 1:1.5:25, removes silicon ether protecting group, is further purified; specifically: add ethyl acetate 500mL dilution; saturated ammonium chloride solution washing 2 times, anhydrous magnesium sulfate drying is passed through in saturated common salt water washing 1 time; filter; filtrate is concentrated, and resistates separates through column chromatography, eluent: V
Sherwood oil/ V
Ethyl acetate=1:2 obtains colorless oil formula III intermediate 14.3g, productive rate 95%.Adopt the German Bruker AVANCE400 of company NMR spectrometer with superconducting magnet, the German Bruker maXis of company electron spray(ES) flight time tandom mass spectrometer that it is carried out proton nmr spectra, high resolution mass spectrum analysis, the result is:
1H NMR (400MHz, CDCl
3) δ (ppm): 4.52-4.49 (m, 1H), 4.35-4.33 (m, 1H), (4.27-4.24 m, 3H), 4.08 (dd, 1H, J=6.0,8.4Hz), 4.00 (dd, 1H, J=4.8,9.0Hz), 3.90 (dd, 1H, J=2.4,8.4Hz), 3.83 (s, 1H), (2.50 dd, 1H, J=6.6,14.4Hz), (1.89 dd, 1H, J=4.8,14.4Hz), (1.46 s, 3H), 1.42 (s, 3H), (1.37 s, 3H), 1.35 (s, 3H), (1.31 t, 3H, J=7.2Hz); ESI-HRMS theoretical value: C
16H
26O
8Na[(M+Na)
+] 369.1525, measured value: 369.1515.Reaction equation is:
(4) get 14.3g formula III intermediate and be dissolved in 10mL water, add again 80mL acetic acid, 45 ℃ were reacted 1.5 hours under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:34:13, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, adding 0.5g sodium hydroxide adjustment pH value is 13,45 ℃ of reactions 1.5 hours, the pH value that adds 2.2g ion exchange resin adjustment solution is 3, removes by filter ion exchange resin, and dropping 0.2mL mass concentration is that 25% ammoniacal liquor adjustment pH value is 12 in the filtrate, 25 ℃ of reactions 2 hours, be further purified, detailed process is: removal of solvent under reduced pressure, and the gained crude product is with 90% aqueous ethanolic solution recrystallization, obtain white solid 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt 7.9g, productive rate 75%.Adopt Tyke, Beijing X-6 of Instr Ltd. type micro melting point apparatus, U.S. Rudolph company dual wavelength automatic polarimeter, the German Bruker AVANCE400 of company NMR spectrometer with superconducting magnet, the German Bruker maXis of company electron spray(ES) flight time tandom mass spectrometer that it is carried out fusing point, proton nmr spectra (referring to Fig. 2), high resolution mass spectrum analysis, the result is: fusing point: 121-123 ℃; [α]
23 D=+39.2 (c0.55, H
2O);
1H NMR (400MHz, D
2O) δ (ppm): 4.77-4.57 (m), 4.43-4.37 (m), 4.34 (dd, J=0.8,2.4Hz), 4.07 (dd, J=1.6,4.0Hz), 3.96-3.90 (m), 3.83 (brs), 3.78-3.65 (m), 3.63-3.48 (m), (3.31 d, J=6.0Hz), 2.47 (dd, J=4.8,9.6Hz), 2.29-2.16 (m), (1.96 dd, J=2.2,9.4Hz), (1.86 t, J=8.4Hz), 1.81 (s), (1.77 dd, J=3.2,8.8Hz), (1.64 t, J=8.2Hz); ESI-HRMS theoretical value: C
8H
13O
8[(M-NH
4)
-] 237.0616, measured value: 237.0572.Reaction equation is:
Embodiment 2
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
(1) gets D-MANNOSE 10g and be dissolved in the 65mL DMF, add 23.9mL2, the 2-Propanal dimethyl acetal, stirring and evenly mixing adds the 0.95g tosic acid in solution, 25 ℃ were reacted 12 hours under the katalysis of tosic acid, D-MANNOSE and 2,2-dimethoxypropane, tosic acid, the mol ratio of DMF is 1:3.5:0.1:15, stop to stir, be further purified, detailed process is: add the 3g sodium bicarbonate in reaction solution, the cancellation reaction, filter, filtrate is removed DMF by the oil pump decompression, adds the dilution of 500mL ethyl acetate, wash with water 2 times, saturated common salt water washing 1 time by anhydrous magnesium sulfate drying, is filtered, use re-crystallizing in ethyl acetate after filtrate is concentrated, obtain white solid formula I intermediate 12.1g, productive rate 84%, reaction equation is:
(2) under nitrogen protection; 15.2g2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the 83.5mL toluene; add 3.7g trimethyl carbinol lithium; stirring at room 1 hour; add 12.1g formula I intermediate; be heated to 100 ℃ of reactions 10 hours; formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate; trimethyl carbinol lithium; the mol ratio of toluene is 1:1:1:17; question response liquid is cooled to room temperature; be further purified, specifically: in reaction solution, add the dilution of 500mL ethyl acetate, wash with water 2 times; saturated common salt water washing 1 time; by anhydrous magnesium sulfate drying, to filter, filtrate is concentrated; resistates separates through column chromatography, and eluent is V
Sherwood oil/ V
Ethyl acetate=8:1 gets colorless oil formula II intermediate 17.6g, (E)-Shi II with (Z)-mol ratio=5:1 of Shi II, productive rate 82%.
