CN107573346A - N9 is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton - Google Patents
N9 is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton Download PDFInfo
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Abstract
The invention discloses the simple synthesis that N9 on a kind of purine skeleton is alkylated nucleoside analog.This method comprises the following steps：By 2,6 substituted purin derivatives and excessive alkyl ether are added in reactor, add non-metallic catalyst and oxidant, oxidative coupling reaction is carried out under condition of heating and stirring, is tracked and reacted using thin-layer chromatographic analysis, after reaction terminates, it is cooled to room temperature, it is concentrated in vacuo and removes solvent, column chromatography purifying, obtains N9 on the purine skeleton and be alkylated nucleoside analog.Synthetic method raw material of the present invention is cheap and easily-available, reaction condition is gentle, reactions steps are few, simple to operate, solving the problems, such as to exist in prior art purine derivative reaction includes that metallic catalyst is easily poisoned, reactive group is difficult compatible and reaction site is more, efficiently synthesizes N9 alkylations nucleoside analog on purine skeleton.
Description
Technical field
The present invention relates to nucleoside analog synthesis technical field, and in particular to N9- is alkylated nucleosides on a kind of purine skeleton
Analog and its simple synthesis.
Background technology
Nucleoside medicine has very important status in clinical antiviral therapy.Ucleosides after engineered or modification
There is certain similitude like thing and natural nucleus glycoside, its action target spot is the polymerization of the reverse transcriptase and DNA virus of RNA virus
Enzyme, and viral DNA chain is competitively embedded in nucleotides, suppress or terminate the extension and synthesis of viral DNA chain, so as to suppress disease
Malicious DNA duplication.Modification and improved nucleoside analog have unique bioactivity, so far, have been used for clinical treatment
Antiviral nucleoside medicine has：ACV (Acyclovir, ACV), may interfere with viral DNA polymerase, suppress answering for virus
System；GCV (Ganciclovir, GAV), competitiveness are combined with viral dna polymerase, prevent the extension of viral DNA；Spray former times
Luo Wei (Penciclovir, PCV), suppress viral DNA polymerase, so as to suppress the synthesis of viral DNA；Adefovirdipivoxil
(Adefovir, PMEA), the activity of archaeal dna polymerase can be suppressed, prevent the synthesis of viral DNA.But the ucleosides medicine of existing application
Thing is still more there is adverse reaction, and toxicity is big, easily the shortcomings of generation drug resistance.Therefore efficient green purine biosynthesis nucleosides medicine
The diversified purine nucleosides storehouse of thing molecule and structure with potential pharmacological activity, has great theory significance and commercial Application
Value.
The synthesis main method of nucleoside analog traditional at present has：1st, parent occurs using halogenated alkyl compounds and purine
Core substitution reaction, this method need to pre-process alkylating reagent, generally also need to add highly basic promotion reaction progress, and nothing
Method avoids the generation of other reaction site accessory substances of purine, causes later separation difficulty (Kotek, V.；Chudíkova′,N.；
Tobrman,T.；Dvoròa′k,D.；Selective Synthesis of 7-Substituted Purines via 7,8-
Dihydropurines.Org.Lett.,2010,12,5724).2nd, traditional transition metal-catalyzed cross-coupling reaction, this
Method needs transition metal as catalyst, and transition metal is general costly, and is easily chelated or be coordinated with purine,
Cause catalyst poisoning (Kim, D.；Jun,H.；Lee,H.；Hong,S-S.；Hong, S., Development of New
Fluorescent Xanthines as Kinase Inhibitors.Org.Lett.,2010,12,1212).3rd, 2011,
Guo haiming seminars are found that with PIDA/I2For catalyst, alkyl ether is alkylating reagent, is sent out through free radical mechanism
Raw purine N9 alkylated reactions, the reaction used the PIDA of costliness as catalyst and substrate application and be limited (Guo,
H.-M.；Xia,C.；Niu,H.-Y.；Zhang,X.-T.；Kong,S.-N.；Wang,D.-C.；Qu,G.-R.,
