CN109761842A - The synthetic method of α-F- β-NHAc- carbonyls - Google Patents
The synthetic method of α-F- β-NHAc- carbonyls Download PDFInfo
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Abstract
The invention discloses the synthetic methods of α-F- β-NHAc- carbonyls, unsaturated ketone compound shown in formula (I) and N-F reagent are dissolved in acetonitrile by it, water is added, 12-48h is reacted at a temperature of 30-100 DEG C, after reaction, reaction solution is post-treated, and to obtain α-F- β-NHAc-- carbonyls, reaction equation shown in formula (II) as follows:In formula (I) and formula (II), substituent R1And R2It is each independently selected from phenyl, thienyl, furyl or substituted-phenyl；The substituent group of the substituted-phenyl is C1-C3 alkyl, C1-C3 alkoxy, nitro, trifluoromethyl, fluorine, chlorine or bromine；The substituent group quantity of the substituted-phenyl is 1~3.The present invention synthesize α-F- β-NHAc-- carbonyls method, be easy to get with raw material, reaction condition is mild, be not necessarily to other catalyst, good reaction selectivity and it is easy to operate the advantages that.
Description
Technical field
The present invention relates to the synthetic methods of α-F- β-NHAc- carbonyls.
Background technique
Fluorinated organic compound has preferable bioactivity and stability, is widely used in drug, pesticide, surface-active
The field of fine chemical such as agent, fluorocarbon coating, because its bring huge economic value and be widely applied due to it is deep by domestic and international the world of medicine,
The concern of academia.Studies have shown that fluorinated organic compound have good bioactivity, antibacterial, it is anti-inflammatory, in terms of
There is remarkable result, has a wide range of applications in field of medicaments.In recent years, the synthesis of α-F- β-NHAc- substituted compound obtains
Extensive concern, and made some progress.
Before the present invention, existing α-F- β-NHAc- substituted compound synthetic method mainly includes following several:
(a) α-F- β-NHAc- substituted compound, such as document are synthesized by α-F- β-OH- substituted compound:
Tetrahedron Letters,2006,47,6753-6756；
(b) N-F reagent is to alkene xenon fluoride amination, such as document: Chem.Commun., and 2001,233-234；
Chem.Commun.,2018,54,5907-5910；J.Org.Chem.2002,67,6415-6420.
The synthetic method of the α-F- β-NHAc- carbonyls of above-mentioned report is less, generally requires through other intermediaries
Matter converts to obtain, and stability is poor, and condition is harsh.N-F reagent generally requires additional Lewis acid to alkene xenon fluoride amination and urges
Change.In addition, existing method can not all be directly realized by the xenon fluoride amination of beta-unsaturated ketone.
N-F reagent due to it safely and effectively, feature easy to operate, avoid big traditional fluorine reagent toxicity, stability and
The disadvantages of selectivity is poor, it has also become synthesize one of the research hotspot of fluorinated organic compound in recent years.Therefore, the present invention utilizes
N-F reagent is able to achieve the xenon fluoride amination of beta-unsaturated ketone, makes to react easier, safety, green；And the invention can be in unsaturation
Aromatic series and heterocyclic compound are introduced on ketone, have expanded the substrate scope of application of reaction.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of easy, efficient, safe and environment-friendly α-F- β-NHAc carbonyls
The synthetic method of based compound.
The synthetic method of α-F- β-NHAc- carbonyls as shown in formula (II), it is characterised in that the synthesis side
Method are as follows: unsaturated ketone compound shown in formula (I) and N-F reagent are dissolved in acetonitrile, water is added, at a temperature of 30-100 DEG C
12-48h is reacted, after reaction, reaction solution is post-treated to obtain α-F- β-NHAc- carbonyls shown in formula (II), instead
Answer formula as follows:
In formula (I) and formula (II), substituent R1And R2It is each independently selected from phenyl, thienyl, furyl or substituted benzene
Base；The substituent group of the substituted-phenyl is C1-C3 alkyl, C1-C3 alkoxy, nitro, trifluoromethyl, fluorine, chlorine or bromine；It is described to take
Substituent group quantity for phenyl is 1~3.