The preparation method of above-mentioned 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is identical with embodiment 1.
(3) modus ponens II intermediate 17.6g is dissolved in the 155mL tetrahydrofuran (THF), adds the 10g tetrabutyl ammonium fluoride, and 26 ℃ were reacted 4 hours; the mol ratio of formula II intermediate and tetrabutyl ammonium fluoride, tetrahydrofuran (THF) is 1:1:50; remove silicon ether protecting group, be further purified, specifically: add ethyl acetate 500mL dilution; saturated ammonium chloride solution washing 2 times; saturated common salt water washing 1 time by anhydrous magnesium sulfate drying, is filtered; filtrate is concentrated, and resistates separates (eluent: V through column chromatography
Sherwood oil/ V
Ethyl acetate=1:2), get colorless oil formula III intermediate 13.1g, yield 99%, reaction equation is:
(4) get 13.1g formula III intermediate and be dissolved in 13.5mL water, add again 108mL acetic acid, 45 ℃ were reacted 1.5 hours under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:50:20, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, adding 0.5g sodium hydroxide adjustment pH value is 13,45 ℃ of reactions 1.5 hours, the pH value that adds 2.2g ion exchange resin adjustment solution was 3, removes by filter ion exchange resin, dropping 0.2mL mass concentration is that 25% ammoniacal liquor adjustment pH value is 12 in the filtrate, 25 ℃ of reactions 2 hours, be further purified, detailed process is: removal of solvent under reduced pressure, the gained crude product is with 90% aqueous ethanolic solution recrystallization, obtain white solid 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt 7.5g, productive rate 78%, reaction equation is:
Embodiment 3
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
(1) gets D-MANNOSE 10g and be dissolved in the 30mL DMF, add 68mL2, the 2-Propanal dimethyl acetal, stirring and evenly mixing adds the 1.9g tosic acid in solution, 25 ℃ were reacted 12 hours under the katalysis of tosic acid, D-MANNOSE and 2,2-dimethoxypropane, tosic acid, the mol ratio of DMF is 1:10:0.2:7, stop to stir, be further purified, detailed process is: add the 3g sodium bicarbonate in reaction solution, the cancellation reaction, filter, filtrate is removed DMF by the oil pump decompression, adds the dilution of 500mL ethyl acetate, wash with water 2 times, saturated common salt water washing 1 time by anhydrous magnesium sulfate drying, is filtered, use re-crystallizing in ethyl acetate after filtrate is concentrated, obtain white solid formula I intermediate 12.4g, productive rate 86%, reaction equation is:
(2) under nitrogen protection; 31.1g2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the 176mL toluene; add 7.6g trimethyl carbinol lithium; stirring at room 1 hour; add 12.4g formula I intermediate; be heated to 100 ℃ of reactions 10 hours; formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate; trimethyl carbinol lithium; the mol ratio of toluene is 1:2:2:35; question response liquid is cooled to room temperature; be further purified, detailed process is: add the dilution of 500mL ethyl acetate in reaction solution, wash with water 2 times; saturated common salt water washing 1 time; by anhydrous magnesium sulfate drying, to filter, filtrate is concentrated; resistates separates through column chromatography, and eluent is V
Sherwood oil/ V
Ethyl acetate=8:1 gets colorless oil formula II intermediate 19.3g, (E)-Shi II with (Z)-mol ratio=5:1 of Shi II, productive rate 88%, reaction equation is:
The preparation method of above-mentioned 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is identical with embodiment 1.
