CN104744540A - Preparation method for regadenoson - Google Patents
Preparation method for regadenoson Download PDFInfo
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- CN104744540A CN104744540A CN201310732545.7A CN201310732545A CN104744540A CN 104744540 A CN104744540 A CN 104744540A CN 201310732545 A CN201310732545 A CN 201310732545A CN 104744540 A CN104744540 A CN 104744540A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention discloses a preparation method for regadenoson, belonging to the field of pharmaceutical chemistry. The preparation method for regadenoson comprises the following steps: with a compound as shown in a formula III as a reaction raw material, subjecting the compound and 2-formyl-3-oxoethyl propanoate to a cyclization reaction in isopropanol so as to produce a compound as shown in a formula IV; then with the compound as shown in the formula IV as a substrate, subjecting the substrate and a methanol solution of methylamine to an acylation reaction so as to produce a compound as shown in a formula V; and reacting the compound as shown in the formula V with tetrabutyl ammonium fluoride in a methanol solution to remove hydroxyl protection so as to prepare regadenoson. According to the preparation method in the invention, the methanol solution of methylamine is used as a reaction medium and reagent, a methanamide compound is produced through one-step reaction under normal pressure, and the acylation reaction is carried out without hydrolysis for formation of a carboxylic acid derivative; thus, reaction steps are reduced, high pressure reaction equipment is not used, cost for production input is lowered, the safety factor of production is increased, and the method is more applicable to large scale production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of method preparing Rui Jiadesong, namely one prepares (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) method of-N-METHYLFORMAMIDE.
Background technology
Rui Jiadesong is a kind of adenosine A with high selectivity
2Areceptor stimulant, for radionuclide scheming Perfusion Imaging stress agent medicine, the cardiovascular diastole agent as cardiac imaging carries out clinical application in the U.S..
Rui Jiadesong, chemistry (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base by name]-adenine-2-base } pyrazoles-4-base)-N-METHYLFORMAMIDE, structural formula is as follows:
No. 6403567th, United States Patent (USP) discloses this compound and the method for the preparation of this compound.Reacted with 2-formyl radical-3-oxopropanoate under reflux conditions in ethanolic soln by 2-hydrazine adenosine; generate 1-{9 [4S, 2R, 3R; 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-ethyl formate.Then; with the nucleoside derivates of this ethyl formate for substrate; be protective material by TERT-BUTYL DIMETHYL CHLORO SILANE; catalyzer is made with imidazoles in DMF; generate 1-{9 [4S, 2R, 3R; 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } trimethylsilyl derivatization of pyrazoles-4-ethyl formate.1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } trimethylsilyl derivatization of pyrazoles-4-ethyl formate is through basic hydrolysis, form carboxylic acid thing, then react with methylamine, generate (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) trimethylsilyl derivatization of-N-METHYLFORMAMIDE.(1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) trimethylsilyl derivatization of-N-METHYLFORMAMIDE reacts with tetrabutyl ammonium fluoride in methanol solution, generate compound (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base)-N-METHYLFORMAMIDE, i.e. Rui Jiadesong.
No. 7732595th, United States Patent (USP) has carried out detailed description to another preparation method of Rui Jiadesong.With 2-chlorine adenosine for substrate, react with hydrazine hydrate at 40-45 DEG C, generate 2-diazanyl adenosine.2-diazanyl adenosine and 2-formyl radical-3-oxopropanoate react, and generate 1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-ethyl formate.The nucleoside analog of this ethyl formate reacts with aqueous methylamine solution at 50-70 DEG C in pressure reactor, generate compound (I) (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base)-N-METHYLFORMAMIDE, i.e. Rui Jiadesong.Reaction formula is as follows:
Simultaneously, people's calendar year 2001s such as the J.Zablocki of CV company are at " NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS(20 (4 – 7), 343 – 360 (2001)) " on delivered preparation method about compound (I) simultaneously, i.e. (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) preparation method of-N-METHYLFORMAMIDE.
