CN104860864B - The synthetic method of the alkynyl azole compounds of 2 carbonyl 5 - Google Patents
The synthetic method of the alkynyl azole compounds of 2 carbonyl 5 Download PDFInfo
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- CN104860864B CN104860864B CN201510303733.7A CN201510303733A CN104860864B CN 104860864 B CN104860864 B CN 104860864B CN 201510303733 A CN201510303733 A CN 201510303733A CN 104860864 B CN104860864 B CN 104860864B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
It is that 0.5 mmol, 1,0.55 mmol 2,0.5 mmol KOAc, 0.5 mmol KHCO are sequentially added in round-bottomed flask the invention discloses a kind of new synthetic method of the alkynyl azole compounds of 2 carbonyl 53, 2 mL DMF are used as solvent；It is heated to 120oC reacts 2 h, TLC tracking reactions；After question response is complete, room temperature is cooled to, reactant is poured into 10 ~ 30 mL water, and is extracted with 20 ~ 30 mL ethyl acetate, saturated aqueous common salt is used（10~20 mL）Washing three times；Use anhydrous Na2SO4Dry, filtering, removal of solvent under reduced pressure；Purified through Flash silica column chromatography（Ethyl acetate/petroleum ether=1：20~50）Obtain product.This method raw material is easy to get, simple to operate, and reactions steps are few, and yield is high, and wide application range of substrates, application prospect is extensive.
Description
Technical field
The present invention relates to the new synthetic method of chemical synthesis, specifically 2- carbonyls -5- alkynyl azole compounds.
Background technology
Pyrroles and its derivative are important heterocyclic compounds, substantial amounts of to be applied to organic synthesis, functional material and medicine
Thing.Pyrroles is the female ring of antalgica tolmetin《GB 1428272(1973)》.2- carbonyl pyrrolidines are in fully synthetic natural products
Important intermediate, such as piece spiral shell element it is fully synthetic《J.Org.Chem.2014,79,529.》.In addition, azole compounds can also
The polycyclic heterocyclic compound of construction, for example, construct indolone《Synlett 2009,2010》.2- carboxylates pyrroles also has to resist and had
Silk division and cytostatic effect《Biorg.Med.Chem.2006,14,4627》.Organic chemists all the time
The research of method for efficiently synthesizing azole compounds is never interrupted.Classical synthetic method has Hantzsch reactions
《A.Hantzsch,Ber.,1890,23,1474》With Paal-Knorr reactions《J.Am.Chem.Soc.,2000,122,3801》,
The cycloaddition method of also many metal catalytics has been reported《Angew.Chem.,Int.Ed.2013,52,6953》, work(
The cycloisomerization of intermediate can be changed.Although reporting so many method synthesis pyrroles, have not yet to see and utilize two
Alkynes acetone and the report that glycinate is Material synthesis azole derivatives.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of new synthetic method of 2- carbonyls -5- alkynyl azole compounds with
And their application.
Realizing the technical scheme of the object of the invention is：
A kind of new synthetic method of 2- carbonyls -5- alkynyl azole compounds, comprises the following steps：
(1) 0.5mmol 1,0.55mmol 2,0.5mmol KOAc, 0.5mmol are sequentially added in round-bottomed flask
KHCO3, 2mL DMF are used as solvent；
(2) 120 DEG C of reaction 2h, TLC tracking reactions are heated to；
(3) after question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and with 20~30mL acetic acid
Ethyl ester is extracted, and is washed three times with saturated aqueous common salt (10~20mL)；
(4) anhydrous Na is used2SO4Dry, filtering, removal of solvent under reduced pressure；
(5) (ethyl acetate/petroleum ether=1 is purified through Flash silica column chromatography：20~50) obtain product.
It is as follows that it synthesizes formula：
In formula：
1 is diine acetone, and 2 be glycine ester hydrochloride, and 3 be the polysubstituted pyrrole with acetylene bond；
R1For phenyl, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- amyl group phenyl, 4- fluorophenyls
R2For phenyl, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- amyl group phenyl, 4- fluorophenyls
R3For alkoxy.
It is an advantage of the invention that：Raw material is easy to get, simple to operate, and yield is considerable, there is good application prospect.
