CN108774229A - A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center - Google Patents

A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center Download PDF

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CN108774229A
CN108774229A CN201810791137.1A CN201810791137A CN108774229A CN 108774229 A CN108774229 A CN 108774229A CN 201810791137 A CN201810791137 A CN 201810791137A CN 108774229 A CN108774229 A CN 108774229A
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pyrazoline
reaction
quaternary carbon
synthetic method
carbon center
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CN108774229B (en
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郭海明
谢明胜
郭真
王东超
王海霞
渠桂荣
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Henan Normal University
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Abstract

The pyrazoline nucleoside analog synthetic method with quaternary carbon center that the invention discloses a kind of, belongs to technical field of organic chemistry.It is raw material with 9- connection alkene purine 1 and alpha-alkyl/aryldiazonium acetic acid esters 2, with DPPB or Pd2(dba)3For catalyst, the pyrazolines purine nucleoside analogs 3 with quaternary carbon center are obtained after reaction, reaction yield is medium to outstanding.In the present invention, by the change of catalyst system and catalyzing, the diversity and unicity of pyrazoline product can be effectively controlled, product obtains pyrazoles purine nucleoside analogs 5 after further hydrogenating.

Description

A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center
Technical field
The present invention relates to the synthesis of purine nucleoside analogs, and in particular to a kind of pyrazoline ucleosides with quaternary carbon center Like the synthetic method of object, belong to the organic synthesis field in organic chemistry.
Background technology
Pyrazoline compounds containing quaternary carbon center generally existing in many bioactive molecules.For such pyrrole The representative example of isoxazoline compound has：In the herbicides and safeners mefenpyrdiethyl of city's sale, insecticide RH 3421, and tool There is the chloro-quinine pyrazoline etc. of good antimalarial active.Therefore, pyrazoline right and wrong of the structure with quaternary carbon center are often with answering With foreground.
1,3- Dipolar Cycloaddition synthesizing pyrazole quinolines using diazo ester are very classical synthetic methods.Alkene or alkynes The cycloaddition reaction of hydrocarbon and alkyl diazonium or diazonium acetate has had very more reports.However, in contrast to this, connection alkene this The report that class cumulene carries out 1.3- dipole-diople interactions with diazonium compound is still rarer.Meanwhile containing The pyrazoline synthesis of quaternary carbon center is also that few documents disclose report.
Invention content
To overcome drawbacks described above, the present invention is used joins alkene purine and alpha-alkyl/aryldiazonium acetic acid esters as raw material using 9-, adds Enter solvent, with DPPB/Pd2(dba)3Catalyst synthesizing pyrazole morpholine nucleoside analog.Novel pyrazoles has been obtained after this method reaction Morpholine nucleoside analog, and provide two kinds of approach control pyrazoline nucleoside analogs, provide the diversity of such compound with And the unicity in methodology control.
A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center, which is characterized in that including operating as follows： It is raw material with 9- connection alkene purine 1 and alpha-alkyl/aryldiazonium acetic acid esters 2, solvent is added, in DPPB or Pd2(dba)3Catalyst In the presence of, pyrazoline nucleoside analog 3 is obtained by the reaction, reaction equation is as follows：
Wherein, R3Selected from H, Cl, R2Selected from OMe, OEt, Cl, NMe2、NEt2、R is selected from Me, Et, n- C5H11,Ph；R1Selected from Me, Et, i-Pr, t-Bu.
Further, work as R3When=H, R2Represent one kind in following groups：OMe,OEt,Cl,NEt2、Work as R3 When=Cl, R2Represent one kind in following groups：OEt,NMe2；R represents one kind in following groups：Me,Et,n-C5H11,Ph； R1Represent one kind in following groups：Me,Et,i-Pr,t-Bu.
Further, in the above-mentioned technical solutions, the catalyst is derived from DPPB or Pd2(dba)3。
Further, in the above-mentioned technical solutions, when required product is mainly 1- pyrazolines, selecting catalyst Pd2 (dba)3；Wherein, 9- joins alkene purine 1, alpha-alkyl/aryldiazonium acetic acid esters 2, Pd2(dba)3The molar ratio of catalyst is 1:4-6: 0.1；
When required product is mainly a variety of pyrazolines, selecting catalyst DPPB；Wherein, 9- joins alkene purine 1, α-alkane Base/aryldiazonium acetic acid esters 2, DPPB catalyst molar ratio be 1:4-6:0.2.