Prepare in the reaction of Rui Jiadesong at US7732595, methylamine and 1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } reaction needed of pyrazoles-4-ethyl formate carries out in pressure reactor in a heated condition, and the equipment requirements for synthetic route is higher, safety coefficient is lower, and equipment cost is higher.Meanwhile, methylamine is revealed in pressure of being heated, larger on ambient air impact.
Prepare in the reaction of Rui Jiadesong at US6403567; need first to be hydrolyzed generation carboxylic acid derivative to ethyl formate derivative; react to generate with methylamine again under the catalysis of DCC and HOBT after separation and prepare (1-{9 [4S; 2R; 3R; 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) trimethylsilyl derivatization of-N-METHYLFORMAMIDE, goes protection to generate Rui Jiadesong.But the too mediocre length of reaction scheme of acidylate after hydrolysis, acidylate manipulation require uses complicated catalyzer, and reaction controlling difficulty, impurity increases.
And at " NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS " bibliographical information in, 1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } trimethylsilyl derivatization of pyrazoles-4-ethyl formate, need silica gel column chromatography separation be carried out, just can carry out dropping into next step hydrolysis reaction, be unfavorable for the quality control of intermediate and produce amplification.
Summary of the invention
In view of this, the object of the invention is to the defect for prior art, a kind of method preparing Rui Jiadesong is provided.Preparation method's reaction scheme of the present invention is shorter, and reaction easily realizes and can prepare Rui Jiadesong on a large scale.
For realizing object of the present invention, the present invention adopts following technical scheme:
Prepare a method of Rui Jiadesong, comprising:
Compound shown in step 1, formula III in aqueous isopropanol with compound shown in 2-formyl radical-3-oxopropanoate generation cyclization production IV;
Compound shown in step 2, formula IV is compound shown in acidylate production V in the methanol solution of methylamine;
Compound shown in step 3, formula V reacts with tetrabutyl ammonium fluoride in methanol solution sloughs hydroxyl protection and get Rui Jiadesong;
As preferably, described in step 1, the mass ratio of compound shown in formula III described in cyclization, 2-formyl radical-3-oxopropanoate and Virahol is 1:(0.23 ~ 0.45): (10 ~ 20).
As preferably, described in step 2, the mass ratio of the methanol solution of compound shown in formula IV and methylamine described in acylation reaction is 1:15 ~ 1:50.
As preferably, 0.8 times ~ 2 times that the consumption of tetrabutyl ammonium fluoride described in deprotection reaction described in step 3 is compound by weight shown in described formula IV.
As preferably, step 3 also comprises Rui Jiadesong separating step, described in be separated into reaction solution to add in normal hexane and after agitation and filtration, collect solid and get Rui Jiadesong.
As preferably, step 3 also comprises Rui Jiadesong purification step, and described purifying is to be separated the Rui Jiadesong that obtains with the mixing solutions of methyl alcohol and methylene dichloride for moving phase carries out silica gel column chromatography.
Present invention also offers compound shown in a kind of formula III,
Present invention also offers the preparation method of compound shown in a kind of formula III, comprising:
Step a, in organic solvent, under catalyst action, take TERT-BUTYL DIMETHYL CHLORO SILANE as protective material, protection is carried out to the hydroxyl of 2-chlorine adenosine and obtains compound shown in formula II;
Compound shown in step b, formula II generates compound shown in formula III with hydrazine hydrate generation substitution reaction in alcoholic solvent;
As preferably, organic solvent described in step a is dimethyl formamide or pyridine.
As preferably, catalyzer described in step a is imidazoles.