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that the N-F reagent is such as formula
(A), formula (B), formula (C) or formula (D) compound represented；
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that unsaturated ketone shown in formula (I)
The molar ratio of compound and N-F reagent is 1:1~5, preferably 1:1~3.
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that shown in the volume and formula (I) of acetonitrile
The ratio between the amount of substance of unsaturated ketone compound be 5-25:1, preferably 7-15:1, the unit of volume is mL, the amount of substance
Unit is mmol.
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that reaction temperature is 40-80 DEG C.
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that the post-treated step of reaction solution
Are as follows: water is added into reaction solution and organic extractant is extracted, liquid separation is organic layer and water layer, and organic layer is through anhydrous sodium sulfate
After drying, solvent is removed by being concentrated under reduced pressure, condensate residue is molten with petroleum ether and ethyl acetate mixing by pillar layer separation
Agent collects the eluent containing target product, solvent is evaporated off and obtains target product to get α-F- shown in formula (II) as eluant, eluent
β-NHAc- carbonyls.
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that the organic extractant is dichloro
Methane or ethyl acetate.
The synthetic method of the α-F- β-NHAc- carbonyls, it is characterised in that the petroleum ether and acetic acid second
The ratio of ester is 10~30:1.
During α-F- β-NHAc- the carbonyls shown in present invention preparation formula (II), reaction route is as follows:
It can be seen that unsaturated ketone compound shown in formula (I) and N-F reagent, acetonitrile reaction, first generate such as formula (III)
Shown in the intermediate state compound containing acetonitrile group, then with water occur hydrolysis, convert acetylamino for acetonitrile group,
Generate (II) shown in α-F- β-NHAc- carbonyls (with by intermediate state compound complete hydrolysis shown in formula (III) at (II)
Shown in α-F- β-NHAc- carbonyls wherein only needed in reaction system a small amount of to determine the water being added in reaction system
Moisture, i.e. hydrolyzable is complete).
The present invention compared with prior art, has the beneficial effect that:
1) using N-F reagent as Fluorine source and Lewis acid, it is not necessarily to additional catalyst, keeps reaction more green, cost is lower.
2) the method for the present invention not only good reaction selectivity, but also easy to operate, product yield high.
3) the xenon fluoride aminating reaction for realizing beta-unsaturated ketone enriches α-F- β-NHAc- carbonyls synthetic method.
4) using acetonitrile as solvent and reactant, without other solvents, keep reaction more green, cost is lower.
In conclusion the present invention provides a kind of synthesis sides of the α-F- β-NHAc- carbonyls of N-F reagent catalysis
Method.This method have many advantages, such as raw material be easy to get, be easy to operate, good substrate applicability and economic and environment-friendly, be it is a kind of have preferably answer
With the green chemical synthesis method of prospect.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
In following embodiment, contain moisture in the acetonitrile of addition.
Embodiment 1
By chalcone (1mmol, 208mg), Selectfluor (1.0mmol, 247mg) is added to 25mL stand up reaction bottle
In, CH is added3CN (7mL) is used as solvent, is warming up to 40 DEG C of reaction 12h.After reaction, reaction solution is through washing, ethyl acetate
Extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation concentration removes solvent and obtains yellow
Grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as elution
Agent collects the eluent containing target compound, solvent is evaporated off and is dried to obtain fluoro- acetamido -1 3- 131mg white solid 2-,
3- diphenyl propane -1- ketone, yield 46%, chemical structural formula are as follows:
Characterize data:1H NMR(400MHz,CDCl3) δ 7.91 (d, J=7.5Hz, 2H), 7.63 (t, J=7.4Hz, 1H),
7.50 (t, J=7.7Hz, 2H), 7.39 (ddd, J=12.9,10.5,7.1Hz, 5H), 6.65 (d, J=8.8Hz, 1H), 5.99
(dd, J=47.2,2.2Hz, 1H), 5.74 (dd, J=27.4,1.8Hz, 0.46H)/5.72 (dd, J=27.6,2.0Hz,
0.46H),1.96(s,3H)。13C NMR(101MHz,CDCl3)δ194.4/194.3,169.6,137.78,134.19,129.0,
128.9,128.6,128.5,128.3,127.1/127.1,94.9/93.0,77.4/77.1/76.8,54.0/53.8,22.9。19F NMR(376MHz,CDCl3)δ-198.19,-202.23。HRMS:m/z Calcd for C17H16FNNaO2,[M+Na]+,
308.1057；Found,308.1086.