Further, in the above-mentioned technical solutions, reaction dissolvent is selected from toluene, 1,2- dichloroethanes, benzotrifluoride or equal Trimethylbenzene.
Further, in the above-mentioned technical solutions, reaction temperature is selected from 60 DEG C to 100 DEG C.
Further, in the above-mentioned technical solutions, entire reaction process needs to operate under inert gas shielding, inert gas It is preferred that nitrogen.
Under the above-described reaction conditions, after reaction purification, for different product separation yields up to 47%-91%.
Further, the product 3 obtained in the above-mentioned technical solutions, can further derive.Either E- formulas are either The product 3 of Z- formulas can obtain unprecedented single hydrogenated products 5 by palladium carbon hydrogenation reaction.
Reaction equation is as follows：
Further, in the above-mentioned technical solutions, the catalyst is derived from palladium-carbon catalyst.
Further, in the above-mentioned technical solutions, reaction dissolvent is selected from methanol.
Further, in the above-mentioned technical solutions, reaction temperature is selected from room temperature.
Further, in the above-mentioned technical solutions, entire reaction process needs hydrogen as hydrogen source.
Under the above-described reaction conditions, after reaction purification, for hydrogenated products yield up to 95%.
Invention advantageous effect：
The invention discloses the novel pyrazoline nucleoside analog with quaternary carbon center, with 9- connection alkene purine 1 and alpha-alkyl/ Aryldiazonium acetic acid esters 2 is raw material, is synthesized by two different methods, wherein using Pd2(dba)3It is obtained when catalyst The product arrived is single.When using DPPB catalyst, the product of the isomers in addition to primary product is obtained, that is, has passed through catalyst It selects to control the diversity and unicity of pyrazoline product.
Specific implementation mode
Embodiment 1
aUnless otherwise noted,reaction conditions were:Cat. (20mol%), 1a (0.05mmol),2a(0.3mmol)in solvent(1.0mL)under N2for 48h.bTotal yield of 3aa and 4aa.cIsolated yield.dDetermined by 1H NMR spectroscopy of the crude reaction mixture.e2a and Pd2(dba)3were added for two times in mesitylene.
In the screening process of reaction condition, influence (entries 1-6,9- of the catalyst to reaction have been primarily looked at 14), it is determined that DPPB is to obtain the optimum catalyst of a variety of pyrazolines, Pd2(dba)3It is most preferably catalyzed to obtain single 1- pyrazolines Agent.
It is fixed in other conditions, only investigate influence (entries 15-17) of the solvent to reaction, it is determined that first Benzene is to obtain the optimum solvent of a variety of pyrazolines, and mesitylene is synthesis 1- pyrazoline optimum solvents.
It is fixed in other conditions, only investigate influence (entries 3,7-8,17- of the reaction temperature to reaction 18), it is determined that 100 DEG C are optimum temperature.
Embodiment 2
By taking 1a and 2a compounds as an example, the reaction is in Pd2(dba)3Reaction step under catalysis is as follows：
It weighs 9.4mg (0.05mmol, 1equiv) compounds 1a to be put in the clean reaction tubes of 15mL, then be added The Pd of 2.3mg2(dba)3(0.005mmol, 5%) catalyst.The seal of tube will be reacted, by three-way pipe by the air in reaction bulb It evacuates, then passes to nitrogen, weigh the compound 2a (0.15mmol, 3equiv) of 19.2mg and be dissolved in mesitylene solution 1mL In, it is added in reaction with syringe, and make that the reaction was complete under a nitrogen atmosphere, 100 degrees Celsius of progress.Wait for reaction 24 hours Afterwards, the Pd of 2.3mg is injected again2(dba)3(0.005mmol, 5%) catalyst, 19.2mg compound 2a (0.15mmol, 3equiv) in mesitylene solvent, the reaction was continued 24 hours.It is detected with TCL and finds that raw material disappears substantially.Reaction solution is taken Go out, is spin-dried for solvent in solution with vacuum rotary evaporator, the method detached using thin-layer chromatography, with petroleum ether and ethyl acetate It is 3:1 expansion system, separation.It is 7.5mg, yield 73% to weigh product 3aa.1H NMR(400MHz,CDCl3)δ8.66 (s, 1H), 8.60 (t, J=2.4Hz, 1H), 8.25 (s, 1H), 4.33-4.25 (m, 2H), 4.24 (s, 3H), 3.32 (dd, J= 16.8,2.4Hz, 1H), 2.61 (dd, J=16.8,2.4Hz, 1H), 1.70 (s, 3H), 1.33 (t, J=7.2Hz, 3H)
13C NMR(150MHz,CDCl3)δ169.9,161.6,153.8,153.5,151.6,139.0,122.7,121.5, 94.4,62.6,54.8,33.5,23.0,14.2.