The method preparing Rui Jiadesong of the present invention, with compound shown in formula III for reaction raw materials and 2-formyl radical-3-oxopropanoate cyclization occur in Virahol, compound shown in production IV; Afterwards with compound shown in formula IV for substrate, with the methanol solution generation acylation reaction of methylamine, compound shown in production V; Then, in methanol solution, compound shown in formula V and tetrabutyl ammonium fluoride react to be sloughed hydroxyl protection and obtains Rui Jiadesong.The method preparing Rui Jiadesong of the present invention with the methanol solution of methylamine for reaction medium and reagent; react in atmospheric conditions; single step reaction generates benzamide compound; carrying out acylation reaction again without the need to forming carboxylic acid derivative after hydrolysis, shortening reactions steps, avoid using high pressure reactor; reduce Productive statistics cost; improve the safety coefficient of production, iodine is more prone to, and is more suitable for scale operation.This reaction yield is high simultaneously, and product purity is high, only need carry out concentrating under reduced pressure, removing methylamine, intermediate, without the need to separation and purification and loaded down with trivial details last handling process, can carry out next step reaction, simplify the post-processing operation of reaction, accelerate reaction process, reduce production cost, improve production efficiency.
Accompanying drawing explanation
Fig. 1 shows that the present invention prepares the reacting flow chart of Rui Jiadesong;
Fig. 2 shows the mass spectrum of the compound 2 that the embodiment of the present invention 1 is obtained;
Fig. 3 shows the mass spectrum of the compound 3 that the embodiment of the present invention 2 is obtained;
Fig. 4 shows the mass spectrum of the compound 4 that the embodiment of the present invention 3 is obtained;
Fig. 5 shows the mass spectrum of the Rui Jiadesong that the embodiment of the present invention 4 is obtained.
Embodiment
The embodiment of the invention discloses a kind of method preparing Rui Jiadesong.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope method as herein described is changed or suitably change with combination, realize and apply the technology of the present invention.
For realizing object of the present invention, the present invention adopts following technical scheme:
Prepare a method of Rui Jiadesong, comprising:
Compound 3 shown in step 1, formula III in aqueous isopropanol with compound 4 shown in 2-formyl radical-3-oxopropanoate generation cyclization production IV;
Compound 4 shown in step 2, formula IV is compound 5 shown in acidylate production V in the methanol solution of methylamine;
Compound 5 shown in step 3, formula V reacts with tetrabutyl ammonium fluoride in methanol solution sloughs hydroxyl protection and get Rui Jiadesong;
The method steps 1 of preparation Rui Jiadesong of the present invention is first with the 2-diazanyl adenosine derivative of the silica-based protection of the 3(of compound shown in formula III) in Virahol, there is cyclization for reaction raw materials and 2-formyl radical-3-oxopropanoate; the 4(1-{9 of compound shown in production IV [4S; 2R; 3R; 5R]-3,4-dihydroxyl-5-(methylols) oxygen Polymorphs-2-base]-adenine-2-base } the silica-based protection derivative of pyrazoles-4-ethyl formate).The reaction formula of this reaction is
Wherein, preferably, described in step 1, the mass ratio of compound 3 shown in formula III described in cyclization, 2-formyl radical-3-oxopropanoate and Virahol is 1:(0.23 ~ 0.45): (10 ~ 20).Be more preferably 1:0.26:14.
Described in the method steps 1 of preparation Rui Jiadesong of the present invention, the temperature of cyclization is preferably 70 DEG C ~ 80 DEG C, and the time of described cyclization is preferably 2 hours.
As preferably, described in the method steps 1 of preparation Rui Jiadesong of the present invention, cyclization preferably carries out under protection of inert gas.Described rare gas element is preferably nitrogen.
The method steps 1 of preparation Rui Jiadesong of the present invention also comprises the step to the purifying of compound 4 shown in formula IV.