(3) modus ponens II intermediate 19.3g is dissolved in the 205mL tetrahydrofuran (THF), adds the 21.9g tetrabutyl ammonium fluoride, and 26 ℃ were reacted 4 hours; the mol ratio of formula II intermediate and tetrabutyl ammonium fluoride, tetrahydrofuran (THF) is 1:2:60, removes silicon ether protecting group, is further purified; detailed process is: add ethyl acetate 500mL dilution; saturated ammonium chloride solution washing 2 times, anhydrous magnesium sulfate drying is passed through in saturated common salt water washing 1 time; filter; filtrate is concentrated, and resistates separates through column chromatography, eluent: V
Sherwood oil/ V
Ethyl acetate=1:2 obtains colorless oil formula III intermediate 13.8g, productive rate 95%, and reaction equation is:
(4) get 13.8g formula III intermediate and be dissolved in 21mL water, add again 182mL acetic acid, 45 ℃ were reacted 1.5 hours under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:80:30, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, adding 0.5g sodium hydroxide adjustment pH value is 13,45 ℃ of reactions 1.5 hours, the pH value that adds 2.2g ion exchange resin adjustment solution was 3, removes by filter ion exchange resin, dropping 0.2mL mass concentration is that 25% ammoniacal liquor adjustment pH value is 12 in the filtrate, 25 ℃ of reactions 2 hours, be further purified, i.e. removal of solvent under reduced pressure, the gained crude product is with 90% aqueous ethanolic solution recrystallization, obtain white solid 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt 7.6g, productive rate 75%, reaction equation is:
Embodiment 4
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
(1) gets D-MANNOSE 10g and be dissolved in the 278mL DMF, add 13.6mL2, the 2-Propanal dimethyl acetal, stirring and evenly mixing adds the 0.48g tosic acid in solution, 25 ℃ were reacted 12 hours under the katalysis of tosic acid, D-MANNOSE and 2,2-dimethoxypropane, tosic acid, the mol ratio of DMF is 1:2:0.05:65, stop to stir, be further purified, detailed process is: add the 3g sodium bicarbonate in reaction solution, the cancellation reaction, filter, filtrate is removed DMF by the oil pump decompression, adds the dilution of 500mL ethyl acetate, wash with water 2 times, saturated common salt water washing 1 time by anhydrous magnesium sulfate drying, is filtered, use re-crystallizing in ethyl acetate after filtrate is concentrated, obtain white solid formula I intermediate 12.6g, productive rate 87%, reaction equation is:
(2) under nitrogen protection; 23.7g2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the 102mL toluene; add 5.8g trimethyl carbinol lithium; stirring at room 1 hour; add 12.6g formula I intermediate; be heated to 100 ℃ of reactions 10 hours; formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate; trimethyl carbinol lithium; the mol ratio of toluene is 1:1.5:1.5:20; question response liquid is cooled to room temperature; be further purified, specifically: in reaction solution, add the dilution of 500mL ethyl acetate, wash with water 2 times; saturated common salt water washing 1 time; by anhydrous magnesium sulfate drying, to filter, filtrate is concentrated; resistates separates through column chromatography, and eluent is V
Sherwood oil/ V
Ethyl acetate=8:1 gets colorless oil formula II intermediate 18.2g, (E)-Shi II with (Z)-mol ratio=5:1 of Shi II, productive rate 82%, reaction equation is:
The preparation method of above-mentioned 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is identical with embodiment 1.