HRMS:exact mass calcd for C14H16N6O3Na(M+Na+)requires m/z 339.1182, found m/z339.1180.
According to above-mentioned reaction condition, change reaction substrate, it is as a result as follows：
Embodiment 3：
By taking 1a and 2a compounds as an example, reaction step of the reaction under bis- (diphenylphosphine) butane DPPB catalysis is as follows：
It weighs 18.8mg (0.1mmol, 1equiv) compounds 1a to be put in the clean reaction tubes of 20mL, then be added DPPB (0.02mmol, 20%) catalyst of 8.5mg.The seal of tube will be reacted, by three-way pipe by the evacuating air in reaction bulb, Nitrogen is then passed to, the compound 2a (0.3mmol, 3equiv) of 38.4mg is weighed and is dissolved in toluene solution 1.5mL, with injection Device is added in reaction, and makes that the reaction was complete under a nitrogen atmosphere, 100 degrees Celsius, carries out.After reaction 48 hours, examined with TCL It surveys and finds that raw material disappears substantially.Reaction solution is taken out, solvent in solution is spin-dried for vacuum rotary evaporator, utilizes column chromatography Method, petroleum ether are 3 with ethyl acetate:1 expansion system crosses post separation.It is spin-dried for solution, obtaining product 3aa and 4aa is respectively 10.7mg, 18.0mg, yield are 34% and 57%.
(E)-Ethyl 5-((6-methoxy-9H-purin-9-yl)methylene)-3-methyl-4,5- dihydro-3H-pyrazole-3-carboxylate(3aa)
1H NMR(400MHz,CDCl3) δ 8.66 (s, 1H), 8.60 (t, J=2.4Hz, 1H), 8.25 (s, 1H), 4.33- 4.25 (m, 2H), 4.24 (s, 3H), 3.32 (dd, J=16.8,2.4Hz, 1H), 2.61 (dd, J=16.8,2.4Hz, 1H), 1.70 (s, 3H), 1.33 (t, J=7.2Hz, 3H)
13C NMR(150MHz,CDCl3)δ169.9,161.6,153.8,153.5,151.6,139.0,122.7,121.5, 94.4,62.6,54.8,33.5,23.0,14.2.
HRMS:exact mass calcd for C14H16N6O3Na(M+Na+)requires m/z 339.1182, found m/z 339.1180.
(Z)-ethyl 4-((6-methoxy-9H-purin-9-yl)methylene)-5-methyl-4,5- dihydro-1H-pyrazole-5-carboxylate(4aa)
1H NMR(600MHz,CDCl3)δ8.60(s,1H),8.14(s,1H),7.45(s,1H),7.07(s,1H),6.84 (s, 1H), 4.37-4.29 (m, 2H), 4.21 (s, 3H), 1.74 (s, 3H), 1.34 (t, J=7.2Hz, 3H)
13C NMR(150MHz,CDCl3)δ171.8,161.5,153.2,151.5,140.5,137.5,135.9,121.4, 112.3,63.0,54.7,26.4,14.2.
HRMS:exact mass calcd for C14H16N6O3Na(M+Na+)requires m/z 339.1182, found m/z 339.1178.
According to above-mentioned reaction condition, change reaction substrate, it is as a result as follows：
aReaction conditions:DPPB (20mol%), 1a (0.1mmol), 2a-2g (0.6mmol) in toluene(1mL)under N2for 48hours.bTotal yield of 3and 4.cIsolated yields.were report dDetermined by 1H NMR spectroscopy of the crude reaction mixture.
(E)-Ethyl 5-((6-ethoxy-9H-purin-9-yl)methylene)-3-methyl-4,5-dihydro- 3H-pyrazole-3-carboxyl ate(3ba)
1H NMR(400 MHz,CDCl3) δ 8.61 (s, 1H), 8.58 (t, J=2.4 Hz, 1H), 8.22 (s, 1H), 4.70 (q, J=7.2 Hz, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.30 (dd, J=16.8,2.4 Hz, 1H), 2.60 (dd, J= 16.8,2.4 Hz, 1H), 1.69 (s, 3H), 1.53 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H)
13C NMR(100 MHz,CDCl3)δ169.8,161.3,153.6,153.4,151.6,138.7,122.7, 121.3,94.3,63.7,62.5,33.3,22.8,14.5,14.1.