In some embodiments, described is join in frozen water by the reaction solution after cyclization to the purifying of compound 4 shown in formula IV, stirs, and filters, with dry after the mixed solution washing and filtering gained solid of ice isopropyl alcohol and water.Wherein, described frozen water is the mixture of ice and water, and temperature is 0 DEG C; The mixed solution of described ice Virahol and water is the mass ratio of Virahol and water is the mixing solutions of 0.33:1.67, and mixed solution is placed as low temperature in 0-4 DEG C of refrigerator and spent the night.And described compound 3 and the mass ratio of frozen water are preferably 1:80; The mixed solution of described ice Virahol and water and the mass ratio of described compound 3 are preferably 2:1.The described mixed solution washing and filtering gained solid with ice isopropyl alcohol and water preferably washes twice; Described drying for after first draining, 40 DEG C of forced air dryings 12 hours.
Of the present invention preparation Rui Jiadesong method steps 2 with compound 4 shown in formula IV for substrate; with the methanol solution generation acylation reaction of methylamine; the i.e. 5((1-{9 of compound shown in production V [4S; 2R; 3R; 5R]-3; 4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) trimethylsilyl derivatization of-N-METHYLFORMAMIDE); then, in methanol solution, compound 5 shown in formula V and tetrabutyl ammonium fluoride react to be sloughed hydroxyl protection and obtains Rui Jiadesong.The reaction formula of this reaction is
Wherein, preferably, compound 4 shown in formula IV described in acylation reaction described in step 2 is 1:15 ~ 1:50 with the mass ratio of the methanol solution of methylamine.The methanol solution of described methylamine is specially the methylamine methanol solution of 33% ~ 35%.
Described in the method steps 2 of preparation Rui Jiadesong of the present invention, the temperature of acylation reaction is preferably 65 DEG C, and the time of described acylation reaction is preferably 24 hours.
Described in the method steps 2 of preparation Rui Jiadesong of the present invention, acylation reaction is preferably carried out at ambient pressure, is specially and carries out in non-pressure reactor.
Preferably, acylation reaction employing TLC tracking described in the method steps 2 preparing Rui Jiadesong of the present invention is to ensure that reaction raw materials is exhausted.
The method steps 3 of preparation Rui Jiadesong of the present invention is in methanol solution, and compound 5 shown in formula V and tetrabutyl ammonium fluoride react to be sloughed hydroxyl protection and obtain Rui Jiadesong.The reaction formula of this reaction is
Wherein, as preferably, 0.8 times ~ 2 times that the consumption of tetrabutyl ammonium fluoride described in deprotection reaction described in step 3 is the weight of compound 4 shown in described formula IV, namely the mass ratio of compound 4 shown in described tetrabutyl ammonium fluoride and described formula IV is 0.8:1 ~ 2:1.Be more preferably the quantitative responses such as compound 4 shown in described tetrabutyl ammonium fluoride and described formula IV, namely the mass ratio of compound 4 shown in described tetrabutyl ammonium fluoride and described formula IV is 1:1.
Described in the method steps 3 of preparation Rui Jiadesong of the present invention, the methylamine in the methanol solution of methylamine excessive in acylation reaction described in step 2 is first removed by deprotection reaction, avoids the impact of the speed of reaction on deprotection.Concrete preferably decompression removing methylamine at 15 DEG C ~ 50 DEG C.
Described in the method steps 3 of preparation Rui Jiadesong of the present invention, the temperature of deprotection reaction is preferably normal temperature, and the time of described deprotection reaction is preferably 12 hours.
As preferably, deprotection reaction described in step 3 also comprises Rui Jiadesong separating step, described in be separated into reaction solution to add in normal hexane and after agitation and filtration, collect solid and get Rui Jiadesong.Wherein, as preferably, 50 times that the consumption of normal hexane is the weight of compound 4 shown in described formula IV, namely the mass ratio of compound 4 shown in described normal hexane and described formula IV is 50:1.
Further; as preferably; deprotection reaction described in step 3 also comprises Rui Jiadesong purification step, and described purifying is be dissolved in and with the mixing solutions of methyl alcohol and methylene dichloride for moving phase carry out silica gel column chromatography in dimethyl sulfoxide (DMSO) by being separated the Rui Jiadesong that obtains and obtain Rui Jiadesong sterling.Wherein, in the mixing solutions of described methyl alcohol and methylene dichloride, the volume ratio of described methyl alcohol and described methylene dichloride is 10:1.
