CN1935152A - Synthesis of 2-aralkoxyadenosines and 2-alkoxyadenosines - Google Patents

Abstract

The invention provides new methods for synthesis of 2-aralkyloxyadenosines and 2-alkoxyadenosines. The invention is particularly useful for synthesis of 2-[2-(4-chlorophenyl)ethoxy]adenosine. Preferred methods of the invention include activating a guanosine compound followed by hydrolysis; alkylating the hydrolyzed compound with subsequent amination to provide a 2-aralkyloxyadenosine or a 2-alkoxyadenosine compound.

Description

Synthesizing of 2-aralkoxy ribosidoadenine and 2-alkoxyl ribosidoadenine

The application is that the application number submitted on October 24th, 2002 is dividing an application of 02826143.7 Chinese patent application.

The application requires the priority of U.S. Provisional Patent Application of submitting to October 25 calendar year 2001 60/335,169 and the U.S. Provisional Patent Application of submitting on April 26th, 2,002 60/375,723, and described application is incorporated by reference in this text by this paper and examines.

Background of invention

Invention field

The invention provides the new method of Synthetic 2-aralkoxy ribosidoadenine and 2-alkoxyl ribosidoadenine.The present invention is particularly useful for Synthetic 2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine.

Technical background

Ribosidoadenine is the endogenous material with multiple biological function.Having many in these biological functions is that it is as P ₁The result of the native ligand effect of purinergic receptor (also claiming the ribosidoadenine receptor).From several mammal things, discerned and cloned the hypotype of four kinds of known ribosidoadenine receptors: A ₁, A _2A, A _2BAnd A ₃These receptors are prototype g protein coupled receptors, by typical their biological activity of signal transduction pathway performance.

The molecule that the chemical modification of ribosidoadenine provides plays the effect of agonist or antagonist, each subclass selective binding of these molecules and ribosidoadenine receptor.The availability of this selective ligands makes it possible to many biological functions of ribosidoadenine are belonged to one receptor subclass.Particularly, verified, when use the part, ribosidoadenine A optionally _2AReceptor stimulating agent can significantly promote the wound healing of animal, and described animal has normal and impaired healing ability.CGS-21680 for example, a kind of 2-(arylalkylamino) ribosidoadenine-5 '-uronic amide (uronamide), can quicken significantly healthy normal mouse wound closure (referring to people such as Montesinos, J.Exp.Med., 1997,186:1615-1620).In addition, compare with untreated rat, aforesaid chemical compound can be promoted the healing of the excision wound of normal rat and diabetes rat, and this is a kind of by the optionally ribosidoadenine A of administration simultaneously _2AThe effect that the receptor antagonist body is blocked.

Other ribosidoadenine chemical compound of paying close attention to is to be called as 2-alkoxyl-and the selectivity ribosidoadenine A of 2-aralkoxy ribosidoadenine _2AAgonist.Particularly, showing in the mice of normal health, 2-[2-(4-chlorophenyl) ethyoxyl recently] ribosidoadenine promotes the faster closure of excision wound, 0.01% the general bright gel of Bekaa that is used for the treatment of diabetic foot ulcer than current approval is rapider.

2-[2-(4-chlorophenyl) ethyoxyl]-preparation of ribosidoadenine and other 2-aralkoxy ribosidoadenine and 2-alkoxyl ribosidoadenine comprises with suitable (virtue) sodium alkoxide or lithium and replaces 2 ', 3 '-O-(ethoxy methylene)-2-chloro ribosidoadenine or 2 ', the cl radical of 3 '-O-(isopropylidene)-2-chloro ribosidoadenine is (referring to people such as Marumoto (1975) Chem.Pharm.Bull.23:759-774; People such as Ueeda (1991a), J.Med.Chem.34:1334-1339; People such as Ueeda (1991b), J.Med.Chem.34:1340-1344), be the purification of deprotection and expected product then.2 '-and the sealing of 3 '-hydroxyl according to state be prevent to form 2 → 2 ' polymerizates necessary (people (1975) such as Marumoto, Chem.Pharm.Bull.23:759-774; People such as Ueeda (1991a), J.Med.Chem., 34:1334-1339).Show that also N-9 → C-1 ' glycosidic bond causes preparing these optionally ribosidoadenine A to the unstability of removing the required acid condition of 2 ', 3 '-blocking group _2AObserved low yield in the agonist (people (1991a) such as Ueeda, J.Med.Chem., 34:1334-1339).

These synthetic routes are tediously long, and often obtain chemical compound with especially low yield.Therefore expect to have the new method of Synthetic 2-aralkoxy ribosidoadenine and 2-alkoxyl ribosidoadenine.Expect to have the new method of Synthetic 2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine especially.

Summary of the invention

We have found the new method of preparation 2-aralkoxy ribosidoadenine and 2-alkoxyl ribosidoadenine now, are included in the formula I chemical compound and the pharmaceutically acceptable salt thereof that hereinafter specify.The present invention is used in particular for Synthetic 2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine and pharmaceutically acceptable salt thereof.

Method of the present invention comprises that (a) is by activating the guanosint glycoside compound as halogenation; (b) chemical compound that obtains of hydrolysis; (c) handle the hydrolysis compound of gained with alkylating agent; (d) handle alkylated compound, obtain 2-aralkoxy ribosidoadenine or 2-alkoxyl ribosidoadenine chemical compound with amine.

Of the present invention one preferred aspect, handle the guanosint glycoside compound with acylating agent; Then preferably particularly by handling acylated compounds with halide source such as chloride source; make its activation, described then chemical compound experience hydrolysis is after preferably handling with activatory nitrogen compound; described nitrogen compound particularly contains oxygen-nitrogen and partly, particularly contains nitrogen oxide thing (NO, NO ₂Deng) chemical compound of functional group, as illustrative nitrites chemical compound; Handling the chemical compound that obtains with alkylating agent then, is amination then, handles with ammonia or other suitable amine as passing through.Especially preferably synthesize 2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine.

The present invention prepares 2-[2-(4-chlorophenyl) ethyoxyl particularly preferred synthetic comprising with acetic anhydride acylation by guanine acyl glycosides in dimethyl formamide and pyridine] ribosidoadenine, use the phosphorus oxychloride chlorination then.Suitably hydrolysis of the intermediate that obtains; carry out diazotization with nitrite tert-butyl then; in dimethyl formamide, in the presence of cesium carbonate, use the alkylation of 2-(4-chlorophenyl) ethyl bromide then, in ethanol, replace the 6-cl part with ammonia then, follow deprotection simultaneously.Can be high yield separate 2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine, as with 2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine starting material be basic about 40 to 50 moles of %.Obtain similar yield from other 2-alkoxyl ribosidoadenine and 2-aralkoxy ribosidoadenine.

