CN103275027B - Synthesis method of alpha-keto amide compound - Google Patents
Synthesis method of alpha-keto amide compound Download PDFInfo
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- CN103275027B CN103275027B CN201310242435.2A CN201310242435A CN103275027B CN 103275027 B CN103275027 B CN 103275027B CN 201310242435 A CN201310242435 A CN 201310242435A CN 103275027 B CN103275027 B CN 103275027B
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- keto amide
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- WGNAANKCNPJMGN-UHFFFAOYSA-N Cc(cc1)ccc1[IH](N(C)C(C(c1ccccc1)=O)=O)=O Chemical compound Cc(cc1)ccc1[IH](N(C)C(C(c1ccccc1)=O)=O)=O WGNAANKCNPJMGN-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a synthesis method of an alpha-keto amide compound, which is shown in formula II. According to the synthesis method, an alynyl-amine compound shown in formula I is used as a raw material and then added into a CH3CN/H2O solvent to react so as to obtain the Alpha-keto amide compound shown in formula II under the action of a copper catalyst/Selectfluor oxidant system. The synthesis method provided by the invention has the advantages that the catalyst is low in cost and small in toxicity, the oxygen source is easy to get, environmental protection is realized, the reaction condition is mild, functional groups are good in universality, and the operation is convenient.
Description
(1) technical field
The invention belongs to organic compound synthesis technical field, be specifically related to a kind of synthetic method of alpha-keto amide compounds.
(2) background technology
Alpha-keto amide is the very important organic compound of a class.Alpha-keto amide structure be many there is physiology or pharmacologically active natural product or synthetic molecule important feature unit (see Petal.D.V. etc., PCTInt.Appl.WO2008073623,2008; Knust, H. etc., PCT Int.Appl.WO2009016087,2009; Crowley, C.A. etc., PCT Int.Appl.WO2007146712,2007; White rugged benevolence is waited so long, and authorizes patent of invention ZL200480036672; Zhang, C. etc., Org.Lett., 2012,14,3280).In addition, alpha-keto amide itself can also be widely used in synthesizing some pharmaceutical intermediates.
At present, the preparation method of alpha-keto amide mainly contains following several: (1) for starting raw material, is that catalyzer synthesizes with halogeno-benzene, carbon monoxide and secondary amine with palladium; the shortcoming of this method needs to use expensive noble metal catalyst, severe reaction conditions, and need use the CO (carbon monoxide converter) gas under high pressure; carbon monoxide has severe toxicity; therefore complicated operation, there is security problems (can reference: Ozawa, F. etc.; Tetrahed ron Lett.; 1982,23,3383; Ozawa, F. etc., J.Am.Chem.Soc., 1985,107,3235).(2) be prepared through polystep reaction process, the usual complex steps of these class methods, and the substrate needing some special (can reference: the people such as Wasserman, H.H., J.Org.Chem., 1994,59,4364; U gi, the people such as I., Chem.Ber., 1961,94,1116; The people such as Chen, J.J., Tetrahedron Lett., 2003,44,8873).
Outside upper bibliographical information, Xu, C.-F. people is waited. reporting with gold is catalyzer, thionyl benzene is oxygen source, be oxidized alkynylamine at 85 ° of C and can prepare alpha-keto amide (Org.Lett., 2011,13,1556) Au catalyst, expensive oxygen source and higher temperature that, obviously use is expensive are the deficiencies of the method.In view of above Problems existing, develop to be participated in by cheap transition metal and oxygen source and the oxidizing reaction of the alkynylamine of reaction conditions gentleness remains and needs the urgent technical need solved.
(3) summary of the invention
Goal of the invention: for the deficiencies in the prior art, the present invention aims to provide a kind of method preparing alpha-keto amide, overcome the shortcoming of prior art, substitute expensive precious metal with inexpensive transition metal, to be easy to get and eco-friendly water and oxygen substitute expensive oxygen source and realizes reacting under the condition of room temperature to facilitate.
In order to reach foregoing invention object, the technical solution used in the present invention is:
A synthetic method for alpha-keto amide compounds, described method is:
Alkynylamine compounds shown in formula I is raw material, under the effect of copper catalyst, described copper catalyst is copper powder, neutralized verdigris, cuprous chloride or cuprous iodide, take Selectfluor as oxygenant, described Selectfluor is 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, in the mixed solvent of acetonitrile and water, stirred at ambient temperature reaction 0.5 ~ 36 hour, reaction terminates reaction solution aftertreatment and prepares the alpha-keto amide compounds shown in formula II;
In formula I or formula II, the H of phenyl ring is not substituted or coverlet substituting group methyl substituted;
R
3for methyl, R
2for one of group shown in following formula a ~ formula c:
Or R
2, R
3ring is connected into, the group for shown in formula d with atom N:
Preferred R
3for methyl, R
2for group shown in formula b or formula c, or R
2, R
3connecting into ring with atom N, is the group shown in formula d.