(3) modus ponens II intermediate 18.2g is dissolved in the 57mL tetrahydrofuran (THF), adds the 10.3g tetrabutyl ammonium fluoride, and 26 ℃ were reacted 4 hours; the mol ratio of formula II intermediate and tetrabutyl ammonium fluoride, tetrahydrofuran (THF) is 1:1:20, removes silicon ether protecting group, is further purified; detailed process is: add ethyl acetate 500mL dilution; saturated ammonium chloride solution washing 2 times, anhydrous magnesium sulfate drying is passed through in saturated common salt water washing 1 time; filter; filtrate is concentrated, and resistates separates through column chromatography, eluent: V
Sherwood oil/ V
Ethyl acetate=1:2 obtains colorless oil formula III intermediate 13.1g, productive rate 96%, and reaction equation is:
(4) get 13.1g formula III intermediate and be dissolved in 12mL water, add again 98mL acetic acid, 45 ℃ were reacted 1.5 hours under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:45:18, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, adding 0.5g sodium hydroxide adjustment pH value is 13,45 ℃ of reactions 1.5 hours, the pH value that adds 2.2g ion exchange resin adjustment solution was 3, removes by filter ion exchange resin, dropping 0.2mL mass concentration is that 25% ammoniacal liquor adjustment pH value is 12 in the filtrate, 25 ℃ of reactions 2 hours, be further purified, detailed process is: removal of solvent under reduced pressure, the gained crude product is with 90% aqueous ethanolic solution recrystallization, obtain white solid 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt 7.1g, productive rate 74%, reaction equation is:
Embodiment 5
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
(1) gets D-MANNOSE 10g and be dissolved in the 13mL DMF, add 136mL2, the 2-Propanal dimethyl acetal, stirring and evenly mixing adds the 4.8g tosic acid in solution, 25 ℃ were reacted 12 hours under the katalysis of tosic acid, D-MANNOSE and 2,2-dimethoxypropane, tosic acid, the mol ratio of DMF is 1:20:0.5:3, stop to stir, be further purified, detailed process is: add the 3g sodium bicarbonate in reaction solution, the cancellation reaction, filter, filtrate is removed DMF by the oil pump decompression, adds the dilution of 500mL ethyl acetate, wash with water 2 times, saturated common salt water washing 1 time by anhydrous magnesium sulfate drying, is filtered, use re-crystallizing in ethyl acetate after filtrate is concentrated, obtain white solid formula I intermediate 11.6g, productive rate 80%, reaction equation is:
(2) under nitrogen protection; 58.2g2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the 495mL toluene; add 14.3g trimethyl carbinol lithium; stirring at room 1 hour; add 11.6g formula I intermediate; be heated to 100 ℃ of reactions 10 hours; formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate; trimethyl carbinol lithium; the mol ratio of toluene is 1:4:4:105; question response liquid is cooled to room temperature; be further purified, specifically: in reaction solution, add the dilution of 500mL ethyl acetate, wash with water 2 times; saturated common salt water washing 1 time; by anhydrous magnesium sulfate drying, to filter, filtrate is concentrated; resistates separates through column chromatography, and eluent is V
Sherwood oil/ V
Ethyl acetate=8:1 gets colorless oil formula II intermediate 16.6g, (E)-Shi II with (Z)-mol ratio=5:1 of Shi II, productive rate 81%.
The preparation method of above-mentioned 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is identical with embodiment 1.
(3) modus ponens II intermediate 16.6g is dissolved in the 320mL tetrahydrofuran (THF), adds the 37.6g tetrabutyl ammonium fluoride, and 26 ℃ were reacted 4 hours; the mol ratio of formula II intermediate and tetrabutyl ammonium fluoride, tetrahydrofuran (THF) is 1:4:110, removes silicon ether protecting group, is further purified; specifically: add ethyl acetate 500mL dilution; saturated ammonium chloride solution washing 2 times, anhydrous magnesium sulfate drying is passed through in saturated common salt water washing 1 time; filter; filtrate is concentrated, and resistates separates through column chromatography, eluent: V
Sherwood oil/ V
Ethyl acetate=1:2 obtains colorless oil formula III intermediate 11.3g, productive rate 91%, and reaction equation is:
(4) get 11.3g formula III intermediate and be dissolved in 32.3mL water, add again 260.7mL acetic acid, 45 ℃ were reacted 1.5 hours under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:140:55, concentrating under reduced pressure is except anhydrating and acetic acid, the gained solid matter is water-soluble, adding 0.5g sodium hydroxide adjustment pH value is 13,45 ℃ of reactions 1.5 hours, the pH value that adds 2.2g ion exchange resin adjustment solution was 3, removes by filter ion exchange resin, dropping 0.2mL mass concentration is that 25% ammoniacal liquor adjustment pH value is 12 in the filtrate, 25 ℃ of reactions 2 hours, be further purified, i.e. removal of solvent under reduced pressure, the gained crude product is with 90% aqueous ethanolic solution recrystallization, obtain white solid 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt 6.1g, productive rate 73%, reaction equation is:
Embodiment 6
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
In step (4), modus ponens III intermediate is water-soluble, add again Amberlite IR120 Hydrogen ion exchange resin, 45 ℃ were reacted 1.5 hours under the acid catalysis of Amberlite IR120 Hydrogen ion exchange resin, the mol ratio of formula III intermediate and Amberlite IR120 Hydrogen ion exchange resin, water is 1:0.3:350, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, adding sodium hydroxide, to adjust the pH value be 13, and other the operation of this step is identical with embodiment 1.