Detailed Description Of The Invention

As mentioned above, we have found preparation 2-aralkoxy ribosidoadenine and 2-alkoxyl ribosidoadenine now, the new method that comprises the following formula I chemical compound, described chemical compound can be used as the selective ligands of ribosidoadenine receptor or are used as the intermediate of the selective ligands of synthetic ribosidoadenine receptor.

In following formula I, R ¹And R ²Form the azetidine ring or contain altogether one to four heteroatomic 5-6 unit heterocycle that is selected from nitrogen, oxygen and sulfur for the aryl of the aralkyl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aralkyl, replacement, aryl, replacement, heteroaryl, heterocycle or with nitrogen-atoms independently;

R ³Arylalkenyl for aralkyl, arylalkenyl or the replacement of the alkynyl of the thiazolinyl of the alkyl of alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aralkyl, replacement.

In one embodiment; a preferred method of the present invention comprises with acylating agent in the presence of alkali and solvent; suitable reaction temperature according to appointment 20 ℃ handle down the times that guanosines are enough to substantially finish reaction, 20 minutes to about 30 hours according to appointment to about 120 ℃.Suitably, in the presence of tertiary amine, in solvent with suitable halide source, chloride source particularly, as phosphorus oxychloride, thionyl chloride/DMF, phosphorus pentachloride, chlorine, carbon tetrachloride/triphenyl phasphine, dichloro triphenyl phosphorane or dichloride antimony triphenyl, in suitable reaction temperature as 10 ℃ of times that the processing reaction product is enough to substantially finish reaction under about 120 ℃ reaction temperature, 5 minutes to about 8 hours according to appointment.

The product in second step to the conversion of corresponding 2-hydroxy derivatives be with nitrites or salt reagent such as alkyl nitrite or sodium nitrite sour as in the presence of the mineral acid, in the mixture of appropriate solvent such as water and lower alcohol, reacted down 20 minutes to about 24 hours according to appointment to about 60 ℃ as-10 ℃ at the proper temperature that promotes reaction.As arriving under about 120 ℃ temperature, in about 30 minutes to about 48 hours time, protected 6-chloro-2-hydroxyl-9-(β-D-ribofuranosyl) purine in solvent is joined in the suitable alkylating agent at 0 ℃.Intermediate is dissolved in the alcoholic solvent, handled about 20 minutes to about 48 hours under about 120 ℃ temperature and one to 50 atmospheric pressure at-70 ℃ with ammonia or suitable primary amine or secondary amine.Evaporation reaction mixture is used from appropriate solvent recrystallization or chromatography or this two kinds of methods then in conjunction with purified product.

According to an embodiment, described acylating agent is selected from chloroacetic chloride, acetic anhydride, propionyl chloride, propionic andydride, Benzenecarbonyl chloride., benzoyl oxide, phenyllacetyl chloride and phenoxy group chloroacetic chloride.

Described alkali is selected from pyridine, 4-dimethylamino naphthyridine, 4-pyrrolidinyl pyridine, N, accelerine, N-ethyl-methylphenylamine, N, N-diethylaniline, trimethylamine, triethylamine, N, N-dimethyl amine, N, N-dimethyl isopropylamine and N, N-diethylmethyl amine.

Described solvent is selected from dimethyl formamide, dimethyl acetylamide, pyridine, acetonitrile, oxolane, hexamethyl phosphoramide and 1,4-dioxane.

In second step of method, described solvent is selected from acetonitrile, dichloromethane, chloroform, carbon tetrachloride, 1,2-dimethoxy-ethane, oxolane, dimethyl formamide, hexamethyl phosphoramide, 1,4-dioxane, 1,2-dichloroethanes, diethyl carbitol and 2-methoxy ethyl ether.Described tertiary amine is selected from N, accelerine, N-ethyl-methylphenylamine, N, N-diethylaniline, trimethylamine, triethylamine, N, N-dimethyl amine, N, N-dimethyl isopropylamine and N, N-diethylmethyl amine.

In the 3rd step, described alkyl nitrite is selected from nitrite tert-butyl, amyl nitrite, amyl nitrite or nitrous acid straight butyl.Lower alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanols, 2-butanols, the tert-butyl alcohol, amylalcohol and isoamyl alcohol.Mineral acid is selected from hydrochloric acid, hydrobromic acid, nitric acid and sulphuric acid.

In the 4th step of method, described solvent is selected from dimethyl formamide, dimethyl acetylamide, dimethyl sulfoxine, hexamethyl phosphoramide, 1,2-dimethoxy-ethane, 1,4-dioxane, oxolane and 2-methoxy ethyl ether.Described alkali is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.

In the 5th step of the inventive method embodiment, described alcoholic solvent is selected from methanol, ethanol, 1-propanol and 2-propanol.

Those skilled in the art can be familiar with, in said method, the selection of suitable alkylating agent is depended on the 2-alkoxyl ribosidoadenine or the 2-aralkoxy ribosidoadenine that will be synthesized and can be selected from and commercially available maybe can pass through the synthetic multiple alkyl chloride of means known in the art, alkyl bromide, alkyl iodide, methanesulfonic acid Arrcostab, trifluoromethanesulfonic acid Arrcostab, toluenesulfonic acid Arrcostab, aralkyl chloride, aralkyl bromide, aralkyl iodide, methanesulfonic acid aralkyl ester, trifluoromethanesulfonic acid aralkyl ester and toluenesulfonic acid aralkyl ester in the step (d).Those skilled in the art can also be familiar with, in said method, the selection of suitable primary amine or secondary amine is guidance with the 2-alkoxyl ribosidoadenine or the 2-aralkoxy ribosidoadenine of expectation equally in the step (e), and can be ammonia or be selected from and commercially available maybe can pass through synthetic multiple primary amine of means known in the art or secondary amine.