Intermolecular Hydrogen Abstraction Reaction between Nitrogen Radicals in
Purine Rings and Alkyl Ethers:A Highly Selective Method for the Synthesis of
N-9 Alkylated Purine Nucleoside Derivatives.Advanced Synthesis&Catalysis
2011,353,53-56.).4th, 2013, Liu jinhua seminars were delivered with CuCl2For catalyst, TBHP is oxidant,
Under the regulating and controlling effect of part, the coupling reaction of purine and ether compound, serial purine N9 derivatives, but the reaction have been synthesized
Need part to regulate and control, add the complexity of course of reaction, have impact on its commercial Application (Huang, R.；Xie,C.；Huang,
L.；Liu,J.,Copper-catalyzed N-alkoxyalkylation of nucleobases involving direct
functionalization of sp3 C–H bonds adjacent to oxygen atoms.Tetrahedron 2013,
69,577-582.)。
So far, the synthesis both at home and abroad to nucleoside analog conducts extensive research.By being carried out to purine skeleton
Modify and transform to synthesize the nucleoside medicine with good biological activity, it is applied in clinical antiviral therapy, to people
Class health will produce far reaching significance.Therefore, seek that a kind of raw material is cheap and easily-available, reaction condition is gentle, reactions steps are few, operation is simple
It is single, the approach that N9- on purine skeleton is alkylated nucleoside analog is efficiently synthesized, based on solving to exist in purine derivative reaction
The problems such as metallic catalyst is easily poisoned, reactive group is difficult compatible, and reaction site is more, and synthesize the nucleosides with potential pharmacological activity
Class medicine is extremely urgent, very urgent.
The content of the invention
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to provide a kind of easy synthesis side of nucleoside analog
Method, the simple synthesis of N9- alkylations nucleoside analog on specially a kind of purine skeleton.This method is substituted fast with 2,6- positions
Purine derivative and alkyl ether are raw material, add catalyst and oxidant, and wherein alkyl ether is both used as reaction reagent, are also served as anti-
Solvent is answered, in air atmosphere, by free radical initiated oxidation coupling reaction, N9- is alkylated ucleosides on purine biosynthesis skeleton
Like thing.
The purpose of the present invention is achieved through the following technical solutions.
N9- is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton, comprises the following steps：
2,6- positions substituted purin derivatives and excessive alkyl ether are added in reactor, add non-metallic catalyst and
Oxidant, oxidative coupling reaction is carried out under condition of heating and stirring, tracked and reacted using thin-layer chromatographic analysis (TLC), reaction terminates
Afterwards, it is cooled to room temperature, is concentrated in vacuo and removes solvent, column chromatography purifying, it is similar obtains N9- alkylations nucleosides on the purine skeleton
Thing.
Further, the chemical structural formula of 2,6- positions substituted purin derivatives is as follows：
Wherein, R1It is H, halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R2Be H,
Halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group.
Further, the alkyl ether also serves as solvent, the chemical structural formula of alkyl ether is such as alkylated reaction reagent
Shown in lower：
Wherein, R3It is alkyl；R4It is H, alkyl or alkoxy.
Further, the product of synthesis, i.e., the chemical structural formula of N9- alkylations nucleoside analog is such as on described purine skeleton
Shown in lower：
Wherein, R1It is H, halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R2Be H,
Halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R3It is alkyl；R4 is H, alkyl or alcoxyl
Base.
Further, the chemical equation of the oxidative coupling reaction is as follows：
Wherein, R1It is H, halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R2Be H,
Halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R3It is alkyl；R4It is H, alkyl or alcoxyl
Base.
Further, the non-metallic catalyst is iodine negative ionization compound, including tetrabutylammonium iodide (Bu4NI,
TBAI)。
Further, the dosage of the non-metallic catalyst is the 10-20mmol% of 2,6- positions substituted purin derivatives.
