CN104844534B - A kind of method that cuprous catalysis benzyl azide synthesizes 2,5 2 replacement azoles with styrene - Google Patents
A kind of method that cuprous catalysis benzyl azide synthesizes 2,5 2 replacement azoles with styrene Download PDFInfo
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- CN104844534B CN104844534B CN201510258617.8A CN201510258617A CN104844534B CN 104844534 B CN104844534 B CN 104844534B CN 201510258617 A CN201510258617 A CN 201510258617A CN 104844534 B CN104844534 B CN 104844534B
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- cuprous
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/06—Halogens; Compounds thereof
- B01J27/08—Halides
- B01J27/122—Halides of copper
Abstract
The invention discloses a kind of cuprous catalysis benzyl azide synthesizes the preparation method of 2,5 two replacement azoles with styrene, comprise the steps：The preparation of 1 replacement nitrine, 2）Nitrine prepares product with cinnamic reaction, and the simple and reaction condition of the method raw material is gentle, and the method for providing has good using value, is suitable for industrialized a large amount of productions.
Description
Technical field
The present invention relates to chemical field, and in particular to a kind of cuprous catalysis benzyl azide synthesizes bis- replacement of 2,5- with styrene
The method of azoles.
Background technology
Azoles ring is important a, heterocycle structure, and heterocyclic compound is always ground in pharmaceutical chemistry and organic synthesis
One of important content that studies carefully, azoles and its azole compounds are important heterocyclic compounds, and they are not only in organic synthesis
In be important synthon and synthetic intermediate.In view of the important use of this kind of compound of azoles, numerous chemists exist always
New simple azoles synthetic method is sought,
Hu Ping reports polysubstituted azoles as the important azoles of a class, synthesize under copper catalysis polysubstituted azoles and
Small molecule bioactive（《Copper catalysis synthesize polysubstituted azoles and small molecule bioactive research》Hu duckweed Chinese science technology
University 2014-05-10）.Zhou Aixin etc. reports the synthesis of (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides derivative and antibacterial activity, and to such derivative
The structure-activity relationship of thing is studied.（Zhou Aixin, Qu Youle, Zhou Tianming, etc. 2- [(4S, 5R) -4- acyl
Amido -5- methyl -3- oxo -2- isoxazole alkyl] -5- oxo -2- tetrahydrofuran formic acid sodium suppression enzyme
[J] is studied with antibacterial activity. Chinese antibiotic magazine, 1996,21 (6):414- 418.）.Brown etc.
[2] synthesize Series of Chiral Zole derivatives, such compound is reported for haemophilus influenzae, moraxelle catarrhalis, gold
The antibacterial activity of the bacteriums such as staphylococcus, streptococcus pyogenes（Brown P , Davies D T , O'hanlon P J , et
al. The Chemistry of Pseudomonic Acid. 15. Synthesis and Antibacterial
Activity of a Series of5- Alkyl , 5- Alkenyl , and 5- Heterosubstituted
Oxazoles [ J ] . J Med Chem , 1996 , 39 : 446- 457.）.Sasaki etc. [19] synthesis system
Row chipal compounds, are shown by activity experiment result, when (R) -6- nitro -2,3- dihydroxy imidazo
When the substituent that azole compounds are 2 is phenoxy group and methyl, compound has potential antibacterial activity.（Sasaki H ,
Haraguchi Y , Itotani M , et al. Synthesis and Antituberculosis Activity of a
Novel Series of Optically Active 6-
Nitro- 2 , 3- dihydroimidazo [ 2 , 1- b ] oxazoles [ J ] . J Med Chem
2006 , 49 : 7 854- 7 860.）
Content of the invention
The purpose of the present invention overcomes the deficiencies in the prior art, provides a kind of cuprous catalysis benzyl azide and synthesizes 2 with styrene,
The method of bis- replacement azoles of 5-.
The technical scheme for realizing the object of the invention is
A kind of cuprous catalysis benzyl azide synthesizes the preparation method of bis- replacement azoles of 2,5- with styrene, comprises the steps of
1）Replace the preparation of nitrine
With Sodium azide/end position bromine（Benzyl bromide a-bromotoluene, alkyl bromide）=4.5：4, two kinds of medicines are proportionally added into, under this ratio, plus
Enter the DMSO of 15-20 mL（As medicine addition increases, then should be scaling up the amount of solvent）, 24 are reacted in 70 DEG C of oil baths
Take out after hour, room temperature is cooled to, product is poured into separatory funnel, 30 mL water dissolves DMSO are added, and uses 30mL ether
It is extracted twice, uses saturated aqueous common salt（30 mL）Washing three times, finally uses anhydrous MgSO4Dry 30 minutes, filter, be removed under reduced pressure
Solvent can be obtained.