As used herein, term " alkyl " refers to straight chain, side chain or cyclic monovalent alkyl, preferably has 1 to 20 carbon atom, most preferably has 1 to 10 carbon atom (" low alkyl group ").This term is by following group example, as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, n-hexyl, 2-methyl-propyl, 3-methyl butyl etc.Term " alkylidene " and " low-grade alkylidene " refer to the divalent group of corresponding alkane.In addition, as used herein, have derived from other group of alkane such as alkoxyl, alkanoyl, thiazolinyl, cycloalkenyl group etc., when modifying with " rudimentary ", it has the carbochain that is no more than ten carbon atoms.Required minimum carbon number greater than those situations as thiazolinyl and alkynyl (minimum is two carbon atoms) and cycloalkyl (minimum is three carbon atoms) in, clearly term " rudimentary " refers to the carbon atom of minimum number at least.

As used herein; term " alkyl of replacement " refers to have 1 to 5 substituent group; preferred 1 to 3 substituent alkyl, described substituent group is selected from alkoxyl; the alkoxyl that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; cycloalkyl; the cycloalkyl that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; alkynyl; the alkynyl that replaces; acyl group; amino; aryl; the aryl that replaces; carboxyl; carboxyalkyl; cyano group; fluorine; hydroxyl; halogen; heteroaryl; heterocyclic radical; nitro; alkylthio group; mercapto; single (alkyl) amino; two (alkyl) amino; single (alkyl of replacement) amino; two (alkyl of replacement) amino; has the different alkyl that is selected from; the alkyl that replaces; aryl; the aryl that replaces; aralkyl; replace amine with substituent asymmetric two of the aralkyl that replaces;-SO-alkyl; the alkyl that-SO-replaces;-SO-aryl; the aryl that-SO-replaces;-SO ₂-alkyl ,-SO ₂The alkyl of-replacement ,-SO ₂-aryl ,-SO ₂The aryl of-replacement.As used herein, the other parts with prefix " replacement " comprise one or more above-mentioned substituent groups.

As used herein, term " thiazolinyl " refers to thiazolinyl straight chain or side chain, has 2 to 20 carbon atoms, and most preferably 2 to 10 carbon atoms have at least 1, preferably have 1 to 3 unsaturated position of thiazolinyl.This term is by following group example, as vinyl (CH=CH ₂), 1-acrylic (CH=CH-CH ₃), 2-acrylic (C (CH ₃)=CH ₂), 3-methyl-pentenyl (CH ₂-CH=C (CH ₃)-CH ₂CH ₃), etc.

As used herein, term " alkynyl " refers to alkynyl straight chain or side chain, has 2 to 20 carbon atoms, and most preferably 2 to 10 carbon atoms have at least 1, preferably have 1 to 2 unsaturated position of alkynyl.This term is by following group example, as acetenyl, 1-propinyl, 2-propynyl, 2-butyne base, 4, and 4-dimethyl-valerylene base etc.

As used herein, term " cycloalkyl " refers to have the cyclic alkyl of 3 to 20 carbon atoms, has monocycle or to condense or that the volution condensed forms connects is multi-ring.This term is by following group example, as cyclopropyl, cyclopenta, cyclohexyl, ring octyl group, norborny, perhydro fluorenyl, adamantyl etc.

As used herein, term " cycloalkenyl group " refers to have the cycloalkyl of 5 to 20 carbon atoms, has monocycle or to condense or that the volution condensed forms connects is multi-ring, has 1, preferred 1 to 2 unsaturated position of thiazolinyl at least.This term is by following group example, as cyclopentenyl, cycloheptenyl, 1, and 3-cyclo-octadiene base, cycloheptatriene base, dicyclo [2.2.1] heptan-2,5-dialkylene etc.

The carbon ring group that as used herein, that term " aryl " refers to is undersaturated, aromatic, have 6 to 20 carbon atoms has monocycle or a plurality of condensed ring.This term is by following group example, as phenyl, 1-naphthyl, 2-naphthyl, anthryl, 1, and 2-benzo anthryl etc.As used herein, term " aryl " refers to that also those wherein one or more aromatic rings are condensed to the hydrocarbon with condensed rings on other non-aromatic ring.In this case, this term is by following group example, as fluorenyl, acenaphthenyl, xenyl, fluoranthene base etc.Unless be subjected to the restriction of aryl substituent definition, otherwise these aryl preferably are selected from the listed substituent group of this paper by one to three and replace optionally with one to five substituent group replacement.

As used herein, term " aralkyl " refers to the aryl that is connected with the alkylidene of alkylidene or replacement or the aryl of replacement, and wherein the alkylidene of the aryl of aryl, replacement, alkylidene and replacement as defined herein.

As used herein, term " heterocycle " refers to have monocycle or a plurality of fused rings, saturated or undersaturated unit price carbon ring group, have 1 to 15 carbon atom and 1 to 5 hetero atom is arranged in one or more rings inside, preferably have 1 to 9 carbon atom and 1 to 4 hetero atom is arranged in one or more rings, described hetero atom is selected from nitrogen, sulfur and oxygen.This term is by following group example, as tetrahydrofuran base, pyrrolinyl, pyrrolidinyl, _ oxazolidinyl, thiazolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl, quininuclidinyl, thio-morpholinyl, morpholinyl, dioxolanyl etc.

As used herein, term " heteroaryl " refers to 5 yuan or 6 yuan of heterocyclic aryls, and it optionally condenses on the aryl rings of aryl or replacement, and wherein the aryl of heterocycle, aryl and replacement as defined herein.This term is by following group example, as pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals, different _ the azoles base, _ azoles base, isothiazolyl, thiazolyl, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, indyl, benzofuranyl, benzotriazole base, quinolyl, isoquinolyl etc.Optionally, heteroaryl can condense on second or the 3rd heteroaryl.Aspect this, this term is by following group example, as 1,2,3-triazoles also [4,5-b] pyridine radicals, s-triazol [1,5-a] pyrimidine radicals, pyrazolo [3,4-d] pyrimidine radicals, purine radicals, petrin base, pteridine radicals, pyrimido [5,4-d] pyrimidine radicals etc.

As used herein; term " acyl group " refer to alkyl-C (O)-, alkyl-C (O) of replacing-, cycloalkyl-C (O)-, cycloalkyl-C (O) of replacing-, aryl-C (O)-, aryl-C (O) of replacing-, heterocyclic radical-C (O)-and heteroaryl-C (O)-group, wherein the aryl of the cycloalkyl of the alkyl of alkyl, replacement, cycloalkyl, replacement, aryl, replacement, heterocyclic radical and heteroaryl are as defined herein.

