CN101402619A - Novel 2-deoxidizedfructofuranose derivative, preparation method and medical uses thereof - Google Patents

Novel 2-deoxidizedfructofuranose derivative, preparation method and medical uses thereof Download PDF

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Publication number
CN101402619A
CN101402619A CNA2008102345415A CN200810234541A CN101402619A CN 101402619 A CN101402619 A CN 101402619A CN A2008102345415 A CNA2008102345415 A CN A2008102345415A CN 200810234541 A CN200810234541 A CN 200810234541A CN 101402619 A CN101402619 A CN 101402619A
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dehydration
sorbitol
deoxidation
fructofuranose
acid
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Chinese (zh)
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孙宏斌
牛犇
柳军
吴晓明
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China Pharmaceutical University
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China Pharmaceutical University
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a novel micromolecule capable of inhibiting and killing tumor cells, a method for preparing a medical preparation of the micromolecule, and application thereof. The structure is shown in general formula (I), wherein R1, R2, R3, R4 and R5 are defined as in the instruction. The compound is used for treating cancers.

Description

Novel 2-deoxidation fructofuranose derivative, its preparation method and medicinal use thereof
Technical field
The present invention relates to have the synthetic and clinical application aspect treatment cancer and relative disease thereof of the brand-new micromolecular compound of therapeutic action.
Background technology
Malignant tumour is the disease of a class serious threat human body health.Optionally suppress or the kill tumor cell, and the normal cell of human body is not had significant toxicity, become the of paramount importance Consideration of chemotherapy process of tumour.Think that now most tumors is that several genes and back change of giving birth to environment cause.Even same type tumour, its malignant cell group kind also is different, different hereditary changes is arranged, and change along with advancing of disease.So, be difficult to come selectivity kill tumor cell by acting on a special genes.The utilization of uniting of so, appropriate multiple special target might the whole tumour cell of effective elimination.
In addition, a good strategy is by utilizing tumour cell and Normocellular essence difference to reach the selectivity and the validity of treatment.Tumour cell and normal cell essence difference are mainly reflected in the energy metabolism aspect.Nineteen twenty-four Germany scientist Warburg finds, tumour mainly provides energy with aerobic glycolysis (aerobic glycolysis), even the competent situation of oxygen also is (Warburg, O.Ueber den stoffwechsel der tumoren.Constable like this, London, 1930).Such as, in the liver tumor tissue of rat, glucolytic flow is 2 to 17 times of (Zu XL﹠amp of normal liver tissue; Guppy M.Biochem Biophys Res Commun, 2004,313 (3): 459-465; Marin-Hernandez A, et al..FEBS J, 2006,273 (9): 1975-1988).
Studies show that: compare with normal cell, enhanced glycolysis-(perhaps pentose phosphate metabolism) also may have the adaptability advantage, can be by allowing excessive pyruvate salt enter the synthetic of lipid or basic anabolic substrate being provided.For example: synthetic ribose (Homem de Bittencourt, P.I., Peres, et al.Biochem Mol Biol Int, 1993,30 (4): 631-641) of providing of nucleic acid are provided.Simultaneously, the glucose of pentose pathway consumption can provide necessary reducing equivalent (NADPH), and the toxicity that has reduced reactive oxygen species is resisted the aging (Kondoh of cell, H., Lieonart, et al.Drug Discov Today, 2005,2 (2): 263-267).Showing that by mathematical model and some observations the tumour cell glycolysis-strengthens partial sour environment of generation, is virose to other normal cell.Also have some evidences to show the degraded of this sour environment energy inducing cell epimatrix, in the transfer process of tumour, play crucial effect (Gatenby, R.A., Gawlinski, E.T., et al.Cancer Res, 2006,66 (10): 5216-5223).In addition, but acidic substance itself are exactly induced mutation material (having suppressed the reparation of DNA).
Because tumour cell mainly relies on anaerobic glycolysis that energy is provided, therefore, can suppress the energy supply of tumour, and slacken acid atmosphere by the generation that suppresses lactic acid by inhibition glycolysis-path, reach the purpose that suppresses tumor growth and transfer.Glycolysis-itself is the production process of a poor efficiency, so glycometabolic relevant enzyme content and activity have increased greatly in the tumor tissues.Such as, compare with the normal liver cell of rat, all glycolytic ferments are expressed and are strengthened 2-4 doubly in the AS-30D liver cancer cell.Wherein pyruvate kinase is crossed and has been expressed 8-10 doubly, hexokinase (HK) and PFK 1 (PFK-1) are crossed expression 17-300 doubly (Marin-Hernandez A, Rodriguez-Enriquez S, et al.FEBS J, 2006,273 (9): 1975-1988); In human cervical cancer 1 HeLa cell, all enzymes (comprising HK and PFK-1) are expressed and have been strengthened 2-7 doubly; Compare with normal liver cell, in the people Morris liver cancer cell increased activity of HK, PFK-1 and pyruvate kinase 5-500 doubly (Stubbs M.Curr Mol Med, 2003,3 (1): 49-59); At human breast cancer cell, the activity of HK, zymohexase (ALD), pyruvate kinase and serum lactic dehydrogenase (LDH) will be higher than healthy tissues 3.7-7 doubly (Balinsky D.J Natl Cancer Inst, 1984,72 (2): 217-224).
HK and PFK-1 are two enzymes of control glycolysis flow most critical.Compare with normal cell, variation (Rapoport TA, Heinrich R﹠amp have also taken place in the hypotype that HK and PFK-1 express in some tumours; Rapoport SM.Biochem J, 1976,154 (2): 449-469; Torres NV, Mateo F, Mele ' ndez-Hevia E, et al.Biochem J, 1986,234,169-174; Torres NV, Souto R﹠amp; Mele ' ndez-Hevia E.Biochem J, 1989,260 (3): 763-769; Kashiwaya YK, Sato K, Tsuchiya N, et al.J Biol Chem, 1994,269 (41), 25502-25514).In mammalian cell, HK have four kinds of hypotypes (HK-I ,-II ,-III and-IV), they have different dynamicss and tissue distribution and Subcellular Localization.At quick growing tumors cell, HK-II mainly expresses.Bibliographical information is arranged, and it is a kind of mechanism (Bustamante E.Proc Natl Acad Sci, 1977,74 (9): 3735-3739) that prevent the blocking-up of G-6-P that HK is combined on the plastosome.The antitumor research of its inhibitor is also more, as 2-deoxyglucose (2-DG), 3-Bromopyruvate (structure is similar to lactic acid molecules, also may block lactic acid and be discharged to the extracellular), Imatinib and lonidamine (Lonidamine) etc.PFK-1 has three kinds of hypotypes (C, L and M), and 2, (F-2 6-P) is the most effective agonist of PFK-1 to the 6-hexose diphosphate, and F-2, and the level of 6-P mainly is controlled by PFK-2 (PFKFB3 genes encoding PFK-2).In some tumour cells, be subjected to the PFKFB3 of HIF-1a inductive high expression level to cause F-2, the increase of 6-P.Increased the flow of glycolysis-path probably in this mechanism of tumour cell, because by F-2, the PFK-1 of 6-P excitement has been easy to overcome inhibition (the Rider MH of Citrate trianion and ATP, Bertrand L, Vertommen D, et al.Biochem J, 2004,381 (3): 561-579; Calvo MN, Bartrons R, Castano E, et al.FEBS Lett, 2006,580 (13): 3308-3314).In addition, PFK-2 can be used as an antineoplastic drug target equally, and 2,5-two dehydration N.F,USP MANNITOL (2-AM) have suppressed PFK-2 and have had certain anti-tumor activity (Patricio T.Riquelme, et al.Proc.Natl.Acad.Sci.1983,80 (14): 4301-4305; Richard J.Bucala, Jason Chesney, Robert A, et al., US 64139391).
Summary of the invention
One of the object of the invention is to disclose the compound that a class has inhibition and kill tumor;
Two of the object of the invention is the preparation method of open above-claimed cpd;
Three of the object of the invention is the clinical application of open above-claimed cpd as the treatment cancer.