Copper catalyst of the present invention is preferably copper powder.
0.1% ~ 30% of the amount of substance that the amount of substance consumption of described copper catalyst is the alkynylamine compounds shown in formula I, is preferably 2.5% ~ 30%, most preferably is 5%.
1 ~ 3 times of the amount of substance that the amount of substance consumption of described Selectfluor is the alkynylamine compounds shown in formula I, is preferably 2 times.
In the mixed solvent of described acetonitrile and water, the volume ratio of acetonitrile, water is 5 ~ 500:1, preferably 5 ~ 200:1, most preferably is 50:1.
The volumetric usage of the mixed solvent of described acetonitrile and water counts 5 ~ 50mL/mmol with the amount of substance of the alkynylamine compounds shown in formula I usually, is preferably 10 ~ 20mL/mmol.
Preferably 0.5 ~ 24 hour time of described reaction, more preferably 9 ~ 24 hours, most preferably 9 hours.
Reaction solution post-treating method of the present invention is: after reaction terminates, column chromatography silica gel is added in gained reaction solution, underpressure distillation is except desolventizing, remaining mixture dress post, through column chromatography for separation, using sherwood oil, the ethyl acetate volume ratio mixed solvent that is 3:1 as eluent, collect the elutriant containing product, elutriant steams and desolventizes the alpha-keto amide compounds obtained shown in formula II.
Comparatively concrete, described method is recommended to carry out according to the following steps: the alkynylamine compounds shown in formula I is raw material, under the effect of copper powder catalyst, take Selectfluor as oxygenant, described Selectfluor is 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, acetonitrile and water volume ratio be 50:1 mixed solvent in, stirred at ambient temperature reaction 9 ~ 24 hours, after reaction terminates, column chromatography silica gel is added in reaction solution, underpressure distillation is except desolventizing, remaining mixture dress post, through column chromatography for separation, with sherwood oil, ethyl acetate volume ratio is that the mixed solvent of 3:1 is as eluent, collect the elutriant containing product, elutriant steams and desolventizes the alpha-keto amide compounds obtained shown in formula II, 5% of the amount of substance that the amount of substance consumption of described copper powder catalyst is the alkynylamine compounds shown in formula I, 2 times of the amount of substance that the amount of substance consumption of described Selectfluor is the alkynylamine compounds shown in formula I.
The raw material alkynylamine compounds that the present invention uses, those skilled in the art can prepare voluntarily according to method disclosed in existing document, such as document people such as [, Org.Lett., 2011,13,1556] Xu, C.-F. etc.
Reaction of the present invention, described catalyzer is cheap and easy to get, and low toxicity is efficient, and assists without the need to extra ligand.
The present invention by alkynylamine under Cu/Selectfluor catalysis/oxidation system effect, with oxygen in water and air for oxygen source, by the bis oxide carbonylation process of alkynylamine obtain α ?keto-amide and derivative thereof, its beneficial effect is: with existing α ?compared with keto-amide preparation method, catalyzer is cheap and easy to get, and toxicity is lower; The oxygen source used is oxygen in water and air, cheap and easy to get and environmental friendliness; Reaction conditions is quite gentle, save energy consumption; In addition, also there is productive rate high, the features such as substrate universality is strong, easy and simple to handle.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, but protection scope of the present invention is not limited thereto:
Embodiment 1
37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 141.7mg (0.4mmol) S electfluor, 0.64mg (0.01mmol) Cu powder are joined in 10mL round-bottomed flask, then adds 2m L acetonitrile/water (V:V=50:1) and make solvent.Then, 9h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, pass through pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product.This material is faint yellow solid, productive rate 92%.Characterization data: mp105-107 ° C; IR (neat) ν=1785,1696 (C=O) cm
-1; .
1h NMR (CDCl
3, 500MHz): δ=7.89 (d, J=7.0Hz, 2H), 7.66 (t, J=7.5Hz, 1H), 7.52 (t, J=8.0Hz, 2H), 4.60 (t, J=8.0Hz, 2H), 4.17 (t, J=8.0Hz, 2H); MS (EI, 70eV): m/z (%)=219 (2) [M
+], 105 (100).
Embodiment 2
37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 141.7mg (0.4mmol) S electfluor, 0.38mg (0.006) mmol Cu powder are joined in 10mL round-bottomed flask, then adds 2mL acetonitrile/water (V:V=50:1) and make solvent.Then, 12h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 90%.
Embodiment 3
37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 141.7mg (0.4mmol) S electfluor, 1.28mg (0.02mmol) Cu powder are joined in 10mL round-bottomed flask, then adds 2m L acetonitrile/water (V:V=50:1) and make solvent.Then, 16h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 60%.