Further, the oxidant includes tert-butyl peroxide (t-BuOOH, TBHP).
Further, the oxidant is the 2-5 equivalents of 2,6- positions substituted purin derivatives.
Further, the oxidative coupling reaction is to carry out in air atmosphere.
Further, the temperature of the oxidative coupling reaction is 60-100 DEG C.
Further, the time of the oxidative coupling reaction is 9-24h.
Further, the eluent of the column chromatography purifying is volume ratio 2-20:1-10:0-1 petroleum ether, ethyl acetate
With the mixed solvent of triethylamine.
The synthetic method of the present invention has following outstanding feature：
Reactions steps are few：Synthetic route avoids the cumbersome of course of reaction, and pair without carrying out pre-activate processing to raw material
Product is less, avoids later separation difficult；
Reaction condition is gentle：Synthetic route need not add alkali, need to only be placed at 60-100 DEG C and react i.e. under air conditionses
Can, avoid the harsh conditions of anhydrous and oxygen-free；
Catalyst cheaply easily obtains：The catalyst of use is iodine negative ionization compound, avoids expensive transition metal palladium, silver
Use, and work well, avoid catalyst poisoning；
Heterocycle reagent easily obtains：The alkyl ether of use, it is cheap easily to obtain, both used as reactant, made again as solvent
With, and be easily recycled.
Compared with prior art, the invention has the advantages that and beneficial effect：
(1) raw material of synthetic method of the present invention is cheap and easily-available, and reaction condition is gentle, simple to operate, and step is few, solves existing
Having in technology purine derivative reaction to exist includes metallic catalyst and is easily poisoned, more than the difficult compatibility of reactive group and reaction site
Problem, efficiently synthesize N9- on purine skeleton and be alkylated nucleoside analog；
(2) synthetic method of the present invention realizes the Atom economy and high selectivity of purine derivatization, has reached quick height
The target in the diversified purine nucleosides storehouse of green syt purine nucleosides drug molecule and structure with potential pharmacological activity is imitated,
With extensive prospects for commercial application；
(3) oxidative coupling reaction that synthetic method of the present invention is triggered with cheap and easily-available raw material by free radical, synthesis are fast
N9- is alkylated nucleoside analog on purine skeleton, and new easy synthetic route is provided for the synthesis of nucleoside analog.
Embodiment
Technical solution of the present invention is described in further detail below in conjunction with specific embodiment, but protection scope of the present invention
Not limited to this.
In the specific embodiment of the invention, N9- is alkylated the simple synthesis of nucleoside analog on purine skeleton, including such as
Lower step：
2,6- positions substituted purin derivatives and excessive alkyl ether are added in reactor, add non-metallic catalyst
TBAI and oxidant TBHP, oxidative coupling reaction 9-24h is carried out under 60-100 DEG C of condition of heating and stirring, using thin-layer chromatographic analysis
(TLC) tracking reaction, after reaction terminates, it is cooled to room temperature, is concentrated in vacuo and removes solvent, column chromatography purifying, obtains the purine bone
N9- is alkylated nucleoside analog on frame；
Specific chemical equation is as follows：
R1It is H, halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R2Be H, halogen,
Amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R3It is alkyl；R4It is H, alkyl or alkoxy.
Specific embodiment, N9- on obtained purine skeleton is characterized using nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data and is alkylated core
The architectural feature of glycosides analog.