Compound provided by the present invention is the compound shown in the general formula (I) or its pharmacy acceptable salt or ester:
Figure A20081023454100181
General formula I
Wherein, R 1Represent hydrogen, general formula (I) is represented 2-deoxidation furans-D-fructose compounds; Work as R 1When representing α hydrogen, general formula (I) is 2,5-dehydration-D-sorbitol compounds; Work as R 1When representing β hydrogen, general formula (I) is 2,5-dehydration-D-N.F,USP MANNITOL compounds;
R 2The independent CH that represents 2X, CH 2OR 6, CH 2OCOR 6, COOR 6, CONHR 6, CON (R 6) 2, CH 2NHR 6, CH 2N (R 6) 2, CH 2NHCOR 6, CH 2SO 2NHR 6, CH 2NHOR 6Or CH 2NHNHR 6
R 3, R 4And R 5Independent respectively OH, the OR of representing 7, OCOR 7
R 6And R 7Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of 1～10 carbon respectively;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, N 3, CF 3, SH, OH, COOH, COOCH 3Or COOC 2H 5
Preferred compound is in the above-claimed cpd:
Wherein, R 1Represent hydrogen, general formula (I) is represented 2-deoxidation furans-D-fructose compounds; Work as R 1When representing hydrogen and being α hydrogen, general formula (I) is 2,5-dehydration-D-sorbitol compounds; Work as R 1When representing hydrogen and being β hydrogen, general formula (I) is 2,5-dehydration-D-N.F,USP MANNITOL compounds;
R 2The independent CH that represents 2X, CH 2OR 6, CH 2OCOR 6, COOR 6, CONHR 6, CON (R 6) 2, CH 2NHR 6, CH 2N (R 6) 2, CH 2NHCOR 6, CH 2SO 2NHR 6, CH 2NHOR 6Or CH 2NHNHR 6
R 3, R 4And R 5Independent respectively OH, OCOPh, the OBn of representing;
R 6Independent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of representing 1～10 carbon;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, N 3, CF 3, SH, OH, COOH, COOCH 3Or COOC 2H 5
More preferred compound is:
1-fluoro-2,5-dehydration-D-sorbitol;
1-sulfydryl-2,5-dehydration-D-sorbitol;
1-O-methyl-2,5-dehydration-D-sorbitol;
1-O-trifluoromethyl-2,5-dehydration-D-sorbitol;
1-O-ethyl-2,5-dehydration-D-sorbitol;
1-O-n-propyl-2,5-dehydration-D-sorbitol;
1-O-sec.-propyl-2,5-dehydration-D-sorbitol;
1-O-normal-butyl-2,5-dehydration-D-sorbitol;
1-O-isobutyl--2,5-dehydration-D-sorbitol;
The 1-O-tertiary butyl-2,5-dehydration-D-sorbitol;
1-O-sec-butyl-2,5-dehydration-D-sorbitol;
1-trifluoromethyl amido-2,5-dehydration-D-sorbitol;
1-ethyl amido-2,5-dehydration-D-sorbitol;
1-n-propyl amido-2,5-dehydration-D-sorbitol;
1-sec.-propyl amido-2,5-dehydration-D-sorbitol;
1-normal-butyl amido-2,5-dehydration-D-sorbitol;
1-isobutyl-amido-2,5-dehydration-D-sorbitol;
1-tertiary butyl amido-2,5-dehydration-D-sorbitol;
1-(2-normal-butyl) amido-2,5-dehydration-D-sorbitol;
1-(N, N-dimethyl) amido-2,5-dehydration-D-sorbitol;
1-(N, N-diethyl) amido-2,5-dehydration-D-sorbitol;
1-(N-methyl-N-ethyl) amido-2,5-dehydration-D-sorbitol;
1-O-ethanoyl-2,5-dehydration-D-sorbitol;
1-O-trifluoroacetyl group-2,5-dehydration-D-sorbitol;
1-O-propionyl-2,5-dehydration-D-sorbitol;
1-O-positive butyryl radicals-2,5-dehydration-D-sorbitol;
1-O-isobutyryl-2,5-dehydration-D-sorbitol;
1-acyl amino-2,5-dehydration-D-sorbitol;
1-propionamido-2,5-dehydration-D-sorbitol;
1-positive butyrylamino-2,5-dehydration-D-sorbitol;
The different positive butyrylamino-2 of 1-, 5-dehydration-D-sorbitol;
2,5-dehydration-maltonic acid ethyl ester;
2,5-dehydration-maltonic acid trifluoro ethyl ester;
2,5-dehydration-maltonic acid n-propyl;
2,5-dehydration-maltonic acid isopropyl ester;
2, the positive butyl ester of 5-dehydration-maltonic acid;
2,5-dehydration-maltonic acid isobutyl ester;
2, the 5-dehydration-maltonic acid tert-butyl ester;
2, the secondary butyl ester of 5-dehydration-maltonic acid;
N-methyl-2,5-dehydration-D-glucose amide;
N-ethyl-2,5-dehydration-D-glucose amide;
N-trifluoroethyl-2,5-dehydration-D-glucose amide;
N, N-dimethyl-2,5-dehydration-D-glucose amide;
N, N-diethyl-2,5-dehydration-D-glucose amide;
N-methyl-N-ethyl-2,5-dehydration-D-glucose amide;
N-n-propyl-2,5-dehydration-D-glucose amide;
N-sec.-propyl-2,5-dehydration-D-glucose amide;
N-normal-butyl-2,5-dehydration-D-glucose amide;
N-isobutyl--2,5-dehydration-D-glucose amide;
The N-tertiary butyl-2,5-dehydration-D-glucose amide;
3,4,6-O-tri-benzoyl-2,5-dehydration-D-sorbitol;
3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol;
3,4,6-O-tribenzyl-2,5-dehydration-maltonic acid;
3,4,6-O-tri-benzoyl-2,5-dehydration-maltonic acid;
1-amido-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol;
1-fluoro-2,5-dehydration-D-N.F,USP MANNITOL;
1-sulfydryl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-methyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-trifluoromethyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-ethyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-n-propyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-sec.-propyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-normal-butyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-isobutyl--2,5-dehydration-D-N.F,USP MANNITOL;
The 1-O-tertiary butyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-sec-butyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-trifluoromethyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-ethyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-n-propyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-sec.-propyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-normal-butyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-isobutyl-amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-tertiary butyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(2-normal-butyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(N, N-dimethyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(N, N-diethyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(N-methyl-N-ethyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-ethanoyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-trifluoroacetyl group-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-propionyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-positive butyryl radicals-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-isobutyryl-2,5-dehydration-D-N.F,USP MANNITOL;
1-acyl amino-2,5-dehydration-D-N.F,USP MANNITOL;
1-propionamido-2,5-dehydration-D-N.F,USP MANNITOL;
1-positive butyrylamino-2,5-dehydration-D-N.F,USP MANNITOL;
The different positive butyrylamino-2 of 1-, 5-dehydration-D-N.F,USP MANNITOL;
2,5-anhydro-D-mannonic acid ethyl ester;
2,5-anhydro-D-mannonic acid trifluoro ethyl ester;
2,5-anhydro-D-mannonic acid n-propyl;
2, the positive butyl ester of 5-anhydro-D-mannonic acid;
2,5-anhydro-D-mannonic acid isobutyl ester;
2, the 5-anhydro-D-mannonic acid tert-butyl ester;
2, the secondary butyl ester of 5-anhydro-D-mannonic acid;
N-methyl-2,5-dehydration-D-seminose acid amides;
N-ethyl-2,5-dehydration-D-seminose acid amides;
N-trifluoroethyl-2,5-dehydration-D-seminose acid amides;
N, N-dimethyl-2,5-dehydration-D-seminose acid amides;
N, N-diethyl-2,5-dehydration-D-seminose acid amides;
N-methyl-N-ethyl-2,5-dehydration-D-seminose acid amides;
N-n-propyl-2,5-dehydration-D-seminose acid amides;
N-sec.-propyl-2,5-dehydration-D-seminose acid amides;
N-normal-butyl-2,5-dehydration-D-seminose acid amides;
N-isobutyl--2,5-dehydration-D-seminose acid amides;
The N-tertiary butyl-2,5-dehydration-D-seminose acid amides;
3,4,6-O-tri-benzoyl-2,5-dehydration-D-N.F,USP MANNITOL;
3,4,6-O-tribenzyl-2,5-anhydro-D-mannonic acid;
1-O-p-toluenesulfonyl-3,4,6-O-tri-benzoyl-2,5-dehydration-D-N.F,USP MANNITOL.
The preparation method of compound provided by the present invention may further comprise the steps:
(1) 3,4,2 of 6-O-three acyl groups protection, the preparation of 5-dehydration-D-sorbitol compound:
Figure A20081023454100231
In the following formula, R 7Described as defined above; R 8Represent the primary hydroxyl protecting group.Selective protection method according to the primary hydroxyl of routine, 4,6-O-dibenzoyl-2,5-dehydration-D-sorbitol and various chlorosilane, bromo-silicane, triphenylmethyl chloride or replacement triphenylmethyl chloride react under base catalysis, obtain 4 of 1 hydroxyl protection, 6-O-dibenzoyl-2,5-dehydration-D-sorbitol; The alkali that is adopted comprises pyridine, triethylamine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, preferentially adopts pyridine.The solvent that is adopted comprises pyridine, methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential pyridine, 1,2-ethylene dichloride, toluene, N, dinethylformamide or the tetrahydrofuran (THF) of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 50 degree as temperature of reaction.
According to the hydroxy esterification method of routine, with various acyl chlorides, acid anhydrides or carboxylic acid reaction, obtain 3,4 of 1 hydroxyl protection more then, 6-O-three acyl groups-2,5-dehydration-D-sorbitol; According to the corresponding conventional method, under acidic conditions, slough the protecting group of primary hydroxyl in the following formula at last, obtain 3,4,2 of 6-O-three acyl groups protection, 5-dehydration-D-sorbitol compound.The acid of being adopted comprises formic acid, acetate, hydrochloric acid, sulfuric acid, tosic acid pyridinium salt.Preferential acetate and the tosic acid pyridinium salt of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.
(2) 3,4,2 of 6-O-three acyl groups protection, the preparation of 5-dehydration-D-N.F,USP MANNITOL compound:
Figure A20081023454100241
In the following formula, R 7Described as defined above.According to the hydroxy esterification method of routine, 1-O-trityl-2,5-dehydration-D-N.F,USP MANNITOL and various acyl chlorides or anhydride reaction obtain 3,4 of 1 hydroxyl protection, 6-O-three acyl groups-2,5-dehydration-D-N.F,USP MANNITOL; According to the corresponding conventional method, under acidic conditions, slough the protecting group of primary hydroxyl in the following formula at last, obtain 3,4,2 of 6-O-three acyl groups protection, 5-dehydration-D-sorbitol compound.The acid of being adopted comprises formic acid, acetate, hydrochloric acid, sulfuric acid, tosic acid pyridinium salt.Preferential acetate and the tosic acid pyridinium salt of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.
(3) 3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound:
Route one:
Figure A20081023454100242
Route two:
Figure A20081023454100251
In the following formula, R 8Described as defined above.In route one, 4 of 1 hydroxyl protection, 6-O-dibenzoyl-2,5-dehydration-D-sorbitol is under alkaline condition, and hydrolysis of ester group obtains 2 of 1 hydroxyl protection, 5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, and sodium ethylate, ammonia, sodium hydroxide or potassium hydroxide preferentially adopt sodium methylate.The solvent that is adopted comprises methyl alcohol, ethanol, acetonitrile and tetrahydrofuran (THF).Then then according to the method for routine with 3,4,6 hydroxyl and benzyl chloride or bromobenzyl react under alkaline condition, obtain 3,4 of 1 hydroxyl protection, 6-O-benzyl-2,5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, the dinethylformamide (DMF) of adopting.According to the method for sloughing 1 protecting group among the preparation method (1), obtain 3,4 then, 6-O-tribenzyl-2,5-dehydration-D-sorbitol.
In route two, 1,3-propylidene base-2,5-dehydration-D-sorbitol and benzyl chloride or bromobenzyl react under alkaline condition, obtain 1,3-propylidene base-O-4,6-dibenzyl-2,5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, the dinethylformamide (DMF) of adopting.Hydrolysis under acidic conditions then obtains 4, and 6-O-two-2,5-dehydration-D-sorbitol, and the acid of being adopted comprises formic acid, acetate, hydrochloric acid, sulfuric acid or tosic acid pyridinium salt.The preferential hydrochloric acid that adopts.React under alkaline condition with various chlorosilanes, bromo-silicane, triphenylmethyl chloride or replacement triphenylmethyl chloride then and obtain 4 of 1 hydroxyl protection, 6-dibenzyl-2,5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, the dinethylformamide (DMF) of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.According to the same method of route one, 4 of 1 hydroxyl protection, 6-dibenzyl-2,5-dehydration-D-sorbitol reacts under alkaline condition with benzyl chloride or bromobenzyl earlier, sloughs 1 protecting group then, obtains 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol.
(4) preparation of 1-O-acyl group-2-deoxidation-D-fructofuranose compound:
Figure A20081023454100261
In the following formula, R 6Described as defined above.According to the hydroxy esterification method of routine, in the following formula 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound and various acyl chlorides, acid anhydrides or carboxylic acid reaction obtains 1-O-acyl group-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.Slough the method for benzyl then according to routine, obtain 1-O-acyl group-2-deoxidation-D-fructofuranose compound.The method of sloughing benzyl preferentially adopts palladium carbon catalysis normal pressure hydrogenation.
