CN110317147A - A method of reduction alpha-keto amide prepares Alpha-hydroxy amide - Google Patents
A method of reduction alpha-keto amide prepares Alpha-hydroxy amide Download PDFInfo
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- CN110317147A CN110317147A CN201910714251.9A CN201910714251A CN110317147A CN 110317147 A CN110317147 A CN 110317147A CN 201910714251 A CN201910714251 A CN 201910714251A CN 110317147 A CN110317147 A CN 110317147A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/04—Formation or introduction of functional groups containing nitrogen of amino groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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Abstract
The present invention relates to a kind of methods for preparing Alpha-hydroxy amide.Alpha-keto amide and inorganic base in organic solvent, react 6-18 hour under the conditions of 110-150 DEG C, and reduction obtains Alpha-hydroxy amide.It is novel that preparation method raw material of the present invention is easy to get, is at low cost, operation is easy and efficient, and obtained Alpha-hydroxy amide is expected to be used widely in field of medicine and chemical technology as synthetic intermediate.
Description
Technical field: the present invention relates to a kind of methods that reduction alpha-keto amide prepares Alpha-hydroxy amide, belong to organic synthesis
Technical field.
Background technique:
Alpha-hydroxy amide is a kind of important compound, for example in many drug molecules, hydroxy amide is all important
Bioactive fragment.Nuclear retinoic acid receptor γ (RAR- γ) agonist BMS-270394 is exactly hydroxy amide class compound, it
It can be used for treating the prevention of acne and Organ Transplantation Patients precancerous lesion.The for another example gamma-secretase of Eli-Lily company exploitation
Inhibitor LY411575 and LY450139 are hydroxy amide class compounds, they have in vivo inhibits PS/ γ-points well
The ability for secreting enzyme can be used for the treatment of Alzheimer disease.
Other than can be as important pharmaceutical activity segment, Alpha-hydroxy amide be also a kind of important ligand, is commonly used for
In the organic synthesis of metal catalytic.In view of important work of the Alpha-hydroxy amides compound in Synthetic Organic Chemistry and pharmaceutical chemistry
With the synthesis of such compound is concerned, therefore the method for developing new more efficient, green such compound of synthesis will be
Significantly.
The synthesis of Alpha-hydroxy amides compound, typically by carrying out selective hydrogen to corresponding alpha-keto amide substrate
Change reduction ketone carbonyl to realize.NaBH4It is common go back original reagent, but he must be with metal reagent such as CeO2Or CuCl2Connection
With ketone carbonyl (A.A.Mishra, B.M.Bhanage, the Asian that could be restored in alpha-keto amide substrate
J.Org.Chem.2018,7,922-931.), obtain corresponding Alpha-hydroxy amide.But with NaBH4It is its disadvantage for reducing agent
Be it will be apparent that if in substrate containing other ketone carbonyls when, can also be reduced simultaneously, therefore there is a problem of selective；It removes
Except this, reported in the literature is all to use polymethyl hydrogen siloxane (PMHS) or other silane compounds as alpha-keto amide
Reducing agent, but to be generally added W metal (N.Chary Mamillapalli, G.Sekar, Chem.Commun.2014,50,
7881-7884.) or Pd (N.C.Mamillapalli, G.Sekar, Adv.Synth.Catal.2015,357,3273-
3283.) it is used as catalyst；From the point of view of Green Chemistry, nonmetal catalyzed reaction will be more attractive, external several classes
Topic group discovery tetrabutyl ammonium fluoride (TBAF) (N.Chary Mamillapalli, G.Sekar, RSC Adv.2014,4,
61077-61085.), potassium phosphate K3PO4(A. Muthukumar,N.C.Mamillapalli,G.Sekar,
) or cesium carbonate Cs Adv.Synth.Catal.2016,358,643-652.2CO3 (G.Kumar,A.Muthukumar,
G.Sekar, Eur.J.Org.Chem.2017,4883-4890.) it can also promote tri-phenyl-silane (Ph3SiH) or PMHS is selected
Property reduction alpha-keto amide, but these catalytic reduction methods are there is also using large excess of silanes reducing agent, atom
Economy is poor.Therefore develop new, cheap practical, more Atom economy and the selectively method of reduction alpha-keto amide
It is meaningful.