Embodiment 2
Reaction time 16h will be extended to, it is fluoro- to finally obtain 114mg white solid 2- with embodiment 1 for other operating conditions
3- acetamido -1,3- diphenyl propane -1- ketone, yield 40%.
Embodiment 3
Solvent inventory in system is changed to CH3CN (10mL), other operating conditions are finally obtained with embodiment 1
Fluoro- 3- acetamido -1, the 3- diphenyl propane -1- ketone of 146mg white solid 2-, yield 51%.
Embodiment 4
Fluorine reagent Selectfluor dosage is increased into 1.2mmol (425mg), other operating conditions are with embodiment 1, most
Fluoro- 3- acetamido -1, the 3- diphenyl propane -1- ketone of 134mg white solid 2-, yield 47% are obtained eventually.
Embodiment 5
The temperature of system is risen to 60 DEG C, it is fluoro- to finally obtain 157mg white solid 2- with embodiment 1 for other operating conditions
3- acetamido -1,3- diphenyl propane -1- ketone, yield 55%.
Embodiment 6
By 1- (4- nitrobenzophenone) -3- phenyl -2- propenone (1.0mmol, 253mg), Selectfluor (2.0mmol,
708mg), it is added in 25mL stand up reaction bottle, CH is added3CN (10mL) is used as solvent, is warming up to 60 DEG C of reaction 18h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and acetic acid second
The mixed liquor of ester volume ratio 20:1 collects the eluent containing target compound, solvent is evaporated off and is dried to obtain as eluant, eluent
122mg faint yellow solid 2- fluoro- 3- acetamido -1- (4- nitrobenzophenone) -3- phenyl-propane -1- ketone, yield 37% are changed
Learn structural formula are as follows:
Characterize data:1HNMR(400MHz,CDCl3) δ 8.32 (d, J=8.9Hz, 2H), 8.02 (d, J=8.7Hz, 2H),
7.45-7.33 (m, 5H), 6.40 (d, J=8.8Hz, 1H), 5.92 (dd, J=47.1,2.3Hz, 1H), 5.73 (dd, J=
26.0,2.3Hz, 0.46H), 5.71 (dd, J=26.2,2.3Hz, 0.44H), 2.03 (d, J=24.8Hz, 3H).13C NMR
(101MHz,CDCl3)δ194.1/193.9,169.6,150.5,139.1,137.0,129.8/129.8,129.1,128.7,
127.2,127.1,123.9,95.4/93.5,53.8/53.6,23.0/23.0。19F NMR(376MHz,CDCl3)δ-
199.77,-199.79。HRMS:m/z Calcd for C17H15FN2NaO4,[M+Na]+,353.0908；Found,
353.0898。
Embodiment 7
By 1- (4- methoxyphenyl) -3- phenyl -2- propenone (1.0mmol, 253mg), Selectfluor
(1.5mmol, 531mg) is added in 25mL stand up reaction bottle, and CH is added3CN (10mL) is used as solvent, is warming up to 70 DEG C of reactions
