CN103421056A - Dioxane derivatives modified by glucosamine, preparation method and applications thereof - Google Patents

Dioxane derivatives modified by glucosamine, preparation method and applications thereof Download PDF

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CN103421056A
CN103421056A CN2012101543684A CN201210154368A CN103421056A CN 103421056 A CN103421056 A CN 103421056A CN 2012101543684 A CN2012101543684 A CN 2012101543684A CN 201210154368 A CN201210154368 A CN 201210154368A CN 103421056 A CN103421056 A CN 103421056A
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dioxane
glucosamine
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CN103421056B (en
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张建伟
彭师奇
赵明
曾莉
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Capital Medical University
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Abstract

The invention relates to dioxane derivatives modified by glucosamine, a preparation method and applications thereof, and specifically relates to dioxane derivatives, which are modified by glucosamine represented by the formula (I), or medically acceptable salts thereof, wherein the R1 is selected from H, benzyl, benzoyl, or alkanoyl with a carbon number of 1 to 10, the R2 is selected from H, alkyl with a carbon number of 1 to 10, alkanoyl with a carbon number of 1 to 10, aryl with a carbon number of 6 to 14, or heterocyclic radical with a carbon number of 5 to 14, the alkyl is optionally substituted by aryl with a carbon number of 6 to 14 or heterocyclic radical with a carbon number of 5 to 14. The invention also relates to a preparation method of a compound represented by the formula (I), a pharmaceutical composition containing the compound represented by the formula (I), and applications of the compound in preparing anti-inflammatory drugs.

Description

Glucosamine-modified 3-dioxane derivatives, Its Preparation Method And Use
Technical field
The present invention relates to a kind of glucosamine-modified 3-dioxane derivatives, their preparation method, the pharmaceutical composition that contains described compound and the above-claimed cpd purposes in preparation treatment anti-inflammatory drug.
Background technology
Antiphlogiston has two large classes: a class is the steroidal anti-inflammatory medicine, i.e. the secreted glucocorticosteroid hydrocortisone of adrenal cortex and the derivative of synthetic thereof.Another kind of is that the non-steroidal anti-inflammatory medicine is as acetylsalicylic acid, Phenylbutazone etc.
Its chemical nature of steroidal anti-inflammatory drugs is natural or the glucocorticosteroid of synthetic.Within 1949, at first the people such as Hench use cortisone treatment of arthritis, rheumatosis etc., though find that it has powerful anti-inflammatory action, its side effect is serious, especially, when heavy dose is applied, not only may produce dependency, and can cause the adrenal cortex function decline.Non-steroidal anti-inflammatory drugs more commonly used has anti-inflammatory or the effect characteristics of antipyretic-antalgic separately now, and alleviated mostly to a certain extent untoward reaction, but its side effect is still obviously, GI toxic reaction particularly, people wish to develop the medicine of the little anti-inflammatory of untoward reaction.
Dioxane is the class I non-steroid anti-inflammatory drug, as far back as Germany scientist Moellar in 1976, the people such as Hinrich (Ger.Offen DE 2526675) just propose to contain 1, and the application of 3-dioxanes compounds in makeup has and alleviate or the effect of inflammation-inhibiting.
American scientist Jiang, the people (PCT Int.Appl.WO9410161 1994) such as Jack B. have reported 1,3-dioxane-5-aminocompound and derivative thereof have the restraining effect of protein kinase C (PKC).It is effective to treatment tumour, reperfusion injury, heart ischemia/reperfusion injury and inflammation.
Studies have reported that recently, in the similar structures of pkc inhibitor, the propagation that 1,3-3-dioxane derivatives can be by suppressing mankind's neutrophil leucocyte and tumour cell and inflammation play the effect of anti-inflammatory, antitumor and protection ischemical reperfusion injury.This research is pointed out, 1,3-dioxane, and 1,, 3-dioxy seven rings, in 1,3-dioxy, eight rings, the activity of dioxane is best.
Aminosugar is distributed in organism widely.Glucosamine is prevailing aminosugar, usually with the N-acetylated form, exists, and is the natural constituents of glycoprotein, and the ability minimizing along with synthesizing amino glucose in the increase body at age, cause Senior osteoarthritis (McDevitt, C.A.; Muir, H.J.Bone Joint Surg.B 1976,58,94-101).Glucosamine sulphate and hydrochloride itself are a kind of medicines and nontoxic, can promote the repair of cartilage of damage.Since W.Bohne in 1969 report glucosamine can be as the relief from osteoarthritis medicine, glucosamine be subject to great concern (Kelly, G.Altern.Med.Rev.1998,3,27-29).Glucosamine has anti-oxidant and anti-inflammatory activity, and in the blocking-up of normal human's bone articular cartilage cell, NO produces.Amino acid not only has the side chain of structure diversity but also can improve the pharmacokinetics of compound, and amino acid whose introducing can increase water-soluble.The contriver recognizes, glucosamine and 1,3-dioxane compound is all the natural product with various active, by glucosamine and amino acid and 1, the coupling of 3-dioxane, to 1,3-dioxane structural modification, attempt to find new have 1 of better activity, the derivative of 3-dioxane.Should be extended to bioactive association from the association of structure.
Summary of the invention
On the one hand, the invention provides a kind of general formula (I) compound or its pharmacy acceptable salt:
Figure BDA00001649077500021
Wherein:
R 1Be selected from H, benzyl, benzoyl or C 1-10Alkyloyl, and
R 2Be selected from H, C 1-10Alkyl, C 1-10Alkoxyl group, C 6-14Aryl or C 5-14Heterocyclic radical, wherein said alkyl is optionally by C 6-14Aryl or C 5-14Heteroaryl replaces.
Preferably, R 1Be selected from hydrogen, benzyl or ethanoyl;
R 2Be selected from H or C 1-6Alkyl, wherein C 1-6Alkyl is optionally replaced by phenyl or indoles.
The preferred following compounds of the present invention or its pharmacy acceptable salt:
Figure BDA00001649077500022
On the other hand, the invention provides a kind of method for preparing general formula (I) compound, comprise the following steps:
1) take methylene dichloride under hydrochloric acid exists generates 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane by 1,1,3,3-tetramethoxy propane and 2，2-dimethyl-1，3-propanediol reaction as solvent;
2) chloro-5 at 2,3-bis-, under 6-dicyan-Isosorbide-5-Nitrae-benzene exists in the mixed solvent of acetonitrile and water; by 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl-1; the 3-dioxane is converted into the 2-aldehyde-base-5 of general formula (II), 5-dimethyl-1,3-dioxane;
3) glucosamine is carried out to selective protection, then with the coupling of tertiary fourth oxygen amic acid, obtain the compound of general formula (III);
4), by the 2-aldehyde-base-5 of general formula (II), the reaction of the compound of 5-dimethyl-1,3-dioxane and general formula (III) obtains the compound of general formula (I),
Figure BDA00001649077500032
R wherein 1And R 2As defined in general formula (I) compound.
Preferably, the amino acid in step 3) is selected from Ile, Phe, Val, Ala, Trp or Leu.R 1Be selected from hydrogen, benzyl or ethanoyl; R 2Be selected from H or C 1-6Alkyl, wherein C 1-6Alkyl is optionally replaced by phenyl or indoles.
Preferably; (2-(5 for the compounds of this invention 2-; 5-dimethyl-1; the 3-dioxane)-ethylamino acyl group)-glucosamine 11a-f, 15a-f, the preparation method of 16a-f; the method can be by following scheme 1, scheme 2 and scheme 3: comprise preparation 2-(2; 2-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane 3.Then by 3 hydrolysis, obtain 2-aldehyde-base-5,5-dimethyl-1,3-dioxane 4.At first prepare tertiary fourth oxygen amido glucose 6 by glucosamine, then through benzyl, prepare the tertiary fourth oxygen of 1,3,4,6-tetrabenzyl-2-amido glucose 7, remove tertiary fourth oxygen acyl protecting group and obtain 1,3,4,6-tetrabenzyl-2-glucosamine 8.Prepare 1,3,4,6-tetrem acyl-2-glucosamine sulphate 12 through acetylize.By 8,12 respectively with tertiary fourth oxygen amic acid (Boc-AA-OH) coupling, obtain the tertiary fourth oxygen of 1,3,4,6-tetrabenzyl-2-amido acyl amino glucose 9a-f, and 1,3,4,6-tetra-acetylated-the tertiary fourth oxygen of 2-amido acyl amino glucose 13a-f.Remove tertiary fourth oxygen acyl protecting group obtain 10a-f and 14a-f respectively with 4 couplings, obtain 1,3; 4; 6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane)-ethylamino acyl group)-glucosamine 11a-f; 1; 3,4,6-is tetra-acetylated-and (2-(5 for 2-; the 5-dimethyl-1,3-dioxane)-ethylamino acyl group)-glucosamine 15a-f.Finally, by 15a-f deprotection base, obtain 2-(2-(5,5-dimethyl-1,3-dioxane)-ethylamino acyl group)-glucosamine 16a-f.
Figure BDA00001649077500041
Scheme 1,2-aldehyde-base-5, the synthetic route of 5-dimethyl-1,3-dioxane 4
Figure BDA00001649077500042
Scheme 2,1,3,4, the synthetic route of 6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane)-ethylamino acyl group)-glucosamine 11a-f
Figure BDA00001649077500051
Scheme 3,2-(2-(5,5-dimethyl-1,3-dioxane)-ethylamino acyl group)-glucosamine 16a-f synthetic route
On the one hand, the invention provides the purposes of a kind of general formula (I) compound in preparing anti-inflammatory drug again.The mouse ear swelling model that the present invention induces by dimethylbenzene is estimated compound 11a-f of the present invention, 15a-f, the anti-inflammatory action of 16a-f.
Another aspect, the invention provides a kind of medicinal compositions, and it contains general formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier or the auxiliary material for the treatment of significant quantity.
General formula of the present invention (I) compound or its pharmacy acceptable salt can impose on people or other Mammalss by number of ways, comprise oral, injection (intravenous injection, intramuscular injection, endoperitoneal injection, subcutaneous injection etc. are similar) comprise the compounds of this invention and suitable pharmaceutically acceptable vehicle or the known in those skilled in the art various formulations of carrier.
The preferred modes of the compounds of this invention is oral.Preferably, these pharmacy goods are with dosage unit form independently.In this kind of form, goods are divided into the dosage device of suitable size, and the active compound that this unit comprises projected dose for example, is effectively measured for its purpose.