Although Existing methods remain portion in conclusion the study on the synthesis of Alpha-hydroxy amide makes some progress
Divide defect, does not have higher universality.Therefore, it is necessary to develop be simple and efficient, Environmental Safety, be suitble to industrialized production conjunction
At the method for Alpha-hydroxy amide.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of raw materials to be easy to get, cost
Reduction alpha-keto amide that is low, easy to operate and not needing to introduce catalyst is come the method for preparing Alpha-hydroxy amide.
The purpose of the present invention can be achieved through the following technical solutions:
A method of reduction alpha-keto amide prepares Alpha-hydroxy amide, which is characterized in that alpha-keto amide and alkali are organic molten
In agent, 6-18 hour is reacted under the conditions of 110-150 DEG C, is selectively restored the ketone carbonyl of alpha-keto amide, is obtained Alpha-hydroxy
Amide, wherein the synthetic reaction formula of target compound are as follows:
The alpha-keto amide has the following structure formula:
Wherein:
R1For alkyl, naphthenic base, aryl (including substituted aryl), heterocycle (including heteroaryl and substituted heteroaryl)；
R2For alkyl, naphthenic base, aryl (including substituted aryl), heterocycle (including heteroaryl and substituted heteroaryl).
The method that a kind of reduction alpha-keto amide prepares Alpha-hydroxy amide, which is characterized in that the alkali is carbonic acid
Sodium, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropylate, potassium tert-butoxide.
The method that a kind of reduction alpha-keto amide prepares Alpha-hydroxy amide, which is characterized in that the organic solvent
For ethyl alcohol, isopropanol, ethylene glycol, N,N-dimethylformamide.
The method that a kind of reduction alpha-keto amide prepares Alpha-hydroxy amide, which is characterized in that the keto-amide with
The molar ratio of alkali is 1:1~2.
A kind of method that reduction alpha-keto amide prepares Alpha-hydroxy amide according to claim 1, which is characterized in that institute
The reaction temperature stated is 110-150 DEG C.
The method that a kind of reduction alpha-keto amide prepares Alpha-hydroxy amide, which is characterized in that reaction time 6-18
A hour.
Specific embodiment
The present invention is further detailed by following embodiment, but following embodiment cannot be not understood as to this hair
The limitation of bright protection scope.Do not departing from technical scope of the present invention, it is any for the present invention it is nonessential improvement and
Variation, all should be comprising within the technical scope of the present invention.
Embodiment 1
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.2g, 5.00mmol) are dissolved in
4.5mLN, in dinethylformamide, gained mixture is in 150 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.98g, yield 98%.
The characterize data of compound 2a:
White solid；1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),7.58-7.66(m,2H),7.58-7.51
(m, 2H), 7.35-7.42 (m, 2H), 7.27-7.35 (m, 1H), 7.12 (d, J=8.4Hz, 2H), 6.46 (d, J=4.7Hz,
1H), 5.12 (d, J=4.7Hz, 1H), 2.27 (s, 3H)；13CNMR(100MHz,DMSO-d6):δ171.4,141.4,136.5,
132.9,129.4,128.5, 128.0,127.0,120.1,74.4,20.9.
Embodiment 2
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.2g, 5.00mmol) are dissolved in
4.5mLN, in dinethylformamide, gained mixture is in 130 DEG C of 12 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.99g, yield 99%.
Embodiment 3
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.20g, 5.00mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 110 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2a 0.93g, yield 93%.
Embodiment 4
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium carbonate (0.53g, 5.00mmol) are dissolved in
In 4.5mL n,N-Dimethylformamide, gained mixture is in 130 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2a 0.26g, yield 26%.
Embodiment 5
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and potassium carbonate (0.69g, 5.00mmol) are dissolved in
In 4.5mL n,N-Dimethylformamide, gained mixture is in 130 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2a 0.47g, yield 47%.
Embodiment 6
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and lithium hydroxide (0.12g, 5.00mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 12 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2a 0.94g, yield 94%.
Embodiment 7
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and potassium hydroxide (0.28g, 5.00mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.92g, yield 92%.
Embodiment 8
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium methoxide (0.27g, 5.00mmol) are dissolved in
In 4.5mL n,N-Dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.89g, yield 89%.
Embodiment 9
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium ethoxide (0.34g, 5.00mmol) are dissolved in
In 4.5mL n,N-Dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.85g, yield 85%.
Embodiment 10
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium isopropylate (0.41g, 5.00mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.83g, yield 83%.
Embodiment 11
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and potassium tert-butoxide (0.56g, 5.0mmol) are dissolved in
4.5mLN, in dinethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a0.78g, yield 78%.