Silica gel column chromatography is different according to the adsorptive power of material on silica gel and carry out purifies and separates.The material that generally polarity is larger is easily by silica gel adsorption, and the more weak material of polarity is not easily by silica gel adsorption, and namely whole chromatography process be Adsorption and desorption, adsorb again, desorption process again.
In some embodiments, silica gel column chromatography of the present invention is 200-400 object column chromatography silica gel.
The method preparing Rui Jiadesong of the present invention with the methanol solution of methylamine for reaction medium and reagent; react in atmospheric conditions; single step reaction generates benzamide compound; carrying out acylation reaction again without the need to forming carboxylic acid derivative after hydrolysis, shortening reactions steps, avoid using high pressure reactor; reduce Productive statistics cost; improve the safety coefficient of production, iodine is more prone to, and is more suitable for scale operation.This reaction yield is high simultaneously, and product purity is high, only need carry out concentrating under reduced pressure, removing methylamine, intermediate, without the need to separation and purification and loaded down with trivial details last handling process, can carry out next step reaction, simplify the post-processing operation of reaction, accelerate reaction process, reduce production cost, improve production efficiency.
Compound 3 shown in formula III of the present invention is a kind of novel compounds.Therefore present invention also offers compound 3 shown in a kind of formula III,
Compound 3 shown in formula III of the present invention is the 2-diazanyl adenosine derivative of silica-based protection, present invention applicant by its called after 2 ', 3 ', 5 '-tri-tert dimethyl silica-based-2-diazanyl adenosine.
The present invention additionally provides the preparation method of compound 3 shown in described formula III simultaneously.
A preparation method for compound shown in formula III, comprising:
Step a, in organic solvent, under catalyst action, take TERT-BUTYL DIMETHYL CHLORO SILANE as protective material, protection is carried out to the hydroxyl of 2-chlorine adenosine and obtains compound 2 shown in formula II;
Compound 2 shown in step b, formula II generates compound 3 shown in formula III with hydrazine hydrate generation substitution reaction in alcoholic solvent;
The preparation method of compound shown in formula III of the present invention, is first protective material with TERT-BUTYL DIMETHYL CHLORO SILANE, carries out protection obtain the 2(2 ' of compound shown in formula II to the hydroxyl of 2-chlorine adenosine, 3 ', 5 '-tri-tert dimethyl silica-based-2-chlorine adenosine); Then shown in alcoholic solvent Chinese style II, compound 2 and hydrazine hydrate generation substitution reaction generate compound 3(2 ' shown in formula III, 3 ', 5 '-tri-tert dimethyl silica-based-2-diazanyl adenosine).The reaction formula of this reaction is
Wherein, organic solvent described in protective reaction described in step a is preferably dimethyl formamide (DMF) or pyridine, and described catalyzer is preferably imidazoles.
2-chlorine adenosine of the present invention commercialization, that can be bought by commercial channel is obtained.
In certain embodiments, in protective reaction described in the preparation method step a of compound shown in formula III of the present invention, the mass ratio of 2-chlorine adenosine, TERT-BUTYL DIMETHYL CHLORO SILANE, imidazoles and pyridine is 1:(3.3 ~ 5.7): (1.5 ~ 2.2): (7 ~ 13).Be more preferably 1:4.2:1.9:10.
Described in the preparation method step a of compound shown in formula III of the present invention, the temperature of protective reaction is preferably 20 DEG C ~ 60 DEG C, is more preferably 25 DEG C ~ 35 DEG C.The time of deprotection reaction described in step a is preferably 24 hours.
As preferably, protective reaction described in step a also comprises the step to the purifying of compound shown in formula II.