HRMS:exact mass calcd for C15H18N6O3Na(M+Na+)requires m/z 353.1338, found m/z 353.1333.
(Z)-Ethyl 4-((6-ethoxy-9H-purin-9-yl)methylene)-5-methyl-4,5-dihydro- 1H-pyrazole-5-carboxylate(4ba)
1H NMR(400 MHz,CDCl3)δ8.58(s,1H),8.13(s,1H),7.46(s,1H),7.07(s,1H),6.84 (s, 1H), 4.70 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.75 (s, 3H), 1.53 (t, J=7.2 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ171.8,161.3,153.2,151.6,140.3,137.5,135.8, 121.3,112.3,69.3,63.7,63.0,26.3,14.6,14.2.
HRMS:exact mass calcd for C15H18N6O3Na(M+Na+)requires m/z 353.1338, found m/z 353.1341.
(E)-Ethyl 5-((6-chloro-9H-purin-9-yl)methylene)-3-methyl-4,5-dihydro- 3H-pyrazole-3-carboxylate(3ca)
1H NMR(600 MHz,CDCl3)δ8.87(s,1H),8.55(s,1H),8.42(s,1H),4.31-4.23(m, 2H), 3.32 (d, J=17.4 Hz, 1H), 2.61 (d, J=17.4 Hz, 1H), 1.70 (s, 3H), 1.32 (t, J=6.6 Hz, 3H).
13C NMR(150MHz,CDCl3)δ169.7,150.0,153.3,152.4,151.3,142.0,131.7,122.1, 94.9,62.8,33.4,22.9,14.2.
HRMS:exact mass calcd for C13H13ClN6O2Na(M+Na+)requires m/z 343.0686, found m/z 343.0680.
(Z)-Ethyl 4-((6-chloro-9H-purin-9-yl)methylene)-5-methyl-4,5-dihydro- 1H-pyrazole-5-carboxylate(4ca)
1H NMR(600 MHz,CDCl3)δ8.82(s,1H),8.33(s,1H),7.39(s,1H),7.04(s,1H),6.91 (s, 1H), 4.30 (q, J=6.6 Hz, 2H), 1.75 (s, 3H), 1.35 (t, J=6.6 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ171.3,152.9,151.9,151.1,143.4,137.4,136.6, 131.3,111.1,69.4,63.0,26.3,14.0.
HRMS:exact mass calcd for C13H14ClN6O2(M+H+)requires m/z 321.0867,found m/z 321.0861.
(E)-Ethyl 5-((6-(diethylamino)-9H-purin-9-yl)methylene)-3-methyl-4,5- dihydro-3H-pyrazole-3-carboxylate(3da)
1H NMR(400 MHz,CDCl3) δ 8.57 (t, J=2.4 Hz, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 4.31- 4.22 (m, 2H), 4.00 (s, 4H), 3.25 (dd, J=16.8,2.4 Hz, 1H), 2.54 (dd, J=16.8,2.4 Hz, 1H), 1.67 (s, 3H), 1.31 (td, J=7.2,2.8 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ170.1,165.2,163.3,154.0,153.8,152.8,134.9, 123.3,94.0,62.5,42.7,33.4,23.0,14.2,6.6.
HRMS:exact mass calcd for C17H23N7O2Na(M+Na+)requires m/z 380.1811, found m/z 380.1808.
(Z)-Ethyl 4-((6-(diethylamino)-9H-purin-9-yl)methylene)-5-methyl-4,5- dihydro-1H-pyrazole-5-carboxylate(4da)
1H NMR(400 MHz,CDCl3)δ8.38(s,1H),7.96(s,1H),7.46(s,1H),7.09(s,1H),6.79 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.99 (s, 4H), 1.73 (s, 3H), 1.31 (t, J=7.2 Hz, 9H)
13C NMR(150 MHz,CDCl3)
HRMS:exact mass calcd for C17H23N7O2Na(M+Na+)requires m/z 380.1811, found m/z 380.1817.