As used herein, term " alkoxyl " refers to " alkyl-O-", " alkyl-O-of replacement ", " cycloalkyl-O-" or " cycloalkyl-O-of replacement ", and wherein the cycloalkyl of the alkyl of alkyl, replacement, cycloalkyl and replacement as defined herein.This term is by following group example, as methoxyl group, ethyoxyl, 1-propoxyl group, 2-propoxyl group, 1-butoxy, tert-butoxy, cyclopentyloxy, cyclohexyl ethyoxyl etc.

As used herein, term " halo " or " halogen " refer to fluorine, chlorine, bromine and iodine.

Comprise one or more substituent any groups as for above-mentioned, be appreciated that for those skilled in the art that these groups do not comprise and anyly spatially be infeasible and/or on synthetic, be infeasible replacement or substitute mode.

All documents of mentioning are introduced into this paper as a reference.Following non-limiting example explanation the present invention:

Embodiment 1:2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine synthetic

Steps A: 2 ', 3 ', the preparation of 5 '-three-O-acetyl group guanosine

In 12 liters of three mouthfuls of round-bottomed flasks that mechanical agitator, Dropping funnel, condenser and argon air inlet are housed, add dimethyl formamide (9 liters) and guanosine (is used P under 80 ℃ ₄O ₁₀Dry 20 hours in advance, 988g, 3.50 moles), be heated to 60 ℃ then.Add pyridine (1.1 liters), add acetic anhydride (2.15 liters, 22.8 moles) then, heating blends was to 90-100 ℃ of reaction 4 hours.Cool to room temperature spends the night, and evaporating mixture makes it become slurry with 10 liters of isopropyl alcohols to remove about 6 liters then, is heated to 70 ℃ of reactions 1 hour.Slowly cooling mixture is to room temperature, and obtaining product is crystalline solid.After filter collecting, wash solid with isopropyl alcohol (2 * 2 liters), then 80 ℃ of following vacuum dryings 17 hours, the intermediate that obtains expecting (1,080g, 75%)

The preparation of step B:2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

In 8 liters of three mouthfuls of round-bottomed flasks that mechanical agitator, condenser, thermometer and argon air inlet are housed, add dry acetonitrile (2.2 liters) and 2 ', 3 ', 5 '-three-O-acetyl group guanosine (550g, 1.344 moles).Add tetraethyl ammonium chloride(TEAC (423g, 2.55 moles) and (use P in advance ₂O ₅Drying is 18 hours under 110 ℃/fine vacuum), obtain clarifying green solution.After being heated to 45-50 ℃, add N, accelerine (179g, 1.48 moles) added phosphorus oxychloride (825g, 5.38 moles) then in 15 minutes, during temperature be elevated to 75 ± 3 ℃.Keep mixture at 75 ± 3 ℃ of temperature totally 15 minutes, flash distillation (T _{Bathe temperature}＜40 ℃), dissolve bolarious residue with dichloromethane (4 liters).Under the vigorous stirring, (2.5L) washes mixture with frozen water, collects organic facies, and (2 * 1L) aqueous phase extracted are with cold water (2 * 2 liters), saturated NaHCO with other dichloromethane ₃Aqueous solution (organic facies that 2 * 2L) washings merge, dry (Na ₂SO ₄), filter, be concentrated to about 1.5 liters.Add absolute ethanol (1.5L), enriched mixture is to about 2 liters.Cool to room temperature, product is separated out at 17 hours post crystallizations of 40 ℃ of following vacuum dryings, is colorless solid (321g, 56%).

The preparation of step C:6-chloro-2-hydroxyl-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

Heating makes amino 6-chloro-9-(2,3, the 5-three-O-acetyl group-β-D-ribofuranosyl) purine of 2-(42.7g, 100 mMs) be dissolved in 2 liters the tert-butyl alcohol: aqueous mixtures (1: 1, v/v) in.Behind the ice bath cooling solution, once add nitrite tert-butyl (50mL, 422 mMs).Remove ice bath, at room temperature stirring the mixture to emit up to gas stops (about 3 hours).Freezing (dry ice/2-propanol) and the lyophilizing intermediate that obtains expecting is a yellow solid then, and it is not purified can to use or immediately-20 ℃ of stored frozen.

¹H-NMR(DMSO-d ₆)：δ8.14(s，1H，H-8)，6.20(d，1H，H-1’，J＝5.6Hz)，5.81(t，1H，H-2’，J＝5.5Hz)，5.57(dd，1H，H-3’，J＝7.5，4.4Hz)，4.47-4.42(m，3H，H-4’，H-5’α，H-5’β)，2.16(s，3H，COCH ₃)，2.15(s，3H，COCH ₃)，2.08(s，3H，COCH ₃)。

Step D:6-chloro-2-[2-(4-chlorophenyl) ethyoxyl]-preparation of 9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

To crude product 6-chloro-2-hydroxyl-9-(2; 3; 5-three-O-acetyl group-β-D-ribofuranosyl) purine (44.0g; about 100 mMs) add 2-(4-chlorophenyl) bromic ether (43.6g in distillation dimethyl formamide (2 liters) solution; 200 mMs); add cesium carbonate (100g, 307 mMs) then.At room temperature stirred the mixture evaporate to dryness (T 24 hours _{Bathe temperature}＜50 ℃), residue distributes between dichloromethane (1 liter) and water (1 liter).Dry (Na ₂SO ₄) organic facies, filter and evaporation.(2 * 500mL) wash residue to remove excessive 2-(4-chlorophenyl) bromic ether with normal hexane, be dissolved in then in the dichloromethane (250mL), be adsorbed onto on the silica gel (100g), carry out silica gel (1000g) chromatographic isolation, use normal hexane and ethyl acetate (30% → 50%) gradient elution.Collection comprises the fraction of product, and the intermediate that evaporate to dryness obtains expecting is yellow foam.

Typical yields: step C and D merge into 40-70%.