Embodiment 1
The synthesis of the chloro- 9- of the fluoro- 6- of 2- (2- tetrahydrofurans) purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add the fluoro- 6-chloropurines of 2- (0.2mmol, 0.0344g), TBAI
(0.04mmol, 0.0148g) and 0.5mL THF, then TBHP (0.6mmol, 0.0547g) is slowly added, will under air conditionses
Tube sealing is placed in agitating and heating 24h in 90 DEG C of oil bath pans；Being tracked and reacted with TLC, after terminating reaction, question response liquid is cooled to room temperature,
It is concentrated in vacuo and removes solvent, purifies that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=2：1, v/v) target product, is obtained
The chloro- 9- of the fluoro- 6- of 2- (2- tetrahydrofurans) purine, yield 87%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.24(s,1H),
6.33-6.27 (m, 1H), 4.32 (dd, J=14.7,6.7Hz, 1H), 4.11 (dd, J=15.8,7.5Hz, 1H), 2.61-2.53
(m,2H),2.23–2.16(m,2H)；13C NMR(100MHz,CDCl3)δ158.2,156.0,152.8,152.6,144.1,
144.1,86.9,70.1,32.6,24.2.HR-MS(ESI)calcd for[M+Na]+:C9H8ClFN4NaO:265.0263,
found:265.0270.
The chemical structural formula of the chloro- 9- of the fluoro- 6- of products therefrom 2- (2- tetrahydrofurans) purine is as follows：
Embodiment 2
The synthesis of 2- chloro- 6- methyl mercaptos -9- (2- tetrahydrofurans) purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add the chloro- 6- methyl mercaptos purine (0.2mmol, 0.0402g) of 2-,
TBAI (0.04mmol, 0.0148g) and 0.5mL THF, then TBHP (0.4mmol, 0.0360g) is slowly added, in air conditionses
Under, tube sealing is placed in agitating and heating 9h in 90 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, question response liquid is cooled to room
Temperature, it is concentrated in vacuo and removes solvent, purify that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=3：1, v/v) target production, is obtained
Thing 2- chloro- 6- methyl mercaptos -9- (2- tetrahydrofurans) purine, yield 89%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.04(s,1H),
6.30-6.26 (m, 1H), 4.28 (dd, J=14.9,6.5Hz, 1H), 4.07 (dd, J=15.7,7.5Hz, 1H), 2.72 (s,
3H),2.54–2.49(m,2H),2.17–2.12(m,2H)；13C NMR(100MHz,CDCl3)δ163.8,153.5,148.8,
141.1,131.0,86.2,70.0,32.7,24.2,12.1.HR-MS(ESI)calcd for[M+Na]+:C10H11ClN4NaOS:
293.0234,found:293.0238.
The chemical structural formula of products therefrom 2- chloro- 6- methyl mercaptos -9- (2- tetrahydrofurans) purine is as follows：
Embodiment 3
The synthesis of 6- lignocaines -9- (2- tetrahydrofurans) purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add 6- lignocaines purine (0.2mmol, 0.0382g), TBAI
(0.04mmol, 0.0148g) and 0.5mL THF, then TBHP (0.6mmol, 0.0547g) is slowly added, will under air conditionses
Reaction tube is placed in agitating and heating 10h in 70 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, question response liquid is cooled to room
Temperature, it is concentrated in vacuo and removes solvent, purify that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=3：1, v/v) target production, is obtained
Thing 6- lignocaines -9- (2- tetrahydrofurans) purine, yield 71%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.25(s,1H),
7.75 (s, 1H), 6.25-6.20 (m, 1H), 4.18 (dd, J=14.8,6.5Hz, 1H), 3.99-3.92 (m, 4H), 2.45-
2.37 (m, 2H), 2.07-2.00 (m, 2H), 1.21 (t, J=7.0Hz, 6H)；13C NMR(100MHz,CDCl3)δ153.7,
152.5,149.8,136.0,120.2,85.5,69.5,43.0,32.4,24.2,13.5.HR-MS(ESI)calcd for[M+
H]+:C13H20N5O:262.1662,found:262.1666.