Unless the phase counter-statement is arranged, otherwise the following term be used in specification sheets and claims had following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, and the alkyl that contains 1 to 10 carbon atom more preferably contains the alkyl of 1 to 6 carbon atom.Non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-trimethylammonium propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl etc.
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely share and adjoin the right ring of carbon atom) group, many rings (being its ring with phase adjacency pair carbon atom) group with π-electron system of conjugation, be preferably 6 to 10 yuan, for example phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
Figure BDA00001649077500061
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Figure BDA00001649077500062
Embodiment
In order further to set forth the present invention, below provide a series of embodiment.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
The experimental technique of unreceipted actual conditions in the embodiment of the present invention, usually according to normal condition, or the condition of advising according to raw material or commodity manufacturer.The reagent in unreceipted concrete source is the conventional reagent of market purchase.
Preparation example 1 2-(2,2-dimethyl-ethyl)-5, the preparation of 5-dimethyl-1,3-dioxane 3
Take 1,1,3,3-tetramethoxy propane 2 (19.7g, 120mmol), the 100ml that adds methylene chloride stirs, add 2，2-dimethyl-1，3-propanediol 1 (3.12g, 30.0mmol), drip 6N hydrochloric acid 0.400ml, room temperature reaction 14 hours, again add 2，2-dimethyl-1，3-propanediol 1 (3.12g, 30.0mmol), room temperature vigorous stirring 10 hours.Add anhydrous sodium carbonate 16.0g, stir, filtration, the concentrated methylene dichloride of removing of filtrate decompression.The reaction mixture underpressure distillation, obtaining title compound 3 (8.00g, 39.2mmol) in the time of 135 ℃ is white solid, productive rate 65%.
ESIMS?m/z?227(M+Na);
1HNMR(300MHz,CDCl 3)δ4.56(t,J=6.0Hz,1H),4.52(t,J=5.4Hz,1H),3.60(d,J=11.1Hz,2H),3.43(d,J=10.8Hz,2H),3.33(s,3H),3.33(s,3H),1.97(t,J=5.7Hz,3H),1.19(s,3H),0.72(s,3H);
13CNMR(75MHz,CDCl 3)δ101.2,99.5,77.2,53.0,38.3,30.2,23.0,21.8。
Preparation example 2 2-aldehyde-bases-5, the preparation of 5-dimethyl-1,3-dioxane 4
Take 2-(2,2-dimethyl-ethyl)-5,5-dimethyl-1,3-dioxane 3 (19.7g, 120mmol), add acetonitrile 100ml, and 2,3-bis-is chloro-5,6-dicyan-para benzoquinone (DDQ) (198mg, 0.860mmol), distilled water 10.0ml.50 ℃ are stirred 2.5 hours, and prolong refluxes.Be chilled to room temperature, adding distil water 400ml, by dichloromethane extraction (100mL * 3), drying, filter, and concentrating under reduced pressure is removed methylene dichloride.(sherwood oil (30 ~ 60): ether=8:1), obtain title compound 4 (1.60g, 10.1mmol) is colourless liquid to column chromatographic isolation and purification, productive rate 51%.
ESIMS?m/z?227(M+Na);
1HNMR(300MHz,CDCl 3)δ9.82~9.81(m,1H),4.87(t,J=4.5Hz,1H),3.62(d,J=11.1Hz,2H),3.45(d,J=11.1Hz,2H),2.68(dd,J 1=2.4Hz,J 2=4.5Hz,2H),1.18(s,3H),0.73(s,3H);
13CNMR(75MHz,CDCl 3)δ199.5,97.8,77.1,48.3,30.0,22.8,21.7。
The preparation of the tertiary fourth oxygen of preparation example 3 amido glucose 6
Glucosamine hydrochloride (2.50g, 11.6mmol) is added to water 12.0ml, add the tert-Butyl dicarbonate (Boc be dissolved in dehydrated alcohol 12.0ml 2O) (4.00g, 18.4mmol), triethylamine (TEA) (1.80ml, 12.9mmol).40 ~ 41 ℃ of oil baths 1.5 hours.Under ice bath, stir about is 1.5 hours, filters, and with the cold ethanol of 25.0ml, washes, and the 50.0ml ether is washed, and obtains white fine powder shape solid, lyophilize.Obtaining title compound 6 (2.30g, 8.24mmol) is white solid.Productive rate 71%.
Preparation example 41, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-amido glucose 7
Add compound 6 (2.00g, 7.17mmol) in anhydrous DMF 40.0ml, add cylite (3.80ml, 30.1mmol) under ice bath, then add sodium hydride (1.20g, 50.0mmol), react 2.5 hours.Add cold water under ice bath, filter, cold wash (10mL * 2), normal hexane is washed (10mL * 2).Drying, filter, and is evaporated to dry.(sherwood oil: acetone=3:1) obtain title compound 7 (1.17g, 1.83mmol) is white solid to column chromatographic isolation and purification.Productive rate 26%.
Preparation example 51, the preparation of 3,4,6-tetrabenzyl-2-glucosamine 8
Under the ice bath cooling conditions, compound 7 (639mg, 1.00mmol) is dissolved in to methylene dichloride 2.00ml, adds trifluoroacetic acid 0.800ml, react 3 hours.Drain solvent.The resistates obtained dissolves, is placed in the 100ml separating funnel with the 50mL methylene dichloride, successively with saturated sodium bicarbonate aqueous solution wash (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3), for organic layer, anhydrous sodium sulfate drying, filtration, filtrate decompression are concentrated into dry.Obtaining title compound 8 (540mg, 1.00mmol) is colorless oil, productive rate 100%.
Preparation example 61, the preparation of 3,4,6-tetrem acyl-2-glucosamine sulphate 12
Take glucosamine hydrochloride (4.30g, 20.0mmol), add diacetyl oxide (15.0ml, 159mmol) under ice bath, slowly drip the vitriol oil (2.00ml, 22mmol), 30 ℃ of oil bath insulation reaction 24 hours.Drip ethanol 5.00ml under ice bath, separate out a large amount of white solids, filter, ethanol is washed, drying.Obtain title compound 12 (7.13g, 16.0mmol) white solid, productive rate 80%.
1HNMR(300MHz,CDCl 3)δ6.16(d,J=3.0Hz,1H),5.16(t,J=9.6Hz,1H),5.05(t,J=9.6Hz,1H),4.28(dd,J 1=4.8Hz,J 2=12.9Hz,1H),4.03(d,J=11.1Hz,2H),3.12(dd,J 1=3.0Hz,J 2=10.2Hz,1H),2.18(s,3H),2.10(s,3H),2.07(s,3H),2.03(s,3H)。
Preparation example 71, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-acyl isoleucyl-glucosamine 9a
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl Isoleucine (127mg with tetrahydrofuran (THF) 10.0ml, 0.55mmol), add successively N-hydroxybenzotriazole (HOBt) (80.0mg, 0.60mmol), dicyclohexyl carbonyl diimine (DCC) (124mg, 0.60mmol), react 20 minutes.Add the compound 8 (270mg, 0.500mmol) dissolved with tetrahydrofuran (THF) 10.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8.Room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained dissolves with the 150mL methylene dichloride, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for dichloromethane layer that merge are concentrated into dry; It is white solid that Shi You Mi – methylene dichloride recrystallization obtains title compound 9a (223mg, 0.297mmol), productive rate 59%.
[α] 25 D+36.9(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3315,1683,1654;
1HNMR(300MHz,CDCl 3):δ7.38~7.27(m,18H),7.14~7.12(m,2H),6.16(d,J=9.3Hz,1H),4.94(d,J=3.6Hz,2H),4.82~4.50(m,8H),4.36(dt,J 1=3.3Hz,J 2=9.3Hz,1H),3.95~3.67(m,6H),1.97~1.87(m,2H),1.45(s,9H),1.39~1.32(m,1H),0.86(d,J=6.9Hz,3H),0.78(t,J=7.5Hz,3H);
13CNMR(75MHz,CDCl 3):δ171.4,155.7,138.3,138.1,138.0,137.2,128.6,128.4,128.3,128.1,128.0,127.8,127.6,127.4,97.1,80.5,78.2,75.0,74.7,73.5,71.2,69.8,68.6,52.9,36.8,33.9,28.3,25.6,24.9,24.3,15.7,11.3;
ESIMS?m/z?753.4(M+1);
HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (753.4109); Measured value, m/z (753.3951).
Preparation example 81, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-acyl phenylalanyl glucosamine 9b
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl phenylalanine (146mg with tetrahydrofuran (THF) 10.0ml, 0.55mmol), add successively N-hydroxybenzotriazole (HOBt) (80.0mg, 0.60mmol), dicyclohexyl carbonyl diimine (DCC) (124mg, 0.60mmol), react 20 minutes.Add the compound 8 (270mg, 0.500mmol) dissolved with tetrahydrofuran (THF) 10.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8.Room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained dissolves with the 150mL methylene dichloride, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for dichloromethane layer that merge are concentrated into dry; It is white solid that sherwood oil methylene dichloride recrystallization obtains title compound 9b (130mg, 0.165mmol), productive rate 33%.
[α] 25 D+51.4(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3323,1687,1654;
1HNMR(500MHz,CDCl 3):δ7.38~7.14(m,26H),6.26(d,J=9.3Hz,1H),4.94(d,J=3.6Hz,2H),4.82~4.50(m,8H),4.36(dt,J 1=3.3Hz,J 2=9.3Hz,1H),3.95~3.67(m,6H),1.97~1.87(m,2H),1.45(s,9H),1.39~1.32(m,1H),0.86(d,J=6.9Hz,3H),0.78(t,J=7.5Hz,3H);
13CNMR(125MHz,CDCl 3):δ171.0,155.3,138.4,138.1,137.1,136.6,129.3,128.6,128.5,128.4,128.3,128.2,128.1,128.0,127.8,127.8,127.7,127.6,127.0,97.3,80.9,80.2,78.0,75.1,75.0,73.5,71.2,69.8,68.6,55.7,52.9,49.2,37.8,33.9,28.2,25.6,25.0;
ESIMS?m/z?787(M+1);
HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (787.3953); Measured value, m/z (787.3898).
Preparation example 91, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-acyl valyl glucosamine 9c
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl α-amino-isovaleric acid (119mg with tetrahydrofuran (THF) 10.0ml, 0.55mmol), add successively N-hydroxybenzotriazole (HOBt) (80.0mg, 0.60mmol), dicyclohexyl carbonyl diimine (DCC) (124mg, 0.60mmol), react 20 minutes.Add the compound 8 (270mg, 0.500mmol) dissolved with tetrahydrofuran (THF) 10.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8.Room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained dissolves with the 150mL methylene dichloride, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for dichloromethane layer that merge are concentrated into dry; It is white solid that Shi You Mi – methylene dichloride recrystallization obtains title compound 9c (177mg, 0.240mmol), productive rate 48%.
