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Fluoro imido sugar compounds, and preparation method and application thereof

A technology of fluorinated iminosugar and substituted iminosugar, which is applied in the field of fluoroiminosugar compound and its preparation and application, and can solve the problems of poor selectivity, lengthy steps, low efficiency, etc.

Inactive Publication Date: 2011-09-28
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of these preparation methods have disadvantages such as poor selectivity, lengthy steps and low efficiency.

Method used

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  • Fluoro imido sugar compounds, and preparation method and application thereof
  • Fluoro imido sugar compounds, and preparation method and application thereof
  • Fluoro imido sugar compounds, and preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0058] The preparation of intermediate IV-1 is carried out with reference to literature [(a) L.S.Jeong, B.B.Lim and V.E.Marquez, Carbohyd.Res., 1994,262,103-114; (b) T.Yoshiaki, U.Chiga, T. .Tsutomu and K.Yoshihiko, Carbohyd.Res., 1993,249,57-76.], the specific preparation method is: diacetone 3-deoxy-3-fluoroglucose (10.3g, 39.3mmol) is dissolved in 50mL tetrahydrofuran 5 mL of 1N hydrochloric acid was added, and stirred overnight at room temperature. Add 1N sodium hydroxide solution to neutralize the acid in the system until the pH value is about 8, evaporate the solvent and water, wash the residue with ethyl acetate and ethanol, discard the insoluble matter, and evaporate the organic phase to dryness to obtain the 5 , a monopropylidene intermediate of 6-propylidene, which is directly used in the next reaction.

[0059] The monopropylidene intermediate obtained in the previous step (calculated by 39.3mmol) was dissolved in 50mL of methanol and 10mL of water, and sodium peri...

Embodiment 1

[0081] Embodiment 1, the preparation of fluoroimino sugar formula (I-1), formula (I-2) and formula (I-3)

[0082] Taking the preparation of fluoroimino sugar formula (I-1), formula (I-2) and formula (I-3) as an example, the synthesis of such fluoroimino from fluoronitrone formula (III-1a) is illustrated Sugar step.

[0083]

[0084] Dissolve fluoronitrone formula (III-1a) (4.0g, 12.2mmol) in 30mL tetrahydrofuran, under nitrogen protection, cool to 0°C, add dropwise 20mL tetrahydrofuran solution of vinylmagnesium chloride (16M, 32.0mmol), reaction 5 Minutes later, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, evaporated to dryness and directly used in the next step.

[0085] Add copper acetate (0.3g, 1.5mmol), reduced iron powder (7.9g, 0.14mol) and 25mL glacial acetic acid into a 100mL flask, and stir for 1 hour until the blue color of copper ions disappears. Add the acetic acid solut...

Embodiment 2

[0093] Embodiment 2, preparation of fluoroimino sugar formula (I-4) and formula (I-5)

[0094] Taking the preparation of fluoroimino sugar formula (I-4) and formula (I-5) as an example, the synthesis of 3-deoxy-3-fluoro LAB from fluorine-containing intermediate XI-1 and its N-alkylation are illustrated product steps.

[0095]

[0096] Intermediate XI-1 (0.2g, 0.6mmol) was dissolved in 10mL of methanol, 40mg of palladium carbon (10%) and 10mL of 6N hydrochloric acid were added, and reacted under hydrogen atmosphere for 72 hours, the palladium carbon was recovered by filtration, and the filtrate was evaporated to dryness. Add concentrated ammonia water to neutralize the remaining acid, evaporate to dryness under reduced pressure again, and separate and purify with strong acidic ion exchange resin to obtain the product formula (I-4), which is dark yellow syrup, 76.6 mg, yield: 89%. δ H (300MHz; D 2 O) 4.67 (1H, d, J = 52.2Hz, H4), 4.27 (1H, ddd, J = 15.9Hz, 2.7Hz, 2.4Hz, H3...

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Abstract

The invention provides fluoro imido sugar compounds, and a preparation method and application thereof. The structures of the fluoro imido sugar compounds provided by the invention are shown in formula (I) and formula (II), wherein n = 1 or 2; X is hydroxyl or fluorine; R1, R2 and R3 are selected from hydrogen, hydroxyl, hydroxymethyl, benzyl, benzyloxyl and benzyloxymethyl; R4 and R6 are selected from hydrogen, fluorine, methyl, methyl substituted with one to three fluorine atoms, hydroxymethyl, ethyl, hydroxyethyl, (1S)-hydroxyl hydroxyethyl, (1R)-hydroxyl hydroxyethyl, hydroethyl substituted with one to four fluorine atoms, propyl, butyl and phenyl substituted by one to five hydroxyl groups or methoxyl groups; R5 is hydrogen or C1-18 straight-chain or branch-chain saturated alkane; and R7 and R8 are hydrogen, fluorine, hydroxyl, methyl, ethyl, propyl, hydroxymethyl or trifluoromethyl. The preparation method of the fluoro imido sugar compounds provided by the invention is simple and efficient. The fluoro imido sugar compounds provided by the invention can be used as potential drugs for inhibiting glycosidase or resisting tumors.

Description

technical field [0001] The invention relates to a fluorinated imino sugar compound and its preparation method and application. Background technique [0002] Iminosugars, also known as polyhydroxy alkaloids, azasaccharides, iminosugars, etc., can be regarded as a kind of sugar mimics in which the oxygen on the sugar ring is replaced by nitrogen from the structure. So far, more than 140 kinds of imino sugar alkaloids have been isolated, and many have been proved to be highly effective and specific glycosidase or glycosyltransferase inhibitors [see (a) A.E.Stütz, Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999; (b) P.Compain and O.R.Martin, eds., Iminosugars: From Synthesis to Therapeutic Applications, 1st edn., Wiley, 2007; (c) N.Asano, R.J.Nash, R.J. Molyneux and G.W.J. Fleet, Tetrahedron: Asymmetry, 2000, 11, 1645-1680; (d) A.A. Watson, G.W.J. Fleet, N. Asano, R.J. Molyneux and R.J. Nash, Phytochemistry, 2001, 56, 265-295; (e) G .Ho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/12C07D498/04C07D487/04A61K31/424A61K31/407A61K31/4015A61P35/00
Inventor 俞初一李意羡贾月梅
Owner INST OF CHEM CHINESE ACAD OF SCI
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