）Nitrine prepares product with cinnamic reaction
The cuprous catalysis agent of nitrine throwing amount 10% is added in reaction bulb（Such as：Stannous chloride, cuprous bromide, cuprous iodide）, plus
Enter the toluene (or benzene, chlorobenzene) equivalent to styrene 15-20 times amount, react under 80 DEG C of oil bath temperatures, 12-24 hour is reacted,
During reaction is carried out, TLC tracking reaction.To be monitored take out and be cooled to room temperature to after react completely, with dichloromethane by thing
Matter is all washed out, and adds 100-200 mesh silica gel, on a rotary evaporator removal of solvent under reduced pressure, through silica gel column chromatography after washing out
Purifying（Ethyl acetate/petroleum ether=1：5～50）.
Specifically chemical equation is：
R1=alkyl, aryl；R2=phenyl, heterocycle
Wherein, Cu+Saline catalyst：Stannous chloride, cuprous bromide, cuprous iodide etc.
Solvent：Toluene, benzene, chlorobenzene
It is an advantage of the invention that
A kind of cuprous catalysis benzyl azide synthesizes the preparation method of bis- replacement azoles of 2,5- with styrene, and raw material is simple and anti-
Mild condition is answered, the method for providing has good using value, be suitable for substantial amounts of industry.
Specific embodiment
The present invention is further elaborated below, but is not limitation of the invention
Embodiment 1
Preparation of the 2- phenyl -5- to fluorophenyl azoles
The benzyl azide of 0.8 mmol is added in reaction bulb, adds nitrine 10%（8 mg) cuprous chloride catalyst with
And 0.5 mmol pfluorostyrene, add finish after add 17 times amount of styrene（1 mL) toluene as solvent, at 80 DEG C
13 hours are reacted in oil bath during reaction is carried out, TLC tracking reaction.After extremely reaction completely to be monitored, take out and be cooled to room
Material is all washed out by temperature with dichloromethane, adds 100-200 mesh silica gel, be removed under reduced pressure on a rotary evaporator molten after washing out
Agent, purifies through silica gel column chromatography（Ethyl acetate/petroleum ether=1：20～50）White solid product 1a 21mg yield 80%.
Being characterized as below for product is shown：
1H NMR (500MHz, CDCl3)δ 8.13 （Dd, J=7.7；1.8Hz, 2H）；7.76-7.69（M, 2H）,
7.55-7.46（M, 3H）, 7.44-7.37（M, 1H）, 7.22-7.13（M, 2H）ppm；13C NMR (126 MHz, CDCl3) δ
161.18（s）, 150.47（s）, 130.39（s）, 128.84（s）, 126.84（D, J=138.2 Hz）, 126.11（D, J=
8.2 Hz）, 123.11（s）, 116.19（s）, 116.02（s）. HRMS (m/z)(ESI)：calcd for C16H11ONF[M-H+]：240.08160；found：240.08160.
Embodiment 2
The preparation of 2- phenyl 5- phenyl azoles
The benzyl azide of 0.8mmol is added in reaction bulb, adds nitrine 10%（8 mg) cuprous bromide catalyst and
The styrene of 0.5 mmol, adds after finishing and adds the chlorobenzene of 1 mL as solvent, react about 17 hours in 80 DEG C of oil baths,
During reaction is carried out, TLC tracking reaction.To be monitored take out and be cooled to room temperature to after react completely, with dichloromethane by thing
Matter is all washed out, and adds 100-200 mesh silica gel, on a rotary evaporator removal of solvent under reduced pressure, through silica gel column chromatography after washing out
Purifying（Ethyl acetate/petroleum ether=1：5～50）White solid product 2a 25mg yield 88%.
Being characterized as below for product is shown：
1H NMR (500 MHz, CDCl3) δ 8.19-8.10 (m, 2H), 7.79-7.70 (m, 2H), 7.55-7.42
(m, 6H), 7.37 (t, J=7.4 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 161.19 (s), 151.31 (s),
130.33 (s), 128.94 (s), 128.82 (s), 128.45 (s), 128.07 (s), 127.50 (s), 126.32 (s),
124.23 (s), 123.46 (s) .HRMS (m/z) (ESI)：calcd for C15H12ON [M-H+]：222.09122；
found: 222.09122.
Embodiment 3
The preparation of 2- phenyl -5- methoxyl group azoles
The benzyl azide of 0.8 mmol is added in reaction bulb, adds nitrine 10%（8 mg) cuprous iodide catalyst with
And 0.5 mmol to methoxy styrene, add after finishing and add the toluene of 1 mL as solvent, react in 80 DEG C of oil baths
About 20 hours, during reaction is carried out, TLC tracking reaction.To be monitored to after react completely, taking-up is cooled to room temperature, uses
Material is all washed out by dichloromethane, adds 100-200 mesh silica gel, on a rotary evaporator removal of solvent under reduced pressure, warp after washing out
Cross silica gel column chromatography purifying（Ethyl acetate/petroleum ether=1：20～50）White solid product 3a 16mg yield 65%.