Other step is identical with embodiment 1, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 7
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
In step (4), modus ponens III intermediate is water-soluble, add again Amberlite IR120 Hydrogen ion exchange resin, 45 ℃ were reacted 1.5 hours under the acid catalysis of Amberlite IR120 Hydrogen ion exchange resin, the mol ratio of formula III intermediate and Amberlite IR120 Hydrogen ion exchange resin, water is 1:0.1:300, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, adding sodium hydroxide, to adjust the pH value be 13, and other the operation of this step is identical with embodiment 1.
Other step is identical with embodiment 1, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 8
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
In step (4), modus ponens III intermediate is water-soluble, add again Amberlite IR120 Hydrogen ion exchange resin, 45 ℃ were reacted 1.5 hours under the acid catalysis of Amberlite IR120 Hydrogen ion exchange resin, the mol ratio of formula III intermediate and Amberlite IR120 Hydrogen ion exchange resin, water is 1:0.4:380, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, adding sodium hydroxide, to adjust the pH value be 13, and other the operation of this step is identical with embodiment 1.
Other step is identical with embodiment 1, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 9
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
In step (4), modus ponens III intermediate is water-soluble, add again Amberlite IR120 Hydrogen ion exchange resin, 45 ℃ were reacted 1.5 hours under the acid catalysis of Amberlite IR120 Hydrogen ion exchange resin, the mol ratio of formula III intermediate and Amberlite IR120 Hydrogen ion exchange resin, water is 1:0.1:200, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, adding sodium hydroxide, to adjust the pH value be 13, and other the operation of this step is identical with embodiment 1.
Other step is identical with embodiment 1, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 10
Get 10g as example take the raw material D-MANNOSE, the method for synthetic 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is comprised of following steps:
In step (4), modus ponens III intermediate is water-soluble, add again Amberlite IR120 Hydrogen ion exchange resin, 45 ℃ were reacted 1.5 hours under the acid catalysis of Amberlite IR120 Hydrogen ion exchange resin, the mol ratio of formula III intermediate and Amberlite IR120 Hydrogen ion exchange resin, water is 1:0.5:400, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, adding sodium hydroxide, to adjust the pH value be 13, and other the operation of this step is identical with embodiment 1.
Other step is identical with embodiment 1, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 11
Synthetic method at the 3-of above-described embodiment 1～10 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, get D-MANNOSE in step (1) and be dissolved in N, in the dinethylformamide, add 2,2-dimethoxypropane, stirring and evenly mixing, in solution, add tosic acid, 0 ℃ was reacted 24 hours under the katalysis of tosic acid, and other operation is identical with corresponding embodiment, obtains formula I intermediate.In step (2); under nitrogen protection; 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the toluene; add trimethyl carbinol lithium; stirring at room 1 hour adds formula I intermediate, is heated to 50 ℃ of reactions 24 hours; other operation is identical with corresponding embodiment, obtains formula II intermediate.In step (3), modus ponens II intermediate is dissolved in the tetrahydrofuran (THF), adds tetrabutyl ammonium fluoride, and-20 ℃ were reacted 24 hours, and other operation is identical with corresponding embodiment, obtains the formula III intermediate.In step (4), modus ponens III intermediate is water-soluble, add again acetic acid, 0 ℃ was reacted 3 hours under the catalysis of acetic acid, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, adding sodium hydroxide adjustment pH value is 12,0 ℃ of reaction 3 hours, the pH value that adds ion exchange resin adjustment solution was 2, removes by filter ion exchange resin, the dropping mass concentration is that 25% ammoniacal liquor adjustment pH value is 10 in the filtrate, 0 ℃ of reaction 3 hours, other operation was identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 12