Embodiment 12
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.20g, 5.00mmol) are dissolved in
In 6mL ethyl alcohol, gained mixture is in 130 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, water 5mL is added, by mixture
It is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), merge organic phase, the drying of 2g anhydrous sodium sulfate, decompression is added
Lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3), obtains white solid fine work 2a
0.77g, yield 77%.
Embodiment 13
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.20g, 5.00mmol) are dissolved in
In 6mL ethylene glycol, gained mixture is in 130 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, water 5mL is added, will mix
Object is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the drying of 2g anhydrous sodium sulfate is added, subtracts
Pressure removes solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3), obtains white solid fine work
2a 0.72g, yield 72%.
Embodiment 14
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.20g, 5.00mmol) are dissolved in
In 5mL isopropanol, gained mixture is in 130 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, water 5mL is added, will mix
Object is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the drying of 2g anhydrous sodium sulfate is added, subtracts
Pressure removes solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3), obtains white solid fine work
2a 0.85g, yield 85%.
Embodiment 15
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.17g, 4.18mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 18 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2a 0.87g, yield 87%.
Embodiment 16
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.24g, 6.00mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.98g, yield 98%.
Embodiment 17
Alpha-keto amide (1.00g, 4.18mmol) shown in formula (1a) and sodium hydroxide (0.33g, 8.36mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2a 0.97g, yield 97%.
Embodiment 18
Alpha-keto amide (1.00g, 3.92mmol) shown in formula (1b) and sodium hydroxide (0.19g, 4.70mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2b 0.98g, yield 97%.
The characterize data of compound 2b:
White solid；1H NMR(400MHz,CDCl3):δ8.03(br s,1H),7.50-7.45(m,2H),7.32-7.44
(m, 5H), 6.90-6.78 (m, 2H), 5.16 (d, J=2.6Hz, 1H), 3.78 (s, 3H), 3.52 (d, J=3.4Hz, 1H)；13C
NMR(100 MHz,CDCl3):δ169.7,156.7,139.1,130.2,129.0,128.9,126.9,121.6,114.2,
74.6,55.5.
Embodiment 19
Alpha-keto amide (1.00g, 3.86mmol) shown in formula (1c) and sodium hydroxide (0.18g, 4.63mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2c 0.96g, yield 95%.
The characterize data of compound 2c:
White solid；1H NMR(400MHz,DMSO-d6):δ10.14(s,1H),7.85-7.74(m,2H),7.60-7.49
(m, 2H), 7.44-7.28 (m, 5H), 6.53 (d, J=4.5Hz, 1H), 5.14 (d, J=4.5Hz, 1H)；13C NMR
(100MHz, DMSO-d6):δ171.8,141.1,138.0,128.9,128.6,128.1,127.6,127.0,121.8,
74.5.
Embodiment 20
Alpha-keto amide (1.00g, 4.11mmol) shown in formula (1d) and sodium hydroxide (0.20g, 4.93mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2d 0.95g, yield 94%.
The characterize data of compound 2d:
White solid；1H NMR(400MHz,CDCl3):δ8.17(br s,1H),7.45-7.55(m,4H),7.44-7.33
(m, 3H), 7.01 (t, J=8.6Hz, 2H), 5.20 (d, J=3.1Hz, 1H), 3.33 (d, J=3.4Hz, 1H)；13C NMR
(100MHz, CDCl3):δ74.7,115.7(d,2JCF=22.0Hz), 121.6 (d,3JCF=8.0Hz), 126.8,129.0,
129.04,133.1,138.9, 159.6(d,1JCF=243.0Hz), 169.8.
Embodiment 21
Alpha-keto amide (1.00g, 3.64mmol) shown in formula (1e) and sodium hydroxide (0.18g, 4.37mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2e 0.75g, yield 74%.
The characterize data of compound 2e:
White solid；1H NMR(400MHz,CDCl3): δ 8.74 (brs, 1H), 7.95 (d, J=7.4Hz, 1H), 7.89-
7.79 (m, 1H), 7.61-7.71 (m, 2H), 7.55-7.33 (m, 8H), 5.24 (d, J=2.8Hz, 1H), 3.96 (d, J=
3.3Hz,1H)；13C NMR(100MHz,CDCl3):δ170.7,139.2,134.0,131.4,129.0,128.9,128.8,
126.9,126.7,126.4, 126.0,125.9,125.7,120.2,120.0,74.9.