[α] 25 D+14.6(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3323,2929,1683;
1HNMR(300MHz,CDCl 3):δ7.39~7.27(m,18H),7.15~7.12(m,2H),6.10(d,J=9.3Hz,1H),4.94(d,J=3.6Hz,2H),4.82~4.50(m,8H),4.35(dt,J 1=3.3Hz,J2=9.6Hz,1H),3.92~3.66(m,6H),2.14~2.08(m,1H),1.98~1.94(m,1H),1.45(s,9H),0.89(d,J=6.9Hz,3H),0.76(d,J=6.6Hz,3H);
13CNMR (75MHz, CDCl 3): δ 171.5,155.7, and 138.3,138.1,138.0,137.1; 128.6,128.4,128.3,128.1,128.0,127.8; 127.6,127.5,97.2,80.5,78.3,77.2; 75.0,74.8,73.5,71.2,69.8,68.6; 60.2,52.9,49.3,33.9,30.6; 28.3,25.6,24.9,19.4,17.1; ESIMS m/z739 (M+1); HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (739.3953); Measured value, m/z (739.3868).
Preparation example 10 1, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-acyl alanyl glucosamine 9d
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl L-Ala (105mg with tetrahydrofuran (THF) 10.0ml, 0.55mmol), add successively N-hydroxybenzotriazole (HOBt) (80.0mg, 0.60mmol), dicyclohexyl carbonyl diimine (DCC) (124mg, 0.60mmol), react 20 minutes.Add the compound 8 (270mg, 0.500mmol) dissolved with tetrahydrofuran (THF) 10.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8.Room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained dissolves with the 150mL methylene dichloride, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for dichloromethane layer that merge are concentrated into dry; It is white solid that Shi You Mi – methylene dichloride recrystallization obtains title compound 9d (203mg, 0.286mmol), productive rate 57%.
[α] 25 D+54.4(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3331,3316,2929,1687,1658;
1HNMR(300MHz,CDCl 3):δ7.42~7.26(m,19H),7.18~7.15(m,2H),6.17(d,J=9.3Hz,1H),4.94(d,J=3.6Hz,2H),4.82~4.50(m,8H),4.35(dt,J 1=3.6Hz,J 2=9.6Hz,1H),4.09~4.04(m,1H),3.90~3.66(m,5H),1.44(s,9H),1.27(d,J=7.2Hz,3H);
13CNMR(75MHz,CDCl 3):δ172.2,155.3,138.4,138.1,138.0,137.2,128.6,128.4,128.3,128.1,128.0,127.8,127.7,127.6,97.2,81.0,80.0,78.2,77.2,75.1,75.0,73.5,71.3,69.8,68.6,52.9,50.4,49.2,33.9,30.6,28.3,25.6,24.9,18.4;
ESIMS?m/z?711(M+1);
HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (711.3640); Measured value, m/z (711.3533).
Preparation example 11 1, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-acyl tryptophyl glucosamine 9e
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl tryptophane (167mg with tetrahydrofuran (THF) 10.0ml, 0.55mmol), add successively N-hydroxybenzotriazole (HOBt) (80.0mg, 0.60mmol), dicyclohexyl carbonyl diimine (DCC) (124mg, 0.60mmol), react 20 minutes.Add the compound 8 (270mg, 0.500mmol) dissolved with tetrahydrofuran (THF) 10.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8.Room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained dissolves with the 150mL methylene dichloride, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for dichloromethane layer that merge are concentrated into dry; It is white solid that sherwood oil-methylene dichloride recrystallization obtains title compound 9e (295mg, 0.358mmol), productive rate 72%.
[α] 25 D+19.7(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3321,1687,1655;
1HNMR(300MHz,CDCl 3):δ7.65(d,J=7.5Hz,2H),7.37~6.95(m,24H),6.20(d,J=9.3Hz,1H),5.00(m,1H),4.77~4.41(m,8H),4.32(dt,J 1=3.6Hz,J 2=9.6Hz,1H),4.09(d,J=11.4Hz,1H),3.81~3.62(m,4H),3.36(dd,J 1=4.8Hz,J 2=14.4Hz,1H),3.14(dd,J 1=6.9Hz,J 2=14.7Hz,1H),1.38(s,9H);
13CNMR(75MHz,CDCl 3)δ171.6,155.3,138.6,138.1,137.2,136.2,128.4,128.3,128.0,127.9,127.8,127.7,127.6,127.5,123.1,122.4,119.8,119.0,111.2,110.5,97.4,80.8,80.1,77.9,77.2,75.0,74.6,73.5,71.1,69.8,68.6,52.9,33.8,28.2;
ESIMS?m/z?826(M+1);
HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (826.4062); Measured value, m/z (826.3886).
Preparation example 12 1, the preparation of the tertiary fourth oxygen of 3,4,6-tetrabenzyl-2-acyl leucylamino glucose 9f
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl leucine (127mg with tetrahydrofuran (THF) 10.0ml, 0.55mmol), add successively N-hydroxybenzotriazole (HOBt) (80.0mg, 0.60mmol), dicyclohexyl carbonyl diimine (DCC) (124mg, 0.60mmol), react 20 minutes.Add the compound 8 (270mg, 0.500mmol) dissolved with tetrahydrofuran (THF) 10.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8.Room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained dissolves with the 150mL methylene dichloride, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for dichloromethane layer that merge are concentrated into dry; It is white solid that Shi You Mi – methylene dichloride recrystallization obtains title compound 9f (244mg, 0.324mmol), productive rate 65%.
[α] 25 D+30.3(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3331,3319,2933,1687,1654;
1HNMR(300MHz,CDCl 3):δ7.40~7.26(m,18H),7.16~7.13(m,2H),6.27(d,J=9.3Hz,1H),4.94(d,J=3.6Hz,2H),4.82~4.50(m,8H),4.37(dt,J 1=3.6Hz,J 2=9.6Hz,1H),4.06(m,1H),3.91~3.74(m,4H),3.68(dd,J 1=1.5Hz,J 2=10.5Hz,1H),1.65~1.55(m,2H),1.44(s,9H),1.40~1.36(m,1H),0.86(d,J=6.0Hz,6H);
13CNMR(75MHz,CDCl 3)δ172.3,155.5,138.4,138.1,137.2,128.6,128.4,128.3,128.1,128.0,127.8,127.7,127.4,97.3,80.9,78.1,77.5,75.0,74.9,73.5,71.2,69.8,68.6,52.9,41.1,33.9,28.3,25.6,24.9,24.7,22.9,21.8;
ESIMS?m/z?753(M+1);
HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (753.4109); Measured value, m/z (753.3983).
Preparation example 13 1,3,4,6-is tetra-acetylated-preparation of the tertiary fourth oxygen of 2-acyl isoleucyl-glucosamine 13a
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl Isoleucine (462mg with tetrahydrofuran (THF) 20.0ml, 2.00mmol), add successively N-hydroxybenzotriazole (HOBt) (270mg, 2.00mmol), dicyclohexyl carbonyl diimine (DCC) (412mg, 2.00mmol), react 20 minutes.Add the compound 12 (890mg, 2.00mmol) dissolved with tetrahydrofuran (THF) 20.0ml, add N-methylmorpholine (NMM) 0.200ml adjust pH to 8.Room temperature reaction 24 hours.Filter, be evaporated to dry.The resistates obtained 150mL acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for ethyl acetate layer that merge are concentrated into dry; It is white solid that Shi You Mi – re-crystallizing in ethyl acetate obtains title compound 13a (624mg, 1.11mmol), productive rate 56%.
[α] 25 D+50.9(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3373,2945,1766,1687;
1HNMR(300MHz,CDCl 3):δ6.28(1H,d,J=9.0Hz,N-H),6.15(1H,d,J=3.6Hz,H-1),5.30(1H,t,J=9.6Hz,H-3),5.19(1H,t,J=9.6Hz,H-4),4.77(1H,d,J=6.9Hz,N-H),4.44(1H,td,J 1=9.6Hz,H-2),4.28(1H,dd,J 1=12.6Hz,J 2=4.4Hz,H-6),4.08-3.91(3H,m,H-6’,H-5,CH),2.22(3H,s,CH 3),2.09(3H,s,CH 3),2.04(3H,s,CH 3),2.02(3H,s,CH 3),1.59(2H,m,CH,CH 2),1.37(1H,m,CH 2),0.91(6H,d,CH 3);
13CNMR(75MHz,CDCl 3)δ172.6,171.2,170.7,169.2,168.6,155.6,90.3,80.3,70.3,69.6,67.6,61.6,53.3,50.9,40.7,28.3,24.8,22.6,22.2,20.9,20.7,20.6,20.6;
ESIMS?m/z?583(M+Na),645(M);
HRMS theoretical value: (C 25H 40N 3O 12+ 1), m/z (561.2654); Measured value, m/z (561.2766).
Preparation example 14 1,3,4,6-is tetra-acetylated-preparation of the tertiary fourth oxygen of 2-acyl phenylalanyl glucosamine 13b
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl phenylalanine (291mg with tetrahydrofuran (THF) 20.0ml, 1.10mmol), add successively N-hydroxybenzotriazole (HOBt) (148mg, 1.10mmol), dicyclohexyl carbonyl diimine (DCC) (227mg, 1.10mmol), react 20 minutes.Add the compound 12 (445mg, 1.00mmol) dissolved with tetrahydrofuran (THF) 20.0ml, add N-methylmorpholine (NMM) 0.100ml adjust pH to 8, room temperature reaction 24 hours.Filter, be evaporated to dry.The resistates obtained 150ml acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for ethyl acetate layer that merge are concentrated into dry; It is white solid that Shi You Mi – re-crystallizing in ethyl acetate obtains title compound 13b (186mg, 0.313mmol), productive rate 31%.