20h.After reaction, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, and organic layer is through anhydrous slufuric acid
After sodium is dry, vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether
Mixed liquor with ethyl acetate volume ratio 25:1 collects the eluent containing target compound, solvent is evaporated off and does as eluant, eluent
It is dry to obtain 154mg light yellow oil 2- fluoro- 3- acetamido -1- (4- methoxyphenyl) -3- phenyl-propane -1- ketone, yield
It is 49%, chemical structural formula are as follows:
Characterize data:1HNMR(400MHz,CDCl3) δ 7.93 (d, J=8.7Hz, 2H), 7.40 (dq, J=28.0,
6.9Hz, 5H), 6.99 (d, J=8.7Hz, 2H), 6.63 (d, J=8.6Hz, 1H), 5.96 (d, J=47.2Hz, 1H), 5.72
(dd, J=27.2,8.8Hz, 1H), 3.91 (s, 3H), 2.00 (s, 3H).13C NMR(101MHz,CDCl3)δ192.6/192.5,
169.5,164.3,137.9,131.0/131.0,128.9/128.9,128.2,127.1,127.0,114.2,94.7/92.8,
55.6/54.2/54.0,23.01。19F NMR(376MHz,CDCl3) δ -197.46 (dd, J=46.9,24.1Hz), -201.37
(dd, J=47.1,27.3Hz).HRMS:m/z Calcd for C18H18FNNaO3,[M+Na]+,338.1168；Found,
338.1180。
Embodiment 8
By 1- thienyl -3- phenyl -2- propenone (1.0mmol, 214mg), Selectfluor (2.5mmol, 886mg),
It is added in 25mL stand up reaction bottle, CH is added3CN (12mL) is used as solvent, is warming up to 70 DEG C of reaction 22h.After reaction,
Reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, decompression is steamed
It evaporates concentration removing solvent and obtains pale tan oil.Pale tan oil is by pillar layer separation, with petroleum ether and ethyl acetate
The mixed liquor of volume ratio 25:1 collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 131mg as eluant, eluent
The fluoro- 3- acetamido -1- thienyl -3- phenyl-propane -1- ketone of pale tan oil 2-, yield 45%, chemical structural formula
Are as follows:
Characterize data:1HNMR (400MHz, DMSO) δ 8.79 (d, J=9.5Hz, 1H), 8.15-8.03 (m, 2H), 7.49
(d, J=7.5Hz, 2H), 7.38 (t, J=7.5Hz, 2H), 7.30 (t, J=4.5Hz, 3H), 6.04 (dd, J=47.2,
3.2Hz, 0.80H), 5.96 (dd, J=48.2,4.4Hz, 0.20H), 5.65 (ddd, J=30.1,9.5,2.9Hz, 0.80H),
5.52 (ddd, J=24.9,8.6,4.7Hz, 0.20H), 1.87 (s, 1H), 1.82 (s, 2H).13C NMR(101MHz,DMSO)δ
187.6/187.6/187.4/187.4,169.5/169.4,140.9/140.8/137.0/136.7/136.7,138.6/
138.6/135.3/135.2/135.2/135.1,129.5,128.8,128.7,128.4,128.1,127.7,96.2/95.5/
94.3/93.6,55.1/54.9/54.3/54.1,22.8/22.7。19F NMR(376MHz,DMSO)δ-196.41,-198.82。
HRMS:m/z Calcd for C15H14FNNaO2S,[M+Na]+,314.0621；Found,314.0625.