¹H-NMR(DMSO-d ₆)：δ8.06(s，1H，H-8)，7.25(s，4H，Ar)，6.10(d，1H，H-1’，J＝4.8Hz)，5.90(dd，1H，H-2’，J＝5.3，5.0Hz)，5.62(dd，1H，H-3’，J＝5.3，5.2Hz)，4.63-4.56(m，2H，OCH ₂-C)，4.43-4.37(m，2H，H-4’&H-5’α)，4.29(dd，1H，H-5’β，J＝12.0，4.1Hz)，3.11(t，2H，O-C-CH ₂-，J＝6.9Hz)，2.10(s，3H，COCH ₃)，2.06(s，3H，COCH ₃)，2.05(s，3H，COCH ₃)。

Step e: 2-[2-(4-chlorophenyl) ethyoxyl] preparation of ribosidoadenine

In 2 liters stainless steel autoclave, add 6-chloro-2-[2-(4-chlorophenyl) ethyoxyl]-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (22.4g, 39.4 mMs) and dehydrated alcohol (800mL), be cooled to-50 ℃.Liquefied ammonia (200mL) condensation, join in the autoclave sealing autoclave, heating blends to 105 ± 5 ℃ maintenance 24 hours.When pressure is reduced to 100psi cooling autoclave and ventilation in ice bath when following.After being evaporated to about 250mL.Add active carbon (2g), mixture heated refluxed 30 minutes, filtered the back evaporate to dryness by Celite_.(3 * 250mL) extracted residues are distributed between ethyl acetate (200mL) and water (250mL) then with ebullient ethyl acetate.Water (100mL) is washed last acetic acid ethyl acetate extract once, dry (Na ₂SO ₄), filter, be added in the initial acetic acid ethyl acetate extract.The organic extract liquid that evaporate to dryness merges, solid ethanol (100mL) recrystallization.Collect crystalline product by filtering, wash with cold ethanol, drying is 24 hours under 75 ℃/2 holders.Obtain second batch of product and can collect the 3rd batch of product by concentrated mother liquor by the chromatographic separation of mother solution.

Typical yields: 62%

¹H-NMR(DMSO-d ₆)：δ8.14(s，1H，H-8)，7.35(s，4H，Ar)，7.27?br.s，2H，NH ₂)，5.78(d，1H，H-1’，J＝6.0Hz)，5.36(d，1H，2’OH，J＝6.2Hz)，5.12(d，1H，3’-OH，J＝4.7Hz)，5.09(t，1H，5’-OH，J＝5.7Hz)，4.58(dd，1H，H-2’，J＝5.8，6.3Hz)，4.40(t，2H，OCH2-C，J＝6.7Hz)，4.14(dd，1H，H-3’，J＝4.7，8.2Hz)，3.92(dd，1H，H-4’，J＝3.7，7.3Hz)，3.65(m，1H，H-5’α)，3.54(m，1H，H-5’β)，3.00(t，2H，O-C-CH _2-，J?6.7Hz)。

Embodiment 2:2-[2-(4-chlorophenyl) ethyoxyl] ribosidoadenine synthetic

The preparation of step C:6-chloro-2-hydroxyl-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

Amino 6-chloro-9-(2,3, the 5-three-O-acetyl group-β-D-ribofuranosyl) purine of heating 2-(291.2g, 0.68 mole, embodiment 1, step B) 2-propanol and aqueous mixtures (1: 1,15,560mL) suspension in reaches uniformity.Cooling solution adds nitrite tert-butyl (357mL, 3.0 moles) then to＜15 ℃.Make reactant be warmed up to room temperature and stirring, calm down up to emitting of gas.Ethyl acetate (7,300mL) and distribute reactant liquor between the water, and make two to be separated.(2 * 7,300mL) further aqueous layer extracted with the organic layer of dried over mgso merging, is filtered, and removal of solvent under reduced pressure obtains heavy-gravity oil with ethyl acetate.Typical yields: quantitatively.

Step D:6-chloro-2-[2-(4-chlorophenyl) ethyoxyl]-preparation of 9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

(embodiment 2 for purine to 6-chloro-2-hydroxyl-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl); step C) 2-(4-chlorophenyl) bromic ether (300.1g; 1.36mol) and dimethyl formamide (7, add cesium carbonate (665g, 2.04 moles) in mixture 280mL).Reaction stirred is 32 hours under inert atmosphere.The concentrating under reduced pressure reactant liquor, and between dichloromethane and water, distribute.The dried over mgso organic layer filters and reduction vaporization.Thick product column chromatography separation and purification is used the ethyl acetate/heptane eluting, obtains yellow solid: 6-chloro-2-[2-(4-chlorophenyl) ethyoxyl]-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine.Typical yields: 64%

Step e: 2-[2-(4-chlorophenyl) ethyoxyl] preparation of ribosidoadenine

In reactor, add 6-chloro-2-[2-(4-chlorophenyl) ethyoxyl]-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (243.8g; 0.43 mole, embodiment 2, step D) and ethanol (3; mixture 660mL), cooling reactor is to below-33 ℃.Add ammonia (1500g) in reactor, sealed reactor is heated to 100 ℃ then, with HPLC monitoring reaction.When finishing (about 5 hours), cooling reactor, ventilation, concentrating under reduced pressure inclusions.The thick product of column chromatography separation and purification is used the methylene chloride eluting.Pure fraction concentrating under reduced pressure is to about four liters of solvents, and vacuum filtration collects product, and pale solid is washed with dichloromethane, and vacuum drying obtains analytical pure (＞99%) products of 82 grams, is linen solid.Merge other fraction and obtain other 73g low-purity (90-98%) product.

The typical yields that merges: 54%.

Embodiment 3-16: other synthetic

By utilizing the step of the foregoing description 1 and 2, synthesized other chemical compound according to the explanation of following examples 3-18.The general formula that the chemical constitution of each synthetic chemical compound is used in chemical compound shown in embodiment top specifies (first structure is used to represent embodiment 3-8, and second structure is used to represent embodiment 9-16).

