CN104478721A - Aryl derivative and copper-catalyzed preparation method of aryl derivative - Google Patents
Aryl derivative and copper-catalyzed preparation method of aryl derivative Download PDFInfo
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- CN104478721A CN104478721A CN201410682842.XA CN201410682842A CN104478721A CN 104478721 A CN104478721 A CN 104478721A CN 201410682842 A CN201410682842 A CN 201410682842A CN 104478721 A CN104478721 A CN 104478721A
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Abstract
The invention provides an aryl derivative with the following structural formula as shown in the description, wherein X is selected from chlorine or bromine; and R is selected from C1-C6 alkyl. The invention also provides a preparation method of the aryl derivative. According to the preparation method, organic copper is utilized as a catalyst; and the aryl derivative is high in yield, mild in reaction condition, and easy to process.
Description
Technical field
The present invention relates to a kind of organic intermediate and preparation method thereof, relate in particular to a kind of aryl derivatives and copper catalysis preparation method thereof.
Background technology
Aryl ketones is the very important organic compound of a class, has both been contained among the multiple natural product having physiologically active, is also widely used in the heterogeneous ring compound synthesizing other.As the classical way of preparation aryl ketones, friedel-crafts acylation has that catalyst levels is large, severe reaction conditions, aftertreatment difficulty, regioselectivity is poor, substrate spectrum is narrower, and acyl chlorides is as reaction reagent preparation difficulty, not easily the shortcoming such as preservation.For the consideration of economy and environment, need to find a kind of more economically, the method preparing aryl ketones of environmental protection and gentleness.The method that aryl ketones is prepared in the hydrocarbon activation of catalysis can solve some the problems referred to above undoubtedly.
At present, the method that metal catalyst catalysis aldehyde and derivative thereof and aryl boric acid prepare aryl ketones mainly contains following several: with rhodium, palladium, platinum, iridium or its title complex as catalyzer.When utilizing above catalyst preparing aryl ketones, still have catalyst toxicity comparatively large, price costly, the shortcoming that severe reaction conditions, selectivity are low, substrate use range is narrow.
Summary of the invention
The invention provides a kind of aryl derivatives with following structural formula, it is as a kind of important medicinal intermediates, can be used for the hypertensive medicine lisinopril of synthesis treatment,
In formula, X is selected from hydrogen, chlorine or bromine, and R is selected from the alkyl of C1 ~ C6.
Further, R is selected from methyl, ethyl or sec.-propyl.
The present invention provides the preparation method of above-mentioned aryl derivatives simultaneously, and synthetic route is:
In formula, X is selected from hydrogen, chlorine or bromine, and R is selected from the alkyl of C1 ~ C6.
Comprise the following steps:
(1) raw material 1 generates compound 2 through azido reaction;
(2) compound 2 and enamine 3 generate compound 4 under organic copper catalyzer.
Further, in azido reaction, nitrine reagent is 4-kharophen Phenylsulfonic acid nitrine or to Methyl benzenesulfonyl nitrine in described step (1).
Further, in described step (1), in azido reaction, alkali is DIPEA, DBU or pyridine.
Further, the organic copper catalyzer in described step (2) is Cu (hfacac)
2, Cu (accy)
2, Cu (tfaccy)
2or Cu (fod)
2.
Compared with prior art, beneficial effect of the present invention at least comprises: provide the preparation method of aryl derivatives to use organic copper as catalyzer, yield is high, and reaction conditions is gentle, easily processes.
Embodiment
Below will describe the present invention.But these embodiments do not limit the present invention, the conversion in the method that those of ordinary skill in the art makes according to these embodiments is all included in protection scope of the present invention.
Aryl derivatives structural formula provided by the invention is as follows,
In formula, X is selected from hydrogen, chlorine or bromine, and R is selected from the alkyl of C1 ~ C6, the further preferable methyl of R, ethyl or sec.-propyl, is bromine in embodiment with X, and R is that methyl is described.
The preparation method of aryl derivatives provided by the invention comprises the following steps: (1) raw material 1 generates compound 2 through azido reaction, nitrine reagent optional 4-kharophen Phenylsulfonic acid nitrine or to Methyl benzenesulfonyl nitrine in this step, the organic bases that the optional alkalescence of alkali used is stronger, preferred DIPEA, DBU or pyridine; (2) compound 2 and enamine 3 generate compound 4 under organic copper catalyzer, use organic copper catalyzer, preferred Cu (hfacac) in this step
2, Cu (accy)
2, Cu (tfaccy)
2or Cu (fod)
2.。
Embodiment 1: synthetic compound 2
Under protection of inert gas; in there-necked flask, add 300ml acetonitrile, 50g raw material 1 and 75g 4-kharophen Phenylsulfonic acid nitrine, be cooled to-5 DEG C ~ 5 DEG C, stir lower dropping 45g DBU; 20min drips complete; 3h is reacted at-5 DEG C ~ 5 DEG C, concentrated, column chromatography (PE:EA=8:1); obtain 47g compound 2; yield 83.3%, purity 98.2%, 1HNMR (CDCl3; 300MHz) δ: 7.90-7.88 (br; 3H), 7.60 (d, 1H); 7.59-7.53 (br; 3H), 3.83 (s, 3H).