(E)-Ethyl 3-methyl-5-((6-(piperidin-1-yl)-9H-purin-9-yl)methylene)-4, 5-dihydro-3H-pyrazole-3-carboxylate(3ea)
1H NMR(400 MHz,CDCl3)δ8.56(s,1H),8.39(s,1H),8.02(s,1H),4.43-4.10(m, 6H), 3.24 (dd, J=16.8,2.4 Hz, 1H), 2.53 (dd, J=16.8,2.4 Hz, 1H), 1.72 (t, J=6.4 Hz, 6H), 1.67 (s, 3H), 1.31 (t, J=7.2 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ170.1,154.1,153.7,152.9,150.9,134.5,123.2, 119.5,94.1,62.6,46.5,33.3,26.3,24.9,23.0,14.2.
HRMS:exact mass calcd for C18H23N7O2Na(M+Na+)requires m/z 392.1811, found m/z 392.1814.
(Z)-Ethyl 5-methyl-4-((6-(piperidin-1-yl)-9H-purin-9-yl)methylene)-4, 5-dihydro-1H-pyrazole-5-carboxylate(4ea)
1H NMR(400 MHz,CDCl3)δ8.37(s,1H),7.95(s,1H),7.44(s,1H),7.08(s,1H),6.80 (s, 1H), 4.22-4.29 (m, 6H), 1.76-1.68 (m, 9H), 1.32 (t, J=7.2 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ172.0,154.0,153.5,150.6,137.8,136.0,134.4, 119.4,113.0,69.3,62.9,46.7,26.3,26.2,24.9,14.2.
HRMS:exact mass calcd for C18H23N7O2Na(M+Na+)requires m/z 392.1811, found m/z 392.1818.
(E)-Ethyl 3-methyl-5-((6-morpholino-9H-purin-9-yl)methylene)-4,5- dihydro-3H-pyrazole-3-carboxylate(3fa)
1H NMR(600 MHz,CDCl3)δ8.57(s,1H),8.43(s,1H),8.03(s,1H),4.35-4.22(m, 4H), 3.85 (s, 4H), 3.26 (d, J=16.8 Hz, 1H), 2.54 (d, J=16.8 Hz, 1H), 1.68 (s, 3H), 1.32 (t, J=6.6 Hz, 3H)
13C NMR(100 MHz,CDCl3)δ170.1,154.1,153.6,153.2,151.0,135.1,123.1, 119.7,94.2,67.1,62.6,45.8,33.4,23.0,14.2.
HRMS:exact mass calcd for C17H21N7O3Na(M+Na+)requires m/z 394.1604, found m/z 394.1596.
(Z)-Ethyl 5-methyl-4-((6-morpholino-9H-purin-9-yl)methylene)-4,5- dihydro-1H-pyrazole-5-carboxylate(4fa)
1H NMR(600 MHz,CDCl3)δ8.42(s,1H),7.97(s,1H),7.41(s,1H),7.07(s,1H),6.82 (s, 1H), 4.32-4.27 (m, 4H), 3.85 (s, 4H), 1.74 (s, 3H), 1.33 (t, J=6.6 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ171.9,154.1,153.4,150.8,137.6,136.6,134.9, 119.6,112.8,69.3,67.2,63.0,45.8,26.3,14.2.
HRMS:exact mass calcd for C17H21N7O3Na(M+Na+)requires m/z 394.1604, found m/z 394.1611
(E)-Ethyl 5-((2-chloro-6-(dimethylamino)-9H-purin-9-yl)methylene)-3- methyl-4,5-dihydro-3H-pyrazole-3-carboxylate(3ga)
1H NMR(400 MHz,CDCl3) δ 8.49 (t, J=2.4 Hz, 1H), 7.98 (s, 1H), 4.32-4.18 (m, 2H), 3.75 (s, 3H), 3.46-3.15 (m, 4H), 2.50 (dd, J=16.8,2.4 Hz, 1H), 1.66 (s, 3H), 1.31 (t, J= 7.2 Hz,3H).
13C NMR(100 MHz,CDCl3)δ170.0,155.3,155.0,153.4,151.5,135.1,122.9, 118.8,94.2,62.6,39.4,33.2,22.9,14.2,8.7.
