CN105481879B - Imidazoles [1,2 c] thiophene [2,3 e] pyrimidine 7（8H）Ketone heterocyclic compound and its synthetic method - Google Patents
Imidazoles [1,2 c] thiophene [2,3 e] pyrimidine 7（8H）Ketone heterocyclic compound and its synthetic method Download PDFInfo
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- CN105481879B CN105481879B CN201610065747.4A CN201610065747A CN105481879B CN 105481879 B CN105481879 B CN 105481879B CN 201610065747 A CN201610065747 A CN 201610065747A CN 105481879 B CN105481879 B CN 105481879B
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- VWKGPFHYXWGWEI-VIFPVBQESA-N CCOC([C@H](c1ccccc1)N)=O Chemical compound CCOC([C@H](c1ccccc1)N)=O VWKGPFHYXWGWEI-VIFPVBQESA-N 0.000 description 1
- WAOLQAAIRMNPBM-CXUHLZMHSA-N CN(C)/C=N/c1c(C#N)[s]c(-c(cc2)ccc2P)c1 Chemical compound CN(C)/C=N/c1c(C#N)[s]c(-c(cc2)ccc2P)c1 WAOLQAAIRMNPBM-CXUHLZMHSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Abstract
The invention discloses a kind of imidazoles [1,2 c] thiophene [2,3 e] pyrimidine 7 (8H) ketone heterocyclic compound and its synthetic method, it is related to organic synthesis and medicinal chemistry art, comprises the following steps：Optically active (S) imidazoles [1 in the following formulas of reaction acquisition in appropriate solvent and during proper temperature the present invention relates to compound 1 and compound 2 or 4,2 c] thiophene [2,3 e] (8H) ketone heterocyclic of pyrimidine 7 compound 3 or (R) imidazoles [1,2 c] thiophene [2,3 e] pyrimidine 7 (8H) ketone heterocyclic compound fused ring compound 5.The features of the present invention and beneficial effect are：1. one pot reaction two heterocycles of formation.2. raw material is easy to get, reaction condition is gentle.3. the reaction time is moderate, it is easy to control, post processing is simple.4. product purity and high income.5. a pair environment does not pollute, the concept of Green Chemistry has been fully demonstrated.
Description
Technical field
The invention belongs to Minute Organic Synthesis and medicinal chemistry art, and in particular to a kind of imidazoles [1,2-c]-thiophene [2,
3-e] (8H) the ketone heterocyclic compound of pyrimidine -7 and its synthetic method.
Background technology
Heterocyclic compound is widely present in drug molecule, is play in pharmaceutical synthesis and discovery procedure very important
Effect, because the presence of heterocycle can not only influence the interaction between drug molecule and acceptor, and is conducive to carrying
The solubility of high drug molecule.In antitumor and cardiovascular drugs, the application of antibacterials and chemotherapy is more and more extensive.Some are miscellaneous
Cycle compound has very strong antitumor activity and gets more and more people's extensive concerning (see following structure I, II, III).
Document International Journal of Research in Pharmacy and Chemistry
Volume 4Issue 3, p501-508, the 2014 and Issue 2 of Medicinal Chemistry Research Volume 22
P 659-673 report the research that the heterocyclic compound containing the class formation is used for antitumor activity, particularly to kinases
CDK2 research.Application of such compound in antibacterial research, such as Acta Pharmaceutica are also reported about document
(Zagreb,Croatia)Volume 61 Issue 2 Pages 171-185 Journal 2011；World Journal of
Chemistry Volume 4 Issue 2 Pages 141-148；Journal of the Chinese Chemical
Society (Taipei, Taiwan), Volume 54, Issue 2, Pages 437-446,2007；Heteroatom
15 Issue of Chemistry Volume 1 Pages 57-62 Journal, 2003.European medical chemistry magazine also reports this
A little compounds in analgesia and anti-inflammatory drug research application (European Journal of Medicinal Chemistry,
Volume 44, p 4572-4584,2009).Therefore, how rapid build heterocyclic molecular skeleton and various structures efficiently to be carried out
Property synthesis, by the very big concern of chemist and pharmaceutical industries circle.
[1,2-c]-thiophene [2,3-e] (8H) ketone heterocyclic of pyrimidine -7 compound (compound 3 and 5) has no report in the literature
Road.Therefore, develop it is new, effective, tool is of great significance by environment more friendly synthetic method.Condensed hetero ring
The synthesis and its application of compound are also always one of focus of Synthetic Organic Chemistry.