(5) preparation of 1-O-alkyl-2-deoxidation-D-fructofuranose compound:
Figure A20081023454100262
In the following formula, R 6Described as defined above.According to the method for the hydroxy alkylated of routine, in the following formula 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound reacts with highly basic earlier, adds various halogenated alkanes reactions then, obtains 1-O-alkyl-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.Slough the method for benzyl then according to routine, obtain 1-O-alkyl-2-deoxidation-D-fructofuranose compound.
(6) 1-amido-3,4, the preparation of 6-O-tribenzyl-2-deoxidation-D-fructofuranose compound:
Figure A20081023454100271
In the following formula, under base catalysis, 3; 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound and Tosyl chloride or benzene sulfonyl chloride reaction obtain 1-O-p-toluenesulfonyl-3; 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose, and then react with sodium azide; obtain 1-nitrine-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose; then under the effect of reductive agent; generate 1-amido-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose.Reductive agent adopts lithium aluminium hydride, palladium hydrocarbonize, sodium borohydride, POTASSIUM BOROHYDRIDE, Virahol/aluminum isopropylate, borine/tetrahydrofuran (THF) or borine/dimethyl sulphide, preferentially adopts lithium aluminium hydride.
(7) preparation of 1-acyl amino-2-deoxidation-D-fructofuranose compound:
Figure A20081023454100272
In the following formula, R 6Described as defined above.According to the amido process for acylating of routine, 1-amido-3,4 in the following formula, 6-O-tribenzyl-2-deoxidation-D-fructofuranose compound and various acyl chlorides, acid anhydrides or carboxylic acid reaction obtains 1-acyl amino-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.Slough the method for benzyl then according to routine, obtain 1-acyl group ammonia-2-deoxidation-D-fructofuranose compound.The method of sloughing benzyl preferentially adopts palladium carbon catalysis normal pressure hydrogenation.
The preparation of (8) 2-deoxidation-D-fructofuranose acid compound:
Figure A20081023454100281
In the following formula, change into the carboxyl common method according to hydroxyl oxygen, with 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose and pyridinium dichromate (PDC) reaction generate 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose acid, slough the method for benzyl then according to routine, obtain 2-deoxidation-D-fructofuranose acid compound.
The preparation of (9) 2-deoxidation-D-fructofuranose ester compound:
Figure A20081023454100282
In the following formula, R 6Described as defined above.According to conventional carboxyalkyl esterification process, the 2-deoxidation in the following formula-D-fructofuranose acid with various halogenated alkane reactions, obtains 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose acid esters under thionyl chloride catalysis.Slough the method for benzyl then according to routine, obtain 2-deoxidation-D-fructofuranose ester compound.
The preparation of (10) 2-deoxidation-D-fructofuranose acid amide compound:
Figure A20081023454100291
In the following formula, R 6Described as defined above.Carboxyl according to routine becomes the acid amides method; 2-deoxidation in the following formula-D-fructofuranose acid elder generation generates acyl chlorides with acylating agent and reacts with kiber alkyl amine then, and the perhaps direct down and kiber alkyl amine reaction with amide condensed dose of catalysis obtains 3; 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose acid acid amides.Slough the method for benzyl then according to routine, obtain 2-deoxidation-D-fructofuranose acid amide compound.
(11) preparation of 1-sulfydryl-2-deoxidation-D-fructofuranose compound:
Figure A20081023454100292
In the following formula, R 7Described as defined above.Hydroxy esterification method according to routine; 1-O-tolysulfonyl-4 in the following formula; 6-O-dibenzoyl-2-deoxidation-D-fructofuranose compound and various acyl chlorides, acid anhydrides or carboxylic acid reaction obtains 1-O-p-toluenesulfonyl-3-O-acyl group-4,6-O-dibenzoyl-2-deoxidation-D-fructofuranose.Be that then the thioacetic acid nak response generates 1-acetyl mercapto-3-O-acyl group-4,6-O-dibenzoyl-2-deoxidation-D-fructofuranose is sloughed the acyl group protection at last under alkaline condition, obtain 1-coloured glaze base-2-deoxidation-D-fructofuranose compound.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, and sodium ethylate, ammonia, sodium hydroxide or potassium hydroxide preferentially adopt sodium methylate.
The preparation of (12) 1-fluoro-2-deoxidation-D-fructofuranose compound:
Route one:
Figure A20081023454100301
Route two:
In the following formula, R 7Described as defined above.In the route one; 3; 4; 6-O-three acyl groups-2-deoxidation-D-fructofuranose generates 1-O-tolysulfonyl-3 with Tosyl chloride under base catalysis; 4; 6-O-three acyl groups-2-deoxidation-D-fructofuranose; and then generate 1-fluoro-3 with the reaction of tetrabutyl fluoride amine or Potassium monofluoride; 4,6-O-three acyl groups-2-deoxidation-D-fructofuranose, 1-fluoro-3; 4; the preparation of 6-O-three acyl groups-2-deoxidation-D-fructofuranose can also be by 3,4, and 6-O-three acyl groups-2-deoxidation-D-fructofuranose and the reaction of diethylamino sulfur trifluoride obtain.Obtaining 1-fluoro-2-deoxidation-D-fructofuranose by basic hydrolysis then.In the route two, 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose generates 1-O-tolysulfonyl-3 with Tosyl chloride under base catalysis, 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose, and then generate 1-fluoro-3 with the reaction of tetrabutyl fluoride amine or Potassium monofluoride, 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose, 1-fluoro-3,4, the preparation of 6-O-tribenzyl-2-deoxidation-D-fructofuranose can also be by 3,4, and 6-O-tribenzyl-2-deoxidation-D-fructofuranose and the reaction of diethylamino sulfur trifluoride obtain.And then palladium carbon catalysis normal pressure hydrogenation is sloughed benzyl and is obtained 1-fluoro-2-deoxidation-D-fructofuranose.
(13) preparation of 1-alkylamino radical-2-deoxidation-D-fructofuranose compound:
Figure A20081023454100311
In the following formula, R 6Described as defined above.1-O-tolysulfonyl-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose and various primary amine reaction obtains 1-alkylamino-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, dinethylformamide or the tetrahydrofuran (THF) of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.Slough the method for benzyl then according to routine, obtain 1-alkylamino-2-deoxidation-D-fructofuranose.
Be part pharmacology test and result below:
Breast tumor cell experiment and result are as follows:
Carry out following cell culture experiments to test 2,5-dehydration-D-sorbitol and analogue thereof are to the toxicity of breast tumor cell.Come the vigor of observation of cell by the minimizing of observing MTT (bromination 3-[4,5-dimethylthiazole-2-yl]-2,5-phenylbenzene tetrazolium).It is the known method of measuring cell viability that MTT measures.
[method]
1. get and be in one bottle in HBT's cell in good condition exponential phase of growth (from the MCF-7 of ATCC), add 0.25% tryptic digestive juice, digestion comes off attached cell, counting 2～4 * 10 4Individual/ml, make cell suspension.
2. obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in 180 μ l/ holes 2Cultivated 24 hours in the incubator.
3. change liquid, add test-compound, cultivated 72 hours in 20 μ l/ holes.
4. MTT is added in 96 orifice plates, 20 μ l/ holes, reaction is 4 hours in the incubator.
5. inhale and remove supernatant liquor, add DMSO, 150 μ l/ holes, jolting is 5 minutes on the dull and stereotyped shaking table.
6. be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, and calculate cell and suppress.
Figure A20081023454100321
Zorubicin is as positive control.In all cases, it is than big 1 or 2 log unit of toxicity (logs) for the examination material.Zorubicin is one of stronger medicine of current use.This experiment selected compounds concentration is 100uM, 10uM, and 1uM judges that active standard is with 10uM (1 * 10 -5Mol/L) and 1uM (1 * 10 -6Mol/L) inhibiting rate is a standard greater than 50%.Part 2, the anti-tumor activity such as the table 1. of 5-dehydration-D-glucitol derivative
Table 1
Figure A20081023454100322
Figure A20081023454100331
Experimental result shows, and is most 2,5-dehydration-D-glucitol derivative have an anti-tumor activity, its anti-tumor activity and Zorubicin quite or be better than Zorubicin and significantly are better than 2-deoxy-D-glucose.
Embodiment
Embodiment 1
3,4,6-O-tri-benzoyl-2, the preparation of 5-dehydration-D-sorbitol
With 4 of 10g; 6-O-dibenzoyl-2; 5-dehydration-D-sorbitol is dissolved in the 100mL pyridine, and the triphenylmethyl chloride that adds 11g then stirs for about 50 ℃ and spends the night, and stops heating; after the cooling reaction solution poured into and reconcile in the 1N hydrochloric acid to acid; extract with ethyl acetate 150mL * 3, add the saturated sodium bicarbonate solution washing, add the saturated common salt water washing at last; get ethyl acetate layer, anhydrous Na 2SO 4Drying, evaporate to dryness gets a syrup.This syrup is dissolved in the 100mL pyridine, ice-water bath slowly drips the Benzoyl chloride of 3mL down, stirred overnight at room temperature, after the cooling reaction solution poured into and reconcile in the 1N hydrochloric acid to acid, extract with ethyl acetate 150mL * 3, add the saturated sodium bicarbonate solution washing, add the saturated common salt water washing at last, get ethyl acetate layer, anhydrous Na 2SO 4Drying, evaporate to dryness adds 80% acetic acid aqueous solution then, and 50 ℃ were stirred 4 hours, with reacting liquid filtering, filtrate decompression concentrates after the cooling, adds saturated sodium bicarbonate solution, extracts with ethyl acetate 150mL * 3, add the saturated common salt water washing at last, get ethyl acetate layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=3: 1), get 3,4,6-O-tri-benzoyl-2,5-dehydration-D-sorbitol 8.8g, yield: 68.5%. 1H?NMR(300MHz，CDCl 3)δppm：δ2.22(br，1H)，3.96-3.98(m，2H)，4.39-4.43(q，1H，J＝4.7and?8.9Hz)，4.61-4.75(m，3H)，4.31-4.48(m，1H)，5.67-5.70(q，1H，J＝2.8and?4.7Hz)，5.76-5.78(t，1H)，7.35-8.10(m，15H)； 13C-NMR(75MHz，CDCl 3)：62.3，64.0，76.6，77.0，77.4，78.8，79.6，81.4，84.0，128.4，128.5，129.0，129.8，129.9，133.1，133.59，133.6，165.7，166.0，166.2；ESI-MS?m/z：477.1[M+H] +.