Synthetic method at the 3-of above-described embodiment 1～10 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, get D-MANNOSE in step (1) and be dissolved in N, in the dinethylformamide, add 2,2-dimethoxypropane, stirring and evenly mixing, in solution, add tosic acid, 50 ℃ were reacted 2 hours under the katalysis of tosic acid, and other operation is identical with corresponding embodiment, obtains formula I intermediate.In step (2); under nitrogen protection; 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the toluene; add trimethyl carbinol lithium; stirring at room 1 hour adds formula I intermediate, is heated to 150 ℃ of reactions 1 hour; other operation is identical with corresponding embodiment, obtains formula II intermediate.In step (3), modus ponens II intermediate is dissolved in the tetrahydrofuran (THF), adds tetrabutyl ammonium fluoride, and 50 ℃ were reacted 1 hour, and other operation is identical with corresponding embodiment, obtains the formula III intermediate.In step (4), modus ponens III intermediate is water-soluble, add again acetic acid, 90 ℃ were reacted 0.5 hour under the catalysis of acetic acid, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, adding sodium hydroxide adjustment pH value is 14,100 ℃ of reactions 0.5 hour, the pH value that adds ion exchange resin adjustment solution was 5, removes by filter ion exchange resin, the dropping mass concentration is that 25% ammoniacal liquor adjustment pH value is 14 in the filtrate, 30 ℃ of reactions 0.5 hour, other operation was identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 13
Synthetic method at the 3-of above-described embodiment 1～12 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, camphorsulfonic acid or the vitriol oil or concentrated hydrochloric acid or Dowex50W X2 Hydrogen ion exchange resin or the replacement of Amberlite IR120 Hydrogen ion exchange resin of equimolar amount of tosic acid in step (1), other step is identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Embodiment 14
Synthetic method at the 3-of above-described embodiment 1～13 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, toluene in step (2) benzene or the N of equimolar amount, dinethylformamide or 1,4-dioxane or tetrahydrofuran (THF) or methylene dichloride or 1, the 2-ethylene dichloride is replaced, other step is identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Synthetic method at the 3-of above-described embodiment 1～14 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, sodium tert-butoxide or potassium tert.-butoxide or sodium hydride or LHMDS or sodium hexamethyldisilazide or the potassium hexamethyldisilazide replacement of equimolar amount of trimethyl carbinol lithium in step (2), other step is identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Synthetic method at the 3-of above-described embodiment 1～15 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, polar solvent tetrahydrofuran (THF) in step (3) is with 1 of equimolar amount, 4-dioxane or methylene dichloride or 1, the 2-ethylene dichloride is replaced, other step is identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Synthetic method at the 3-of above-described embodiment 1～16 deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt; Neutral ammonium fluoride or Potassium monofluoride or the replacement of hydrofluoric acid pyridine of equimolar amount of fluorine-containing deprotecting regent tetrabutyl ammonium fluoride in step (3); other step is identical with corresponding embodiment, obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
The final product that the applicant is synthesized embodiment 1 and commercially available 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt sample detect contrast by the method for fusing point, specific rotation, mass spectrum, proton nmr spectra, and be specific as follows:
Detecting instrument: fusing point is measured with Tyke, Beijing X-6 of Instr Ltd. type micro melting point apparatus in the compound test; Specific rotation is measured with U.S. Rudolph company dual wavelength automatic polarimeter; Mass spectrum is measured with the German Bruker maXis of company electron spray(ES) flight time tandom mass spectrometer; Proton nmr spectra is measured with the German Bruker AVANCE400 of company NMR spectrometer with superconducting magnet.
Commercially available sample is that the result is referring to Fig. 1 for its proton nmr spectra analyzing and testing, fusing point: 121 ℃ from the 3-deoxidation of SIGMA-ALDRICH company purchase-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt; [α]
23 D=+39.0 (c0.50, H
2O);
1H NMR (400MHz, D
2O) δ: 4.58-4.43 (m), 4.23-4.11 (m), 3.97-3.80 (m), 3.69-3.60 (m), 2.61 (dd, J=14.2,6.7Hz), 2.39 (dd, 1H, J=14.2,5.5Hz), 2.19-1.87 (m); ESI-HRMS theoretical value: C
8H
13O
8[(M-NH
4)
-] 237.0616, measured value: 237.0590.