In some embodiments; described purification step is except the organic solvent in the reaction solution of protective reaction gained; add methylene dichloride to dissolve; in system, add saturated sodium bicarbonate saturated solution, stir, separatory; collect methylene dichloride and use anhydrous sodium sulfate drying mutually 2 hours; filter, concentrating under reduced pressure at 40 DEG C ~ 60 DEG C, 40 DEG C of forced air dryings 12 hours.
Be that the reaction solution of protective reaction gained is removed pyridine under concentrating under reduced pressure at 40 DEG C ~ 60 DEG C to the step of the purifying of compound shown in formula II described in some specific embodiments; add methylene dichloride to dissolve; saturated sodium bicarbonate saturated solution is added in system; stir; separatory, methylene dichloride washs once with saturated sodium bicarbonate saturated solution mutually.Three times are washed again with saturated nacl aqueous solution.Methylene dichloride uses anhydrous sodium sulfate drying 2 hours mutually, filters, concentrating under reduced pressure at 40 DEG C ~ 60 DEG C, 40 DEG C of forced air dryings 12 hours.
Wherein, the mass ratio of described methylene dichloride, saturated sodium bicarbonate solution, saturated nacl aqueous solution, anhydrous sodium sulphate and 2-chlorine adenosine is preferably (10 ~ 16): (4 ~ 8): (6 ~ 10): 2:1.Be more preferably 13:6:8:2:1.The described churning time adding saturated sodium bicarbonate saturated solution is preferably 20 ~ 40 minutes.
Substitution reaction described in step b is in certain embodiments specially the alcoholic solvent of compound 2 shown in formula II and dissolves, and reacts under protection of inert gas with hydrazine hydrate.
Described in the preparation method step b of compound shown in formula III of the present invention, described in substitution reaction, alcoholic solvent is preferably ethanol, methyl alcohol or Virahol.
Described in the preparation method step b of compound shown in formula III of the present invention, described in substitution reaction, hydrazine hydrate is preferably 80% 1 hydrazine hydrate.Described in the preparation method step b of compound shown in formula III of the present invention, the temperature of substitution reaction is preferably 65 DEG C ~ 80 DEG C, and the time of described substitution reaction is preferably 20 hours.
As preferably, substitution reaction described in the preparation method step b of compound shown in described formula III is preferably carried out under protection of inert gas.Described rare gas element is preferably nitrogen.
Described in the preparation method step b of compound shown in formula III of the present invention, described in substitution reaction, the mass ratio of compound 2, hydrazine hydrate, dehydrated alcohol is preferably 1:(1.0 ~ 2.2): (3 ~ 5).Be more preferably 1:1.6:4.Wherein, described hydrazine hydrate is 80% 1 hydrazine hydrate.
Preferably, substitution reaction described in the preparation method step b of compound shown in formula III of the present invention adopts TLC to follow the tracks of to ensure that reaction raw materials is exhausted.
As preferably, step b also comprises the step to the purifying of compound shown in formula III.
In some embodiments, described purification step is poured in frozen water by the mixed solution of substitution reaction gained to stir, filtration cakes torrefaction after filtering.Wherein, described churning time is preferably 1 hour.Described drying is preferably 40 DEG C of forced air dryings.Be preferably 12 hours time of drying.Further, preferably, after described filtration, filter cake washes three times with water.Described frozen water is the mixture of ice and water.In some embodiments, shown in described bath water and formula II, the mass ratio of compound 2 is preferably 1:2.
Shown in formula III of the present invention, the preparation method of compound reacts simple, processing ease, and each step reaction yield is high.Shown in simultaneously obtained formula III, compound purity is high.
In order to understand the present invention further, below in conjunction with embodiment, a kind of method that the invention provides Rui Jiadesong of preparation is described in detail.Wherein, described water is all preferably purified water.Compound 1(2-chlorine adenosine of the present invention) purchased from Shanghai Mai Ruier chemical technology company limited.