HRMS:exact mass calcd for C15H18ClN7O2Na(M+Na+)requires m/z 386.1108, found m/z 386.1113
(Z)-Ethyl 4-((2-chloro-6-(dimethylamino)-9H-purin-9-yl)methylene)-5- methyl-4,5-dihydro-1H-pyrazole-5-carboxylate(4ga)
1H NMR(600 MHz,CDCl3)δ7.90(s,1H),7.39(s,1H),7.02(s,1H),6.81(s,1H),4.28 (q, J=6.4Hz, 2H), 3.75 (s, 3H), 3.31 (s, 3H), 1.72 (s, 3H), 1.34 (t, J=6.8 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ171.8,155.3,154.9,151.4,137.3,136.6,135.0, 118.7,112.7,69.4,63.0,38.2,26.1,14.1.
HRMS:exact mass calcd for C15H18ClN7O2Na(M+Na+)requires m/z 386.1108, found m/z 386.1101
(E)-iso-Propyl 3-ethyl-5-((6-methoxy-9H-purin-9-yl)methylene)-4,5- dihydro-3H-pyrazole-3-carboxylate(3ab)
1H NMR(600 MHz,CDCl3)δ8.65(s,1H),8.57(s,1H),8.28(s,1H),5.1-5.2(m,1H), 4.23 (s, 3H), 3.26 (d, J=17.2 Hz, 1H), 2.62 (d, J=17.2 Hz, 1H), 2.33-2.26 (m, 1H), 1.9- 2.0 (m, 1H), 1.32 (dd, J=17.8,6.4 Hz, 6H), 0.92 (t, J=7.2 Hz, 3H)
13C NMR(100 MHz,CDCl3)δ169.0,161.6,153.9,153.5,151.7,139.0,122.5, 121.5,99.6,70.4,54.7,30.0,29.6,21.8,21.8,8.4.
HRMS:exact mass calcd for C16H20N6O3Na(M+Na+)requires m/z 367.1495, found m/z 367.1485.
(Z)-iso-Propyl 5-ethyl-4-((6-methoxy-9H-purin-9-yl)methylene)-4,5- dihydro-1H-pyrazole-5-carboxylate(4ab)
1H NMR(400 MHz,CDCl3)δ8.60(s,1H),8.13(s,1H),7.40(s,1H),7.04(s,1H),6.84 (s,1H),5.17–5.02(m,1H),4.22(s,3H),2.17(s,1H),2.0-2.1(m,1H),1.9-2.0(m,1H),1.33 (t, J=5.2 Hz, 6H), 0.99 (t, J=7.2 Hz, 3H)
13C NMR(150 MHz,CDCl3)δ170.8,161.5,153.1,151.6,140.5,137.6,135.0, 112.2,73.3,70.9,54.6,33.6,29.8,21.8,21.7,8.6.
HRMS:exact mass calcd for C16H20N6O3Na(M+Na+)requires m/z 367.1495, found m/z 367.1489.
(E)-tert-Butyl 3-ethyl-5-((6-methoxy-9H-purin-9-yl)methylene)-4,5- dihydro-3H-pyrazole-3-carboxylate(3ac)
1H NMR(600 MHz,CDCl3)δ8.64(s,1H),8.56(s,1H),8.28(s,1H),4.23(s,3H),3.23 (d, J=17.2Hz, 1H), 2.57 (d, J=17.2 Hz, 1H), 2.25-2.32 (m, 1H), 1.92-1.97 (m, 1H), 1.51 (s, 9H), 0.92 (t, J=7.2Hz, 3H)
13C NMR(150 MHz,CDCl3)δ170.3,161.5,153.2,151.6,140.4,137.6,135.1, 121.3,112.1,84.0,73.7,54.6,33.7,28.0,8.6.
HRMS:exact mass calcd for C17H22N6O3Na(M+Na+)requires m/z 381.1651, found m/z 381.1647.
(Z)-tert-Butyl 5-ethyl-4-((6-methoxy-9H-purin-9-yl)methylene)-4,5- dihydro-1H-pyrazole-5-carboxylate(4ac)
1H NMR(600 MHz,CDCl3)δ8.59(s,1H),8.13(s,1H),7.39(s,1H),7.02(s,1H),6.83 (s, 1H), 14.21 (s, 3H), 2.03-2.10 (m, 1H), 1.89-1.96 (m, 1H), 1.53 (s, 9H), 0.98 (t, J=7.2 Hz,3H).
13C NMR(150 MHz,CDCl3)δ170.3,161.5,153.2,151.6,140.4,137.6,135.1, 121.3,112.1,84.0,73.7,54.6,33.7,28.0,8.60.