Embodiment 9
By 1- (4- trifluoromethyl) -3- phenyl -2- propenone (1.0mmol, 276mg), Selectfluor
(1.5mmol, 531mg) is added in 25mL stand up reaction bottle, and CH is added3CN (12mL) is used as solvent, is warming up to 80 DEG C of reactions
35h.After reaction, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, and organic layer is through anhydrous slufuric acid
After sodium is dry, vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether
Mixed liquor with ethyl acetate volume ratio 30:1 collects the eluent containing target compound, solvent is evaporated off and does as eluant, eluent
It is dry to obtain 155mg light yellow oil 2- fluoro- 3- acetamido -1- (4- trifluoromethyl) -3- phenyl-propane -1- ketone, it receives
Rate is 44%, chemical structural formula are as follows:
Characterize data:1HNMR(400MHz,CDCl3) δ 8.00 (d, J=8.1Hz, 2H), 7.77 (d, J=8.1Hz, 2H),
7.47-7.34 (m, 5H), 6.64 (t, J=7.0Hz, 1H), 5.95 (dd, J=47.2,1.6Hz, 1H), 5.83-5.68 (m,
1H),2.03(s,0.15H)/1.99(s,2.85H)。13C NMR(101MHz,CDCl3)δ194.3/194.1,169.7,137.3/
137.3,135.6/134.6,135.3/135.0,129.1,128.6,127.2,126.0,125.9,124.8/122.09,
95.4/93.5,53.9/53.7,23.0。19F NMR(376MHz,CDCl3) δ -63.25, -200.55 (dd, J=47.1,
26.7Hz)。HRMS:m/z Calcd for C18H15F4NNaO2,[M+Na]+,276.0937；Found,276.0977.
Embodiment 10
By 1- phenyl -3- (4- aminomethyl phenyl) -2- propenone (1.0mmol, 222mg), Selectfluor (1.5mmol,
531mg), it is added in 25mL stand up reaction bottle, CH is added3CN (12mL) is used as solvent, is warming up to 60 DEG C of reaction 38h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and acetic acid second
The mixed liquor of ester volume ratio 30:1 collects the eluent containing target compound, solvent is evaporated off and is dried to obtain as eluant, eluent
159mg white half grease 2- fluoro- 3- acetamido -1- (4- aminomethyl phenyl) -3- phenyl-propane -1- ketone, yield 53%,
Chemical structural formula are as follows:
Characterize data:1HNMR(400MHz,CDCl3) δ 7.99-7.88 (m, 2H), 7.64 (t, J=7.4Hz, 1H), 7.51
(t, J=7.7Hz, 2H), 7.32 (d, J=8.0Hz, 2H), 7.21 (d, J=7.9Hz, 2H), 6.47 (d, J=8.0Hz, 1H),
5.98 (dd, J=47.2,2.1Hz, 1H), 5.75-5.62 (m, 1H), 2.37 (s, 3H), 1.97 (s, 3H).13C NMR
(101MHz,CDCl3)δ194.4/194.23,169.4/169.4,138.1,134.8,134.2,134.2,129.6/129.5,
129.0/128.9,128.6/128.5,126.9,94.9/93.0,53.7/53.5,23.0,21.1。19F NMR(376MHz,
CDCl3) δ -202.54 (dd, J=23.5,8.5Hz), -203.62 (d, J=14.4Hz).HRMS:m/z Calcd for
C18H18FNNaO2,[M+Na]+,322.1214；Found,322.1214.
Embodiment 11
By 1- phenyl -3- (4- methoxyphenyl) -2- propenone (1.0mmol, 238mg), Selectfluor
(2.0mmol, 708mg) is added in 25mL stand up reaction bottle, and CH is added3CN (10mL) is used as solvent, is warming up to 80 DEG C of reactions
42h.After reaction, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, and organic layer is through anhydrous slufuric acid
After sodium is dry, vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether
Mixed liquor with ethyl acetate volume ratio 20:1 collects the eluent containing target compound, solvent is evaporated off and does as eluant, eluent
It is dry to obtain 142mg light yellow oil 2- fluoro- 3- acetamido -1- (4- methoxyphenyl) -3- phenyl-propane -1- ketone, yield
It is 45%, chemical structural formula are as follows:
Characterize data:1H NMR(400MHz,CDCl3) δ 7.92 (d, J=7.7Hz, 2H), 7.65 (t, J=7.3Hz, 1H),
7.52 (t, J=7.7Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 6.96 (dd, J=20.9,8.5Hz, 2H), 6.58 (dd, J=
36.0,8.7Hz, 1H), 5.97 (dd, J=47.2,2.0Hz, 0.78H), 5.94 (dd, J=47.2,2.0Hz, 0.12H), 5.68
(dd, J=26.6,9.6Hz, 1H), 3.91 (s, 0.35H)/3.83 (s, 2.63H), 1.99 (s, 3H).13C NMR(101MHz,
CDCl3)δ194.6/194.4,169.5,159.5,134.4,134.3/134.2,129.9,129.1/129.0,128.6/
128.6,128.4,114.3,95.0/93.1,55.4,53.5/53.3,23.0。19F NMR(376MHz,CDCl3)δ-201.37
(dd, J=47.1,27.0Hz), -201.93 (dd, J=47.2,27.2Hz).HRMS:m/z Calcd for C18H18FNNaO3,
[M+Na]+,338.1168；Found,338.1182.