The content of the invention
The purpose of the present invention is just to provide for a kind of imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic
Compound and its synthetic method.
To achieve these goals, the present invention is adopted the following technical scheme that：
Imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic compound, structural formula is：
The R1For-H ,-F ,-Cl ,-Br ,-I ,-OMe, or Ar,
R2For-H ,-F ,-Cl or-OMe,
R3For-H, C1-C4Alkyl,
R4For phenyl ring, C1-C4Alkyl.
The synthetic method of above-mentioned imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic compound, step is as follows：
Compound 1, compound 2 or compound 4, solvent in molar ratio 1：1-20：1-70 is mixed, in 25 DEG C of -160 DEG C of conditions
Lower reaction 3-48 hours is (preferably：Reacted 6-12 hours under the conditions of 90 DEG C~110 DEG C), after purification, acquisition imidazoles [1,2-c]-
Thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic compound.
It is preferred that：Purify as extraction, recrystallization, column chromatography or distillation.
It is preferred that：The solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, methanol, ethanol, propyl alcohol, uncle
One or more of butanol, acetic acid, trifluoracetic acid, n Propanoic acid, isopropyl acid, butyric acid.
The chemical equation of the preparation method of imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic compound is such as
Under：
R in compound 2 and 45It is defined as follows：
2 and 4 be following compound：
The preparation method of above-claimed cpd 1 is as follows：
(solvent is dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile for compound A, compound B and solvent
One or more of) by a certain percentage (1：1-15：1-30) put into reaction bulb, 1-48 hours are reacted at 0-80 DEG C (preferably：
Reacted 8 hours under the conditions of 70 DEG C), obtain head product intermediate 1.
R1For independent-H ,-F ,-Cl ,-Br ,-I ,-OMe,-Ar；
R2For independent-H ,-F ,-Cl ,-Br ,-OMe；
R3For independent-H, C1-C4Alkyl and C3-C6Cycloalkyl.
Beneficial effects of the present invention：
1st, the present invention is by the way that there is provided a kind of new heterocyclic compound and preparation method thereof, the preparation method can be applied to
Laboratory, industrialization and the synthetic method with environment-friendly type.This method step is few, yield is high, toxicity is low (reagent such as not phosphorous)
And it is easy to operate, overcome the deficiency in existing similar heterocyclic compound synthetic method.
2nd, product prepared by method of the invention has antitumor and anti-cardiovascular effect.
3. one pot reaction two heterocycles of formation；Raw material is easy to get, and reaction condition is gentle；Reaction time is moderate, it is easy to control, after
Processing is simple, and product purity and high income do not pollute to environment, have fully demonstrated the concept of Green Chemistry.
Embodiment
With reference to embodiment, the invention will be further described.
Embodiment 1
The first step of reaction
43.6 grams of 3- amino -5- (4- fluorophenyls) thiophene -2- formonitrile HCNs are added in 100mL single necked round bottom flask, and (0.2 rubs
You) and 50 grams of DMF dimethylacetal, then add 20mL toluene and acetonitrile mixed solvent (toluene and acetonitrile
Volume ratio be 1:1), reactant mixture is stirred 8 hours at 70 DEG C.The reaction of TLC and HPLC analysis shows is completed.Revolving removes molten
Agent and N,N-dimethylformamide dimethylacetal.Residue is washed with cold ether, and be then dried in vacuo pure is light yellow
Intermediate (E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl methyl miaows【(E)-N'-(2-cyano-5-(4-
fluorophenyl)thiophen-3-yl)-N,N-dimethylformimidamide】53.2 gram, yield 97%.1H NMR
(DMSOd6)300MHz(ppm):7.88(1H,s),7.80(2H,m),7.61(1H,s),7.41(2H,m),2.96(3H,s),
2.99(3H,s)；MS:m/z(M+1)274.11.
The second step of reaction
(E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl is added in 250mL single necked round bottom flask
27.3 grams of first miaow (0.1 mole) and 32.4 grams of hydrochloride of (R) -2- amino -2- ethyl phenylacetates (0.15 mole), are then added
Glacial acetic acid 100mL.Reactant mixture heats (110 DEG C) 6 hours under agitation.TLC and HPLC tracking reactions.After the completion of question response
Revolving remove glacial acetic acid, residue recrystallized from DMF, glacial acetic acid purify (R) -2- (- fluorophenyl) -8- phenyl imidazoles [1,
2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone【(R)-2-(4-fluorophenyl)-8-phenylimidazo[1,2-c]
thieno[2,3-e]pyrimidin-7(8H)-one】35 grams of products (light gray), yield 97%.1H NMR(DMSOd6)
300MHz(ppm)：8.34(1H,s),7.81(1H,s),7.71(2H,m),7.43(2H,m)；7.29-7.35(M,5H),3.79
(S,1H)；MS:m/z(M+1)362.10.