The chemical structural formula of products therefrom 6- lignocaines -9- (2- tetrahydrofurans) purine is as follows：
Embodiment 4
The synthesis of 9- (2- tetrahydrofurans) adenine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add adenine (0.2mmol, 0.0270g), TBAI (0.04mmol,
0.0148g) and 0.5mL THF, then TBHP (0.6mmol, 0.0547g) is slowly added, under air conditionses, reaction tube is placed in
Agitating and heating 12h in 90 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, question response liquid is cooled to room temperature, is concentrated in vacuo
Solvent is removed, purifies that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate：Triethylamine=20：10：1, v/v) target production, is obtained
Thing 9- (2- tetrahydrofurans) adenine, yield 90%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.27(s,1H),
7.85 (s, 1H), 6.27-6.19 (m, 1H), 6.04 (s, 2H), 4.20 (dd, J=14.7,6.7Hz, 1H), 3.99 (dd, J=
15.5,7.5Hz,1H),2.48–2.40(m,2H),2.09–2.03(m,2H)；13C NMR(100MHz,CDCl3)δ155.6,
152.9,149.3,138.4,120.2,85.9,69.6,32.5,24.3.HR-MS(ESI)calcd for[M+H]+:C9H12N5O:
206.1036,found:206.1037.
The chemical structural formula of products therefrom 9- (2- tetrahydrofurans) adenine is as follows：
Embodiment 5
The synthesis of 2- (two t-butoxycarbonyl aminos) -6- chloro- 9- (2- tetrahydrofurans) purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add 2- (two t-butoxycarbonyl aminos) -6-chloropurine (0.1mmol,
0.0369g), TBAI (0.02mmol, 0.0074g) and 0.5mL THF, then TBHP (0.3mmol, 0.0270g) is slowly added,
Under air conditionses, reaction tube is placed in agitating and heating 20h in 90 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, treated anti-
Answer liquid to be cooled to room temperature, be concentrated in vacuo and remove solvent, purify that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=4：1, v/
V), target product 2- (two t-butoxycarbonyl aminos) -6- chloro- 9- (2- tetrahydrofurans) purine, yield 81% are obtained.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.18(s,1H),
6.23 (dd, J=6.4,3.1Hz, 1H), 4.22 (dd, J=14.9,6.5Hz, 1H), 4.01 (dd, J=15.7,7.4Hz, 1H),
2.54–2.40(m,2H),2.12–2.04(m,2H),1.38(s,18H)；13C NMR(100MHz,CDCl3)δ151.7,151.6,
151.1,150.6,144.3,130.7,86.8,83.6,70.0,32.5,27.9,24.2.HR-MS(ESI)calcd for[M+
Na]+:C19H26ClN5NaO5:462.1515,found:462.1524.
The chemical structural formula of products therefrom 2- (two t-butoxycarbonyl aminos) -6- chloro- 9- (2- tetrahydrofurans) purine is as follows
It is shown：
Embodiment 6
The synthesis of the chloro- 9- of 6- [2- (5- methyltetrahydrofurans)] purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add 6-chloropurine (0.2mmol, 0.0308g), TBAI
(0.04mmol, 0.0148g) and 0.5mL 2- methyltetrahydrofurans, then TBHP (0.8mmol, 0.0721g) is slowly added, in sky
Under the conditions of gas, reaction tube is placed in agitating and heating 10h in 100 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, question response
Liquid is cooled to room temperature, is concentrated in vacuo and removes solvent, purifies that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=3：1, v/v),
Obtain the chloro- 9- of target product 6- [2- (5- methyltetrahydrofurans)] purine, yield 70% (obtain for 1：1 alloisomerism
Body).