Embodiment 12
By 1- phenyl -3- (2- chlorphenyl) -2- propenone (1.0mmol, 243mg), Selectfluor (3.0mmol,
1.063g), it is added in 25mL stand up reaction bottle, CH is added3CN (15mL) is used as solvent, is warming up to 80 DEG C of reaction 16h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and acetic acid second
The mixed liquor of ester volume ratio 20:1 collects the eluent containing target compound, solvent is evaporated off and is dried to obtain as eluant, eluent
99mg yellow oil 2- fluoro- 3- acetamido -1- (2- chlorphenyl) -3- phenyl-propane -1- ketone, yield 31%, chemistry
Structural formula are as follows:
Characterize data:1H NMR(400MHz,CDCl3) δ 8.12 (dd, J=24.9,7.6Hz, 2H), 7.70 (t, J=
7.4Hz, 1H), 7.57 (t, J=7.7Hz, 2H), 7.48 (dt, J=8.3,5.3Hz, 2H), 7.34 (dd, J=9.1,5.4Hz,
2H), 6.92 (d, J=8.4Hz, 1H), 6.16 (dd, J=46.8,1.6Hz, 1H), 6.09 (dd, J=30.0,9.2Hz, 1H),
2.00(s,3H)。13C NMR(101MHz,CDCl3)δ194.0/193.8,169.6,135.0,134.6,133.7,133.2,
132.2,130.1,129.8/129.4,129.1/128.7,128.5/128.4,127.3,92.8/90.9,51.8/51.6,
22.7。19F NMR(376MHz,CDCl3) δ -205.53 (dd, J=46.9,30.8Hz).HRMS:m/z Calcd for
C17H15ClFNNaO2,[M+Na]+,342.0668；Found,342.0673.
Embodiment 13
By 1- phenyl -3- (2- bromophenyl) -2- propenone (1.0mmol, 287mg), Selectfluor (1.2mmol,
1.063g), it is added in 25mL stand up reaction bottle, CH is added3CN (7mL) is used as solvent, is warming up to 50 DEG C of reaction 48h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains light yellow oil.Light yellow oil is by pillar layer separation, with petroleum ether and second
The mixed liquor of acetoacetic ester volume ratio 30:1 collects the eluent containing target compound as eluant, eluent, and solvent and dry is evaporated off
To 160mg light yellow oil 2- fluoro- 3- acetamido -1- (2- bromophenyl) -3- phenyl-propane -1- ketone, yield 44%,
Chemical structural formula are as follows:
Characterize data:1HNMR(400MHz,CDCl3) δ 8.12 (d, J=7.6Hz, 2H), 7.69 (dd, J=16.9,
7.9Hz, 2H), 7.57 (t, J=7.7Hz, 2H), 7.45 (d, J=7.7Hz, 1H), 7.39 (t, J=7.5Hz, 1H), 7.25 (t,
J=7.1Hz, 1H), 6.78 (d, J=8.1Hz, 1H), 6.23-5.97 (m, 2H), 1.99 (s, 3H).13C NMR(101MHz,
CDCl3)δ193.9/193.7,169.3,136.6,134.5,133.8,133.8,133.2,129.7,129.0,128.6,
127.8,122.6,92.6/90.7,54.0/53.8,22.8。19F NMR(376MHz,CDCl3) δ -204.86 (dd, J=46.4,
27.5Hz), -205.73 (dd, J=46.9,30.7Hz).HRMS:m/z Calcd for C17H15BrFNNaO2,[M+Na]+,
386.0162；Found,386.0196.