Embodiment 2
4,6-O-dibenzyl-2, the preparation of 5-dehydration-D-sorbitol
With 1 of 5g, 3-O-propylidene base-2, (Liebigs Annalen der Chemie (1987), (3) 205-14) are dissolved among the exsiccant 40mLDMF 5-dehydration-D-sorbitol, and ice-water bath adds the 3mL cylite down, stir the sodium hydride that in batches adds 2g down.Room temperature reaction spends the night, and reaction solution is poured in the frozen water, extracts with ether 100mL * 3, adds the saturated common salt water washing at last, gets ether layer, anhydrous Na 2SO 4Drying, evaporate to dryness gets an oily matter.Add tetrahydrofuran (THF) and 2N hydrochloric acid (1: 1) solution 50mL then, stirred 5 hours about 50 ℃, reaction solution adds sodium-chlor, isolates the tetrahydrofuran (THF) layer, and water extracts with ethyl acetate 100mL * 3, merges organic phase, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=2: 1), get 4,6-O-dibenzoyl-2,5-dehydration-D-sorbitol 5.1g, yield: 60.0%. 1H?NMR(300MHz，CDCl 3)δppm：3.49-3.55(dd，1H，J＝7.0and9.8Hz)，3.61-3.67(dd，1H，J＝5，6and9.8Hz)，3.96-3.98(m，2H)，4.11-4.15(m，1H)，4.21-4.32(m，2H)，4.32-4.36(m，1H)，4.42-4.63(m，4H)，，7.21-7.34(m，10H) 13C-NMR(75MHz，CDCl 3)：128.5，128.3，127.88，127.86，127.8，127.7，127.6，83.1，83.0，78.9，73.3，71.5，70.3，63.3，20.9，ESI-MS?m/z：367.2[M+Na] +.
Embodiment 3
3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol
With 4 of 5g, 6-O-dibenzyl-2,5-dehydration-D-sorbitol is dissolved in the exsiccant 40mL pyridine, and the triphenylmethyl chloride that adds 6g stirs for about 50 ℃ and spends the night, and stops heating, after the cooling reaction solution poured into and reconcile in the 1N hydrochloric acid to acid, extract with ethyl acetate 150mL * 3, add the saturated sodium bicarbonate solution washing, add the saturated common salt water washing at last, get ethyl acetate layer, anhydrous Na 2SO 4Drying, evaporate to dryness ,-syrup, be dissolved in then among the exsiccant 40mLDMF, ice-water bath adds the 1.8mL cylite down, stirs the sodium hydride that in batches adds 1.2g down.Room temperature reaction spends the night, and reaction solution is poured in the frozen water, extracts with ether 70mL * 3, adds the saturated common salt water washing at last, gets ether layer, anhydrous Na 2SO 4Drying, evaporate to dryness adds 80% acetic acid aqueous solution then, and 50 ℃ were stirred 4 hours, with reacting liquid filtering, filtrate decompression concentrates after the cooling, adds saturated sodium bicarbonate solution, extracts with ethyl acetate 150mL * 3, add the saturated common salt water washing at last, get ethyl acetate layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=2: 1), get 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 4.1g, yield: 65.0%. 1H?NMR(300MHz，CDCl 3)δppm：3.59-3.61(m，2H)，3.82-3.85(m，2H)，4.06-4.13(m，4H)，7.24-7.45(m，15H)；ESI-MS?m/z：457.2[M+Na] +.
Embodiment 4
1-O-methyl-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound
With 3,4 of 200mg, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved among the DMF of exsiccant 4mL, ice-water bath adds the sodium hydride of 50mg down, and stirring at room added the methyl iodide of 100 μ L after 2 hours, continue to stir after 2 hours, reaction solution is poured in the water, extracted, add the saturated common salt water washing with ether 20mL * 3, get ether layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=20: 1), get 1-O-methyl-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 180mg, yield: 87.0%. 1H?NMR(300MHz，CDCl 3)δppm：3.38(s，3H)，3.51-3.56(dd，J＝6.9Hz，10.0Hz，6H)，3.63-3.65(m，2H)，4.08-4.13(m，1H)，4.17-4.22(m，1H)，4.36-4.59(m，6H)，7.22-7.36(m，15H)，5.02-5.12(m，2H)，5.23(t，J＝3.2Hz，1H)，7.26-7.36(m，5H)； 13C?NMR(300MHz，CDCl 3)δppm：59.2，70.5，71.0，71.5，71.6，73.3，80.0，82.8，83.0，83.8，127.6，127.64，127.8，128.3，128.39，128.41，137.91，137.96，138.3；ESI-MS?m/z：465.3[M+H] +.
Embodiment 5
1-O-methyl-2, the preparation of 5-dehydration-D-sorbitol compound
1-O-methyl-3 with 150mg, 4,6-O-tribenzyl-2,5-dehydration-D-sorbitol compound dissolution is in the 5mL dehydrated alcohol, 10% the palladium carbon that the back is added catalytic amount, normal pressure hydrogenation 72 hours is then with palladium carbon filtering in the reaction solution, concentrating under reduced pressure, rapid column chromatography (methylene dichloride: methyl alcohol=15: 1), get 1-O-methyl-2,5-dehydration-D-sorbitol compound 38mg, yield: 64.0%. 1H?NMR(300MHz，d 6-DMSO)δppm：3.24(s，3H)，3.34-3.49(m，3H)，3.50-3.61(m，2H)，3.75-3.78(m，2H)，3.91-3.95(m，1H)，4.82-4.86(t，J＝5.3Hz，1H)，4.87-4.89(d，J＝5.9Hz，1H)，5.08-5.09(d，J＝4.1Hz，1H)； 13CNMR(75MHz，d 6-DMSO)δppm：58.2，62.1，71.1，76.9，78.5，79.5，86.1；ESI-MS?m/z：179.0[M+H] +.
Embodiment 6
1-O-ethanoyl-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound
With 3,4 of 190mg, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved in the 5mL pyridine, the diacetyl oxide that adds 0.1mL under ice-water bath, stirring at room be after 2 hours, concentrating under reduced pressure, rapid column chromatography (sherwood oil: ethyl acetate=15: 1), get 1-acetylaminohydroxyphenylarsonic acid 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 180mg, yield: 87.0%. 1H?NMR(300MHz，CDCl 3)δppm：2.03(s，1H)，3.49-3.55(dd，1H，J＝7.0and9.8Hz)，3.61-3.67(dd，1H，J＝5，6and9.8Hz)，3.96-3.98(m，2H)，4.11-4.15(m，1H)，4.21-4.32(m，2H)，4.32-4.36(m，1H)，4.42-4.63(m，6H)，7.21-7.34(m，15H)； 13C-NMR(75MHz)：128.5，128.3，127.88，127.86，127.8，127.7，127.6，83.1，83.0，78.9，73.3，71.5，70.3，63.3，20.9.ESI-MS?m/z：499.2[M+Na] +.
Embodiment 7
1-O-ethanoyl-2, the preparation of 5-dehydration-D-sorbitol compound
With 1-O-ethanoyl-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol is a raw material, makes 1-O-ethanoyl-2,5-dehydration-D-sorbitol with reference to the method for embodiment 5. 1H?NMR(300MHz，d 6-DMSO)δppm：2.02(s，3H)，3.42-3.46(m，2H)，3.59-3.61(m，1H)，3.77-3.80(m，1H)，3.83-3.85(m，1H)，3.85-4.03(m，2H)，4.17-4.24(m，1H)，4.86-4.90(t，1H，J＝5.3Hz)，5.08-5.10(d，1H，J＝5.7Hz)，5.16-5.18(d，1H，J＝4.2Hz). 13C-NMR(75MHz，d 6-DMSO)：170.3，86.2，78.2，76.8，63.5，61.9，20.6.ESI-MS?m/z：240.9[M+Cl] -.
Embodiment 8
1-O-p-toluenesulfonyl-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound:
With 3,4 of 500mg, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved in the exsiccant 10mL pyridine, ice-water bath adds the 650mg Tosyl chloride down, and stirring at room adds 0.5mL water after 5 hours, continues reaction after 0.5 hour, reaction solution is poured in the frozen water, extract with methylene dichloride 30mL * 3, add in the 1N hydrochloric acid and reconcile, wash with water then to neutrality to acid, get dichloromethane layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=15: 1), get 1-O-p-toluenesulfonyl-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 630mg, yield: 93.0%. 1H?NMR(300MHz，CDCl 3)δppm：2.39(s，3H)，3.41-3.46(dd，J＝6.6Hz，10.0Hz，1H)，3.50-3.55(dd，J＝5.8Hz，10.0Hz，1H)，3.90-3.91(m，1H)，3.95-3.96(m，1H)，4.05-4.10(m，1H)，4.14-4.25(m，2H)，4.28-4.35(m，2H)，4.40-4.54(m，5H)，7.25-7.77(m，20H)； 13C?NMR(75MHz，CDCl 3)δppm：21.5，67.8，70.4，71.6，71.9，73.4，78.4，82.5，83.1，83.4，127.6，127.7，127.86，127.90，128.0，128.4，128.5，129.8，137.5，138.3，144.6；ESI-MS?m/z：611.2[M+Na] +.
Embodiment 9
1-azido--3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound:
1-O-p-toluenesulfonyl-3 with 500mg; 4; 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved among the DMF of exsiccant 7mL, and ice-water bath adds the 160mg sodium azide down; stir after 4 hours about 65 ℃; reaction solution is poured in the water, extracted, add the saturated common salt water washing at last with ether 30mL * 3; get ether layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=10: 1), get 1-azido--3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 347mg, yield: 89.0%. 1H?NMR(300MHz，CDCl 3)δppm：3.47-3.60(m，4H)，3.96-4.00(m，2H)，4.11-4.20(m，2H)，4.36-4.59(m，6H)，7.21-7.34(m，15H)； 13C?NMR(300MHz，CDCl 3)δppm：50.2，70.5，71.7，71.8，73.5，79.7，82.9，83.1，83.3，127.8，127.87，127.89，128.0，128.1，128.5，128.6，137.6，137.8，138.3；ESI-MS?m/z：460.2[M+H] +.
Embodiment 10
1-amido-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound
1-azido--3 with 400mg, 4,6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved in the exsiccant 15mL ether, add in the lithium aluminium hydride that is cooled under 0 ℃ 250mg in batches, return to room temperature and continue to stir 4 hours, add the excessive lithium aluminium hydride of sal glauberi cancellation then, filter, filter cake washs 30mL * 3, merging filtrate, evaporate to dryness with ether, rapid column chromatography (sherwood oil: ethyl acetate: ammoniacal liquor=100: 50: 1), get 1-amido-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 347mg, yield: 89.0%. 1H?NMR(300MHz，CDCl 3)δppm：2.90-2.95(m，2H)，3.47-3.60(ddd，J＝5.7Hz，J＝6.0Hz，J＝10.0Hz，2H)，3.90-4.07(m，3H)，4.30-4.56(m，6H)，7.19-7.30(m，15H)； 13C?NMR(300MHz，CDCl 3)δppm：41.5，70.6，71.55，71.65，73.4，82.30，82.35，83.4，83.8，127.64，127.68，127.78，127.81，127.9，128.35，128.45，128.50，137.8，137.9，138.2；ESI-MS?m/z：434.2[M+H] +.