[α] 25 D+66.8(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3354,1743,1676,1028;
1HNMR(500MHz,CDCl 3):δ7.32-7.23(3H,m,Ph),7.16(2H,d,J=7.3Hz,Ph),6.30(1H,d,J=8.3Hz,N-H),6.15(1H,d,J=3.6Hz,H-1),5.20(2H,m,H-3,H-4),4.79(1H,d,J=5.3Hz,N-H),4.41(1H,m,CH),4.28(2H,m,CH,H-6),4.07(1H,dd,J 1=12.4Hz,J 2=1.7Hz,H-6’),3.98(1H,d,J＝9.0Hz,H-5),3.05(2H,d,J=6.6Hz,CH 2),2.14(3H,s,CH 3),2.10(3H,s,CH 3),2.04(3H,s,CH 3),1.91(3H,s,CH 3),1.42(9H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ171.6,171.3,170.6,169.1,168.5,155.4,136.2,129.2,128.8,127.0,90.3,80.5,70.1,69.6,67.7,61.6,55.7,51.2,37.5,28.3,20.9,20.7,20.6,20.5;
ESIMS?m/z?594(M);
HRMS theoretical value: (C 28H 38N 2O 12+ 1), m/z (595.2498); Measured value, m/z (595.2588).
Preparation example 15 1,3,4,6-is tetra-acetylated-preparation of the tertiary fourth oxygen of 2-acyl valyl glucosamine 13c
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl α-amino-isovaleric acid (2.33g with tetrahydrofuran (THF) 20.0ml, 10.0mmol), add successively N-hydroxybenzotriazole (HOBt) (14.8mg, 11.0mmol), dicyclohexyl carbonyl diimine (DCC) (2.27mg, 11.0mmol), react 20 minutes.Add the compound 12 (4.45mg, 10.0mmol) dissolved with tetrahydrofuran (THF) 20.0ml, add N-methylmorpholine (NMM) 2.00ml adjust pH to 8.Room temperature reaction 24 hours.Filter, be evaporated to dry.The resistates obtained 150ml acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (60mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (60mL * 3), 5% aqueous potassium hydrogen sulfate and wash (60mL * 3), saturated sodium-chloride water solution and wash that (60mL * 3), saturated sodium bicarbonate aqueous solution are washed (60mL * 3), saturated sodium-chloride water solution is washed (60mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for ethyl acetate layer that merge are concentrated into dry; It is white solid that Shi You Mi – re-crystallizing in ethyl acetate obtains title compound 13c (1.80g, 3.30mmol), productive rate 33%.
[α] 25 D+45.8(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3358,1747,1697;
1HNMR(500MHz,CDCl 3):δ6.18(1H,d,J=7.9Hz,N-H),6.17(1H,d,J=4.1Hz,H-1),5.31(1H,t,J=9.9Hz,H-3),5.20(1H,t,J=9.9Hz,H-4),4.93(1H,d,J=7.8Hz,N-H),4.45(1H,m,H-2),4.28(1H,dd,J 1=12.4Hz,J 2=4.1Hz,H-6),4.08(1H,dd,J 1=12.4Hz,J 2=2.05Hz,H-6’),4.02(1H,m,H-5),3.71(1H,t,J=7.4Hz,CH),2.21(3H,s,CH 3),2.09(3H,s,CH 3),2.05(3H,s,CH 3),2.04(1H,m,CH),2.03(3H,s,CH 3),1.43(9H,s,CH 3),0.90(3H,d,J=6.8Hz,CH 3),0.88(3H,d,J=6.8Hz,CH 3);
13CNMR(125MHz,CDCl 3)δ172.0,171.3,170.7,169.2,168.6,155.9,90.2,80.2,70.2,69.6,67.7,61.6,60.5,51.0,33.7,30.2,20.8,20.7,20.6,20.5;
ESIMS?m/z?547(M+1),569(M+Na);
HRMS theoretical value: (C 24H 38N 2O 12+ 1), m/z (547.2498); Measured value, m/z (547.2616).
Preparation example 16 1,3,4,6-is tetra-acetylated-preparation of the tertiary fourth oxygen of 2-acyl alanyl glucosamine 13d
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl L-Ala (1.89g with tetrahydrofuran (THF) 20.0ml, 10.0mmol), add successively N-hydroxybenzotriazole (HOBt) (13.5mg, 10.0mmol), dicyclohexyl carbonyl diimine (DCC) (2.06mg, 10.0mmol), react 20 minutes.Add the compound 12 (4.01mg, 9.01mmol) dissolved with tetrahydrofuran (THF) 20.0ml, add N-methylmorpholine (NMM) 2.00ml adjust pH to 8, room temperature reaction 24 hours.Filter, be evaporated to dry.The resistates obtained 150ml acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (60mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (60mL * 3), 5% aqueous potassium hydrogen sulfate and wash (60mL * 3), saturated sodium-chloride water solution and wash that (60mL * 3), saturated sodium bicarbonate aqueous solution are washed (60mL * 3), saturated sodium-chloride water solution is washed (60mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for ethyl acetate layer that merge are concentrated into dry; It is white solid that the petroleum ether-ethyl acetate recrystallization obtains title compound 13d (2.12g, 4.09mmol), productive rate 45%.
[α] 25 D+61.9(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3365,1751,1676;
1HNMR(500MHz,CDCl 3):δ6.28(1H,d,J=6.9Hz,N-H),6.16(1H,d,J=3.6Hz,H-1),5.29(1H,t,J=9.6Hz,H-3),5.20(1H,t,J=9.7Hz,H-4),4.91(1H,d,J=6.5Hz,N-H),4.45(1H,td,J 1=9.9Hz,J 2=3.7Hz,H-2),4.27(1H,dd,J 1=12.5Hz,J 2=4.2Hz,H-6),4.07(1H,dd,J 1=12.5Hz,J 2=2.3Hz,H-6’),4.02(2H,m,H-5,CH),2.21(3H,s,CH 3),2.09(3H,s,CH 3),2.05(3H,s,CH 3),2.04(3H,s,CH 3),1.44(9H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ172.8,171.3,170.7,169.1,168.6,155.4,90.4,80.3,70.5,69.7,67.6,61.6,51.0,50.2,28.3,20.9,20.7,20.6,20.5,18.1;
ESIMS?m/z?541(M+Na);
HRMS theoretical value: (C 22H 34N 2O 12+ 1), m/z (519.2185); Measured value, m/z (519.2313).
Preparation example 17 1,3,4,6-is tetra-acetylated-preparation of the tertiary fourth oxygen of 2-acyl tryptophyl glucosamine 13e
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl phenylalanine (790mg with tetrahydrofuran (THF) 20.0ml, 2.60mmol), add successively N-hydroxybenzotriazole (HOBt) (351mg, 2.60mmol), dicyclohexyl carbonyl diimine (DCC) (536mg, 2.60mmol), react 20 minutes.Add the compound 12 (1.16g, 2.60mmol) dissolved with tetrahydrofuran (THF) 20.0ml, add N-methylmorpholine (NMM) 1.00ml adjust pH to 8, room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained 150ml acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for ethyl acetate layer that merge are concentrated into dry; It is white solid that Shi You Mi – re-crystallizing in ethyl acetate obtains title compound 13e (891mg, 1.41mmol), productive rate 54%.
[α] 25 D+65.5(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3408,1751,1680,738;
1HNMR(300MHz,CDCl 3):δ8.27(1H,brs,N-H),7.63(1H,d,Ar-H),7.37(1H,d,J=7.8Hz,Ar-H),7.22(1H,t,=6.6Hz,Ar-H),7.16(1H,t,=6.9Hz,Ar-H),6.98(1H,d,J=2.1Hz,Ar-H),6.25(1H,d,J=8.4Hz,N-H),6.01(1H,d,J=3.0Hz,H-1),5.17(2H,m,H-3,H-4),4.97(1H,d,J=5.1Hz,N-H),4.45(2H,m,H-2,CH),4.25(1H,dd,J 1=12.6Hz,J 2=3.9Hz,H-6),4.05(1H,dd,J 1=12.6Hz,J 2=2.1Hz,H-6’),3.94(1H,m,H-5),3.32(1H,dd,J 1=14.7Hz,J 2=5.4Hz,CH 2),3.17(1H,dd,J 1=14.7Hz,J 2=6.3Hz,CH 2),2.09(3H,s,CH 3),2.02(3H,s,CH 3),1.98(3H,s,CH 3),1.90(3H,s,CH 3),1.43(9H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ172.2,171.4,170.7,169.2,168.9,155.5,136.1,127.4,123.4,122.4,120.0,118.4,111.3,109.9,90.3,80.4,70.0,69.6,67.6,61.5,55.4,51.1,28.3,27.5,20.9,20.7,20.6,20.5,20.4;
ESIMS?m/z?656(M+Na);
HRMS theoretical value: (C 30H 39N 3O 12+ 1), m/z (634.2607); Measured value, m/z (634.2608).
Preparation example 18 1,3,4,6-is tetra-acetylated-preparation of the tertiary fourth oxygen of 2-acyl leucylamino glucose 13f
Under the ice bath cooling conditions, dissolve tertiary fourth oxygen acyl leucine (3.81g with tetrahydrofuran (THF) 100ml, 16.5mmol), add successively N-hydroxybenzotriazole (HOBt) (2.23g, 16.5mmol), dicyclohexyl carbonyl diimine (DCC) (3.40mg, 16.5mmol), react 20 minutes.Add the compound 12 (6.67g, 15.0mmol) dissolved with tetrahydrofuran (THF) 20.0ml, add N-methylmorpholine (NMM) 3.00ml adjust pH to 8, room temperature reaction 15 hours.Filter, be evaporated to dry.The resistates obtained 150ml acetic acid ethyl dissolution, be placed in the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3); Anhydrous sodium sulfate drying, filtration, the filtrate decompression for ethyl acetate layer that merge are concentrated into dry; It is white solid that Shi You Mi – re-crystallizing in ethyl acetate obtains title compound 13f (3.24g, 5.79mmol), productive rate 39%.
[α] 25 D+49.5(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3365,2972,1751,1676;
1HNMR(300MHz,CDCl 3):δ6.29(1H,d,J=9.0Hz,N-H),6.15(1H,d,J=3.6Hz,H-1),5.23(1H,t,J=9.6Hz,H-3),5.19(1H,t,J=9.9Hz,H-4),4.78(1H,d,J=7.1Hz,N-H),4.43(1H,td,J 1=9.9Hz,J 2=3.6Hz,H-2),4.28(1H,dd,J 1=12.3Hz,J 2=3.6Hz,H-6),4.08-3.91(3H,m,H-6’,H-5,CH),2.22(3H,s,CH 3),2.09(3H,s,CH 3),2.04(3H,s,CH 3),2.03(3H,s,CH 3),1.60(2H,m,CH 2),1.42(9H,s,CH 3),1.38(1H,m,CH),0.91(6H,d,J=6.3Hz,CH 3);
13CNMR(75MHz,CDCl 3)δ172.6,171.2,170.7,169.2,168.7,155.6,90.3,80.3,70.3,69.6,67.6,61.6,53.3,50.9,40.7,28.3,24.8,22.6,22.2,20.9,20.7,20.6,20.5;
ESIMS?m/z?583(M+Na);
HRMS theoretical value: (C 25H 40N 2O 12+ 1), m/z (561.2654); Measured value, m/z (561.2763).