Embodiment 14
By 1- phenyl -3- (4- bromophenyl) -2- propenone (1.0mmol, 287mg), Selectfluor (1.2mmol,
1.063g), it is added in 25mL stand up reaction bottle, CH is added3CN (15mL) is used as solvent, is warming up to 50 DEG C of reaction 22h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains light yellow oil.Light yellow oil is by pillar layer separation, with petroleum ether and second
The mixed liquor of acetoacetic ester volume ratio 30:1 collects the eluent containing target compound as eluant, eluent, and solvent and dry is evaporated off
To 153mg light yellow oil 2- fluoro- 3- acetamido -1- (4- bromophenyl) -3- phenyl-propane -1- ketone, yield 42%,
Chemical structural formula are as follows:
Characterize data:1H NMR(400MHz,CDCl3) δ 7.91 (d, J=7.1Hz, 2H), 7.67 (t, J=6.6Hz, 1H),
7.53 (d, J=4.1Hz, 4H), 7.32 (d, J=8.0Hz, 2H), 6.65 (d, J=7.3Hz, 1H), 5.95 (d, J=47.1Hz,
1H), 5.69 (dd, J=27.0,7.9Hz, 1H), 1.99 (s, 3H).13C NMR(101MHz,CDCl3)δ194.3/194.1,
169.6,136.8,134.3,134.1,132.0,129.0,128.9,128.6/128.6,122.3,94.6/92.7,53.5//
53.3,23.0。19F NMR(376MHz,CDCl3) δ -197.72 (dd, J=47.2,25.4Hz), -201.47 (dd, J=46.8,
27.2Hz)。HRMS:m/z Calcd for C17H15BrFNNaO2,[M+Na]+,386.0162；Found,386.0199.
Embodiment 15
By 1- phenyl -3- (4- fluorophenyl) -2- propenone (1.0mmol, 226mg), Selectfluor (2.5mmol,
886mg), it is added in 25mL stand up reaction bottle, CH is added3CN (12mL) is used as solvent, is warming up to 70 DEG C of reaction 48h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and acetic acid second
The mixed liquor of ester volume ratio 30:1 collects the eluent containing target compound, solvent is evaporated off and is dried to obtain as eluant, eluent
112mg white semi-solid grease 2- fluoro- 3- acetamido -1- (4- fluorophenyl) -3- phenyl-propane -1- ketone, yield 37%,
Its chemical structural formula are as follows:
Characterize data:1H NMR(400MHz,CDCl3) δ 7.91 (d, J=7.7Hz, 2H), 7.66 (t, J=7.4Hz, 1H),
7.53 (t, J=7.7Hz, 2H), 7.43 (dd, J=8.0,5.4Hz, 2H), 7.09 (t, J=8.5Hz, 2H), 6.68 (d, J=
8.6Hz, 1H), 5.96 (dd, J=47.1,1.9Hz, 1H), 5.72 (dd, J=26.7,8.2Hz, 1H), 1.99 (s, 3H).13C
NMR(101MHz,CDCl3)δ194.4/194.2,169.6,163.7/161.3,134.3,134.1,133.6,133.6,
129.0/129.0/128.9,128.6/128.5,115.9/115.7,94.8/92.9,53.4/53.2,22.9。19F NMR
(376MHz,CDCl3) δ -112.50--117.46 (m), -201.44 (dd, J=47.1,27.2Hz).HRMS:m/z Calcd
for C17H15F2NNaO2,[M+Na]+,326.0969；Found,326.0986.