Embodiment
Embodiment 1：
The preparation of 2- carboxyethyl -3- phenyl -5- (2- phenylacetylene bases) pyrroles
1,5-diphenyl-1,4- diines-propione 0.5mmol (0.115g), glycine is sequentially added in round-bottomed flask
Ethyl acetate hydrochloride 0.55mmol (0.0757g), KOAc 0.5mmol (0.0491g), KHCO30.5mmol (0.05g), it is molten
Agent DMF 2mL, are heated to 120 DEG C of reaction 2h, TLC tracking reactions.After question response is complete, room temperature is cooled to, reactant is poured into
In 10~30mL water, and extracted, washed three times with saturated aqueous common salt (10~20mL), finally with nothing with 20~30mL ethyl acetate
Water Na2SO4Dry, filtering, removal of solvent under reduced pressure purifies (ethyl acetate/petroleum ether=1 through Flash silica column chromatography：20~50)
Obtain yellow solid 3aa, yield 85%.
Characterization of The Products：
1H NMR(400MHz,CDCl3)δ9.88(s,1H),7.64–7.60(m,2H),7.58–7.54(m,2H),7.44–
7.39 (m, 2H), 7.38-7.31 (m, 5H), 6.74 (d, J=2.9Hz, 1H), 4.46-4.35 (m, 2H), 1.44 (t, J=
7.1Hz,4H).
13C NMR(100MHz,CDCl3)δ161.0,136.0,131.4,130.6,129.0,128.3,128.1,128.0,
125.0,124.4,123.7,111.9,92.5,83.7,61.0,14.4.
Embodiment 2：
The preparation of 2- carboxyethyls -3- (4- aminomethyl phenyls) -5- (2- is to methyl phenylacetylene base) pyrroles
P-methylphenyl -1,4- the diines of 1,5- bis--propione 0.5mmol (0.1421g), utamic acid carbethoxy hydrochloride
0.55mmol(0.0757g),KOAc 0.5mmol(0.0491g),KHCO30.5mmol (0.05g), solvent DMF 2mL, heating
To 120 DEG C of reaction 2h, TLC tracking reactions.After question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and
Extracted with 20~30mL ethyl acetate, washed three times with saturated aqueous common salt (10~20mL), finally use anhydrous Na2SO4Dry, mistake
Filter, removal of solvent under reduced pressure purifies (ethyl acetate/petroleum ether=1 through Flash silica column chromatography：20~yellow solid 3ba 50) is obtained,
Yield 86%.
Characterization of The Products：
1H NMR(400MHz,CDCl3) δ 9.49 (s, 1H), 7.48 (s, 1H), 7.45 (d, J=4.3Hz, 2H), 7.43 (s,
1H), 7.23 (d, J=8.0Hz, 3H), 7.16 (d, J=8.0Hz, 3H), 6.67 (d, J=2.9Hz, 1H), 4.40 (q, J=
7.1Hz, 3H), 2.38 (s, 3H), 2.37 (s, 2H), 1.43 (t, J=7.1Hz, 4H)
13C NMR(100MHz,CDCl3)δ160.9,138.2,138.1,136.0,131.3,129.7,129.1,127.8,
124.7,123.9,120.7,112.1,111.4,92.7,83.0,60.8,21.5,21.2,14.5.
Embodiment 3：
2- carboxyethyls -3- (4- ethylphenyls) -5- (2- p-ethyl-phenylacetylenes base) preparation
1,5- bis- is to ethylphenyl -1,4- diines-propione 0.5mmol (0.1431g), utamic acid carbethoxy hydrochloride
0.55mmol(0.0757g),KOAc 0.5mmol(0.0491g),KHCO30.5mmol (0.05g), solvent DMF 2mL, heating
To 120 DEG C of reaction 2h, TLC tracking reactions.After question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and
Extracted with 20~30mL ethyl acetate, washed three times with saturated aqueous common salt (10~20mL), finally use anhydrous Na2SO4Dry, mistake
Filter, removal of solvent under reduced pressure purifies (ethyl acetate/petroleum ether=1 through Flash silica column chromatography：20~yellow solid 3ca 50) is obtained,
Yield 89%.