HRMS:exact mass calcd for C17H22N6O3Na(M+Na+)requires m/z 381.1651, found m/z 381.1654.
(E)-Methyl 3-ethyl-5-((6-methoxy-9H-purin-9-yl)methylene)-4,5- dihydro-3H-pyrazole-3-carboxylate(3ad)
1H NMR(600MHz,CDCl3)δ8.65(s,1H),8.58(s,1H),8.27(s,1H),4.23(s,3H),3.84 (s, 3H), 3.27 (d, J=17.2Hz, 1H), 2.66 (d, J=17.2Hz, 1H), 2.26-2.32 (m, 1H), 2.07-2.20 (m, 1H), 0.92 (t, J=7.2Hz, 3H)
13C NMR(150MHz,CDCl3)δ169.9,161.6,153.8,153.5,151.6,139.0,122.7,121.5, 94.4,62.6,54.8,33.5,23.0,14.2.
HRMS:exact mass calcd for C14H16N6O3Na(M+Na+)requires m/z 339.1182, found m/z 339.1188.
(Z)-Methyl 5-ethyl-4-((6-methoxy-9H-purin-9-yl)methylene)-4,5- dihydro-1H-pyrazole-5-carboxylate(4ad)
1H NMR(600MHz,CDCl3)δ8.60(s,1H),8.13(s,1H),7.42(s,1H),7.04(s,1H),6.82 (s, 1H), 4.21 (s, 3H), 3.85 (s, 3H), 2.11-2.16 (m, 1H), 1.95-2.01 (m, 1H), 0.98 (t, J=7.2Hz, 3H).
13C NMR(150MHz,CDCl3)δ172.0,161.5,153.2,151.5,140.6,137.6,134.6,121.3, 112.4,73.4,54.6,53.8,33.5,8.6.
HRMS:exact mass calcd for C14H16N6O3Na(M+Na+)requires m/z 339.1182, found m/z 339.1186.
Embodiment 4：
By taking 6- methoxypurine products 3aa as an example, derivative steps are as follows：
3aa (0.1mmol, 31.6mg) is weighed, is transferred in a clean 15mL reaction tube, 2mL methanol is added, is weighed The palladium of 0.2 equivalent/carbon reagent (0.02mmol, 2.12mg), is transferred in reaction tube, reaction system replacing hydrogen, and plug hydrogen Balloon keeps certain pressure.It is reacted 3 hours under room temperature, reaction terminates, and 3aa is converted completely, and only there are one products.Cross diatomite Remove palladium/carbon, column chromatography for separation.Obtain product 7aa, yield 30.2mg, yield 95%.
Ethyl 5-((6-methoxy-9H-purin-9-yl)methyl)-3-methyl-4,5-dihydro-3H- pyrazole-3-carboxylate(5aa)
1H NMR(400MHz,CDCl3)δ8.55(s,1H),7.95(s,1H),5.06(s,2H),4.12-4.19(m,6H), 3.14 (d, J=17.2Hz, 1H), 2.50 (d, J=17.2Hz, 1H), 1.46 (s, 3H), 1.21 (d, J=7.2Hz, 3H)
13C NMR(100MHz,CDCl3)δ174.7,161.4,152.5,152.1,149.0,142.1,77.5,69.2, 62.2,54.5,43.1,42.8,23.9,14.2.
HRMS:exact mass calcd for C14H18N6O3Na(M+Na+)requires m/z 341.1338, found m/z 341.1333.
Embodiment above describes the basic principles and main features and advantage of the present invention.The technical staff of the industry should Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within In the scope of protection of the invention.

Claims (9)

1. a kind of pyrazoline nucleoside analog synthetic method with quaternary carbon center, reaction equation are as follows：
It is characterised in that it includes following steps：It is raw material with 9- connection alkene purine 1 and alpha-alkyl/aryldiazonium acetic acid esters 2, is added Solvent, in DPPB or Pd2(dba)3In the presence of catalyst, pyrazoline nucleoside analog 3 is obtained by the reaction.
2. according to a kind of pyrazoline nucleoside analog synthetic method with quaternary carbon center in claim 1, it is characterised in that：R3 Selected from H, Cl, R2Selected from OMe, OEt, Cl, NMe2、NEt2、；R is selected from Me, Et, n-C5H11,Ph；R1It is selected from Me、Et、i-Pr、t-Bu。
3. being existed according to a kind of pyrazoline nucleoside analog synthetic method with quaternary carbon center, feature in claims 1 or 2 In：When the catalyst is selected from DPPB, pyrazoline 3 and pyrazoline 4 are generated；The catalyst is selected from Pd2(dba)3When, it is main raw At product 3.