Contrasted as can be known by Fig. 1 and Fig. 2, the detected result of embodiment 1 (Fig. 2) is consistent with the analytical results (Fig. 1) of this commercially available sample, determines that thus the final product that embodiment 1 is synthesized is 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
Claims (10)
1. the synthetic method of 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt is characterized in that may further comprise the steps:
(1) gets D-MANNOSE and be dissolved in N, in the dinethylformamide, add 2,2-dimethoxypropane, stirring and evenly mixing, organic acid, mineral acid or ion exchange resin as the katalysis of catalyzer under 0～50 ℃ the reaction 2～24 hours, D-MANNOSE and 2,2-dimethoxypropane, catalyzer, N, the mol ratio of dinethylformamide is 1:2～20:0.05～0.5:3～65, purifying obtains formula I intermediate, and reaction equation is:
(2) under nitrogen protection; getting 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the non-protonic solvent; add highly basic; stirring at room 0.5～2 hour adds formula I intermediate, and 50～150 ℃ were reacted 1～24 hour; the mol ratio of formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate, highly basic, non-protonic solvent is 1:1～4:1～4:17～105; purifying obtains formula II intermediate, and reaction equation is:
(3) formula II intermediate is dissolved in polar solvent, adds fluorine-containing deprotecting regent, and-20～50 ℃ were reacted 1～24 hour; the mol ratio of formula II intermediate and fluorine-containing deprotecting regent, polar solvent is 1:1～4:20～110; purifying obtains the formula III intermediate, and reaction equation is:
(4) the formula III intermediate is water-soluble, 0～90 ℃ was reacted 0.5～3 hour under the katalysis of acetic acid or ion exchange resin, formula III intermediate and acetic acid, the mol ratio of water is 1:34～140:13～55 or formula III intermediate and ion exchange resin, the mol ratio of water is 1:0.1～0.5:200～400, concentrating under reduced pressure except anhydrate and acetic acid or remove by filter ion exchange resin after concentrating under reduced pressure except anhydrating, the gained material is water-soluble, add sodium hydroxide, it is 10～14 that potassium hydroxide or lithium hydroxide are adjusted pH, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate is 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying, obtain 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, reaction equation is:
Above-mentioned organic acid is tosic acid or camphorsulfonic acid;
Above-mentioned mineral acid is the vitriol oil or concentrated hydrochloric acid;
Above-mentioned non-protonic solvent is toluene, benzene, DMF, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), methylene dichloride or 1,2-ethylene dichloride;
Above-mentioned highly basic is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide, sodium hydride, LHMDS, sodium hexamethyldisilazide or potassium hexamethyldisilazide;
Above-mentioned polar solvent is tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride or 1,2-ethylene dichloride;
Above-mentioned fluorine-containing deprotecting regent is tetrabutyl ammonium fluoride, Neutral ammonium fluoride, Potassium monofluoride or hydrofluoric acid pyridine.
2. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, it is characterized in that: D-MANNOSE is dissolved in N in the described step (1), in the dinethylformamide, add 2, the 2-Propanal dimethyl acetal, mixing, organic acid, mineral acid or ion exchange resin as the katalysis of catalyzer under 0～50 ℃ the reaction 2～24 hours, D-MANNOSE and 2,2-Propanal dimethyl acetal, catalyzer, N, the mol ratio of dinethylformamide is 1:3.5～10:0.1～0.2:7～15, and purifying obtains formula I intermediate.
3. the synthetic method of 3-deoxidation according to claim 1 and 2-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, it is characterized in that: D-MANNOSE is dissolved in N in the described step (1), in the dinethylformamide, add 2, the 2-Propanal dimethyl acetal, mixing, organic acid, mineral acid or ion exchange resin as the katalysis of catalyzer under 0～50 ℃ the reaction 2～24 hours, D-MANNOSE and 2,2-Propanal dimethyl acetal, catalyzer, N, the mol ratio of dinethylformamide is 1:4:0.15:10, and purifying obtains formula I intermediate.
4. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt; it is characterized in that: described step (2) is under nitrogen protection; getting 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the non-protonic solvent; add highly basic; stirring at room 0.5～2 hour; adding formula I intermediate; 50～150 ℃ were reacted 1～24 hour; formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate; highly basic; the mol ratio of non-protonic solvent is 1:1.2～2:1.2～2:20～35; purifying obtains formula II intermediate.