Embodiment 11, the preparation of 3,4,6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl isoleucyl-)-glucosamine 11a
Under the ice bath cooling conditions, compound 9a (104mg, 0.138mmol) is dissolved in 4N HCl/EtOAc (4.00ml), reacts 2 hours, and reaction is still muddy, adds 4N HCl/EtOAc (10.0ml), then reacts 2h, drains.Add methyl alcohol (5.00ml) and dissolve, add molecular sieve (76.0mg), compound 4 (40.0mg, 0.253mmol), after reacting 15 minutes, add NaBH 3CN (18.0mg, 0.286mmol), react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:1) obtain compound 11a (50.0mg, 0.0630mmol) is white solid to column chromatography, productive rate 46%.
[α] 25 D+47.1(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3302,1635,741,694;
1HNMR(300MHz,CDCl 3):δ7.60(1H,d,J=9.6Hz,N-H),7.38-7.13(20H,m,Ph),4.93(1H,d,J=3.6Hz,H-1),4.86-4.42(8H,m,CH 2),4.39(2H,m,H-2,CH),3.92(1H,m,H-5),3.81(4H,m,CH 2),3.53(2H,m,H-3,H-6),3.29(2H,m,H-4,H-6’),2.93(1H,d,J=3.6Hz,CH),2.54(2H,t,J=6.3Hz,CH 2),1.70(4H,m,N-H,CH,CH 2),1.39(2H,m,CH 2),1.16(1H,m,CH 2),1.14(3H,s,CH 3),0.93(3H,d,J=6.9Hz,CH 3),0.85(3H,t,J=7.5Hz,CH 3),0.67(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ173.6,138.6,138.2,138.1,137.2,128.5,128.4,128.3,128.2,128.0,127.9,127.7,127.6,127.5,127.2,127.1,101.1,97.4,81.0,78.3,77.2,74.9,74.5,73.5,71.3,69.6,68.7,68.2,52.5,51.1,44.9,44.8,38.0,34.0,30.0,25.7,25.0,24.6,23.0,21.8;
ESIMS?m/z?795(M+1);
HRMS theoretical value: (C 48H 63N 2O 8+ 1), m/z (795.4579); Measured value, m/z (795.4693).
Embodiment 21, the preparation of 3,4,6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethylbenzene alanyl)-glucosamine 11b
Under the ice bath cooling conditions, compound 9b (90.0mg, 0.114mmol) is dissolved in 4N HCl/EtOAc (4.00ml), reacts 2 hours, drains.Add methyl alcohol (5.00ml) and dissolve, add molecular sieve (35.0mg), compound 4 (18.0mg, 0.114mmol), after reacting 15 minutes, add NaBH 3CN (8.00mg, 0.127mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:1) obtain compound 11b (45.0mg, 0.0543mmol) is white solid to column chromatography, productive rate 47%.
[α] 25 D+28.6(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3309,1635,694;
1HNMR(300MHz,CDCl 3):δ7.64(1H,d,J=9.6Hz,N-H),7.41-7.13(25H,m,Ph),4.86(1H,d,J=3.9Hz,H-1),4.81-4.41(8H,m,CH 2),4.37(1H,m,H-2),4.16(1H,t,J=5.7Hz,CH),3.90(1H,m,H-5),3.92-3.70(4H,m,CH 2),3.40(2H,m,H-3,H-4),3.31(1H,dd,J 1=9.6Hz,J 2=3.6Hz,H-6),3.15(3H,m,CH,CH 2,H-6’),2.64(1H,dd,J 1=13.8Hz,J 2=9.6Hz,CH 2),2.47(2H,m,CH 2),1.56(3H,m,N-H,CH 2),1.04(3H,s,CH 3),0.62(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ173.7,138.6,138.2,138.1,137.7,137.3,129.2,128.8,128.5,128.4,128.3,128.0,127.9,127.8,127.7,127.6,127.3,127.1,126.8,100.7,97.4,81.2,78.3,76.9,74.9,74.7,73.5,71.3,69.6,68.7,64.1,52.4,43.9,39.5,34.4,29.9,22.9,21.8;
ESIMS?m/z?829(M+1);
HRMS theoretical value: (C 51H 61N 2O 8+ 1), m/z (829.4422); Measured value, m/z (829.4573).
Embodiment 31, the preparation of 3,4,6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl valyl)-glucosamine 11c
Under the ice bath cooling conditions, compound 9c (143mg, 0.194mmol) is dissolved in 4N HCl/EtOAc (40.0ml), reacts 8 hours, drains.Add methyl alcohol (5.00ml) and dissolve, add molecular sieve (58.0mg), compound 4 (31.0mg, 0.196mmol), after reacting 15 minutes, add NaBH 3CN (14.0g, 0.222mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:1) obtain compound 11c (50.0mg, 0.0642mmol) is white solid to column chromatography, productive rate 33%.
[α] 25 D+51.9(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3302,1635,740;
1HNMR(300MHz,CDCl 3):δ7.68(1H,d,J=9.6Hz,N-H),7.40-7.26(18H,m,Ph),7.15(2H,m,Ph),4.93(1H,d,J=3.6Hz,H-1),4.87-4.46(8H,m,CH 2),4.39(2H,m,H-3,CH),3.90(1H,m,H-5),3.79(4H,m,CH 2),3.53(2H,m,H-2,H-6),3.29(2H,m,H-4,H-6’),2.91(1H,d,J=3.6Hz,CH),2.55(1H,t,J＝6.3Hz,CH 2),2.16(1H,m,CH),1.71(3H,m,N-H,CH 2),1.15(3H,s,CH 3),0.98(3H,d,J=6.9Hz,CH 3),0.83(3H,d,J=6.9Hz,CH 3),0.67(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ173.6,138.6,138.2,137.1,128.6,128.5,128.4,128.3,128.1,128.0,127.9,127.7,127.6,127.3,127.1,127.0,101.1,97.5,81.0,78.4,77.0,74.9,74.6,73.5,71.3,69.6,68.7,68.6,52.5,44.8,34.5,34.0,31.1,30.0,23.0,21.8,19.8,17.3;
ESIMS?m/z?781(M+1);
HRMS theoretical value: (C 47H 61N 2O 8+ 1), m/z (781.4422); Measured value, m/z (781.4555).
Embodiment 41, the preparation of 3,4,6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl alanyl)-glucosamine 11d
Under the ice bath cooling conditions, compound 9d (170mg, 0.239mmol) is dissolved in 4N HCl/EtOAc (4.00ml), reacts 2 hours, drains.Add methyl alcohol (5.00ml) and dissolve, add molecular sieve (72.0mg), compound 4 (38.0mg, 0.241mmol), after reacting 15 minutes, add NaBH 3CN (17.0mg, 0.270mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:1) obtain compound 11d (98.0mg, 0.130mmol) is white solid to column chromatography, productive rate 54%.
[α] 25 D+48.0(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3287,1634,694;
1HNMR(300MHz,CDCl 3):δ7.56(1H,d,J=9.6Hz,N-H),7.39-7.16(20H,m,Ph),4.92(1H,d,J=3.3Hz,H-1),4.88-4.53(8H,m,CH 2),4.44(1H,t,J=4.5Hz,CH),4.35(1H,t,J=9.9Hz,H-2),3.95(1H,m,H-5),3.83(4H,m,CH 2),3.56(2H,m,H-3,H-4),3.34(2H,m,H-6,H-6’),3.21(1H,q,J=6.9Hz,CH),2.65(2H,m,CH 2),1.76(2H,dd,J=5.7Hz,CH 2),1.28(3H,d,J=6.9Hz,CH 3),1.16(3H,s,CH 3),0.69(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ174.3,138.6,138.2,137.2,128.5,128.4,128.3,128.0,127.9,127.8,127.7,127.6,127.4,127.3,100.8,97.0,81.1,78.4,77.1,75.0,74.8,73.5,71.3,69.4,68.7,58.3,52.5,43.6,34.3,30.0,23.0,21.8,19.4;
ESIMS?m/z?753(M+1);
HRMS theoretical value: (C 45H 57N 2O 8+ 1), m/z (753.4109); Measured value, m/z (753.4251).
Embodiment 51, the preparation of 3,4,6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl tryptophyl)-glucosamine 11e
Under the ice bath cooling conditions, compound 9e (263mg, 0.319mmol) is dissolved in 4N HCl/EtOAc (40.0ml), and reaction 8h, drain.Add methyl alcohol (5.00ml) and dissolve, add molecular sieve (96.0mg), compound 4 (51.0mg, 0.323mmol), after reacting 15 minutes, add NaBH 3CN (23.0mg, 0.365mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:1) obtain compound 11e (125mg, 0.144mmol) is white solid to column chromatography, productive rate 45%.
[α] 25 D+29.9(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3310,1659,741;
1HNMR(300MHz,CDCl 3):δ8.22(1H,brs,N-H),7.70(2H,m,Ar-H),7.41-7.04(23H,m,Ar-H),4.85-4.52(7H,m,CH 2),4.72(1H,d,J=3.6Hz,H-1),4.40(1H,t,J=9.9Hz,H-2),4.23(1H,d,J=11.7Hz,CH 2),4.11(1H,t,J=4.8Hz,CH),3.87(1H,m,H-5),3.76(4H,dd,J=10.5Hz,CH 2),3.48-3.25(4H,m,H-3,H-6,H-6’,CH),3.01(3H,m,CH 2,H-4),2.52(2H,m,CH 2),1.57(2H,m,CH 2),1.01(3H,s,CH 3),0.58(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ174.3,138.6,138.2,138.1,137.3,136.4,128.4,128.3,128.2,127.9,127.8,127.7,127.6,127.3,127.2,122.9,122.3,119.7,111.7,111.2,100.5,97.5,81.2,78.3,76.8,76.7,74.9,74.7,73.5,71.2,69.7,68.7,63.6,52.4,43.9,34.6,29.8,29.1,22.8,21.7;
ESIMS?m/z?868(M+1);
HRMS theoretical value: (C 53H 62N 3O 8+ 1), m/z (868.4531); Measured value, m/z (868.4657).