Embodiment 2
React first step be the same as Example 1.
React second step：
(E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl methyls is added in 50mL single necked round bottom flask
2.73 grams of miaow (0.01 mole) and 3.24 grams of hydrochloride of (R) -2- amino -2- ethyl phenylacetates (0.015 mole), are then added
Glacial acetic acid 15mL.Reactant mixture is stirred lower heating (100 DEG C) 8 hours.TLC and HPLC tracking reactions.After the completion of question response
Revolving removes part glacial acetic acid, and the mixed solution of reaction is stood overnight
(R) -2- (- fluorophenyl) -8- phenyl imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone【(R)-2-(4-
fluorophenyl)-8-phenylimidazo[1,2-c]thieno[2,3-e]pyrimidin-7(8H)-one】3.1 grams of productions
Thing (greyish crystals), yield 86%.
Embodiment 3
React first step be the same as Example 1.
React second step：
(E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl methyls is added in 10mL single necked round bottom flask
1.37 grams of miaow (0.005 mole) and 2.15 grams of hydrochloride of (R) -2- amino -2- ethyl phenylacetates (0.01 mole), are then added
Glacial acetic acid 10mL.Reactant mixture is stirred lower heating (90 DEG C) 12 hours.TLC and HPLC tracking reactions.After the completion of question response
Revolving removes glacial acetic acid, and residue is through silica gel column chromatography (solvent volume ratio ethyl acetate：N-hexane 1：4) (R) -2- (- fluorine is obtained
Phenyl) -8- phenyl imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone【(R)-2-(4-fluorophenyl)-8-
phenylimidazo[1,2-c]thieno[2,3-e]pyrimidin-7(8H)-one】1.4 grams of products (gray crystals), yield
78%.
Embodiment 4
React first step be the same as Example 1.
React second step：
(E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl is added in 250mL single necked round bottom flask
27.3 grams of first miaow (0.1 mole) and 32.4 grams of hydrochloride of (S) -2- amino -2- ethyl phenylacetates (0.15 mole), are then added
Glacial acetic acid 100mL.Reactant mixture is stirred lower heating (110 DEG C) 6 hours.TLC and HPLC tracking reactions.Question response is completed
Revolving removes glacial acetic acid afterwards, and residue is recrystallized from DMF, glacial acetic acid purifies (S) -2- (- fluorophenyl) -8- phenyl imidazoles
[1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone【(R)-2-(4-fluorophenyl)-8-phenylimidazo[1,2-c]
thieno[2,3-e]pyrimidin-7(8H)-one】33.1 grams of products (light gray), yield 92%.1H NMR(DMSOd6)
300MHz(ppm)：8.34(1H,s),7.81(1H,s),7.71(2H,m),7.43(2H,m)；7.29-7.35(M,5H),3.77
(S,1H)；MS:m/z(M+1)362.08.
Embodiment 5
(E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl is added in a 50mL single necked round bottom flask
2.73 grams of first miaow (0.01 mole) and 3.24 grams of hydrochloride of (S) -2- amino -2- ethyl phenylacetates (0.015 mole), Ran Houjia
Enter glacial acetic acid 15mL.Reactant mixture is stirred lower heating (100 DEG C) 8 hours.TLC and HPLC tracking reactions.Question response is completed
Revolving removes part glacial acetic acid afterwards, and the mixed solution of reaction stands overnight (S) -2- (- fluorophenyl) -8- phenyl imidazoles [1,2-
C]-thiophene [2,3-e] pyrimidine -7 (8H) ketone【(R)-2-(4-fluorophenyl)-8-phenylimidazo[1,2-c]
thieno[2,3-e]pyrimidin-7(8H)-one】2.9 grams of products (gray crystals), yield 80%.
Embodiment 6
(E)-N ' -2- formonitrile HCNs -5- (4- fluorophenyls thiophene) -3-N, N- dimethyl is added in a 10mL single necked round bottom flask
1.37 grams of first miaow (0.005 mole) and 2.15 grams of hydrochloride of (S) -2- amino -2- ethyl phenylacetates (0.01 mole), Ran Houjia
Enter glacial acetic acid 10mL.Reactant mixture is stirred lower heating (90 DEG C) 12 hours.TLC and HPLC tracking reactions.Question response is completed
Revolving removes glacial acetic acid afterwards, and residue is through silica gel column chromatography (solvent ethyl acetate：N-hexane 1：4) (S) -2- (- fluorobenzene is obtained
Base) -8- phenyl imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone【(R)-2-(4-fluorophenyl)-8-
phenylimidazo[1,2-c]thieno[2,3-e]pyrimidin-7(8H)-one】1.1 grams of products (gray crystals), yield
61%.