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.72(s,2H),
8.30(s,1H),8.24(s,1H),6.36(s,1H),6.30(s,1H),4.66–4.57(m,1H),4.40–4.27(m,1H),
2.65 (dd, J=16.1,8.9Hz, 1H), 2.56 (dd, J=9.1,4.5Hz, 1H), 2.31 (dd, J=12.8,6.5Hz, 1H),
2.21 (dd, J=10.0,4.7Hz, 1H), 1.80-1.71 (m, 1H), 1.44 (d, J=5.9Hz, 2H), 1.33 (d, J=
5.9Hz,2H)；13CNMR(100MHz,CDCl3)δ151.8,151.8,151.0,150.9,150.9,150.8,143.6,
143.4,132.4,132.4,86.5,86.2,78.7,77.7,33.4,32.3,31.8,31.4,20.9,20.7.HR-MS
(ESI)calcd for[M+Na]+:C10H11ClN4NaO:261.0514,found:261.0518.
The chemical structural formula of the chloro- 9- of products therefrom 6- [2- (5- methyltetrahydrofurans)] purine is as follows：
Embodiment 7
The synthesis of the chloro- 9- of 6- (1- methoxyl group -2- ethoxyethyl groups) purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add 6-chloropurine (0.2mmol, 0.0308g), TBAI
(0.02mmol, 0.0074g) and 1mL glycol dimethyl ethers, then TBHP (1mmol, 0.0901g) is slowly added, in air conditionses
Under, reaction tube is placed in agitating and heating 16h in 90 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, the cooling of question response liquid
To room temperature, it is concentrated in vacuo and removes solvent, purifies that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=3：1, v/v) mesh, is obtained
Mark product 6- chloro- 9- (1- methoxyl group -2- ethoxyethyl groups) purine, yield 41%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.74(s,1H),
8.36 (s, 1H), 5.88 (t, J=4.7Hz, 1H), 3.90 (dd, J=10.5,5.1Hz, 1H), 3.80 (dd, J=10.5,
4.2Hz, 1H), 3.36 (d, J=11.1Hz, 6H)13C NMR(100MHz,CDCl3)δ152.2,152.1,151.2,143.9,
131.5,84.6,72.8,59.7,57.3.HR-MS(ESI)calcd for[M+Na]+:C9H11ClN4NaO2:265.0463,
found:265.0466.
The chemical structural formula of the chloro- 9- of products therefrom 6- (1- methoxyl group -2- ethoxyethyl groups) purine is as follows：
Embodiment 8
The synthesis of 6- chloro- 9- (t-butoxymethyl) purine, specifically comprises the following steps：
Take a drying to add the 35mL tube sealings of magneton, add 6-chloropurine (0.2mmol, 0.0308g), TBAI
(0.04mmol, 0.0148g) and 0.5mL methyl tertiary butyl ether(MTBE)s, then TBHP (0.6mmol, 0.0547g) is slowly added, in air
Under the conditions of, reaction tube is placed in agitating and heating 12h in 60 DEG C of oil bath pans；Tracked and reacted with TLC, after terminating reaction, question response liquid
It is cooled to room temperature, is concentrated in vacuo and removes solvent, purifies that (eluant, eluent is petroleum ether through column chromatography：Ethyl acetate=2：1, v/v), obtain
To target product 6- chloro- 9- (t-butoxymethyl) purine, yield 83%.
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon modal data characterization result are as follows：1H NMR(400MHz,CDCl3)δ8.68(s,1H),
8.27(s,1H),5.64(s,2H),1.18(s,9H).13CNMR(100MHz,CDCl3)δ152.0,151.2,150.8,145.3,
131.4,76.2,67.5,27.7.HR-MS(ESI)calcd for[M+Na]+:C10H13ClN4NaO:263.0670,found:
263.0672.
The chemical structural formula of products therefrom 6- chloro- 9- (t-butoxymethyl) purine is as follows：
It should be appreciated that those skilled in the art is according to true spirit of the present invention, in the specific embodiment of the invention
On the basis of any modification, replacement or the change made etc., should all cover within the scope of the present invention.