4. being existed according to a kind of pyrazoline nucleoside analog synthetic method with quaternary carbon center, feature in claims 1 or 2 In：Reaction dissolvent is selected from toluene, 1,2- dichloroethanes, benzotrifluoride or mesitylene.
5. according to a kind of pyrazoline compounds synthetic method with quaternary carbon center in claims 1 or 2, it is characterised in that： 9- joins alkene purine 1, alpha-alkyl/aryldiazonium acetic acid esters 2 and Pd2(dba)3Catalyst molar ratio is 1:4-6:0.1.
6. according to the method for simultaneously synthesizing a variety of unusual pyrazoline nucleoside analogs in claims 1 or 2, feature exists In：9- join alkene purine 1, alpha-alkyl/aryldiazonium acetic acid esters 2, DPPB catalyst molar ratio be 1:4-6:0.2.
7. being existed according to a kind of pyrazoline nucleoside analog synthetic method with quaternary carbon center, feature in claims 1 or 2 In：Reaction temperature is selected from 60-100 DEG C.
8. according to a kind of pyrazoline nucleoside analog synthetic method with quaternary carbon center in claim 1, it is characterised in that：It is whole A reaction process needs to operate under inert gas protection.
9. a kind of 5 synthetic method of pyrazoles purine nucleoside analogs with quaternary carbon center, which is characterized in that reaction equation is such as Under：
Including operating as follows：It is catalyzed by palladium carbon according to the pyrazoline nucleoside analog 3 of the synthesis of method described in claim 1-7 Pyrazoles purine nucleoside analogs 5 are obtained after hydrogenation.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102099367A (en) * 2007-01-17 2011-06-15 蒙特利尔临床研究所 Nucleoside and nucleotide analogues with quaternary carbon centers and methods of use
CN105693725A (en) * 2016-03-22 2016-06-22 河南师范大学 Method for synthesizing chiral ternary purine carbocyclic nucleoside analogue through intramolecular asymmetric cycloaddition
CN105732631A (en) * 2016-01-28 2016-07-06 河南师范大学 N9 vinylpurine and synthesis method thereof, and method for synthesizing polysubstituted chiral azacyclonucleoside analogs from N9 vinylpurine
CN107602559A (en) * 2017-09-29 2018-01-19 河南师范大学 A kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition
CN107698590A (en) * 2017-09-29 2018-02-16 河南师范大学 A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102099367A (en) * 2007-01-17 2011-06-15 蒙特利尔临床研究所 Nucleoside and nucleotide analogues with quaternary carbon centers and methods of use
CN105732631A (en) * 2016-01-28 2016-07-06 河南师范大学 N9 vinylpurine and synthesis method thereof, and method for synthesizing polysubstituted chiral azacyclonucleoside analogs from N9 vinylpurine
CN105693725A (en) * 2016-03-22 2016-06-22 河南师范大学 Method for synthesizing chiral ternary purine carbocyclic nucleoside analogue through intramolecular asymmetric cycloaddition
CN107602559A (en) * 2017-09-29 2018-01-19 河南师范大学 A kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition
CN107698590A (en) * 2017-09-29 2018-02-16 河南师范大学 A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
R. A. NOVIKOV 等: "Reactions of diazo esters with electron deficient alkenes in the presence of Lewis acids", 《RUSSIAN CHEMICAL BULLETIN, INTERNATIONAL EDITION》 *
ROMAN A. NOVIKOV 等: "Stereoselective Double Lewis Acid/Organo-Catalyzed Dimerization of Donor−Acceptor Cyclopropanes into Substituted 2-Oxabicyclo[3.3.0]octanes", 《J. ORG. CHEM.》 *
W. R. DOLBIER 等: "The Regiochemistry and Stereochemistry of 1,3-Dipolar Cycloadditions of 1-Fluoro- and l,l-Diftuoroallene", 《TETRAHEDRON》 *
WEI-SHENG HUANG 等: "9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation: Design, Synthesis, and Biological Evaluation", 《J. MED. CHEM.》 *
郭真: "基于9-联烯嘌呤与重氮酯构建含季碳中心的吡唑啉衍生物", 《河南师范大学硕士学位论文》 *

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