Embodiment 4
By 37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 212.6 (0.6) mmol Select fluor, 1.81mg (0.01mmol) Cu (OAc)
2join in 10mL round-bottomed flask, then add 2m L acetonitrile/water (V:V=50:1) and make solvent.Then, 0.5h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 50%.
Embodiment 5
37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 141.7mg (0.4mmol) S electfluor, 0.99mg (0.01) mmol CuCl are joined in 10mL round-bottomed flask, then adds 2m L acetonitrile/water (V:V=200:1) and make solvent.Then, 9h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 85%.
Embodiment 6
37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 141.7mg (0.4mmol) S electfluor, 0.64mg (0.01mmol) Cu powder are joined in 10mL round-bottomed flask, then adds 2m L acetonitrile/water (V:V=5:1) and make solvent.Then, 24h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 78%.
Embodiment 7
37.4mg (0.2mmol) N-phenylacetylene base-oxazoline-2-ketone, 70.9mg (0.2mmol) Sel ectfluor, 0.32mg (0.005) mmol Cu powder are joined in 10mL round-bottomed flask, then adds 2m L acetonitrile/water (V:V=50:1) and make solvent.Then, 9h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 64%.
Embodiment 8
57mg (0.2mmol) N-methyl-N-(phenylacetylene base)-para toluene sulfonamide, 141.7mg (0.4mmol) Selectfluor, 0.64 (0.01mmol) Cu powder are joined in 10mL round-bottomed flask, then adds 2mL acetonitrile/water (V:V=500:1) and make solvent.Then, 0.5h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 53%.
Characterization data: IR (neat) ν=1694,1596 (C=O) cm
-1; .
1h NMR (CDCl
3, 500MHz): δ=7.71 (d, J=7.5Hz, 2H), 7.33-7.28 (m, 5H), 7.15 (d, J=6.5Hz, 2H), 3.29 (s, 3H), 2.46 (s, 3H); MS (EI, 70eV): m/z (%)=317 (8) [M
+], 105 (100).
Embodiment 9
59.8mg (0.2mmol) N-methyl-N-(4-methylbenzene ethynyl)-para toluene sulfonamide, 141.7mg (0.4mmol) Selectfluor, 0.64mg (0.01mmol) Cu powder are joined in 10mL round-bottomed flask, then adds 2mL acetonitrile/water (V:V=50:1) and make solvent.Then, 9h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, by pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product, productive rate 67%.
Characterization data: IR (neat) ν=1670,1640 (C=O) cm
-1; .
1h NMR (CDCl
3, 500MHz): δ=7.88 (d, J=10.0Hz, 2H), 7.82 (d, J=10.0Hz, 2H), 7.39-7.30 (m, 4H), 3.23 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H); MS (EI, 70eV): m/z (%)=331 (2) [M
+], 119 (100).
Embodiment 10
70mg (0.2mmol) N-methyl-N-(phenylacetylene base)-brosyl amine, 141.7mg (0.4mmol) Selectfluor, 0.38mg (0.06mmol) Cu powder are joined in 10mL round-bottomed flask, then adds 2mL acetonitrile/water (V:V=50:1) and make solvent.Then, 24h is stirred in room temperature condition lower magnetic force.Then, 10g column chromatography silica gel (100-200 order) is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, pass through pillar layer separation, using petrol ether/ethyl acetate (V:V=3:1) as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product.This material is pale yellow oily liquid body, productive rate 38%.
Characterization data: IR (neat) ν=1680,1651 (C=O) cm
-1; .
1h NMR (CDCl
3, 500MHz): δ=7.92 (d, J=9.0Hz, 2H), 7.87 (d, J=9.0Hz, 2H), 7.76-7.51 (m, 5H), 3.26 (s, 3H); MS (EI, 70eV): m/z (%)=381 (2) [M
+].
Claims (1)
1. a synthetic method for alpha-keto amide compounds, described alpha-keto amide compounds is shown below, and it is characterized in that described method is:
37.4mg N-phenylacetylene base-oxazoline-2-ketone, 141.7mg Selectfluor, 0.64mgCu powder are joined in 10mL round-bottomed flask, add 2mL acetonitrile/water V:V=50:1 again and make solvent, then, 9h is stirred in room temperature condition lower magnetic force, then, 10g column chromatography silica gel 100-200 order is added in reaction solution, and by underpressure distillation except desolventizing, residuum dress post, pass through pillar layer separation, using petrol ether/ethyl acetate V:V=3:1 as eluent, collect the elutriant containing product, elutriant steams to desolventize and obtains pure product; Described Selectfluor is 1-chloromethyl-4-fluoro-Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt.
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