Embodiment 61, the preparation of 3,4,6-tetrabenzyl-2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl leucyl)-glucosamine 11f
Under the ice bath cooling conditions, compound 9f (98.3mg, 0.131mmol) is dissolved in 4N HCl/EtOAc (14.00ml), reacts 4 hours, drains.Add methyl alcohol (5.00ml) and dissolve, add molecular sieve (80.0mg), compound 4 (60.0mg, 0.380mmol), after reacting 15 minutes, add NaBH 3CN (40.0mg, 0.634mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:1) obtain compound 11f (50.0mg, 0.0630mmol) is white solid to column chromatography, productive rate 48%.
[α] 25 D+46.4(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3302,1636,694;
1HNMR(300MHz,CDCl 3):δ7.66(1H,d,J=9.9Hz,N-H),7.38-7.13(20H,m,Ph),4.91(1H,d,J=3.6Hz,H-1),4.87-4.50(8H,m,CH 2),4.34(2H,m,CH,H-3),3.92(1H,m,H-5),3.82(4H,m,CH 2),3.54(2H,m,H-2,H-4),3.31(1H,dd,J 1=11.1Hz,J 2=5.4Hz,H-6),3.30(1H,t,J＝5.7Hz,CH),3.06(1H,dd,J 1=11.4Hz,J 2=3.6Hz,H-6’),2.56(2H,t,J＝6.3Hz,CH 2),1.67(5H,m,N-H,CH 2),1.33(1H,m,CH),1.15(3H,s,CH 3),0.95(3H,d,J＝7.2Hz,CH 3),0.93(3H,d,J＝6.9Hz,CH 3),0.68(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ175.1,138.6,138.2,137.3,128.5,128.4,128.3,128.2,128.0,127.9,127.8,127.7,127.6,127.3,127.0,101.2,97.0,81.0,78.3,77.2,77.1,74.9,74.5,73.5,71.2,69.4,68.7,61.8,52.4,44.1,42.8,34.6,30.0,25.1,23.5,22.9,21.8,21.6;
ESIMS?m/z?795(M+1);
HRMS theoretical value: (C 48H 63N 2O 8+ 1), m/z (795.4579); Measured value, m/z (795.4705).
Embodiment 71, and 3,4,6-is tetra-acetylated-preparation of 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl isoleucyl-)-glucosamine 15a
Under the ice bath cooling conditions, compound 13a (383mg, 0.684mmol) is dissolved in 4N HCl/EtOAc (10.0ml), reacts 2 hours, drains.Add methyl alcohol (10.0ml) and dissolve, add molecular sieve (206mg), compound 4 (108mg, 0.684mmol), after reacting 15 minutes, add NaBH 3CN (43.0mg, 0.684mmol), then react 1.5 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:2) obtain compound 15a (290mg, 0.482mmol) is white solid to column chromatography, productive rate 70%.
[α] 25 D+47.0(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 2962,1743,1226;
1HNMR(300MHz,CDCl 3):δ7.55(1H,d,J=8.7Hz,N-H),6.19(1H,d,J=3.6Hz,H-1),5.34(1H,t,J=9.1Hz,H-3),5.18(1H,t,J=9.9Hz,H-4),4.51(1H,t,J=3.5Hz,CH),4.40(1H,m,H-2),4.26(1H,dd,J 1=12.3Hz,J 2=3.6Hz,H-6),4.06(1H,dd,J 1=12.3Hz,J 2=2.1Hz,H-6’),3.99(1H,m,H-5),3.59(2H,d,J=10.8Hz,CH 2),3.41(2H,d,J=10.8Hz,CH 2),2.89(1H,d,J=4.2Hz,CH),2.59(1H,m,CH 2),2.47(1H,m,CH 2),2.15(3H,s,CH 3),2.08(3H,s,CH 3),2.04(3H,s,CH 3),2.01(3H,s,CH 3),1.81(2H,m,CH 2),1.72(1H,m,CH),1.30(1H,m,CH 2),1.17(3H,s,CH 3),1.09(1H,m,CH?CH 2),0.87(3H,d,J=6.9Hz,CH 3),0.82(3H,d,J=7.2Hz,CH 3),0.72(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ174.0,170.9,170.7,169.2,168.6,101.5,90.2,77.2,77.0,70.1,69.6,67.9,67.8,61.6,50.6,44.7,38.1,34.3,30.1,24.7,23.0,21.8,20.7,20.6,20.5,15.8,11.7;
ESIMS?m/z?603(M+1);
HRMS theoretical value: (C 28H 46N 2O 12+ 1), m/z (603.3123); Measured value, m/z (603.3219).
Embodiment 81, and 3,4,6-is tetra-acetylated-preparation of 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethylbenzene alanyl)-glucosamine 15b
Under the ice bath cooling conditions, compound 13b (224mg, 0.377mmol) is dissolved in 4N HCl/EtOAc (10.0ml), reacts 2 hours, drains.Add methyl alcohol (8.00ml) and dissolve, add molecular sieve (120mg), compound 4 (63.0mg, 0.399mmol), after reacting 15 minutes, add NaBH 3CN (24.0mg, 0.381mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:2) obtain compound 15b (188mg, 0.296mmol) is white solid to column chromatography, productive rate 79%.
[α] 25 D+24.0(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 1751,1226;
1HNMR(500MHz,CDCl 3):δ7.54(1H,d,J=8.1Hz,N-H),7.32-7.16(5H,m,Ph),6.20(1H,d,J=3.6Hz,H-1),5.33(1H,t,J=10.0Hz,H-3),5.21(1H,t,J=10.0Hz,H-4),4.43(1H,m,H-2),4.28(1H,dd,J 1=12.4Hz,J 2=4.1Hz,H-6),4.26(1H,t,J＝4.0Hz,CH),4.09(1H,dd,J 1=12.4Hz,J 2=2.2Hz,H-6’),4.04(1H,dt,J 1=10.0Hz,J 2=2.4Hz,H-5),3.45(2H,d,J=11.1Hz,CH 2),3.28(2H,d,J=11.1Hz,CH 2),3.25(1H,t,J＝11.2Hz,CH),3,14(1H,dd,J 1=13.8Hz,J 2=3.05Hz,CH 2),2.54(1H,m,CH 2),2.46(2H,m,CH 2),2.18(3H,s,CH 3),2.11(3H,s,CH 3),2.05(3H,s,CH 3),2.02(3H,s,CH 3),1.69(3H,m,N-H,CH 2),1.05(3H,s,CH 3),0.68(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ174.3,170.8,170.7,169.2,168.6,137.3,129.0,128.8,128.7,126.9,101.1,90.5,77.0,70.2,69.7,67.9,63.9,61.6,50.7,43.9,39.4,34.1,30.0,22.9,21.8,20.9,20.7,20.6,20.5;
ESIMS?m/z?637(M+1);
HRMS theoretical value: (C 31H 45N 2O 12+ 1), m/z (637.2967); Measured value, m/z (637.3076).
Embodiment 91, and 3,4,6-is tetra-acetylated-preparation of 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl valyl)-glucosamine 15c
Under the ice bath cooling conditions, compound 13c (546mg, 1.00mmol) is dissolved in 4N HCl/EtOAc (10.0ml), reacts 2 hours, drains.Add methyl alcohol (20.0ml) and dissolve, add molecular sieve (300mg), compound 4 (158mg, 1.00mmol), after reacting 15 minutes, add NaBH 3CN (63.0mg, 1.00mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:2) obtain compound 15c (390mg, 0.663mmol) is white solid to column chromatography, productive rate 66%.
[α] 25 D+47.7(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3340,1743;
1HNMR(500MHz,CDCl 3):δ7.55(1H,d,J=7.4Hz,N-H),6.20(1H,d,J=3.6Hz,H-1),5.35(1H,t,J=10.0Hz,H-3),5.19(1H,t,J=10.0Hz,H-4),4.53(1H,t,J=4.5Hz,CH),4.42(1H,m,H-2),4.27(1H,dd,J 1=12.5Hz,J 2=4.0Hz,H-6),4.07(1H,dd,J 1=12.5Hz,J 2=1.9Hz,H-6’),4.02(1H,m,H-5),3.60(2H,d,J=10.9Hz,CH 2),3.43(2H,d,J=10.9Hz,CH 2),2.84(1H,s,CH),2.54(2H,m,CH 2),2.16(3H,s,CH 3),2.09(3H,s,CH 3),2.04(3H,s,CH 3),2.02(3H,s,CH 3),1.82(2H,m,CH 2),1.73(1H,m,CH),1.18(3H,s,CH 3),0.94(3H,d,J=7.0Hz,CH 3),0.79(3H,d,J=7.0Hz,CH 3),0.73(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ174.2,170.9,170.7,169.2,168.6,101.5,90.4,77.2,77.1,70.1,69.7,68.4,67.9,61.6,50.6,44.7,34.3,31.2,30.1,29.7,23.0,21.8,20.8,20.7,20.6,19.5,17.3;
ESIMS?m/z?589(M+1);
HRMS theoretical value: (C 27H 45N 2O 12+ 1), m/z (589.2967); Measured value, m/z (589.3048).
Embodiment 10 1, and 3,4,6-is tetra-acetylated-preparation of 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl alanyl)-glucosamine 15d
Under the ice bath cooling conditions, compound 13d (1.04g, 2.00mmol) is dissolved in 4N HCl/EtOAc (20.0ml), reacts 2 hours, drains.Add methyl alcohol (20.0ml) and dissolve, add molecular sieve (600mg), compound 4 (316mg, 2.00mmol), after reacting 15 minutes, add NaBH 3CN (126mg, 2.00mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:2) obtain compound 15d (556mg, 0.993mmol) is white solid to column chromatography, productive rate 50%.
[α] 25 D+48.9(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3340,1743;
1HNMR(300MHz,CDCl 3):δ7.48(1H,d,J=9.0Hz,N-H),6.21(1H,d,J=3.6Hz,H-1),5.32(1H,t,J=9.5Hz,H-3),5.18(1H,t,J=9.9Hz,H-4),4.51(1H,t,J=4.5Hz,CH),4.39(1H,m,H-2),4.26(1H,dd,J 1=12.3Hz,J 2=4.2Hz,H-6),4.07(1H,dd,J 1=12.3Hz,J 2=2.1Hz,H-6’),4.01(1H,m,H-5),3.59(2H,d,J=10.8Hz,CH 2),3.41(2H,d,J=10.8Hz,CH 2),3.10(1H,q,J=6.9Hz,CH),2.67(1H,m,CH 2),2.49(1H,m,CH 2),2.16(3H,s,CH 3),2.18(3H,s,CH 3),2.09(3H,s,CH 3),2.04(3H,s,CH 3),2.02(3H,s,CH 3),1.80(2H,m,CH 2),1.20(3H,d,J=6.9Hz,CH 3),1.17(3H,s,CH 3),0.72(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ175.5,170.9,170.6,169.2,168.6,101.2,90.4,77.2,77.1,70.1,69.8,68.4,67.9,61.6,58.2,50.6,43.7,34.4,30.0,22.9,21.8,20.8,20.7,20.5,19.7;
ESIMS?m/z?561(M+1);
HRMS theoretical value: (C 25H 41N 2O 12+ 1), m/z (561.2654); Measured value, m/z (561.2765).