Embodiment 2: synthetic compound 2
Under protection of inert gas; in there-necked flask, add 300ml acetonitrile, 50g raw material 1 and 38g to Methyl benzenesulfonyl nitrine, be cooled to-5 DEG C ~ 5 DEG C, stir lower dropping 32g DIPEA; 20min drips complete; 3h is reacted at-5 DEG C ~ 5 DEG C, concentrated, column chromatography (PE:EA=8:1); obtain 43g compound 2; yield 77.2%, purity 96.9%, 1HNMR (CDCl3; 300MHz) δ: 7.90-7.88 (br; 3H), 7.60 (d, 1H); 7.59-7.53 (br; 3H), 3.83 (s, 3H).
Embodiment 3: synthetic compound 3
Under protection of inert gas, in there-necked flask, add 600g normal hexane, 100g parabromoacetophenone and 245g morpholine, be cooled to-5 DEG C ~ 5 DEG C; drip 30ml titanium tetrachloride, 20min drips complete, room temperature reaction 24h under protection of inert gas; suction filtration, mother liquor concentrations, residuum underpressure distillation obtains 84g compound 3; yield 62.5%; purity 95.3%, 1HNMR (CDCl3,300MHz) δ: 7.50 (d, 2H); 7.33 (d; 2H), 4.33 (s, 1H); 4.20 (s; 1H), 3.77 (t, 4H); 2.79 (t, 4H).
Embodiment 4: synthetic compound 4
Under protection of inert gas, in there-necked flask, add 30g compound 3,0.32g Cu (accy)
2with 270ml DCM, be warming up to 35 DEG C ~ 45 DEG C, reaction 0.5h, be cooled to 20 DEG C ~ 30 DEG C, the DCM solution (200ml) of 20g compound 2 is dropped in above-mentioned solution, 45min drips complete, be warming up to 35 DEG C ~ 45 DEG C, reaction 1h, cooling, concentrated, column chromatography (PE:EA=8:1), obtain 28.1g compound 4, yield 80.8%, purity 98.3%, 1HNMR (CDCl3, 300MHz) δ: 7.85-7.70 (m, 6H), 7.55 (d, 2H), 7.48-7.42 (m, 3H), 4.41 (dd, 1H), 3.98 (dd, 1H), 3.69 (s, 3H), 3.22 (dd, 1H).
Embodiment 5: synthetic compound 4
Under protection of inert gas, 30g compound 3 is added in there-necked flask, 0.25g Cu (hfacac) and 270ml DCM, be warming up to 35 DEG C ~ 45 DEG C, reaction 0.5h, be cooled to 20 DEG C ~ 30 DEG C, the DCM solution (200ml) of 20g compound 2 is dropped in above-mentioned solution, 45min drips complete, be warming up to 35 DEG C ~ 45 DEG C, reaction 1h, cooling, concentrated, column chromatography (PE:EA=8:1), obtain 28.8g compound 4, yield 82.1%, purity 97.1%, 1HNMR (CDCl3, 300MHz) δ: 7.85-7.70 (m, 6H), 7.55 (d, 2H), 7.48-7.42 (m, 3H), 4.41 (dd, 1H), 3.98 (dd, 1H), 3.69 (s, 3H), 3.22 (dd, 1H).
Be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.
Claims (6)
1. there is an aryl derivatives for following structural formula,
In formula, X is selected from hydrogen, chlorine or bromine, and R is selected from the alkyl of C1 ~ C6.
2. aryl derivatives according to claim 1, is characterized in that, R is selected from methyl, ethyl or sec.-propyl.
3. a preparation method for aryl derivatives described in claim 1, is characterized in that, synthetic route is:
In formula, X is selected from hydrogen, chlorine or bromine, and R is selected from the alkyl of C1 ~ C6;
Comprise the following steps:
(1) raw material 1 generates compound 2 through azido reaction;
(2) compound 2 and enamine 3 generate compound 4 under organic copper catalyzer.
4. the preparation method of aryl derivatives according to claim 3, is characterized in that, in described step (1), in azido reaction, nitrine reagent is 4-kharophen Phenylsulfonic acid nitrine or to Methyl benzenesulfonyl nitrine.
5. the preparation method of aryl derivatives according to claim 3, is characterized in that, in described step (1), in azido reaction, alkali is DIPEA, DBU or pyridine.
6. the preparation method of aryl derivatives according to claim 3, it is characterized in that, the organic copper catalyzer in described step (2) is Cu (hfacac)
2, Cu (accy)
2, Cu (tfaccy)
2or Cu (fod)
2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110982806A (en) * | 2019-08-30 | 2020-04-10 | 浙江工业大学 | Protein aryl derivative and preparation method thereof |
-
2014
- 2014-11-24 CN CN201410682842.XA patent/CN104478721A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| WEI JIE ZHAO ET AL.: "New reaction of enamines with aryldiazoacetates catalyzed by transition metal complexes", 《TETRAHEDRON》 * |
| 吴健龙等: "赖诺普利合成新工艺研究", 《江西化工》 * |
| 赵伟杰等: "催化合成γ-酮酯的新反应研究", 《化学世界》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110982806A (en) * | 2019-08-30 | 2020-04-10 | 浙江工业大学 | Protein aryl derivative and preparation method thereof |
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Application publication date: 20150401 |