Embodiment 11
1-acetylaminohydroxyphenylarsonic acid 3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound
With the 1-amido-3,4 of 150mg, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved in the 5mL pyridine, add the 0.1mL diacetyl oxide under ice-water bath, stirring at room is after 2 hours, concentrating under reduced pressure, rapid column chromatography (sherwood oil: ethyl acetate=4: 1), get 1-acetylaminohydroxyphenylarsonic acid 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 140mg, yield: 85.0%. 1H?NMR(300MHz，CDCl 3)δppm：1.85(s，3H)，3.33-3.39(m，1H)，3.53-3.62(m，2H)，3.73-3.79(m，1H)，3.94-3.96(m，2H)，4.04-4.12(m，2H)，4.48-4.59(m，6H)，5.88(br，s，1H)，4.96-4.98(d，J＝5.1Hz，1H)，5.09-5.11(d，J＝4.2Hz，1H)，7.92-7.96(m，1H)，7.24-7.34(m，15H)； 13C?NMR(75MHz，CDCl 3)δppm：23.2，39.3，70.4，71.7，73.4，79.2，82.5，83.2，83.4，127.70，127.74，127.8，127.9，128.0，128.4，128.5，128.6，137.5，137.7，138.0，170.0；ESI-MS?m/z：498.2[M+Na] +.
Embodiment 12
1-acetylaminohydroxyphenylarsonic acid 2, the preparation of 5-dehydration-D-sorbitol compound
With 1-acetylaminohydroxyphenylarsonic acid 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol is a raw material, makes 1-acetylaminohydroxyphenylarsonic acid 2,5-dehydration-D-sorbitol with reference to the method for embodiment 5. 1H?NMR(300MHz，d 6-DMSO)δppm：1.81(s，3H)，3.10-3.12(m，1H)，3.26-3.33(m，1H)，3.37-3.47(m，2H)，3.56-3.58(m，1H)，3.72-3.75(m，1H)，3.79-3.83(m，2H)，4.78-4.82(t，J＝5.4Hz，1H)，4.96-4.98(d，J＝5.1Hz，1H)，5.09-5.11(d，J＝4.2Hz，1H)，7.92-7.96(m，1H)； 13C?NMR(75MHz，d 6-DMSO)δppm：22.4，38.3，61.9，76.6，78.0，79.3，86.0，169.7；ESI-MS?m/z：228.1[M+Na] +.
Embodiment 13
1-Tri N-Propyl Amine base-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound
With the 1-O-p-toluenesulfonyl-3,4 of 300mg, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved among the DMF of 5mL, and the Tri N-Propyl Amine that adds 1mL refluxes and spends the night.Concentrating under reduced pressure is removed excessive Tri N-Propyl Amine then, reaction is poured in the water, extract with ether 20mL * 3, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate: ammoniacal liquor=150: 50: 1), get 1-Tri N-Propyl Amine base-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 157mg, yield: 65.0%. 1H?NMR(300MHz，CDCl 3)δppm：1.41-1.48(q，J＝7.3Hz，J＝14.6Hz，2H)，1.57(br，s，1H)，2.55-2.59(t，J＝7.3Hz，2H)，2.84-2.93(ddd，J＝5.0Hz，J＝7.7Hz，J＝12.3Hz，3H)，3.51-3.65(ddd，J＝5.7Hz，J＝6.0Hz，J＝9.9Hz，2H)，3.93-3.95(m，2H)，4.07-4.16(m，2H)，4.35-4.60(m，6H)，7.24-7.36(m，J＝3.2Hz，1H)，7.26-7.36(m，5H)； 13C?NMR(75MHz，CDCl 3)δppm：11.7，23.2，48.8，52.1，70.7，71.47，71.54，73.3，80.4，82.5，82.8，83.2，83.5，83.9，127.58，127.62，127.64，127.8，128.3，128.4，137.9，138.3；ESI-MS?m/z：476.3[M+H] +.
Embodiment 14
1-Tri N-Propyl Amine base-2, the preparation of 5-dehydration-D-sorbitol compound
With 1-Tri N-Propyl Amine base-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol is a raw material, makes 1-Tri N-Propyl Amine base-2,5-dehydration-D-sorbitol with reference to the method for embodiment 5. 1H?NMR(300MHz，CDCl 3)δppm：0.59(s，3H)，0.88(s，6H)，0.90(s，3H)，0.92(s，3H)，1.05(s，3H)，1.16(s，3H)，2.92(dd，J＝4.0Hz，14.1Hz，1H)，5.02-5.12(m，2H)，5.23(t，J＝3.2Hz，1H)，7.26-7.36(m，5H)； 13?CNMR(300MHz，CDCl 3)δppm：16.4，16.6，19.1，23.1，23.3，23.6，25.8，27.6，30.7，32.3，32.4，33.1，33.5，33.9，39.2，39.8，41.4，41.9，42.8，45.9，46.8，47.3，55.6，55.7，56.4，66.0，122.1，127.9，128.0，128.4，136.4，143.8，177.3，211.8；ESI-MS?m/z：206.1[M+K] +.
Embodiment 15
1-fluoro-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound.
With the 1-O-p-toluenesulfonyl-3,4 of 300mg, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved in the anhydrous tetrahydro furan of 5mL, and the tetrahydrofuran solution 2mL that adds the 1N tetrabutyl ammonium fluoride refluxes and spends the night.Concentrating under reduced pressure extracts with ether 20mL * 3 then, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=10: 1), get 1-fluoro-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol 140mg, yield: 62.0%. 1H?NMR(300MHz，CDCl 3)δppm：3.51-3.56(dd，J＝6.5Hz，10.0Hz，1H)，3.61-3.66(dd，J＝5.7Hz，10.0Hz，1H)，3.90-3.91(m，1H)，3.97-3.99(m，1H)，4.02-4.04(m，1H)，4.12-4.17(m，1H)，4.28-4.40(m，2H)，4.47-4.60(m，6H)，4.69-4.71(m，1H)，7.20-7.36(m，15H)； 13C?NMR(75MHz，CDCl 3)δppm：70.5，71.7，71.9，73.4，79.1，79.4，80.8，82.9，82.92，83.04，83.6，127.6，127.7，127.76，127.84，127.9，128.4，128.5，137.7，137.9，138.3；ESI-MS?m/z：459.1[M+Na] +.
Embodiment 16
1-fluoro-2,5-dehydration-D-sorbitol compound
With 1-fluoro-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol is a raw material, makes 1-fluoro-2,5-dehydration-D-sorbitol with reference to the method for embodiment 5. 1H?NMR(300MHz，D 2O)δppm：3.73-3.79(dd，J＝6.0Hz，12.1Hz，1H)，3.82-3.87(dd，J＝3.6Hz，12.1Hz，1H)，3.90-3.95(m，1H)，4.07-4.09(m，1H)，4.31-4.45(m，2H)，4.55-4.87(m，2H)； 13C?NMR(75MHz，D 2O)δppm：64.3，79.3，79.4，80.2，81.5，84.5，86.6，87.0；ESI-MS?m/z：167.1[M+H] +.
Embodiment 17
1-O-p-toluenesulfonyl-3-O-ethanoyl-4,6-O-dibenzoyl-2, the preparation of 5-dehydration-D-sorbitol compound
1-O-p-toluenesulfonyl-4 with 2.0g; 6-O-dibenzoyl-2; (preparation can be with reference to Azeez M.Mubarak and Daniel M.Brown.J.C.S.Perkin I.1982 for 5-dehydration-D-sorbitol; 809-813) be dissolved in the 25mL pyridine; the Benzoyl chloride that under ice-water bath, slowly adds 0.65mL, stirred overnight at room temperature.Concentrating under reduced pressure, rapid column chromatography (sherwood oil: ethyl acetate=10: 1), get 1-O-p-toluenesulfonyl-3-O-ethanoyl-4,6-O-dibenzoyl-2,5-dehydration-D-sorbitol compound 1.9g, yield: 89.0%. 1H?NMR(300MHz，CDCl 3)δppm：2.02(s，3H)，2.42(s，6H)，4.08-4.33(m，3H)，4.43-4.60(m，3H)，5.34-5.36(dd，J＝1.4Hz，3.4Hz，1H)，5.50-5.52(dd，J＝1.4Hz，3.9Hz，1H)，7.26-8.07(m，14H)； 13C?NMR(75MHz，CDCl 3)δppm：20.5，21.6，63.8，66.3，76.2，77.6，78.8，82.0，128.0，128.4，128.5，128.9，129.75，129.81，129.9，132.7，133.1，133.7，145.1，165.1，166.1，169.4；ESI-MS?m/z：591.1[M+Na] +.
Embodiment 18
3,4,6-O-tri-benzoyl-2, the preparation of 5-dehydration-D-N.F,USP MANNITOL compound
With the 1-O-trityl-2 of 2.0g, 5-dehydration-D-N.F,USP MANNITOL is dissolved in the 20mL exsiccant pyridine, adds the Benzoyl chloride of 2mL under ice bath.Stirred overnight at room temperature is poured reaction solution in the frozen water into, with methylene dichloride 60mL * 3 extractions, adds in the 1N hydrochloric acid and reconciles to acid, washes with water then to neutrality, gets dichloromethane layer, anhydrous Na 2SO 4Drying, evaporate to dryness adds 80% acetic acid aqueous solution then, and 50 ℃ were stirred 4 hours, with reacting liquid filtering, filtrate decompression concentrates after the cooling, adds saturated sodium bicarbonate solution, extracts with ethyl acetate 150mL * 3, add the saturated common salt water washing at last, get ethyl acetate layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=4: 1), get 3,4,6-O-tri-benzoyl-2,5-dehydration-D-N.F,USP MANNITOL 1.6g, yield: 67.0%. 1H?NMR(300MHz，CDCl 3)δppm：3.96-3.98(m，2H)，4.40-4.63(m，1H)，4.64-4.73(m，3H)，5.67-5.70(m，1H)，5.76-5.77(m，1H)，7.38-8.10(m，15H)； 13C?NMR(75MHz，CDCl 3)δppm：62.3，64.0，76.6，77.0，77.4，78.8，79.6，81.4，84.0，128.4，128.5，128.6，128.97，129.05，129.8，129.9，133.1，133.59，133.62，165.7，166.0，166.2；ESI-MS?m/z：499.2[M+Na] +.