5. according to claim 1 or the synthetic method of 4 described 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salts, it is characterized in that: the 2-dimethoxy phosphoroso-described in the step (2)-2-dimethyl tertiary butyl siloxy ethyl acetate is prepared by following methods:
A) the D-diethyl tartrate is dissolved in the methyl alcohol, adds sodium periodate, the mol ratio of D-diethyl tartrate and sodium periodate, methyl alcohol is 1:2:49, reflux 1 hour, and purifying obtains Compound I;
B) Compound I is dissolved in toluene, adds dimethylphosphite, the mol ratio of Compound I and dimethylphosphite, toluene is 1:1:9.5, heating reflux reaction 3 hours, and concentrating under reduced pressure is removed toluene, obtains Compound I I;
C) Compound I I and imidazoles, TERT-BUTYL DIMETHYL CHLORO SILANE are dissolved in anhydrous N, in the dinethylformamide, Compound I I and imidazoles, TERT-BUTYL DIMETHYL CHLORO SILANE, N, the mol ratio of dinethylformamide is 1:1.3:1.3:13, stirring at room 15 hours, purifying gets 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate;
6. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt; it is characterized in that: described step (3) Chinese style II intermediate is dissolved in polar solvent; add fluorine-containing deprotecting regent;-20～50 ℃ were reacted 1～24 hour; the mol ratio of formula II intermediate and fluorine-containing deprotecting regent, polar solvent is 1:1.5～2:25～60; remove silicon ether protecting group, purifying obtains the formula III intermediate.
7. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, it is characterized in that: the formula III intermediate is water-soluble in the described step (4), 0～90 ℃ was reacted 0.5～3 hour under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:45～80:20～30, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, add sodium hydroxide, it is 10～14 that potassium hydroxide or lithium hydroxide are adjusted pH, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate is 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying obtained 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
8. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, it is characterized in that: water-soluble 0～90 ℃ of reaction 0.5～3 hour under the catalysis of ion exchange resin of formula III intermediate in the described step (4), formula III intermediate and ion exchange resin, the mol ratio of water is 1:0.3～0.4:300～380, concentrating under reduced pressure is except anhydrating after removing by filter ion exchange resin, the gained liquid substance is water-soluble, add sodium hydroxide, it is 12～14 that potassium hydroxide or lithium hydroxide are adjusted the pH value, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate is 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
9. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, it is characterized in that: described step (2) is under nitrogen protection, getting 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate is dissolved in the non-protonic solvent, add highly basic, stirring at room 0.5～2 hour, adding formula I intermediate, 50～150 ℃ were reacted 1～24 hour, formula I intermediate and 2-dimethoxy phosphoroso--2-dimethyl tertiary butyl siloxy ethyl acetate, highly basic, the mol ratio of non-protonic solvent is 1:1.5:1.5:20, purifying obtains formula II intermediate;
The formula III intermediate is water-soluble in the described step (4), 0～90 ℃ was reacted 0.5～3 hour under the catalysis of acetic acid, formula III intermediate and acetic acid, the mol ratio of water is 1:50:20, concentrating under reduced pressure is except anhydrating and acetic acid, the gained liquid substance is water-soluble, add sodium hydroxide, it is 10～14 that potassium hydroxide or lithium hydroxide are adjusted pH, 0～100 ℃ of reaction 0.5～3 hour, the pH value that adds ion exchange resin adjustment solution is 2～5, remove by filter ion exchange resin, dripping ammoniacal liquor adjustment pH value in the filtrate was 10～14,0～30 ℃ of reaction 0.5～3 hour, purifying obtains 3-deoxidation-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt.
10. the synthetic method of 3-deoxidation according to claim 1-D-sweet dew-methyln-hexyl ketone saccharic acid ammonium salt, it is characterized in that: described ion exchange resin is Hydrogen ion exchange resin.
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| CN103588825A (en) * | 2013-11-14 | 2014-02-19 | 大连九信生物化工科技有限公司 | Method for protecting D-glucosamine derivative by using benzaldehyde dimethyl acetal |
| CN112679456A (en) * | 2021-01-08 | 2021-04-20 | 陕西师范大学 | Kdo-based glycolipid derivatives, their preparation and their antibacterial applications |
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| CN108929346A (en) * | 2018-08-16 | 2018-12-04 | 陕西师范大学 | A kind of building α-of high-efficient solid selectivity and β-glycosidic bond method |
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| CN103588825A (en) * | 2013-11-14 | 2014-02-19 | 大连九信生物化工科技有限公司 | Method for protecting D-glucosamine derivative by using benzaldehyde dimethyl acetal |
| CN103588825B (en) * | 2013-11-14 | 2016-06-22 | 大连九信生物化工科技有限公司 | A kind of method of benzaldehyde dimethyl acetal protection D-glucosamine derivant |
| CN112679456A (en) * | 2021-01-08 | 2021-04-20 | 陕西师范大学 | Kdo-based glycolipid derivatives, their preparation and their antibacterial applications |
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