Experimental example：The biological activity determination of compound
Human breast carcinoma MDA-MB-231 is inoculated in 96 well culture plates with the density in 8000/hole, and every group sets 5 parallel holes,
In 37 DEG C, 5%CO2In incubator cultivate, in the nutrient solution containing 10% calf serum cultivate 24h after, test group be changed to containing
Continue to cultivate in the nutrient solution of the compound [concentration is respectively 0.2ug/mL, 0.6ug/mL, 1.0ug/mL] of embodiment 1, blank
Control group adds equivalent culture medium.Cultivate after 24h, plus MTT 20uL (5mg/mL) are further cultured for 3h, abandon supernatant, add 100uL diformazans
Sulfoxide (DMSO), is vibrated 20 minutes, after its sediment is completely dissolved, and in 570nm wavelength in enzyme-linked detection analysis instrument, blank is adjusted
Zero, each hole OD values are determined, above-mentioned every group is repeated 3 times.
Inhibiting rate=(control group OD- experimental group OD)/control group OD × 100%
Although the above-mentioned embodiment in conjunction with the embodiments to the present invention is described, not to present invention protection
The limitation of scope, one of ordinary skill in the art should be understood that on the basis of technical scheme, those skilled in the art
Various modifications or deform still within protection scope of the present invention that creative work can make need not be paid.
Claims (9)
1. imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic structural formula of compound is：
The R1For-H ,-F ,-Cl ,-Br ,-I ,-OMe, R2For-H ,-F ,-Cl ,-OMe, R3For-H, C1-C4Alkyl, R4For benzene
Ring, C1-C4Alkyl.
2. the synthetic method of imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic compound described in claim 1,
It is characterized in that：Step is as follows：Compound 1, compound 2 or compound 4, solvent in molar ratio 1：1-20：1-70 is mixed, 25
3-48 hour, after purification, acquisition imidazoles [1,2-c]-thiophene [2,3-e] pyrimidine -7 (8H) ketone heterocyclic are reacted under the conditions of DEG C -160 DEG C
Compound；
The structural formula of the compound 1 is：R1For independent-H ,-F ,-Cl ,-Br ,-I ,-
OMe, R2For independent-H ,-F ,-Cl ,-OMe, R3For independent-H, C1-C4Alkyl；
The compound 2 or compound 4 are：
3. synthetic method as claimed in claim 2, it is characterized in that：Reacted 6-12 hours under the conditions of 90 DEG C -110 DEG C.
4. synthetic method as claimed in claim 2, it is characterized in that：The purifying is extraction, recrystallization, column chromatography or distillation.
5. synthetic method as claimed in claim 2, it is characterized in that：The solvent is dichloromethane, chloroform, tetrahydrofuran, second
In acetoacetic ester, acetonitrile, methanol, ethanol, propyl alcohol, the tert-butyl alcohol, acetic acid, trifluoracetic acid, n Propanoic acid, isopropyl acid, butyric acid it is a kind of with
On.
6. synthetic method as claimed in claim 2, it is characterized in that：The synthetic method of the compound 1, step is as follows：
Compound A, compound B and solvent in molar ratio 1：1-15：1-30 is mixed, and is reacted 1-48 hours at 0-80 DEG C, is obtained chemical combination
Thing 1；
The structural formula of the compound A and compound B is respectively：R1To be only
Vertical-H ,-F ,-Cl ,-I ,-OMe, R2For independent-H ,-F ,-Cl ,-OMe, R3For independent-H, C1-C4Alkyl.
7. synthetic method as claimed in claim 6, it is characterized in that：The solvent is toluene, dichloromethane, chloroform, tetrahydrochysene furan
Mutter, one or more of ethyl acetate, acetonitrile.
8. synthetic method as claimed in claim 6, it is characterized in that：The solvent is toluene and acetonitrile by volume 1:1 mixing.
9. imidazoles [1,2-c] as claimed in claim 1-thiophene [2,3-e] pyrimidine-7 (8H) ketone heterocyclic compound is anti-in preparation
Application in tumour medicine.
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