Embodiment 3-8:

The preparation of embodiment 3:2-benzyloxy-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

By using benzyl bromide a-bromotoluene to prepare the chemical compound of following formula structure, wherein substituent R as alkylating agent ³For-CH ₂C ₆H ₅(benzyl).According to the description of step C and D among the embodiment 2,2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 1, step B) is carried out deaminizating and alkylation, separate obtaining chemical compound (C with 65% yield ₂₃H ₂₃ClN ₄O ₈), be grease. ¹H-NMR(DMSO-d ₆)：δ1.93(s，3H)；2.10(s，3H)；2.16(s，3H)；4.25(m，1H)；4.39(m，2H)；5.47(s，2H)；5.76(t，1H，J＝6)；6.00(t，1H，J＝6)；6.27(d，1H，J＝6)；7.45(m，5H)；8.64(s，1H)。

The preparation of embodiment 4:6-chloro-2-(4-nitro benzyloxy)-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

By using 4-nitrobenzyl bromine to prepare the chemical compound of following formula structure, wherein substituent R as alkylating agent ³For-CH ₂(4-NO ₂C ₆H ₄) (4-nitrobenzyl).According to the description of step C and D among the embodiment 2,, obtain chemical compound (C with the separation of 60% yield with 2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 1, step B) deaminizating and alkylation ₂₃H ₂₂ClN ₅O ₁₀), being solid, fusing point is 178-180 ℃. ¹H-NMR(DMSO-d ₆)：δ1.94(s，3H)；2.05(s，3H)；2.11(s，3H)；4.10(m，1H)；4.33(m，2H)；5.65(s，2H)；5.72(t，1H，J＝6)；5.97(t，1H，J＝6)；6.26(d，1H，J＝4)；7.74(d，2H，J＝8)；8.27(d，2H，J＝8)；8.66(s，1H)。

The preparation of embodiment 5:2-butoxy-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

By using the 1-butyl bromide to prepare the chemical compound of following formula structure, wherein substituent R as alkylating agent ³For-CH ₂CH ₂CH ₂CH ₃(normal-butyl).According to the description of step C and D among the embodiment 2,, obtain chemical compound (C with the separation of 55% yield with 2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 1, step B) deaminizating and alkylation ₂₀H ₂₅ClN ₄O ₈), be grease. ¹H-NMR(DMSO-d6)：δ0.89(t，3H，J＝6)；1.42(m，2H)；1.73(m，2H)；1.95(s，3H)；2.06(s，3H)；2.10(s，3H)；4.00(m，1H)；4.20(m，2H)；4.40(m，2H)；5.72(t，1H，J＝6)；5.99(t，1H，J＝6)；6.25(d，1H，J＝4)；8.61(s，1H)。

Embodiment 6:(6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine-2-yl) preparation of the fluoroacetic acid tert-butyl ester

By using the monobromo-acetic acid tert-butyl ester (BrCH ₂C (=O) OC (CH ₃) ₃) prepared the chemical compound of following formula structure, wherein substituent R as alkylating agent ³For-CH ₂C (=O) OC (CH ₃) ₃According to the description of step C and D among the embodiment 2,, obtain chemical compound (C with the separation of 40% yield with 2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 1, step B) deaminizating and alkylation ₂₂H ₂₇ClN ₄O ₁₀), be grease.

Embodiment 7:6-chloro-2-[3-(3-methoxyphenyl) propoxyl group]-preparation of 9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

By using 3-(3-methoxyphenyl) propyl bromide (BrCH ₂CH ₂CH ₂(3-OCH ₃) C ₆H ₄) prepared the chemical compound of following formula structure, wherein substituent R as alkylating agent ³For-CH ₂CH ₂CH ₂(3-OCH ₃) C ₆H ₄According to the description of step C and D among the embodiment 2,, obtain chemical compound (C with the separation of 30% yield with 2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 1, step B) deaminizating and alkylation ₂₆H ₂₉ClN ₄O ₉), be grease.

Embodiment 8:2-(the 4-tert-butyl group) benzyloxy)-preparation of 6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine

By using 4-(tert-butyl group) benzyl bromide a-bromotoluene (BrCH ₂-4-(C (CH ₃) ₃) C ₆H ₄) prepared the chemical compound of following formula structure, wherein substituent R as alkylating agent ³For-CH ₂-4-(C (CH ₃) ₃) C ₆H ₄(4-tert-butyl group benzyl).According to the description of step C and D among the embodiment 2,, obtain chemical compound (C with the separation of 45% yield with 2-amino-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 1, step B) deaminizating and alkylation ₂₇H ₃₁ClN ₄O ₈), being solid, fusing point is 58-60 ℃. ¹H-NMR(DMSO-d ₆)：δ1.32(s，9H)；2.08(s，3H)；2.10(s，3H)；2.15(s，3H)；4.37(m，3H)；5.48(s，2H)；5.63(t，1H，J＝6)；5.89(t，1H，J＝6)；6.5(d，1H，J＝4)；7.43(bs，4H)；8.09(s，1H)。

Embodiment 9-16:

The preparation of embodiment 9:2-benzyloxy ribosidoadenine

The chemical compound that has prepared the following formula structure, wherein substituent R ¹And R ²Be hydrogen, R ³Be benzyl (CH ₂C ₆H ₅).According to the description of step e among the embodiment 2, by making ammonia and 2-benzyloxy-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 3) this chemical compound of prepared in reaction (C ₁₇H ₁₉N ₅O ₅), obtain final products with the separation of 70% yield, be solid, fusing point is 178-179 ℃. ¹H-NMR(DMSO-d ₆)：δ3.49(m，1H)；3.61(m，1H)；3.9(m，1H)；4.12(m，1H)；4.58(m，1H)；5.18(d，2H，J＝4)；5.3(s，2H)；5.42(d，1H，J＝6)；5.79(d，1H，J＝6)；7.37(m，7H)；8.16(s，1H)。

Embodiment 10:2-benzyloxy-N ⁶The preparation of-ethyl adenine nucleoside

The chemical compound that has prepared the following formula structure, wherein substituent R ¹For-CH ₂CH ₃And R ²Be hydrogen, R ³Be benzyl (CH ₂C ₆H ₅).According to the description of step e among the embodiment 2, by making ethamine and 2-benzyloxy-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 3) this chemical compound of prepared in reaction (C ₁₉H ₂₃N ₅O ₅), obtain final products with the separation of 40% yield, be solid, fusing point is 170-171 ℃. ¹H-NMR(DMSO-d ₆)：δ1.13(t，3H，J＝8)；3.6(m，4H)；3.9(m，1H)；4.1(m，1H)；4.5(m，1H)；5.18(m，2H)；5.32(s，2H)；5.42(d，1H，J＝6)；5.78(d，1H，J＝6)；7.41(m，5H)；7.93(bm，1H)；8.15(s，1H)。

Embodiment 11:2-(4-nitrobenzyl) oxygen base-N ⁶The preparation of-ethyl adenine nucleoside