Embodiment 19
1-acetyl mercapto-3-O-ethanoyl-4,6-O-dibenzoyl-2, the preparation of 5-dehydration-D-sorbitol compound
1-O-p-toluenesulfonyl-3-O-ethanoyl-4 with 1.5g; 6-O-dibenzoyl-2; 5-dehydration-D-sorbitol is dissolved among the exsiccant DMF; the thioacetic acid potassium that adds 600mg, 65 ℃ of nitrogen protections are stirred after 4 hours down, and reaction solution is poured in the frozen water; extract with ether 50mL * 3; add the saturated common salt water washing at last, get ether layer, anhydrous Na 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=15: 1), get 1-acetyl mercapto-3-O-ethanoyl-4,6-O-dibenzoyl-2,5-dehydration-D-sorbitol compound 848mg, yield: 68.0%. 1H?NMR(300MHz，CDCl 3)δppm：2.10(s，3H)，2.35(s，6H)，3.11-3.28(ddd，J＝6.5Hz，7.1Hz，13.7Hz，2H)，4.29-4.34(m，2H)，4.56-4.68(m，2H)，5.36-5.49(m，2H)，7.27-8.10(m，10H)； 13C?NMR(75MHz，CDCl 3)δppm：20.6，30.4，63.9，76.8，79.4，79.5，82.0，128.3，128.5，129.1，129.79，129.83，130.0，133.0，133.5，165.2，166.2，169.4，194.5ESI-MS?m/z：473.1[M+H] +.
Embodiment 20
1-sulfydryl-2, the preparation of 5-dehydration-D-sorbitol compound
With 1-acetyl mercapto-3-O-ethanoyl-4 of 300mg, 6-O-dibenzoyl-2,5-dehydration-D-sorbitol is dissolved in the 5mL exsiccant methyl alcohol, adds the sodium methylate of catalytic amount then, room temperature reaction 5 hours.Use strong cationic resin neutralization reaction liquid then, filter, resin methanol wash three times, merging filtrate.Evaporate to dryness, rapid column chromatography (methylene dichloride: methyl alcohol=10: 1), get 1-sulfydryl-2,5-dehydration-D-sorbitol 63mg, yield: 55.0%. 1H?NMR(300MHz，D 2O)δppm：2.84-2.91(dd，J＝8.0Hz，13.9Hz，1H)，2.98-3.05(dd，J＝5.4Hz，13.9Hz，1H)，3.59-3.71(m，2H)，3.77-3.81(m，1H)，3.98-4.00(m，1H)，4.07-4.08(m，1H)，4.28-4.30(m，1H)； 13C?NMR(75MHz，D 2O)δppm：39.6，64.3，79.7，80.9，82.2，87.7；ESI-MS?m/z：195.1[M-H] -.
Embodiment 21
3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-maltonic acid compound
With 3,4 of 1g, 6-O-tribenzyl-2,5-dehydration-D-sorbitol is dissolved among the 20mLDMF, and ice-water bath adds 4.3g pyridinium dichromate (PDC) down.Room temperature vigorous stirring 24 hours.Then reaction solution is poured in the frozen water, extracted anhydrous Na with ether 60mL * 3 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate: acetate=300: 100: 1), get 3,4,6-O-tribenzyl-2,5-dehydration-maltonic acid 774mg, yield: 55.0%.δppm：3.55-3.70(ddd，J＝4.1Hz，4.7Hz，10.1Hz，1H)，4.07-4.10(m，1H)，4.15-4.20(q，J＝5.6Hz，9.1Hz，1H)，4.35-4.38(q，J＝4.2Hz，6.1Hz，1H)，4.42-4.80(m，6H)，7.21-7.58(m，15H)； 13C?NMR(75MHz，CDCl 3)δppm：68.4，72.2，73.0，73.5，79.8，81.3，82.2，83.1，127.8，128.0，128.13，128.2，128.47，128.5，128.6，136.8，137.0，137.4，169.7；ESI-MS?m/z：471.2[M+Na] +.
Embodiment 22
2, the preparation of 5-dehydration-maltonic acid compound
With 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol is a raw material, makes 2,5-dehydration-maltonic acid with reference to the method for embodiment 5. 1H?NMR(300MHz，D 2O)δppm：3.65-3.74(m，2H)，3.88-3.93(m，1H)，4.02-4.03(m，1H)，4.20-4.32(dd，J＝1.9Hz，4.4Hz，1H)，4.64-4.67(m，1H)； 13C?NMR(75MHz，D 2O)δppm：64.1，80.0，80.2，83.3，88.6，175.8；ESI-MS?m/z：167.1[M+H] +.
Embodiment 23
3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-maltonic acid ethyl ester compound
With 3,4 of 224mg, 6-O-tribenzyl-2,5-dehydration-maltonic acid are dissolved in the ethanol of 4mL, add the sulfur oxychloride of 0.4mL under ice-water bath, stirred overnight at room temperature.Add saturated sodium bicarbonate solution then in the reaction solution and reconcile, use dichloromethane extraction (20mL * 3) then, anhydrous Na to neutral 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=15: 1), get 3,4,6-O-tribenzyl-2,5-dehydration-maltonic acid ethyl ester 160mg, yield: 67.2%. 1H?NMR(300MHz，CDC] 3)δppm：1.23(t，J＝7.1Hz，3H)，3.59-3.65(dd，J＝7.6Hz，9.8Hz，1H)，3.76-3.81(dd，J＝5.8Hz，9.8Hz，1H)，4.02(s，1H)，4.18-4.26(m，4H)，4.45-4.64(m，6H)，4.71-4.72(d，J＝4.8Hz，1H)，7.20-7.38(m，15H)； 13C?NMR(75MHz，CDCl 3)δppm：14.2，61.0，70.2，71.6，72.2，73.4，80.4，82.8，83.3，83.8，123.2，127.6，127.68，127.72，127.8，127.9，128.0，128.26，128.32，128.4，128.5，137.4，137.6，168.9；ESI-MS?m/z：485.2[M+Na] +.
Embodiment 24
2,5-dehydration-maltonic acid ethyl ester compound
With 3,4,6-O-tribenzyl-2,5-dehydration-maltonic acid ethyl ester is a raw material, makes 2,5-dehydration-maltonic acid ethyl ester with reference to the method for embodiment 5. 1H?NMR(300MHz，d 6-DMSO)δppm：1.16-1.21(t，J＝7.1Hz，3H)，3.49-3.54(m，2H)，3.68-3.73(m，1H)，3.83-3.86(m，1H)，4.03-4.13(m，3H)，4.45-4.47(m，1H)，4.87-4.90(t，J＝5.3Hz，1H)，5.27-5.28(d，J＝4.2Hz，1H)，5.39-5.41(d，J＝6.1Hz，1H)； 13C?NMR(75MHz，d 6-DMSO)δppm：14.1，59.8，61.7，77.2，77.9，80.2，86.6，169.3；ESI-MS?m/z：167.1[M+H] +.
Embodiment 25
N-n-propyl-3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-glucose acylamine compound
With 3,4 of 250mg, 6-O-tribenzyl-2,5-dehydration-maltonic acid are dissolved in the sulfur oxychloride of 4mL, reflux and stir after 3 hours.Concentrating under reduced pressure adds exsiccant 5mL methylene dichloride and Tri N-Propyl Amine (50 μ L) then in the reaction solution.After the stirring at room 1 hour, reaction solution with the dilution of 20mL methylene dichloride, is washed anhydrous Na with the NaOH solution of 1N, hydrochloric acid soln, water and the saturated common salt of 1N successively 2SO 4Drying, evaporate to dryness, rapid column chromatography (sherwood oil: ethyl acetate=5: 1), get N-n-propyl-3,4,6-O-tribenzyl-2,5-dehydration-D-glucose amide 169mg, yield: 60.0%. 1H?NMR(300MHz，CDCl 3)δppm：0.83(t，J＝7.4Hz，3H)，1.36-1.48(m，2H)3.11-3.20(m，2H)，3.55-3.67(m，2H)，3.91-3.92(m，1H)，4.12-4.19(m，1H)，4.29-4.31(m，1H)，4.40-4.63(m，7H)，6.80(br，s，1H)，7.23-7.35(m，15H)； 13C?NMR(75MHz，CDCl 3)δppm：11.3，22.8，40.6，69.8，71.7，72.8，73.4，81.2，82.77，82.82，127.75，127.83，127.86，127.89，128.3，128.47，128.48，137.54，137.8，168.6；ESI-MS?m/z：498.2[M+Na] +.