Characterization of The Products：
1H NMR(400MHz,CDCl3) δ 9.74 (s, 1H), 7.53 (d, J=8.1Hz, 2H), 7.48 (d, J=8.0Hz,
2H), 7.25 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.0Hz, 2H), 6.69 (d, J=2.7Hz, 1H), 4.41 (q, J=
7.1Hz, 2H), 2.68 (q, J=7.3Hz, 4H), 1.44 (t, J=7.1Hz, 3H), δ 1.26 (td, J=7.5,1.4Hz, 6H)
13C NMR(100MHz,CDCl3)δ161.0,144.44,144.35,136.2,131.4,128.5,128.2,
127.8,125.0,124.1,121.0,112.2,111.5,92.7,83.1,60.8,28.8,28.6,15.4,15.3,14.5.
Embodiment 4：
2- carboxyethyls -3- (4- amyl groups phenyl) -5- (2- is to amyl group phenylacetylene base) preparation
1,5- bis- is to amyl group phenyl -1,4- diines-propione 0.5mmol (0.1853g), utamic acid carbethoxy hydrochloride
0.55mmol(0.0757g),KOAc 0.5mmol(0.0491g),KHCO30.5mmol (0.05g), solvent DMF 2mL, heating
To 120 DEG C of reaction 2h, TLC tracking reactions.After question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and
Extracted with 20~30mL ethyl acetate, washed three times with saturated aqueous common salt (10~20mL), finally use anhydrous Na2SO4Dry, mistake
Filter, removal of solvent under reduced pressure purifies (ethyl acetate/petroleum ether=1 through Flash silica column chromatography：20~yellow solid 3ea 50) is obtained,
Yield 87%.
Characterization of The Products：
1H NMR(400MHz,CDCl3) δ 9.87 (s, 1H), 7.54 (d, J=8.0Hz, 2H), 7.48 (d, J=8.0Hz,
2H), 7.23 (d, J=8.0Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 6.69 (d, J=2.7Hz, 1H), 4.40 (q, J=
7.1Hz, 2H), 2.63 (t, J=7.7Hz, 4H), 1.64 (dt, J=14.4,7.4Hz, 4H), 1.44 (t, J=7.1Hz, 3H),
1.35 (d, J=3.2Hz, 6H), 0.92 (t, J=6.7Hz, 6H)
13C NMR(100MHz,CDCl3)δ161.2,143.2,136.4,131.4,129.1,128.5,128.2,125.0,
124.1,121.0,112.3,111.6,92.8,83.2,60.9,35.9,35.7,31.5,31.1,31.0,22.6,14.5,
14.1.
Embodiment 5：
2- carboxyethyls -3- (4- methoxyl group bases phenyl) -5- (2- is to Methoxy-phenylacetylene base) preparation
1,5- di-p-methoxy phenyl -1,4- diines-propione 0.5mmol (0.1452g), utamic acid ethyl ester
Salt 0.55mmol (0.0757g), KOAc 0.5mmol (0.0491g), KHCO30.5mmol (0.05g), solvent DMF 2mL, plus
Heat is reacted to 120 DEG C of reaction 2h, TLC tracking.After question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water,
And extracted with 20~30mL ethyl acetate, washed three times with saturated aqueous common salt (10~20mL), finally use anhydrous Na2SO4Dry,
Filtering, removal of solvent under reduced pressure purifies (ethyl acetate/petroleum ether=1 through Flash silica column chromatography：20~50) obtain yellow solid
3fa, yield 88%.
Characterization of The Products：
1H NMR(400MHz,CDCl3) δ 9.55 (s, 1H), 7.52 (dd, J=12.4,8.7Hz, 4H), 6.94 (dd, J=
24.7,8.1Hz, 4H), 6.63 (s, 1H), 4.41 (d, J=6.9Hz, 2H), 3.86 (s, 6H), 1.45 (t, J=6.7Hz, 3H)
13C NMR(100MHz,CDCl3)δ161.0,159.7,159.5,136.0,132.9,126.3,123.7,123.5,
116.0,114.5,114.0,112.4,111.0,92.6,82.4,60.8,55.4,55.3,14.5.