The chemical compound that has prepared the following formula structure, wherein substituent R ¹For-CH ₂CH ₃And R ²Be hydrogen, R ³Be 4-nitrobenzyl (CH ₂(4-NO ₂) C ₆H ₄).According to the description of step e among the embodiment 2, by making ethamine and 6-chloro-2-(4-nitrobenzyl) oxygen-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 4) this chemical compound of prepared in reaction (C ₁₉H ₂₂N ₆O ₇), obtain final products with the separation of 60% yield, be solid, fusing point is 210-213 ℃. ¹H-NMR(DMSO-d ₆)：δ1.05(1，3H，J＝8)；3.4(m，2H)；3.5(m，1H)；3.6(m，1H)；3.85(m，1H)；4.05(m，1H)；4.6(m，1H)；5.2(m，2H)；5.4(d，1H，J＝6)；5.45(s，2H)；5.8(d，1H，J＝6)；7.8(d，2H，J＝8)；8(bt，1H)；8.2(s，1H)；8.25(d，2H，J＝8)。

The preparation of embodiment 12:2-(4-nitrobenzyl) oxygen base ribosidoadenine

The chemical compound that has prepared the following formula structure, wherein substituent R ¹And R ²Be hydrogen, R ³Be 4-nitrobenzyl (CH ₂(4-NO ₂) C ₆H ₄).According to the description of step e among the embodiment 2, by making ammonia and 6-chloro-2-(4-nitro benzyloxy)-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 4) this chemical compound of prepared in reaction (C ₁₇H ₁₈N ₆O ₇), obtain final products with the separation of 80% yield, be solid, fusing point is 174-176 ℃. ¹H-NMR(DMSO-d ₆)：δ3.5(m，1H)；3.6(m，1H)；3.8(d，1H，J＝4)；4.1(m，1H)；4.56(m，1H)；5.16(m，2H)；5.4(d，1H，J＝6)；5.47(s，2H)；5.77(d，1H，J＝6)；7.43(bs，2H)；7.7(d，2H，J＝8)；8.18(s，1H)；8.24(d，2H，J＝8)。

The preparation of embodiment 13:2-butoxy ribosidoadenine

The chemical compound that has prepared the following formula structure, wherein substituent R ¹And R ²Be hydrogen, R ³Be normal-butyl (CH ₂CH ₂CH ₂CH ₃).According to the description of step e among the embodiment 2, by making ammonia and 2-butoxy-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 5) this chemical compound of prepared in reaction (C ₁₄H ₂₁N ₅O ₅), obtain final products with the separation of 30% yield, be solid, fusing point is 145-146 ℃. ¹H-NMR(DMSO-d ₆)：δ0.9(t，3H)；1.37(m，2H，J＝8)；1.65(m，2H，J＝8)；3.66(m，2H)；3.97(m，1H)；4.18(m，3H)；4.57(m，1H)；4.95(d，1H，J＝6)；5.23(m，2H)；5.78(d，1H，J＝6)；6.9(bs，2H)；7.94(s，1H)。

The preparation of embodiment 14:2-carboxyl methoxyl group ribosidoadenine

The chemical compound that has prepared the following formula structure, wherein substituent R ¹And R ²Be hydrogen, R ³For-CH ₂COOH.According to the description of step e among the embodiment 2, by making ammonia and (6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine-2-yl) the fluoroacetic acid tert-butyl ester (embodiment 6) this chemical compound of prepared in reaction (C ₁₂H ₁₅N ₅O ₇), obtain final products with the separation of 70% yield, be solid, fusing point is 200-203 ℃. ¹H-NMR(DMSO-d ₆)：δ3.4(m，1H)；3.55(m，1H)；3.91(m，1H)；4.11(m，1H)；4.56(m，1H)；4.74(bs，1H)；4.78(s，2H)；5.3(bs，2H)；5.75(d，1H，J＝6)；7.36(bs，2H)；8.15(s，1H)；12.6(bs，1H)。

Embodiment 15:2-[3-(3-methoxyphenyl) propoxyl group] preparation of ribosidoadenine

The chemical compound that has prepared the following formula structure, wherein substituent R ¹And R ²Be hydrogen, R ³For-CH ₂CH ₂CH ₂(3-OCH ₃) C ₆H ₄According to the description of step e among the embodiment 2, by making ammonia and 6-chloro-2-[3-(3-methoxyphenyl) propoxyl group]-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 7) this chemical compound of prepared in reaction (C ₂₀H ₂₅N ₅O ₆), obtain final products with the separation of 10% yield, be solid, fusing point is 85-87 ℃. ¹H-NMR(DMSO-d ₆)：δ1.97(t，2H，J＝6)；2.69(t，2H，J＝6)；3.54(m，2H)；3.71(s，3H)；3.95(m，1H)；4.15(m，3H)；4.58(m，1H)；5.19(m，2H)；5.42(d，1H，J＝6)；5.77(d，1H，J＝6)；6.77(m，3H)；7.19(t，1H，8)；7.3(bs，2H)；8.14(s，1H)。

Embodiment 16:2-[4-(tert-butyl group) benzyloxy]-N ⁶The preparation of-cyclopenta ribosidoadenine

The chemical compound that has prepared the following formula structure, wherein substituent R ¹Be cyclopenta, R ²Be hydrogen, R ³For-CH ₂(4-(C (CH ₃) ₃C ₆H ₄(4-tert-butyl group benzyl).According to the description of step e among the embodiment 2, by making Aminocyclopentane and 2-[4-(tert-butyl group) benzyloxy]-6-chloro-9-(2,3,5-three-O-acetyl group-β-D-ribofuranosyl) purine (embodiment 8) this chemical compound of prepared in reaction (C ₂₅H ₃₅N ₅O ₅), obtain final products with the separation of 50% yield, be solid, fusing point is 118-120 ℃. ¹H-NMR(DMSO-d ₆)：δ1.3(s，9H)；1.6(m，6H)；2.0(m，2H)；3.46(m，3H)；3.75(m，1H)；3.89(m，1H)；4.28(s，1H)；4.42(m，2H)；5.1(m，1H)；5.29(s，2H)；5.7(d，1H)；5.7(m，1H)；7.35(s，4H)；7.57(bs，1H)。

This paper is with reference to following document.These lists of references are incorporated by reference in this text by this paper and examine.

1.Montesinos，M.C.；Gadangi，P.；Longaker，M.；Sung，J.；Levine，J.，Nilsen，D.；Reibman，J.；Li，M.；Jiang，C.-K.；Hirschhorn，R.；Recht，P.A.；Ostad，E.；Levin，R.I.；Cronstein，B.N.Wound?healing?is?accelerated?by?agonists?of?adenosine?A ₂(G _as-linked)receptors.J.Exp.Med.，1997，186，1615-1620.