Embodiment 22
Alpha-keto amide (1.00g, 3.72mmol) shown in formula (1f) and sodium hydroxide (0.18g, 4.46mmol) are dissolved in
In 4.5mL N, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2f0.94g, yield 93%.
The characterize data of compound 2f:
White solid；1H NMR(400MHz,CDCl3): δ 8.03 (brs, 1H), 7.39 (d, J=7.0Hz, 2H), 7.37
(d, J=7.2 Hz, 2H), 7.11 (d, J=8.3Hz, 2H), 6.91 (d, J=8.7Hz, 2H), 5.11 (d, J=2.5Hz, 1H),
3.80 (s, 3H), 3.44 (d, J=3.1Hz, 1H), 2.31 (s, 3H)；13C NMR(100MHz,CDCl3):δ170.1,160.0,
134.6,134.3, 131.2,129.5,128.4,119.8,114.4,74.3,55.4,20.9.
Embodiment 23
Alpha-keto amide (1.00g, 4.08mmol) shown in formula (1g) and sodium hydroxide (0.19g, 4.90mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2g 0.76g, yield 75%.
The characterize data of compound 2g:
White solid；1H NMR(400MHz,CDCl3): δ 8.08 (brs, 1H), 7.41 (d, J=8.4Hz, 2H), 7.33
(dd, J=5.1,1.3Hz, 1H), 7.20 (dt, J=3.5,1.0Hz, 1H), 7.13 (d, J=8.2Hz, 2H), 7.02 (dd, J
=5.1,3.5Hz, 1H), 5.46 (d, J=3.7Hz, 1H), 3.66 (d, J=3.8Hz, 1H), 2.31 (s, 3H)；13C NMR
(100MHz,CDCl3):δ168.6, 141.9,134.6,134.3,129.6,127.1,126.5,126.3,119.9,70.6,
20.9.
Embodiment 24
Alpha-keto amide (1.00g, 3.15mmol) shown in formula (1h) and sodium hydroxide (0.15g, 3.78mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2h 0.88g, yield 87%.
The characterize data of compound 2h:
White solid；1H NMR(400MHz,DMSO-d6): δ 9.89 (s, 1H), 7.65-7.55 (m, 4H), 7.50 (d, J=
8.4Hz, 2H), 7.13 (d, J=8.2Hz, 2H), 6.55 (d, J=4.8Hz, 1H), 5.12 (d, J=4.8Hz, 1H), 2.27
(s,3H)；13C NMR(100MHz,DMSO-d6):δ170.9,140.8,136.4,133.02,131.4,129.5,129.2,
121.2,120.2,73.7, 20.9；HRMS(ESI/TOF)Calcd for C15H13NO2Br[(M-H)-]:318.0130,
found 318.0131.
Embodiment 25
Alpha-keto amide (1.00g, 3.15mmol) shown in formula (1i) and sodium hydroxide (0.15g, 3.78mmol) are dissolved in
In 4.5mL N, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2i 0.81g, yield 80%.
The characterize data of compound 2i:
White solid；1H NMR(400MHz,CDCl3): δ 8.06 (brs, 1H), 7.60 (dd, J=8.0,0.9Hz, 1H),
7.49 (dd, J=7.8,1.6Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 7.38-7.31 (m, 1H), 7.21 (td, J=7.9,
1.7Hz, 1H), 7.12 (d, J=8.2Hz, 2H), 5.63 (d, J=4.4Hz, 1H), 4.07 (d, J=4.6Hz, 1H), 2.31
(s,3H)；13C NMR(100 MHz,CDCl3):δ169.2,138.7,134.6,134.4,133.1,130.3,129.6,
128.9,128.4,122.9,119.9,72.7, 20.9.
Embodiment 26
Alpha-keto amide (1.00g, 3.66mmol) shown in formula (1j) and sodium hydroxide (0.18g, 4.39mmol) are dissolved in
In 4.5mL N, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, adds
Enter water 5mL, mixture is transferred in separatory funnel, be extracted with dichloromethane (5mL × 3), merge organic phase, it is anhydrous that 2g is added
Sodium sulphate is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized with ethyl acetate/petroleum ether (volume ratio 1:3),
Obtain white solid fine work 2j 0.90g, yield 89%.