Being characterized as below for product is shown：
1H NMR (500 MHz, CDCl3) δ 8.15 8.09 (m, 2H), 7.69 (d, J=8.7 Hz, 2H),
7.54 7.45 (m, 3H), 7.36 (s, 1H), 7.29 (s, 1H), 7.01 (d, J=8.6 Hz, 2H), 3.89 (d, J=
3.8 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 160.60 (s), 159.89 (s), 151.36 (s), 130.11
(s), 128.78 (s), 127.62 (s), 126.17 (s), 125.78 (s), 121.97 (s), 120.94 (s), 114.45
(s), 55.38 (s) .HRMS (m/z) (ESI)：calcd for C16H14O2N[M-H+]：252.10143； found：
252.10143.
Embodiment 4
The preparation of 2- p-bromophenyl -5- phenyl azoles
With Sodium azide/to bromobenzyl bromine=4.5：4, two kinds of medicines are proportionally added into, under this ratio, add the DMSO of 15 mL
Take out after reacting 24 hours in 70 DEG C of oil baths, room temperature is cooled to, product is poured into separatory funnel, add 30 mL water-soluble
Solution DMSO, and be extracted twice with 30mL ether, use saturated aqueous common salt（30 mL）Washing three times, finally uses anhydrous MgSO4Dry 30
Minute, filtering, removal of solvent under reduced pressure is obtained to bromobenzyl nitrine.The benzyl azide of 1mmol is added in sealing test tube, is added folded
Nitrogen 10%（Cuprous iodide catalyst 10mg) and the styrene of 0.5mmol, add after finishing and add the benzene of 1mL as solvent,
React in 80 DEG C of oil baths about 15 hours, during reaction is carried out, TLC tracking reaction.After extremely reaction completely to be monitored, take
Go out room temperature is cooled to, all washed out the material in test tube is sealed with dichloromethane, 100-200 mesh silica gel after washing out, is added,
Removal of solvent under reduced pressure on Rotary Evaporators, purifies through silica gel column chromatography（Ethyl acetate/petroleum ether=1：20～50）Yellow solid
Product 4a 28mg yield 80%.
Being characterized as below for product is shown：
1H NMR (500 MHz, CDCl3) δ 8.03-7.95 (m, 2H), 7.77-7.70 (m, 2H), 7.67-7.60
(m, 2H), 7.51-7.43 (m, 3H), 7.38 (t, J=7.4 Hz, 1H).13C NMR (126 MHz, CDCl3), 160.28
(s), 151.60 (s), 132.09 (s), 128.98 (s), 128.62 (s), 127.78 (d, J=15.6 Hz), 126.41
(s), 124.76 (s), 124.27 (s), 123.60 (s), 77.29 (s), 77.04 (s), 76.79 (s), 31.45 (s),
30.24 (s), 29.71 (s), 0.00 (s). HRMS (m/z) (ESI)：calcd for C15H11ONBr[M-H+]：
300.00144；found：300.00144.
Embodiment 5
2- cyclohexyl -5- phenyl azoles
With Sodium azide/bromomethylcyclohexane=4.5：4, two kinds of medicines are proportionally added into, under this ratio, add 15 mL's
DMSO is taken out after reacting 24 hours in 70 DEG C of oil baths, is cooled to room temperature, and product is poured into separatory funnel, adds 30 mL
Water dissolves DMSO, and be extracted twice with 30mL ether, use saturated aqueous common salt（30 mL）Washing three times, finally uses anhydrous MgSO4Dry
Dry 30 minutes, filter, removal of solvent under reduced pressure obtains hexamethylene methyl azide.The benzyl azide of 1mmol is added in sealing test tube, then
Add nitrine 10%（10 mg) cuprous chloride catalyst and 0.5 mmol styrene, add and after finishing, add the first of 1 mL
Benzene is reacted about 12 hours as solvent in 80 DEG C of oil baths, during reaction is carried out, TLC tracking reaction.To be monitored to anti-
After answering completely, take out and room temperature is cooled to, all washed out the material in test tube is sealed with dichloromethane, after washing out, add 100-
200 mesh silica gel, removal of solvent under reduced pressure, purifies through silica gel column chromatography on a rotary evaporator（Ethyl acetate/petroleum ether=1：20
～50）20 mg yield 70% of white solid product 5a.