Embodiment 1: compound 2, the i.e. preparation of 2 ', 3 ', 5 '-tri-tert dimethylsilyl bis-2-chlorine adenosine
50g compound 1 is added in 500g pyridine.Continue under stirring to add 210g TERT-BUTYL DIMETHYL CHLORO SILANE and 90g imidazoles, at 25 DEG C, stirring and dissolving is complete, reacts 24 hours.TLC analyzes tracking, raw material consumption is complete, at 50 DEG C, and 100Pa concetrated under reduced pressure removing pyridine, participate in adding 650g methylene dichloride in solid to dissolve gradually, in system, add 300g saturated sodium bicarbonate saturated solution, stir 30 minutes, have a large amount of bubble to produce, treat bubble collapse, static 30 minutes, separatory, methylene dichloride washed once with 300g saturated sodium bicarbonate saturated solution mutually.Methylene dichloride saturated nacl aqueous solution washs three times, each 400g.Methylene dichloride uses 100g anhydrous sodium sulfate drying 2 hours mutually, filters, 100Pa concentrating under reduced pressure at 50 DEG C, 40 DEG C of forced air dryings 12 hours.Obtain compound 2, yield 86%, purity 92%, mass spectrometric detection, [M+Na]
+=666.
Embodiment 2: compound 3, the i.e. preparation of 2 ', 3 ', 5 '-tri-tert dimethylsilyl bis-2-diazanyl adenosine
50g compound 2 is dissolved in 200g dehydrated alcohol, stirring and dissolving at 50 DEG C.Under nitrogen protection, add 80g80% mono-hydrazine hydrate, temperature rises to 70 DEG C.React 20 hours, TLC follows the tracks of reaction process, and raw material consumption is complete, is slowly poured into by reaction solution in 2kg frozen water, stirs 1 hour, filters.Filter cake purified water washs three times, each 100g.Drain.40 DEG C of forced air dryings 12 hours, obtain compound 3.Yield 94%, purity 92%.Mass spectrometric detection [M+Na]
+=662.
Embodiment 3: compound 4,1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } the silica-based protection derivative preparation of pyrazoles-4-ethyl formate.
Under nitrogen protection 50g compound 3 is dissolved in Virahol, is heated to 80 DEG C, add 13g2-formyl radical-3-oxopropanoate; react end in 2 hours, TLC monitors reaction process, after raw material consumption; reaction system is imported in the purified water of 4kg ice, stir 30 minutes.Filter, the mixed solution being 1:6 than water with ice Virahol, washing leaching cake twice, each 100g, after filter cake is drained, 40 DEG C of forced air dryings 12 hours, obtain compound 4.Yield 90%, purity 88%.Mass spectrometric detection [M+Na]
+=770.
Embodiment 4: Rui Jiadesong, (1-{9 [4S, 2R, 3R, 5R]-3,4-dihydroxyl-5-(methylol) oxygen Polymorphs-2-base]-adenine-2-base } pyrazoles-4-base) preparation of-N-METHYLFORMAMIDE
At ambient pressure, 25g compound 4 is dissolved in the methanol solution of 500g methylamine, after stirring, is warming up to 65 DEG C, react 24 hours.After raw material consumption, 30 DEG C of decompression removing methylamines, under normal temperature, in reaction solution, directly add 25g tetrabutyl ammonium fluoride, react 12 hours, solid is separated out, filtration, 40 DEG C of forced air dryings 12 hours, the crude product of get Rui Jiadesong.Yield 50%, purity 88%.
Rui Jiadesong crude product 10g, is dissolved in 15mL DMSO solution, is added to the top layer of chromatography column evenly, and with methylene dichloride: methyl alcohol (v/v)=10:1 is eluent, TLC follows the tracks of, and obtains highly purified Rui Jiadesong sterling.Yield 80%, purity 99%.Mass spectrometric detection, [M+Na]
+=413.