Embodiment 11 1, and 3,4,6-is tetra-acetylated-preparation of 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl tryptophyl)-glucosamine 15e
Under the ice bath cooling conditions, compound 13e (695mg, 1.10mmol) is dissolved in 4N HCl/EtOAc (20.0ml), reacts 2 hours, drains.Add methyl alcohol (20.0ml) and dissolve, add molecular sieve (330mg), compound 4 (174mg, 1.10mmol), after reacting 15 minutes, add NaBH 3CN (69.0mg, 1.10mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:2) obtain compound 15e (376mg, 0.557mmol) is white solid to column chromatography, productive rate 51%.
[α] 25 D+31.8(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 1751,1227;
1HNMR(300MHz,CDCl 3):δ8.23(1H,brs,N-H),7.61(2H,m,Ar-H,N-H),7.37(1H,d,J=7.8Hz,Ar-H),7.20(1H,t,J=6.9Hz,Ar-H),7.15(1H,t,J=7.8Hz,Ar-H),7.00(1H,d,J=1.2Hz,Ar-H),6.15(1H,d,J=3.6Hz,H-1),5.33(1H,t,J=9.6Hz,H-3),5.21(1H,t,J=9.6Hz,H-4),4.46(1H,td,J 1=9.6Hz,J 2=3.6Hz,H-2),4.30(1H,dd,J 1=12.8Hz,J 2=4.2Hz,H-6),4.19(1H,t,J＝4.5Hz,CH),4.09(1H,dd,J 1=12.3Hz,J 2=2.1Hz,H-6’),4.03(1H,m,H-5),3.36(3H,m,CH,CH 2),3.25(1H,dd,J 1=14.7Hz,J 2=3.6Hz,CH 2),3.13(1H,dd,J 1=15.3Hz,J 2=8.1Hz,CH 2),2.85(1H,dd,J 1=14.7Hz,J 2=5.7Hz,CH 2),2.51(1H,m,CH 2),2.11(3H,s,CH 3),2.09(3H,s,CH 3),2.04(3H,s,CH 3),2.01(3H,s,CH 3),1.81(1H,m,N-H),1.66(2H,m,CH 2),1.01(3H,s,CH 3),0.63(3H,s,CH 3);
13CNMR(75MHz,CDCl 3)δ174.7,170.8,170.7,169.3,168.8,136.3,127.6,122.9,122.2,119.7,118.6,111.3,100.8,90.5,76.9,76.8,70.1,69.7,67.9,63.5,61.6,50.6,43.9,34.3,29.9,28.9,22.8,21.7,20.8,20.7,20.6;
ESIMS?m/z?676(M+1);
HRMS theoretical value: (C 33H 46N 3O 12+ 1), m/z (676.3067); Measured value, m/z (637.3189).
Embodiment 12 1, and 3,4,6-is tetra-acetylated-preparation of 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl leucyl)-glucosamine 15f
Under the ice bath cooling conditions, compound 13f (560mg, 1.00mmol) is dissolved in 4N HCl/EtOAc (10.0ml), reacts 2 hours, drains.Add methyl alcohol (20.0ml) and dissolve, add molecular sieve (300mg), compound 4 (158mg, 1.00mmol), after reacting 15 minutes, add NaBH 3CN (63.0mg, 1.00mmol), then react 2 hours.The filtering molecular sieve, remove methyl alcohol under reduced pressure, adds EtOAc (10.0ml), the filtering insolubles, and saturated NaCl washes (30mL * 3), and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dry.(sherwood oil: ethyl acetate=1:2) obtain compound 15f (262mg, 0.436mmol) is white solid to column chromatography, productive rate 44%.
[α] 25 D+41.6(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 2962,1743;
1HNMR(300MHz,CDCl 3):δ7.51(1H,d,J=7.8Hz,N-H),6.21(1H,d,J=3.6Hz,H-1),5.32(1H,t,J=9.9Hz,H-3),5.18(1H,t,J=9.6Hz,H-4),4.51(1H,t,J=4.5Hz,CH),4.38(1H,m,H-2),4.26(1H,dd,J 1=12.3Hz,J 2=3.9Hz,H-6),4.06(1H,dd,J 1=12.3Hz,J 2=2.1Hz,H-6’),4.03(1H,m,H-5),3.58(2H,d,J=11.1Hz,CH 2),3.40(2H,d,J=10.8Hz,CH 2),3.04(1H,m,CH),2.61(1H,m,CH 2),2.46(1H,m,CH 2),2.17(3H,s,CH 3),2.08(3H,s,CH 3),2.03(3H,s,CH 3),2.01(3H,s,CH 3),1.64(1H,m,CH),1.62(1H,m,CH 2),1.46(1H,m,CH 2),1.24(1H,m,CH),1.16(3H,s,CH 3),0.91(3H,d,J=4.5Hz,CH 3),0.89(3H,d,J=4.8Hz,CH 3),0.72(3H,s,CH 3);
13CNMR (75MHz, CDCl 3) δ 175.4,170.9,170.6,169.2,168.6,101.5,90.3,77.2,77.0,70.1,69.7,67.9,61.6,61.5,50.6,44.1,42.8,34.3,30.0,24.9,23.2,22.9,21.7,20.8,20.7,20.5; ESIMS m/z 603 (M+1); HRMS theoretical value: (C 28H 46N 2O 12+ 1), m/z (603.3124); Measured value, m/z (603.3231).
The preparation of embodiment 13 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl isoleucyl-)-glucosamine 16a
Under the ice bath cooling conditions, compound 15a (100mg, 0.166mmol) is dissolved in methyl alcohol (10.0ml), adds CH 3ONa (50.0mg, 0.926mmol), react 4 hours.Add HCl/EA adjust pH to 7, be evaporated to dryly, the methylene chloride-methanol thin-layer chromatography obtains compound 16a (37.0mg, 0.0853mmol), productive rate 51%.
[α] 25 D+28.0(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3368,2959,1655;
1HNMR(500MHz,CDCl 3):δ7.84(1H,brs,N-H),5.23(1H,s,H-1),4.70(1H,m,H-3),4.59(1H,m,CH),3.96-3.73(3H,m,H-2,H-4,H-5),3.61(3H,m,H-6,CH 2),3.49(3H,m,H-6’,CH 2),3.17(1H,m,CH),2.82(2H,m,CH 2),1.89(3H,m,CH,CH 2),1.51(1H,m,CH 2),1.24(1H,m,CH 2),1.18(3H,s,CH 3),0.95(6H,m,CH 3),0.73(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ178.6,101.3,91.5,76.2,74.0,71.2,71.0,67.2,54.1,53.4,43.7,37.2,33.4,30.1,29.7,25.2,23.8,23.1,21.8;
ESIMS?m/z?435(M+1);
HRMS theoretical value: (C 20H 39N 2O 8+ 1), m/z (435.2701); Measured value, m/z (435.2771).
The preparation of embodiment 14 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethylbenzene alanyl)-glucosamine 16b
Under the ice bath cooling conditions, compound 15b (100mg, 0.157mmol) is dissolved in methyl alcohol (10.0ml), adds CH 3ONa (50.0mg, 0.926mmol), react 4 hours.Add HCl/EtOAc adjust pH to 7, be evaporated to dryly, the methylene chloride-methanol thin-layer chromatography obtains compound 16b (34.0mg, 0.0726mmol), productive rate 46%.
[α] 25 D-11.6(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3314,1678,1543,733;
1HNMR(500MHz,CDCl 3):δ7.34-7.09(5H,m,Ph),5.32(1H,s,H-1),4.51(1H,m,CH),4.38(1H,m,H-5),4.28(2H,m,H-2,H-3),4.08(1H,m,CH),3.77(2H,m,H-4,H-6),3.64(1H,m,H6’),3.53(2H,m,CH 2),3.37(2H,m,CH 2),3.18(2H,m,CH 2),3.06(1H,m,CH 2),2.73(1H,m,CH 2),2.06(2H,m,CH 2),1.07(3H,s,CH 3),0.68(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ175.1,135.5,129.4,129.0,127.2,117.8,98.3,77.2,76.8,74.5,71.0,65.8,63.0,53.4,53.1,38.0,34.7,31.9,29.9,22.9,21.6;
ESIMS?m/z?469(M+1);
HRMS theoretical value: (C 23H 37N 2O 8+ 1), m/z (469.2544); Measured value, m/z (469.2560).
The preparation of embodiment 14 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl valyl)-glucosamine 16c
Under the ice bath cooling conditions, compound 15c (100mg, 0.170mmol) is dissolved in methyl alcohol (10.0ml), adds CH 3ONa (50.0mg, 0.926mmol), react 4 hours.Add HCl/EtOAc adjust pH to 7, be evaporated to dryly, the methylene chloride-methanol thin-layer chromatography obtains compound 16c (30.0mg, 0.0714mmol), productive rate 42%.
[α] 25 D+43.0(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3302,2924,1655;
1HNMR(500MHz,CDCl 3):δ7.74(1H,brs,N-H),5.21(1H,s,H-1),4.58(1H,s,CH),3.94-3.79(4H,m,H-2,H-3,H-5,CH),3.72(1H,dd,J 1=14.0Hz,J 2=7.0Hz,H-6),3.61-3.44(6H,m,H-4,H-6,CH 2),2.94(1H,brs,N-H),2.73(2H,m,CH 2),2.02(1H,m,CH),1.85(2H,m,CH 2),1.17(3H,s,CH 3),0.96(3H,d,J＝5.5Hz,CH 3),0.89(3H,d,J＝6.5Hz,CH 3),0.73(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ175.0,101.5,91.4,77.1,76.9,71.8,71.7,68.6,65.9,61.4,58.3,43.9,34.1,30.9,30.1,23.1,21.8,19.5,18.1;
ESIMS?m/z?419(M-1),420(M);
HRMS theoretical value: (C 19H 37N 2O 8+ 1), m/z (421.2544); Measured value, m/z (421.2597).