Being characterized as below for product is shown：
1H NMR (500 MHz, CDCl3) δ 7.64 (d, J=7.4 Hz, 2H), 7.46-7.39 (m, 2H), 7.33
(d, J=7.5 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 2.89 (tt, J=11.3,3.6 Hz, 1H), 1.86
(ddd, J=23.2,13.6,10.1 Hz, 2H), 1.74 (dd, J=14.9,11.3 Hz, 2H), 1.68-1.61 (m,
2H), 1.51-1.41 (m, 2H), 1.39-1.33 (m, 2H).13C NMR (126 MHzCDCl3) δ 150.49 (s),
128.80 (s), 128.43 (s), 128.00 (s), 123.98 (s), 121.61 (s), 37.61 (s), 30.65 (s),
25.82 (s), 25.64 (s). HRMS (m/z) (ESI)：calcd for C15H18ON[M-H+]：228.13806;
found：228.13806.
Embodiment 6
2- mesitylene base -5- phenyl azoles
With Sodium azide/equal trimethyl benzyl bromine=4.5：4, two kinds of medicines are proportionally added into, under this ratio, add 15 mL
DMSO react 24 hours in 70 DEG C of oil baths after take out, be cooled to room temperature, product poured into separatory funnel, add 30
ML water dissolves DMSO, and be extracted twice with 30mL ether, use saturated aqueous common salt（30 mL）Washing three times, finally uses anhydrous MgSO4
Dry 30 minutes, filter, removal of solvent under reduced pressure obtains equal trimethyl benzyl nitrine.The benzyl of 1 mmol is added to fold in sealing test tube
Nitrogen, adds nitrine 10%（10 mg) cuprous chloride catalyst and 0.5 mmol styrene, add finish after add 1
The toluene of mL is reacted about 12 hours as solvent in 80 DEG C of oil baths, during reaction is carried out, TLC tracking reaction.Wait to supervise
After surveying to reaction completely, take out and room temperature is cooled to, all washed out the material in test tube is sealed with dichloromethane, add after washing out
100-200 mesh silica gel, removal of solvent under reduced pressure, purifies through silica gel column chromatography on a rotary evaporator（Ethyl acetate/petroleum ether=
1：20～50）50 mg yield 85% of white solid product 6a.
Being characterized as below for product is shown：
1H NMR (500 MHz, CDCl3) δ 7.76-7.69 (m, 2H), 7.54 (s, 1H), 7.47 (t, J=7.7
Hz, 2H), 7.37 (t, J=7.4 Hz, 1H), 7.01 (s, 2H), 2.38 (d, J=10.3 Hz, 9H).13C NMR (126
MHz, CDCl3) δ 160.97 (s), 151.12 (s), 139.83 (s), 138.51 (s), and 128.96 (s), 128.71
(s), 128.33 (s), 125.25 (s), 124.14 (s), 122.43 (s), 21.24 (s), 20.51 (s). HRMS (m/
z) (ESI)：calcd for C18H28ON[M-H+]：264.13771；found：264.13771.
Claims (3)
1. a kind of cuprous catalysis benzyl azide and the preparation method of styrene synthesis bis- replacement azoles of 2,5-, is characterized in that, comprising
Following steps：
(1) replace the preparation of nitrine
With Sodium azide/end position bromine=4.5 4, two kinds of medicines are proportionally added into, the DMSO of 15-20mL under this ratio, is added,
Take out after reacting 24 hours in 70 DEG C of oil baths, room temperature is cooled to, product is poured into separatory funnel, add 30mL water dissolves
DMSO, and being extracted twice with 30mL ether, with saturated common salt water washing three times, finally uses anhydrous MgSO4Dry 30 minutes, mistake
Filter, removal of solvent under reduced pressure can be obtained；
(2) nitrine prepares product with cinnamic reaction
Add the cuprous catalysis agent of nitrine throwing amount 10% in reaction bulb, add toluene equivalent to styrene 15-20 times amount, benzene or
Chlorobenzene, reacts under 80 DEG C of oil bath temperatures, reacts 12-24 hour, during reaction is carried out, TLC tracking reaction；
(3) to be monitored to after react completely, taking-up is cooled to room temperature, all washes out material with dichloromethane, adds after washing out
100-200 mesh silica gel, removal of solvent under reduced pressure, purifies through silica gel column chromatography on a rotary evaporator；
Specifically chemical equation is：
In formula：R1=phenyl；R2=phenyl, heterocycle；
Cu+Saline catalyst is：Stannous chloride, cuprous bromide or cuprous iodide.
2. preparation method according to claim 1, is characterized in that：End position bromine described in step (1) is benzyl bromide a-bromotoluene.
3. preparation method according to claim 1, is characterized in that：Washing in the silica gel column chromatography purifying described in step (3)
De- agent is ethyl acetate petroleum ether=1 5～50.
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