Embodiment 26
N-n-propyl-2, the preparation of 5-dehydration-D-glucose acylamine compound
With N-n-propyl-3,4,6-O-tribenzyl-2,5-dehydration-D-glucose amide is a raw material, makes N-n-propyl-2,5-dehydration-D-glucose amide with reference to the method for embodiment 5. 1H?NMR(300MHz，d 6-DMSO+D 2O)δppm：0.79-0.84(t，J＝7.4Hz，3H)，1.36-1.46(m，2H)，2.50-2.62(m，2H)，3.33-3.46(m，3H)，3.76-3.77(m，2H)，3.90-3.91(m，1H)； 13C?NMR(75MHz，d 6-DMSO)δppm：11.6，19.5，47.6，52.3，55.4，62.1，77.8，78.5，86.1；ESI-MS?m/z：218.1[M-H] -。

Claims (10)

1, following general formula (I) compound and pharmacy acceptable salt or ester:
General formula I
Wherein, R 1Represent hydrogen, general formula (I) is represented 2-deoxidation furans-D-fructose compounds; Work as R 1When representing α hydrogen, general formula (I) is 2,5-dehydration-D-sorbitol compounds; Work as R 1When representing β hydrogen, general formula (I) is 2,5-dehydration-D-N.F,USP MANNITOL compounds;
R 2The independent CH that represents 2X, CH 2OR 6, CH 2OCOR 6, COOR 6, CONHR 6, CON (R 6) 2, CH 2NHR 6, CH 2N (R 6) 2, CH 2NHCOR 6, CH 2SO 2NHR 6, CH 2NHOR 6Or CH 2NHNHR 6
R 3, R 4And R 5Independent respectively OH, the OR of representing 7, OCOR 7
R 6And R 7Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of 1～10 carbon respectively;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, N 3, CF 3, SH, OH, COOH, COOCH 3Or COOC 2H 5
2, according to the 2-deoxidation furans-D-fructose compounds of claim 1:
Wherein, R 1Represent hydrogen, general formula (I) is represented 2-deoxidation furans-D-fructose compounds; Work as R 1When representing α hydrogen, general formula (I) is 2,5-dehydration-D-sorbitol compounds; Work as R 1When representing β hydrogen, general formula (I) is 2,5-dehydration-D-N.F,USP MANNITOL compounds;
R 2The independent CH that represents 2X, CH 2OR 6, CH 2OCOR 6, COOR 6, CONHR 6, CON (R 6) 2, CH 2NHR 6, CH 2N (R 6) 2, CH 2NHCOR 6, CH 2SO 2NHR 6, CH 2NHOR 6Or CH 2NHNHR 6
R 3, R 4And R 5Independent respectively OH, OCOPh, the OBn of representing;
R 6Independent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of representing 1 ~ 10 carbon;
X represents H, F, Cl, Br, I, CN, NO 2, NH 2, N 3, CF 3, SH, OH, COOH, COOCH 3Or COOC 2H 5
3, its preferred compound of compound provided by the present invention is following arbitrary compound and medicinal salt or ester thereof:
1-fluoro-2,5-dehydration-D-sorbitol;
1-sulfydryl-2,5-dehydration-D-sorbitol;
1-O-methyl-2,5-dehydration-D-sorbitol;
1-O-trifluoromethyl-2,5-dehydration-D-sorbitol;
1-O-ethyl-2,5-dehydration-D-sorbitol;
1-O-n-propyl-2,5-dehydration-D-sorbitol;
1-O-sec.-propyl-2,5-dehydration-D-sorbitol;
1-O-normal-butyl-2,5-dehydration-D-sorbitol;
1-O-isobutyl--2,5-dehydration-D-sorbitol;
The 1-O-tertiary butyl-2,5-dehydration-D-sorbitol;
1-O-sec-butyl-2,5-dehydration-D-sorbitol;
1-trifluoromethyl amido-2,5-dehydration-D-sorbitol;
1-ethyl amido-2,5-dehydration-D-sorbitol;
1-n-propyl amido-2,5-dehydration-D-sorbitol;
1-sec.-propyl amido-2,5-dehydration-D-sorbitol;
1-normal-butyl amido-2,5-dehydration-D-sorbitol;
1-isobutyl-amido-2,5-dehydration-D-sorbitol;
1-tertiary butyl amido-2,5-dehydration-D-sorbitol;
1-(2-normal-butyl) amido-2,5-dehydration-D-sorbitol;
1-(N, N-dimethyl) amido-2,5-dehydration-D-sorbitol;
1-(N, N-diethyl) amido-2,5-dehydration-D-sorbitol;
1-(N-methyl-N-ethyl) amido-2,5-dehydration-D-sorbitol;
1-O-ethanoyl-2,5-dehydration-D-sorbitol;
1-O-trifluoroacetyl group-2,5-dehydration-D-sorbitol;
1-O-propionyl-2,5-dehydration-D-sorbitol;
1-O-positive butyryl radicals-2,5-dehydration-D-sorbitol;
1-O-isobutyryl-2,5-dehydration-D-sorbitol;
1-acyl amino-2,5-dehydration-D-sorbitol;
1-propionamido-2,5-dehydration-D-sorbitol;
1-positive butyrylamino-2,5-dehydration-D-sorbitol;
The different positive butyrylamino-2 of 1-, 5-dehydration-D-sorbitol;
2,5-dehydration-maltonic acid ethyl ester;
2,5-dehydration-maltonic acid trifluoro ethyl ester;
2,5-dehydration-maltonic acid n-propyl;
2,5-dehydration-maltonic acid isopropyl ester;
2, the positive butyl ester of 5-dehydration-maltonic acid;
2,5-dehydration-maltonic acid isobutyl ester;
2, the 5-dehydration-maltonic acid tert-butyl ester;
2, the secondary butyl ester of 5-dehydration-maltonic acid;
N-methyl-2,5-dehydration-D-glucose amide;
N-ethyl-2,5-dehydration-D-glucose amide;
N-trifluoroethyl-2,5-dehydration-D-glucose amide;
N, N-dimethyl-2,5-dehydration-D-glucose amide;
N, N-diethyl-2,5-dehydration-D-glucose amide;
N-methyl-N-ethyl-2,5-dehydration-D-glucose amide;
N-n-propyl-2,5-dehydration-D-glucose amide;
N-sec.-propyl-2,5-dehydration-D-glucose amide;
N-normal-butyl-2,5-dehydration-D-glucose amide;
N-isobutyl--2,5-dehydration-D-glucose amide;
The N-tertiary butyl-2,5-dehydration-D-glucose amide;
3,4,6-O-tri-benzoyl-2,5-dehydration-D-sorbitol;
3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol;
3,4,6-O-tribenzyl-2,5-dehydration-maltonic acid;
3,4,6-O-tri-benzoyl-2,5-dehydration-maltonic acid;
1-amido-3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol;
1-fluoro-2,5-dehydration-D-N.F,USP MANNITOL;
1-sulfydryl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-methyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-trifluoromethyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-ethyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-n-propyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-sec.-propyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-normal-butyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-isobutyl--2,5-dehydration-D-N.F,USP MANNITOL;
The 1-O-tertiary butyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-sec-butyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-trifluoromethyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-ethyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-n-propyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-sec.-propyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-normal-butyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-isobutyl-amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-tertiary butyl amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(2-normal-butyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(N, N-dimethyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(N, N-diethyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-(N-methyl-N-ethyl) amido-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-ethanoyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-trifluoroacetyl group-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-propionyl-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-positive butyryl radicals-2,5-dehydration-D-N.F,USP MANNITOL;
1-O-isobutyryl-2,5-dehydration-D-N.F,USP MANNITOL;
1-acyl amino-2,5-dehydration-D-N.F,USP MANNITOL;
1-propionamido-2,5-dehydration-D-N.F,USP MANNITOL;
1-positive butyrylamino-2,5-dehydration-D-N.F,USP MANNITOL;
The different positive butyrylamino-2 of 1-, 5-dehydration-D-N.F,USP MANNITOL;
2,5-anhydro-D-mannonic acid ethyl ester;
2,5-anhydro-D-mannonic acid trifluoro ethyl ester;
2,5-anhydro-D-mannonic acid n-propyl;
2, the positive butyl ester of 5-anhydro-D-mannonic acid;
2,5-anhydro-D-mannonic acid isobutyl ester;
2, the 5-anhydro-D-mannonic acid tert-butyl ester;
2, the secondary butyl ester of 5-anhydro-D-mannonic acid;
N-methyl-2,5-dehydration-D-seminose acid amides;
N-ethyl-2,5-dehydration-D-seminose acid amides;
N-trifluoroethyl-2,5-dehydration-D-seminose acid amides;
N, N-dimethyl-2,5-dehydration-D-seminose acid amides;
N, N-diethyl-2,5-dehydration-D-seminose acid amides;
N-methyl-N-ethyl-2,5-dehydration-D-seminose acid amides;
N-n-propyl-2,5-dehydration-D-seminose acid amides;
N-sec.-propyl-2,5-dehydration-D-seminose acid amides;
N-normal-butyl-2,5-dehydration-D-seminose acid amides;
N-isobutyl--2,5-dehydration-D-seminose acid amides;
The N-tertiary butyl-2,5-dehydration-D-seminose acid amides;
3,4,6-O-tri-benzoyl-2,5-dehydration-D-N.F,USP MANNITOL;
3,4,6-O-tribenzyl-2,5-anhydro-D-mannonic acid;
1-O-p-toluenesulfonyl-3,4,6-O-tri-benzoyl-2,5-dehydration-D-N.F,USP MANNITOL.
4, the preparation method of the compound of claim 1 comprises:
(1) 3,4,2 of 6-O-three acyl groups protection, the preparation of 5-dehydration-D-sorbitol compound:
Figure A2008102345410007C1
In the following formula, R 7Described as defined above; R 8Represent the primary hydroxyl protecting group.Selective protection method according to the primary hydroxyl of routine, 4,6-O-dibenzoyl-2,5-dehydration-D-sorbitol and various chlorosilane, bromo-silicane, triphenylmethyl chloride or replacement triphenylmethyl chloride react under base catalysis, obtain 4 of 1 hydroxyl protection, 6-O-dibenzoyl-2,5-dehydration-D-sorbitol; The alkali that is adopted comprises pyridine, triethylamine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, preferentially adopts pyridine.The solvent that is adopted comprises pyridine, methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential pyridine, 1,2-ethylene dichloride, toluene, N, dinethylformamide or the tetrahydrofuran (THF) of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 50 degree as temperature of reaction.
According to the hydroxy esterification method of routine, with various acyl chlorides, acid anhydrides or carboxylic acid reaction, obtain 3,4 of 1 hydroxyl protection more then, 6-O-three acyl groups-2,5-dehydration-D-sorbitol; According to the corresponding conventional method, under acidic conditions, slough the protecting group of primary hydroxyl in the following formula at last, obtain 3,4,2 of 6-O-three acyl groups protection, 5-dehydration-D-sorbitol compound.The acid of being adopted comprises formic acid, acetate, hydrochloric acid, sulfuric acid, tosic acid pyridinium salt.Preferential acetate and the tosic acid pyridinium salt of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.
(2) 3,4,2 of 6-O-three acyl groups protection, the preparation of 5-dehydration-D-N.F,USP MANNITOL compound:
Figure A2008102345410008C1
In the following formula, R 7Described as defined above.According to the hydroxy esterification method of routine, 1-O-trityl-2,5-dehydration-D-N.F,USP MANNITOL and various acyl chlorides or anhydride reaction obtain 3,4 of 1 hydroxyl protection, 6-O-three acyl groups-2,5-dehydration-D-N.F,USP MANNITOL; According to the corresponding conventional method, under acidic conditions, slough the protecting group of primary hydroxyl in the following formula at last, obtain 3,4,2 of 6-O-three acyl groups protection, 5-dehydration-D-sorbitol compound.The acid of being adopted comprises formic acid, acetate, hydrochloric acid, sulfuric acid, tosic acid pyridinium salt.Preferential acetate and the tosic acid pyridinium salt of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.
(3) 3,4,6-O-tribenzyl-2, the preparation of 5-dehydration-D-sorbitol compound:
Route one:
Figure A2008102345410008C2
Route two:
Figure A2008102345410009C1
In the following formula, R 8Described as defined above.In route one, 4 of 1 hydroxyl protection, 6-O-dibenzoyl-2,5-dehydration-D-sorbitol is under alkaline condition, and hydrolysis of ester group obtains 2 of 1 hydroxyl protection, 5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, and sodium ethylate, ammonia, sodium hydroxide or potassium hydroxide preferentially adopt sodium methylate.The solvent that is adopted comprises methyl alcohol, ethanol, acetonitrile and tetrahydrofuran (THF).Then then according to the method for routine with 3,4,6 hydroxyl and benzyl chloride or bromobenzyl react under alkaline condition, obtain 3,4 of 1 hydroxyl protection, 6-O-benzyl-2,5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, the dinethylformamide (DMF) of adopting.According to the method for sloughing 1 protecting group among the preparation method (1), obtain 3,4 then, 6-O-tribenzyl-2,5-dehydration-D-sorbitol.