Embodiment 6：
2- carboxyethyls -3- (4- fluorophenyls) -5- (2- is to fluorophenylethynyl) preparation
P-fluorophenyl -1,4- the diines of 1,5- bis--propione 0.5mmol (0.1331g), utamic acid carbethoxy hydrochloride
0.55mmol(0.0757g),KOAc 0.5mmol(0.0491g),KHCO30.5mmol (0.05g), solvent DMF 2mL, heating
To 120 DEG C of reaction 2h, TLC tracking reactions.After question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and
Extracted with 20~30mL ethyl acetate, washed three times with saturated aqueous common salt (10~20mL), finally use anhydrous Na2SO4Dry, mistake
Filter, removal of solvent under reduced pressure purifies (ethyl acetate/petroleum ether=1 through Flash silica column chromatography：20~50) obtain dark red solid
3ha, yield 73%.
Characterization of The Products：
1H NMR(400MHz,CDCl3) δ 9.62 (s, 1H), 7.56 (ddd, J=18.5,8.6,5.3Hz, 4H), 7.15 (t,
J=8.5Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 6.67 (d, J=2.7Hz, 1H), 4.42 (q, J=7.1Hz, 2H), 1.45
(t, J=7.1Hz, 3H)
13C NMR(100MHz,CDCl3)δ163.9,163.7,161.4,161.2,160.8,135.1,133.4,133.3,
126.9,126.8,124.5,119.8,116.3,116.1,115.8,115.6,111.9,111.8,91.6,83.2,61.0,
14.5.
Embodiment 7：
2- carboxyethyl -3- propyl group -5- (valerylene base) preparation
4,7- diine -6- hendecanones 0.5mmol (0.0811g), utamic acid carbethoxy hydrochloride 0.55mmol
(0.0757g),KOAc 0.5mmol(0.0491g),KHCO30.5mmol (0.05g), solvent DMF 2mL, are heated to 120 DEG C instead
Answer 2h, TLC tracking reactions.After question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and with 20~
30mL ethyl acetate is extracted, and is washed three times with saturated aqueous common salt (10~20mL), is finally used anhydrous Na2SO4Dry, filter, decompression
Solvent is removed, (ethyl acetate/petroleum ether=1 is purified through Flash silica column chromatography：20~50) obtain yellow solid 3ab, yield
63%.
Characterization of The Products：
1H NMR(400MHz,CDCl3) δ 8.98 (s, 1H), 6.06 (t, J=11.1Hz, 1H), 4.33 (q, J=7.1Hz,
2H), 2.53 (t, J=7.5Hz, 2H), 2.41 (t, J=7.0Hz, 2H), 1.63 (dd, J=14.6,7.3Hz, 4H), 1.37 (t,
J=7.1Hz, 3H), 1.05 (t, J=7.4Hz, 3H), 0.93 (t, J=7.4Hz, 3H)
13C NMR(100MHz,CDCl3)δ160.9,137.4,122.1,112.5,111.9,93.3,83.1,74.8,
60.4,29.6,22.3,22.3,21.8,14.4,13.7,13.6.
The invention provides the method for a synthesis 2- carbonyl -5- alkynyl azole derivatives, this method raw material is easy to get, and operates
Simply, reactions steps are few, and yield is high, and wide application range of substrates, application prospect is extensive.
Claims (2)
1. a kind of synthetic method of 2- carbonyls -5- alkynyl azole compounds, it is characterized in that：Comprise the following steps：
(1) 0.5mmol diine acetone, 0.55mmol glycine ester hydrochlorides, 0.5mmol are sequentially added in round-bottomed flask
KOAc,0.5mmol KHCO3, 2mL DMF are used as solvent；
(2) 120 DEG C of reaction 2h, TLC tracking reactions are heated to；
(3) after question response is complete, room temperature is cooled to, reactant is poured into 10~30mL water, and with 20~30mL ethyl acetate
Extraction, with 10mL saturated common salts water washing three times；
(4) anhydrous Na is used2SO4Dry, filtering, removal of solvent under reduced pressure；
(5) purified through Flash silica column chromatography, with ethyl acetate/petroleum ether by volume=1：20~50 elutions, obtain product.
2. synthetic method according to claim 1, it is characterized in that：It is as follows that it synthesizes formula：
In formula：
1 is diine acetone, and 2 be glycine ester hydrochloride, and 3 be the polysubstituted pyrrole with acetylene bond；
R1For phenyl, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- amyl group phenyl, 4- fluorophenyls
R2For phenyl, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- amyl group phenyl, 4- fluorophenyls
R3For alkoxy.
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