The preparation of embodiment 15 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl alanyl)-glucosamine 16d
Under the ice bath cooling conditions, compound 15d (100mg, 0.179mmol) is dissolved in methyl alcohol (10.0ml), adds CH 3ONa (50.0mg, 0.926mmol), react 4 hours.Add HCl/EtOAc adjust pH to 7, be evaporated to dryly, the methylene chloride-methanol thin-layer chromatography obtains compound 16d (34.0mg, 0.0868mmol), productive rate 49%.
[α] 25 D+0.545(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3302,2924,1655;
1HNMR(500MHz,CDCl 3):δ5.32(1H,s,H-1),5.21-4.75(3H,m,OH),4.60(1H,s,CH),4.41(2H,m,H-3,H-5),4.06(1H,m?H-2),3.74(2H,m,H-6,CH),3.61(2H,m,CH 2),3.42(2H,m,CH 2),2.97(1H,m,H-6’),2.61(2H,m,CH 2),2.20(1H,brs,N-H),2.02(2H,m,CH 2),1.17(3H,s,CH 3),1.13(3H,s,CH 3),0.74(3H,s,CH 3),0.73(3H,d,J＝7.5Hz,CH 3);
13CNMR(125MHz,CDCl 3)δ176.0,99.6,98.3,77.1,76.9,74.5,71.0,62.8,53.4,38.4,34.3,30.2,23.0,21.8,21.7;
ESIMS?m/z?393(M+1);
HRMS theoretical value: (C 17H 32N 2O 8+ 1), m/z (393.2231); Measured value, m/z (393.2290).
The preparation of embodiment 16 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl tryptophyl)-glucosamine 16e
Under the ice bath cooling conditions, compound 15e (100mg, 0.148mmol) is dissolved in methyl alcohol (10.0ml), adds CH 3ONa (50.0mg, 0.926mmol), react 4 hours.Add HCl/EtOAc adjust pH to 7, be evaporated to dryly, the methylene chloride-methanol thin-layer chromatography obtains compound 16e (31.0mg, 0.0611mmol), productive rate 41%.
[α] 25 D-3.14(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3279,1654,744;
1HNMR(500MHz,CDCl 3):δ10.94(1H,s,N-H),7.63(1H,d,J＝8.5Hz,N-H),7.56(1H,d,J＝8.0Hz,Ar-H),7.36(1H,d,J＝8.0Hz,Ar-H),7.23(1H,s,Ar-H),7.08(1H,t,J＝7.5Hz,Ar-H),6.99(1H,t,J＝7.5Hz,Ar-H),4.94(1H,d,J＝3.0Hz,H-1),4.17(1H,t,J＝5.0Hz,CH)3.65(2H,m,CH 2),3.51(2H,m,CH 2),3.43(1H,m,H-5),3.32(2H,m,H-3,CH),3.29(1H,m?H-6),3.19(2H,m,H-2),3.09(3H,m,H-4,H-6’,CH 2),2.74(1H,dd,J 1=14.0Hz,J 2=9.0Hz,CH 2),2.59(1H,m,CH 2),2.39(1H,m,CH 2),1.53(2H,m,CH 2),0.94(3H,s,CH 3),0.59(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ174.1,136.8,127.8,124.4,121.4,118.8,118.7,111.9,110.8,100.5,91.2,76.3,76.2,72.7,71.6,71.5,63.2,61.5,54.3,43.4,34.5,30.0,29.5,23.1,21.8;
ESIMS?m/z?508(M+1);
HRMS theoretical value: (C 25H 38N 3O 8+ 1), m/z (508.2653); Measured value, m/z (508.2732).
The preparation of embodiment 17 2-(2-(5,5-dimethyl-1,3-dioxane-2-yl)-ethyl leucyl)-glucosamine 16f
Under the ice bath cooling conditions, compound 15f (100mg, 0.166mmol) is dissolved in methyl alcohol (10.0ml), adds CH 3ONa (50.0mg, 0.926mmol), react 4 hours.Add HCl/EtOAc adjust pH to 7, be evaporated to dryly, the methylene chloride-methanol thin-layer chromatography obtains compound 16f (28.0mg, 0.0645mmol), productive rate 39%.
[α] 25 D-6.33(c?0.1,CHCl 3);
IR (cm -1, KBr, pressed disc method): 3321,2959,1643;
1HNMR(500MHz,CDCl 3):δ7.24(1H,s,N-H),5.24(1H,s,H-1),4.61(1H,m,CH),4.42(1H,m,H-3),3.85(3H,m?H-2,H-5,H-6),3.63(3H,m,H-6’,CH 2),3.47(3H,m,H-4,CH 2),2.85(2H,m,CH 2),2.22(1H,m,CH 2),1.90(2H,m,CH 2),1.68(1H,m,CH 2),1.61(1H,m,CH),1.47(1H,m,CH),1.16(3H,s,CH 3),0.91(3H,d,J＝7.0Hz,CH 3)0.90(3H,d,J＝7.0Hz,CH 3)0.72(3H,s,CH 3);
13CNMR(125MHz,CDCl 3)δ167.3,101.2,98.2,77.2,76.9,74.5,71.8,60.9,52.6,43.1,41.4,35.2,30.1,28.1,24.8,23.0,22.8,21.8,21.7;
ESIMS?m/z?435(M+1);
HRMS theoretical value: (C 20H 39N 2O 8+ 1), m/z (435.2701); Measured value, m/z (435.2767).
Experimental example 1 mouse ear dimethylbenzene inflammatory model experiment
Compound of the present invention is all with the preparation of the distilled water containing 0.5%CMCNa, dosage is 10 μ mol/kg, and administering mode is oral, the positive contrast of acetylsalicylic acid (Jinghuayaobang Medical Science & Technology Co., Ltd., Beijing), dosage is 555 μ mol/kg, and administering mode is oral.
Select the ICR male mice (Beijing Vital River Experimental Animals Technology Co., Ltd.) of 21 ± 3g; be divided at random 24 groups; every group 12; 24 groups are respectively CMCNa, acetylsalicylic acid, 4,1,3,4; 6-is tetra-acetylated-2-glucosamine 12,1; 3,4,6-tetrabenzyl-2-glucosamine 8,2-glucosamine 5,11a, 11b, 11c, 11d, 11e, 11f, 15a, 15b, 15c, 15d, 15e, 15f, 16a, 16b, 16c, 16d, 16e, 15f.Give respectively every group of mouse stomach administration 0.2ml.After 30 minutes, capture mouse one side, expose left ear, with liquid-transfering gun, draw 30 μ l dimethylbenzene, smear evenly along interior auricle.Put to death after 2 hours, cut the left and right ear, with pounding the sheet apparatus, two ears are pounded into to disk of a size.Weigh, calculate the interaural difference value.Anti-inflammatory inhibiting rate %=(1-interaural difference/auris dextra weight) %.
It is active that the mouse ear inflammation that table 1 dimethylbenzene is induced suppresses
Figure BDA00001649077500261
Trial compound oral dosage=10 μ mol/kg, aspirin dose=555 μ mol/kg; N=12.
A compares p<0.01 with blank group (CMCNa);
B compares p<0.01 with blank group (CMCNa), with compound 5 (2-glucosamine) group, compares p<0.05.
The anti-inflammatory activity of experimental example 2 compound 16a and the relation of dosage
Animal experiment method is with experimental example 1, and test-compound 16a is respectively by 10 μ mol/kg, and the dosed administration of 1 μ mol/kg and 0.1 μ mol/kg, all adopt the gavage single-dose.Experimental result is in Table 2.
The restraining effect of table 2 various dose 16a to mice ear
Figure BDA00001649077500271
A acetylsalicylic acid=positive control, the blank group of CMCNa=, n=12.
B with the CMCNa group than p<0.01, with 1 μ mol/kg group than p<0.01;
C with the CMCNa group than p<0.01, with 0.1 μ mol/kg group than p<0.05.

Claims (10)

1. the compound of a general formula (I) or its pharmacy acceptable salt:
Figure FDA00001649077400011
Wherein: R 1Be selected from H, benzyl, benzoyl or C 1-10Alkyloyl, and
R 2Be selected from H, C 1-10Alkyl, C 1-10Alkoxyl group, C 6-14Aryl or C 5-14Heterocyclic radical, wherein said alkyl is optionally by C 6-14Aryl or C 5-14Heteroaryl replaces.
2. compound according to claim 1 or its pharmacy acceptable salt, wherein R 1Be selected from hydrogen, benzyl or ethanoyl.
3. compound according to claim 1 or its pharmacy acceptable salt, wherein R 2Be selected from H or C 1-6Alkyl, wherein C 1-6Alkyl is optionally replaced by phenyl or indoles.
4. compound according to claim 1 or its pharmacy acceptable salt, it is following compound or its pharmacy acceptable salt:
Figure FDA00001649077400012
Figure FDA00001649077400021
5. a method for preparing compound according to claim 1, is characterized in that the method comprises the following steps:
1) take methylene dichloride under hydrochloric acid exists generates 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl-1,3-dioxane by 1,1,3,3-tetramethoxy propane and 2，2-dimethyl-1，3-propanediol reaction as solvent;
2) chloro-5 at 2,3-bis-, under 6-dicyan-Isosorbide-5-Nitrae-benzene exists in the mixed solvent of acetonitrile and water; by 2-(2,2-dimethoxy-ethyl)-5,5-dimethyl-1; the 3-dioxane is converted into the 2-aldehyde-base-5 of general formula (II), 5-dimethyl-1,3-dioxane;
3) glucosamine is carried out to selective protection, then with the coupling of tertiary fourth oxygen amic acid, obtain the compound of general formula (III);
4), by the 2-aldehyde-base-5 of general formula (II), the reaction of the compound of 5-dimethyl-1,3-dioxane and general formula (III) obtains the compound of general formula (I),
Figure FDA00001649077400022
R wherein 1And R 2As defined in claim 1.
6. method according to claim 5, wherein the amino acid in step 3) is selected from Ile, Phe, Val, Ala, Trp or Leu.
7. method according to claim 5, wherein R 1Be selected from hydrogen, benzyl or ethanoyl; R 2Be selected from H or C 1-6Alkyl, wherein C 1-6Alkyl is optionally replaced by phenyl or indoles.
8. compound according to claim 1 or the purposes of its pharmacy acceptable salt in preparing anti-inflammatory drug.
9. a medicinal compositions, it contains compound according to claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier or the auxiliary material for the treatment of significant quantity.
10. the purposes of pharmaceutical composition according to claim 9 in preparing anti-inflammatory drug.
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