2.Marumoto，R.；?Yoshioka，Y.；Miyashita，O.；Shima，S.；Imai，K.；Kawazoe，K.；Honjo，M.，Synthesis?and?coronary?vasodilating?activity?of?2-substituted?adenosines.Chem.Pharm.Bull.1975?23，759-774.

3.Ueeda，M.；Thompson，R.D.；Arroyo，L.H.；Olsson，R.A.2-Alkoxyadenosines：Potent?and?selective?agonists?at?the?coronary?artery?A ₂?adenosine?receptor.J.?Med.Chem，1991，34，1334-1339.

4.Ueeda，M.；Thompson，R.D.；Arroyo，L.H.；Olsson，R.A.，2-Aralkoxyadenosines；Potent?and?selective?agonists?at?the?coronary?artery?A ₂?adenosine?receptor.J.?Med.Chem.，1991，34，l340-1344.

Write up the present invention with reference to its preferred embodiment. Yet, think and considering On the basis of the present disclosure, those skilled in the art can modify in spirit and scope of the invention And improvement.

Claims (18)

1. adenosine A _2AReceptor antagonist is used for promoting the application of the topical remedy of wound healing, wherein said adenosine A in manufacturing _2AReceptor antagonist is selected from the chemical compound of formula I:

Wherein:

R ¹And R ²Be aralkyl, the aryl of cycloalkenyl group, aralkyl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkynyl, cycloalkyl, the replacement of thiazolinyl, alkynyl, the replacement of alkyl, thiazolinyl, the replacement of hydrogen, alkyl, replacement, aryl, heteroaryl or the heterocyclic radical of replacement independently; Or

R ¹And R ²The nitrogen-atoms that connects with them forms the azetidine ring or contains one to four first heterocycle of heteroatomic 5-6 that is selected from nitrogen, oxygen and sulfur altogether;

R ³Arylalkenyl for aralkyl, arylalkenyl or the replacement of the alkynyl of the thiazolinyl of the alkyl of alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aralkyl, replacement;

Wherein

Term " replacement " is meant to have 1 to 5 substituent any above-mentioned group, described substituent group be selected from that alkoxyl, cycloalkyloxy, cycloalkyl, cycloalkenyl group, alkynyl, acyl group, amino, aryl, carboxyl, carboxyalkyl, cyano group, fluorine, hydroxyl, halogen, heteroaryl, heterocyclic radical, nitro, alkylthio group, mercapto, list (alkyl) are amino, two (alkyl) is amino and have different be selected from alkyl, aryl, aralkyl ,-the SO-alkyl ,-the SO-aryl ,-SO ₂-alkyl and-SO ₂The substituent asymmetric disubstituted amido of-aryl;

The adenosine A of its Chinese style I _2AReceptor antagonist can obtain by the method that comprises the following steps:

(a) handle guanosine with acylating agent and obtain acylated compounds;

(b) handle this acylated compounds with halide source, obtain halogenated compound;

(c) diazotising of the amino part of the 2-by this halogenated compound and this halogenated compound of hydrolysis obtains the 2-hydroxy compounds;

(d) handle this 2-hydroxy compounds with alkylating agent, obtain alkylated compound; With

(e) handle this alkylated compound with ammonia or amine, obtain the chemical compound of formula I.

2. the application of claim 1, wherein the product of step (e) is 2-[2-(4-chlorophenyl) ethyoxyl] adenosine.

3. claim 1 or 2 application, wherein the acylating agent in the step (a) is acyl halide or anhydride.

4. the application of claim 3, wherein the acylating agent in the step (a) is selected from chloroacetic chloride, acetic anhydride, propionyl chloride, propionic andydride, Benzenecarbonyl chloride., benzoyl oxide, phenyllacetyl chloride and phenoxy group chloroacetic chloride.

5. the application of claim 3, wherein step (a) is carried out in the presence of alkali.

6. the application of claim 5, wherein the alkali in the step (a) is selected from pyridine, 4-dimethylamino naphthyridine, 4-pyrrolidinyl pyridine, N, accelerine, N-ethyl-methylphenylamine, N, N-diethylaniline, trimethylamine, triethylamine, N, N-dimethyl amine, N, N-dimethyl isopropylamine and N, N-diethylmethyl amine or its combination.

7. claim 1 or 2 application, wherein the halide source in the step (b) is a chloride source.

8. the application of claim 7, wherein the chloride source in the step (b) is selected from phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, chlorine, carbon tetrachloride-triphenyl phasphine, dichloro triphenyl phosphorane and dichloride antimony triphenyl.

9. the application of claim 7, wherein step (b) is carried out in the presence of tertiary amine.

10. the application of claim 9, wherein the tertiary amine in the step (b) is selected from N, accelerine, N-ethyl-methylphenylamine, N, N-diethylaniline, trimethylamine, triethylamine, N, N-dimethyl amine, N, N-dimethyl isopropylamine and N, N-diethylmethyl amine.

11. the application of claim 1 or 2, wherein the diazotising in the step (c) is carried out in the presence of nitrite (ester) reagent and mineral acid.

12. the application of claim 11, wherein nitrite (ester) reagent in the step (c) is selected from sodium nitrite, nitrite tert-butyl, amyl nitrite, amyl nitrite and nitrous acid straight butyl.

13. the application of claim 11, wherein the mineral acid in the step (c) is selected from hydrochloric acid, hydrobromic acid, nitric acid and sulphuric acid.

14. the application of claim 1 or 2, wherein the alkylating agent in the step (d) is selected from 2-(4-chlorophenyl) ethyl chloride, 2-(4-chlorophenyl) bromic ether, 2-(4-chlorophenyl) ethyl iodide, methanesulfonic acid-2-(4-chlorophenyl) ethyl ester, trifluoromethanesulfonic acid-2-(4-chlorophenyl) ethyl ester and toluenesulfonic acid-2-(4-chlorophenyl) ethyl ester.

15. the application of claim 14, wherein step (d) is carried out in the presence of alkali.

16. the application of claim 15, wherein the alkali in the step (d) is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide and potassium tert-butoxide.

17. the alkylated compound in the ammonia treating step (e) is wherein used in the application of claim 1 or 2.

18. the application of claim 1 or 2, wherein wound is a diabetic foot ulcer.