1HNMR(CD3OD)δ2.90（s，3H），3.78(m，1H)，3.91(m，1H)，4.13（d，1H），4.34（d，1H），4.64（m，1H），6.06（d，1H），7.11（s，1H），8.38（s，1H），9.05（s，1H）.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (10)
1. prepare a method of Rui Jiadesong, it is characterized in that, comprising:
Compound shown in step 1, formula III in aqueous isopropanol with compound shown in 2-formyl radical-3-oxopropanoate generation cyclization production IV;
Compound shown in step 2, formula IV is compound shown in acidylate production V in the methanol solution of methylamine;
Compound shown in step 3, formula V reacts with tetrabutyl ammonium fluoride in methanol solution sloughs hydroxyl protection and get Rui Jiadesong;
2. method according to claim 1, is characterized in that, described in step 1, the mass ratio of compound shown in formula III described in cyclization, 2-formyl radical-3-oxopropanoate and Virahol is 1:(0.23 ~ 0.45): (10 ~ 20).
3. method according to claim 1, is characterized in that, described in step 2, the mass ratio of the methanol solution of compound shown in formula IV and methylamine described in acylation reaction is 1:15 ~ 1:50.
4. method according to claim 1, is characterized in that, 0.8 times ~ 2 times that the consumption of tetrabutyl ammonium fluoride described in deprotection reaction described in step 3 is compound by weight shown in described formula IV.
5. method according to claim 1, is characterized in that, step 3 also comprises Rui Jiadesong separating step, described in be separated into reaction solution to add in normal hexane and after agitation and filtration, collect solid and get Rui Jiadesong.
6. method according to claim 5, is characterized in that, step 3 also comprises Rui Jiadesong purification step, and described purifying is to be separated the Rui Jiadesong that obtains with the mixing solutions of methyl alcohol and methylene dichloride for moving phase carries out silica gel column chromatography.
7. a compound shown in formula III,
8. a preparation method for compound shown in formula III, is characterized in that, comprising:
Step a, in organic solvent, under catalyst action, take TERT-BUTYL DIMETHYL CHLORO SILANE as protective material, protection is carried out to the hydroxyl of 2-chlorine adenosine and obtains compound shown in formula II;
Compound shown in step b, formula II generates compound shown in formula III with hydrazine hydrate generation substitution reaction in alcoholic solvent;
9. method according to claim 8, is characterized in that, organic solvent described in step a is dimethyl formamide or pyridine.
10. method according to claim 8, is characterized in that, catalyzer described in step a is imidazoles.
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| CN106397442A (en) * | 2015-07-28 | 2017-02-15 | 国药集团国瑞药业有限公司 | Regadenoson purification method |
| CN110483602A (en) * | 2019-09-20 | 2019-11-22 | 常州方圆制药有限公司 | A kind of preparation method of Rui Jiadesong |
| CN111909156A (en) * | 2020-08-25 | 2020-11-10 | 常州齐晖药业有限公司 | Preparation method of olatinib maleate |
| CN113943334A (en) * | 2020-06-30 | 2022-01-18 | 常州方圆制药有限公司 | A2AAdenosine receptor agonists |
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| CN106397442B (en) * | 2015-07-28 | 2020-03-27 | 国药集团国瑞药业有限公司 | Purification method of regadenoson |
| CN105866290A (en) * | 2016-05-15 | 2016-08-17 | 南京海融医药科技有限公司 | High performance liquid chromatographic analysis method for related substances of regadenoson |
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| CN113943334A (en) * | 2020-06-30 | 2022-01-18 | 常州方圆制药有限公司 | A2AAdenosine receptor agonists |
| CN113943334B (en) * | 2020-06-30 | 2024-04-09 | 常州方圆制药有限公司 | A, A 2A Process for preparing adenosine receptor agonists |
| CN111909156A (en) * | 2020-08-25 | 2020-11-10 | 常州齐晖药业有限公司 | Preparation method of olatinib maleate |
| CN111909156B (en) * | 2020-08-25 | 2022-04-05 | 常州齐晖药业有限公司 | Preparation method of olatinib maleate |
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