Claims (10)
1. N9- is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton, it is characterised in that including following step
Suddenly：
2,6- positions substituted purin derivatives and excessive alkyl ether are added in reactor, add non-metallic catalyst and oxidation
Agent, oxidative coupling reaction is carried out under condition of heating and stirring, tracked and reacted using thin-layer chromatographic analysis, after reaction terminates, be cooled to room
Temperature, it is concentrated in vacuo and removes solvent, column chromatography purifying, obtains N9- on the purine skeleton and be alkylated nucleoside analog.
2. according to the method for claim 1, it is characterised in that the chemical structural formula of 2,6- positions substituted purin derivatives
It is as follows：
Wherein, R1It is H, halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R2Be H, halogen,
Amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；
The chemical structural formula of the alkyl ether is as follows：
Wherein, R3It is alkyl；R4It is H, alkyl or alkoxy.
3. according to the method for claim 2, it is characterised in that the chemical equation of the oxidative coupling reaction is as follows：
Wherein, R1It is H, halogen, amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R2Be H, halogen,
Amino, alkyl, N- alkyl aminos, dialkyl amido, alkoxy or alkylthio group；R3It is alkyl；R4It is H, alkyl or alkoxy.
4. according to the method for claim 1, it is characterised in that the non-metallic catalyst is iodine negative ionization compound, bag
Include tetrabutylammonium iodide.
5. according to the method for claim 1, it is characterised in that the dosage of the non-metallic catalyst is that the substitution of 2,6- positions is fast
The 10-20mmol% of purine derivative.
6. according to the method for claim 1, it is characterised in that the oxidant includes tert-butyl peroxide.
7. according to the method for claim 1, it is characterised in that the oxidant is the 2- of 2,6- positions substituted purin derivatives
5 equivalents.
8. according to the method for claim 1, it is characterised in that the oxidative coupling reaction is to carry out in air atmosphere.
9. according to the method for claim 1, it is characterised in that the temperature of the oxidative coupling reaction is 60-100 DEG C.
10. according to the method for claim 1, it is characterised in that the time of the oxidative coupling reaction is 9-24h.
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| CN109608462A (en) * | 2018-12-15 | 2019-04-12 | 华南理工大学 | A kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds and its synthetic method and the application in drug |
| CN111925372A (en) * | 2020-08-11 | 2020-11-13 | 五邑大学 | Method for modifying purine nucleoside compound |
| CN114249730A (en) * | 2022-01-07 | 2022-03-29 | 杭州师范大学 | One-step synthesis method of 2 '3' -dideoxynucleoside |
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| EP2336133A1 (en) * | 2001-10-30 | 2011-06-22 | Conforma Therapeutics Corporation | Purine analogs having HSP90-inhibiting activity |
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| EP2336133A1 (en) * | 2001-10-30 | 2011-06-22 | Conforma Therapeutics Corporation | Purine analogs having HSP90-inhibiting activity |
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| HAI-MING GUO ET AL.: "Intermolecular Hydrogen Abstraction Reaction between Nitrogen Radicals in Purine Rings and Alkyl Ethers: A Highly Selective Method for the Synthesis of N-9 Alkylated Purine Nucleoside Derivatives", 《ADV. SYNTH. CATAL.》 * |
| HARIPRASAD ARURI ET AL.: "Cross-Dehydrogenative Coupling of Azoles with α-C(sp3)-H of Ethers and Thioethers under Metal-Free Conditions: Functionalization of H-N Azoles via C-H Activation", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109608462A (en) * | 2018-12-15 | 2019-04-12 | 华南理工大学 | A kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds and its synthetic method and the application in drug |
| CN109608462B (en) * | 2018-12-15 | 2021-11-23 | 华南理工大学 | 7-alkyl-9-alkoxy/thiopurine-8-ketone compound, and synthesis method and application thereof in medicines |
| CN111925372A (en) * | 2020-08-11 | 2020-11-13 | 五邑大学 | Method for modifying purine nucleoside compound |
| CN114249730A (en) * | 2022-01-07 | 2022-03-29 | 杭州师范大学 | One-step synthesis method of 2 '3' -dideoxynucleoside |
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