The characterize data of compound 2j:
Yellow oil；1H NMR(400MHz,CDCl3):δ8.17(brs,1H),7.30-7.45(m,6H),7.11(d,J
=8.2Hz, 2H), 5.12 (s, 1H), 3.67 (brs, 1H), 2.31 (s, 3H)；13C NMR(100MHz,CDCl3):δ169.3,
137.5,134.7, 134.6,134.3,129.6,129.1,128.2,119.8,73.9,20.9.
Embodiment 27
Alpha-keto amide (1.00g, 4.32mmol) shown in formula (1k) and sodium hydroxide (0.21g, 5.18mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains crude white solid.It is recrystallized, is obtained with ethyl acetate/petroleum ether (volume ratio 1:3)
White solid fine work 2k 0.98g, yield 97%.
The characterize data of compound 2k:
Yellow oil；1H NMR(400MHz,CDCl3):1H NMR(400MHz,CDCl3):δ7.42-7.28(m,5H),
6.10 (br s, 1H), 4.94 (d, J=3.0Hz, 1H), 3.98-3.79 (m, 1H), 3.79-3.62 (m, 1H), 1.78-1.92
(m,2H), 1.71-1.52(m,3H),1.43-1.21(m,2H),1.21-0.98(m,3H)；13C NMR(100MHz,CDCl3):
δ171.2, 139.7,128.8,128.6,126.9,74.0,48.4,32.9,32.8,25.4,24.7,24.7.
Embodiment 28
Alpha-keto amide (1.00g, 5.64mmol) shown in formula (1l) and sodium hydroxide (0.27g, 6.77mmol) are dissolved in
In 4.5mLN, N- dimethylformamide, gained mixture is in 130 DEG C of 6 hours of reaction.Then solvent is evaporated off under depressurizing, is added
Water 5mL, mixture is transferred in separatory funnel, is extracted with dichloromethane (5mL × 3), and organic phase is merged, and the anhydrous sulphur of 2g is added
Sour sodium is dry, depressurizes lower removing solvent, obtains liquid crude product.Fine work 2l is chromatographed to obtain with ethyl acetate/petroleum ether (volume ratio 1:3) column
0.41g, yield 40%.
The characterize data of compound 2l:
Colorless oil；1H NMR(400MHz,CDCl3):1H NMR(400MHz,CDCl3):δ8.55(brs,1H),
7.39 (d, J=8.3Hz, 2H), 7.10 (d, J=8.3Hz, 2H), 4.28 (q, J=6.8Hz, 1H), 3.94 (brs, 1H),
2.30 (s, 3H), 1.47 (d, J=6.8Hz, 3H)；13C NMR(100MHz,CDCl3):δ173.1,134.5,134.3,
129.6,120.0,68.7,21.1, 20.9.
Claims (7)
1. a kind of method for preparing Alpha-hydroxy amide by restoring alpha-keto amide, which is characterized in that alpha-keto amide and alkali are organic
In solvent, 6-18 hour is reacted under the conditions of 110-150 DEG C, is restored the ketone carbonyl in alpha-keto amide, is obtained Alpha-hydroxy amide,
Wherein, the synthetic reaction formula of target compound are as follows:
2. a kind of method that reduction alpha-keto amide prepares Alpha-hydroxy amide according to claim 1, which is characterized in that α -one
Amide has the following structure formula:
Wherein:
R1For hydrogen, alkyl, naphthenic base, aryl (including substituted aryl), heterocycle (including heteroaryl and substituted heteroaryl)；
R2For hydrogen, alkyl, naphthenic base, aryl (including substituted aryl), heterocycle (including heteroaryl and substituted heteroaryl).
3. a kind of method that reduction alpha-keto amide prepares Alpha-hydroxy amide according to claim 1, which is characterized in that described
Alkali be sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropylate, the tert-butyl alcohol
Potassium.
4. a kind of method that reduction alpha-keto amide prepares Alpha-hydroxy amide according to claim 1, which is characterized in that described
Organic solvent be ethyl alcohol, isopropanol, ethylene glycol, N,N-dimethylformamide.
5. a kind of method that reduction alpha-keto amide prepares Alpha-hydroxy amide according to claim 1, which is characterized in that described
Keto-amide and alkali molar ratio be 1:1~2.
6. a kind of method that reduction alpha-keto amide prepares Alpha-hydroxy amide according to claim 1, which is characterized in that described
Reaction temperature be 110-150 DEG C.
7. the method that a kind of selective reduction alpha-keto amide ketone carbonyl according to claim 1 prepares Alpha-hydroxy amide,
It is characterized in that, the reaction time is 6-18 hour.
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