In route two, 1,3-propylidene base-2,5-dehydration-D-sorbitol and benzyl chloride or bromobenzyl react under alkaline condition, obtain 1,3-propylidene base-O-4,6-dibenzyl-2,5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, the dinethylformamide (DMF) of adopting.Hydrolysis under acidic conditions then obtains 4, and 6-O-two-2,5-dehydration-D-sorbitol, and the acid of being adopted comprises formic acid, acetate, hydrochloric acid, sulfuric acid or tosic acid pyridinium salt.The preferential hydrochloric acid that adopts.React under alkaline condition with various chlorosilanes, bromo-silicane, triphenylmethyl chloride or replacement triphenylmethyl chloride then and obtain 4 of 1 hydroxyl protection, 6-dibenzyl-2,5-dehydration-D-sorbitol.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, the dinethylformamide (DMF) of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.According to the same method of route one, 4 of 1 hydroxyl protection, 6-dibenzyl-2,5-dehydration-D-sorbitol reacts under alkaline condition with benzyl chloride or bromobenzyl earlier, sloughs 1 protecting group then, obtains 3,4,6-O-tribenzyl-2,5-dehydration-D-sorbitol.
(4) preparation of 1-O-acyl group-2-deoxidation-D-fructofuranose compound:
Figure A2008102345410010C1
In the following formula, R 6Described as defined above.According to the hydroxy esterification method of routine, in the following formula 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound and various acyl chlorides, acid anhydrides or carboxylic acid reaction obtains 1-O-acyl group-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.Slough the method for benzyl then according to routine, obtain 1-O-acyl group-2-deoxidation-D-fructofuranose compound.The method of sloughing benzyl preferentially adopts palladium carbon catalysis normal pressure hydrogenation.
(5) preparation of 1-O-alkyl-2-deoxidation-D-fructofuranose compound:
Figure A2008102345410010C2
In the following formula, R 6Described as defined above.According to the method for the hydroxy alkylated of routine, in the following formula 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound reacts with highly basic earlier, adds various halogenated alkanes reactions then, obtains 1-O-alkyl-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, sodium ethylate, sodium hydride, hydrolith, sodium hydroxide or potassium hydroxide.The preferential sodium hydride that adopts.Slough the method for benzyl then according to routine, obtain 1-O-alkyl-2-deoxidation-D-fructofuranose compound.
(6) 1-amido-3,4, the preparation of 6-O-tribenzyl-2-deoxidation-D-fructofuranose compound:
Figure A2008102345410011C1
In the following formula, under base catalysis, 3; 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound and Tosyl chloride or benzene sulfonyl chloride reaction obtain 1-O-p-toluenesulfonyl-3; 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose, and then react with sodium azide; obtain 1-nitrine-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose; then under the effect of reductive agent; generate 1-amido-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose.Reductive agent adopts lithium aluminium hydride, palladium hydrocarbonize, sodium borohydride, POTASSIUM BOROHYDRIDE, Virahol/aluminum isopropylate, borine/tetrahydrofuran (THF) or borine/dimethyl sulphide, preferentially adopts lithium aluminium hydride.
(7) preparation of 1-acyl amino-2-deoxidation-D-fructofuranose compound:
In the following formula, R 6Described as defined above.According to the amido process for acylating of routine, 1-amido-3,4 in the following formula, 6-O-tribenzyl-2-deoxidation-D-fructofuranose compound and various acyl chlorides, acid anhydrides or carboxylic acid reaction obtains 1-acyl amino-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.Slough the method for benzyl then according to routine, obtain 1-acyl group ammonia-2-deoxidation-D-fructofuranose compound.The method of sloughing benzyl preferentially adopts palladium carbon catalysis normal pressure hydrogenation.
The preparation of (8) 2-deoxidation-D-fructofuranose acid compound:
Figure A2008102345410012C1
In the following formula, change into the carboxyl common method according to hydroxyl oxygen, with 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose and pyridinium dichromate (PDC) reaction generate 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose acid, slough the method for benzyl then according to routine, obtain 2-deoxidation-D-fructofuranose acid compound.
The preparation of (9) 2-deoxidation-D-fructofuranose ester compound:
Figure A2008102345410012C2
In the following formula, R 6Described as defined above.According to conventional carboxyalkyl esterification process, the 2-deoxidation in the following formula-D-fructofuranose acid with various halogenated alkane reactions, obtains 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose acid esters under thionyl chloride catalysis.Slough the method for benzyl then according to routine, obtain 2-deoxidation-D-fructofuranose ester compound.
The preparation of (10) 2-deoxidation-D-fructofuranose acid amide compound:
Figure A2008102345410013C1
In the following formula, R 6Described as defined above.Carboxyl according to routine becomes the acid amides method; 2-deoxidation in the following formula-D-fructofuranose acid elder generation generates acyl chlorides with acylating agent and reacts with kiber alkyl amine then, and the perhaps direct down and kiber alkyl amine reaction with amide condensed dose of catalysis obtains 3; 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose acid acid amides.Slough the method for benzyl then according to routine, obtain 2-deoxidation-D-fructofuranose acid amide compound.
(11) preparation of 1-sulfydryl-2-deoxidation-D-fructofuranose compound:
Figure A2008102345410013C2
In the following formula, R 7Described as defined above.Hydroxy esterification method according to routine; 1-O-tolysulfonyl-4 in the following formula; 6-O-dibenzoyl-2-deoxidation-D-fructofuranose compound and various acyl chlorides, acid anhydrides or carboxylic acid reaction obtains 1-O-p-toluenesulfonyl-3-O-acyl group-4,6-O-dibenzoyl-2-deoxidation-D-fructofuranose.Be that then the thioacetic acid nak response generates 1-acetyl mercapto-3-O-acyl group-4,6-O-dibenzoyl-2-deoxidation-D-fructofuranose is sloughed the acyl group protection at last under alkaline condition, obtain 1-sulfydryl-2-deoxidation-D-fructofuranose compound.The alkali that is adopted comprises salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium methylate, and sodium ethylate, ammonia, sodium hydroxide or potassium hydroxide preferentially adopt sodium methylate.
The preparation of (12) 1-fluoro-2-deoxidation-D-fructofuranose compound:
Route one:
Figure A2008102345410014C1
Route two:
In the following formula, R 7Described as defined above.In the route one; 3; 4; 6-O-three acyl groups-2-deoxidation-D-fructofuranose generates 1-O-tolysulfonyl-3 with Tosyl chloride under base catalysis; 4; 6-O-three acyl groups-2-deoxidation-D-fructofuranose; and then generate 1-fluoro-3 with the reaction of tetrabutyl fluoride amine or Potassium monofluoride; 4,6-O-three acyl groups-2-deoxidation-D-fructofuranose, 1-fluoro-3; 4; the preparation of 6-O-three acyl groups-2-deoxidation-D-fructofuranose can also be by 3,4, and 6-O-three acyl groups-2-deoxidation-D-fructofuranose and the reaction of diethylamino sulfur trifluoride obtain.Obtaining 1-fluoro-2-deoxidation-D-fructofuranose by basic hydrolysis then.In the route two, 3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose generates 1-O-tolysulfonyl-3 with Tosyl chloride under base catalysis, 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose, and then generate 1-fluoro-3 with the reaction of tetrabutyl fluoride amine or Potassium monofluoride, 4,6-O-tribenzyl-2-deoxidation-D-fructofuranose, 1-fluoro-3,4, the preparation of 6-O-tribenzyl-2-deoxidation-D-fructofuranose can also be by 3,4, and 6-O-tribenzyl-2-deoxidation-D-fructofuranose and the reaction of diethylamino sulfur trifluoride obtain.And then palladium carbon catalysis normal pressure hydrogenation is sloughed benzyl and is obtained 1-fluoro-2-deoxidation-D-fructofuranose.
(13) preparation of 1-alkylamino radical-2-deoxidation-D-fructofuranose compound:
Figure A2008102345410015C1
In the following formula, R 6Described as defined above.1-O-tolysulfonyl-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose and various primary amine reaction obtains 1-alkylamino-3,4,6-O-tribenzyl-2-deoxidation-D-fructofuranose compound.The solvent that is adopted comprises methylene dichloride, 1,2-ethylene dichloride, chloroform, toluene, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), acetonitrile, tetrahydrofuran (THF) or dioxane, perhaps with the optional mixed solvent of forming of these solvents, preferential N, dinethylformamide or the tetrahydrofuran (THF) of adopting.Temperature of reaction can be controlled in 0 degree to 150 degree, preferentially adopts room temperature to 100 degree as temperature of reaction.Slough the method for benzyl then according to routine, obtain 1-alkylamino-2-deoxidation-D-fructofuranose.
5, have and suppress and the medicinal preparations of kill tumor cell, it is characterized in that, its preparation active ingredient is made up of the derivative of the 2-deoxidation-D-fructofuranose shown in claim 1 formula of (I) or its salt and pharmaceutical carrier auxiliary material or thinner.
6, medicinal preparations according to claim 5 is characterized in that, described preparation is used for the treatment of cancer and relevant disease thereof.
7, medicinal preparations according to claim 5 is characterized in that, the content of its contained active principle is between 0.0001～200mg.
8, medicinal preparations according to claim 5 is characterized in that, its application method can be per os, intranasal, through skin, through modes such as lung, intramuscular injection or intravenous injections.
9, the medicinal preparations that is used for the treatment of cancer and relevant disease thereof according to claim 6 is characterized in that described effective dose is per kilogram of body weight medication every day 0.0001～200mg.
10, compound as claimed in claim 1 is characterized in that, the medicinal preparations of this compound can with tumor chemical therapy drug combination commonly used, be used for the treatment of cancer and relative disease thereof, can add one or more pharmaceutical carrier auxiliary material or thinners.
CNA2008102345415A 2008-11-21 2008-11-21 Novel 2-deoxidizedfructofuranose derivative, preparation method and medical uses thereof Pending CN101402619A (en)

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CN103193570A (en) * 2013-04-09 2013-07-10 湖北来凤腾升香料化工有限公司 High-selectivity protection method of hydroxy
CN103193570B (en) * 2013-04-09 2014-01-22 湖北来凤腾升香料化工有限公司 High-selectivity protection method of hydroxy
JP2017525659A (en) * 2014-06-13 2017-09-07 テレオス・スターチ・アンド・スウィートナーズ・ベルギーＴｅｒｅｏｓ Ｓｔａｒｃｈ ＆ Ｓｗｅｅｔｅｎｅｒｓ Ｂｅｌｇｉｕｍ Composition of monoalkyl ether of monoanhydro-hexitol, process for its production and use thereof
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