Embodiment 16
By 1- phenyl -3- (3- aminomethyl phenyl) -2- propenone (1.0mmol, 222mg), Selectfluor (1.5mmol,
531mg), it is added in 25mL stand up reaction bottle, CH is added3CN (15mL) is used as solvent, is warming up to 60 DEG C of reaction 44h.Reaction
After, reaction solution is extracted through washing, ethyl acetate, and liquid separation is organic layer and water layer, after organic layer is dried over anhydrous sodium sulfate,
Vacuum distillation concentration removes solvent and obtains yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and acetic acid second
The mixed liquor of ester volume ratio 20:1 collects the eluent containing target compound, solvent is evaporated off and is dried to obtain as eluant, eluent
129mg brown oil 2- fluoro- 3- acetamido -1- (3- aminomethyl phenyl) -3- phenyl-propane -1- ketone, yield 43% are changed
Learn structural formula are as follows:
Characterize data:1HNMR (400MHz, DMSO) δ 8.70 (d, J=9.5Hz, 1H), 7.95 (d, J=7.6Hz, 2H),
7.68 (t, J=7.3Hz, 1H), 7.56 (t, J=7.6Hz, 2H), 7.30 (s, 1H), 7.26 (d, J=4.7Hz, 2H), 7.11
(d, J=3.9Hz, 1H), 6.34 (dd, J=46.5,2.3Hz, 1H), 5.55 (dd, J=31.1,9.5Hz, 1H), 2.32 (s,
3H),1.80(s,3H)。13C NMR(101MHz,CDCl3)δ199.7/199.5,174.0,143.6,142.7,139.6,
138.9,134.0,133.6,133.5,133.3,133.0,129.5,100.5/98.6,58.4/58.2,27.4,26.3。19F
NMR (376MHz, DMSO) δ -198.93 (dd, J=47.8,24.9Hz), -202.42 (dd, J=46.4,31.2Hz).HRMS:
m/z Calcd for C36H37F2N2O4,[2M+H]+,599.2716；Found,599.2741.
Claims (8)
1. the synthetic method of α-F- β-NHAc- carbonyls as shown in formula (II), it is characterised in that the synthetic method
Are as follows: unsaturated ketone compound shown in formula (I) and N-F reagent are dissolved in acetonitrile, water is added, it is anti-at a temperature of 30-100 DEG C
12-48h is answered, after reaction, reaction solution is post-treated to obtain α-F- β-NHAc- carbonyls shown in formula (II), reaction
Formula is as follows:
In formula (I) and formula (II), substituent R1And R2It is each independently selected from phenyl, thienyl, furyl or substituted-phenyl；Institute
The substituent group for stating substituted-phenyl is C1-C3 alkyl, C1-C3 alkoxy, nitro, trifluoromethyl, fluorine, chlorine or bromine；The substituted benzene
The substituent group quantity of base is 1~3.
2. the synthetic method of α-F- β-NHAc- carbonyls according to claim 1, it is characterised in that the N-F
Reagent is such as formula (A), formula (B), formula (C) or formula (D) compound represented；
3. the synthetic method of α-F- β-NHAc- carbonyls according to claim 1, it is characterised in that shown in formula (I)
Unsaturated ketone compound and the molar ratio of N-F reagent be 1:1~5, preferably 1:1~3.
4. the synthetic method of α-F- β-NHAc- carbonyls according to claim 1, it is characterised in that the volume of acetonitrile
It is 5-25:1 with the ratio between the amount of substance of unsaturated ketone compound shown in formula (I), the unit of preferably 7-15:1, volume are
ML, the amount unit of substance are mmol.
5. the synthetic method of α-F- β-NHAc- carbonyls according to claim 1, it is characterised in that reaction temperature is
40-80℃。
6. the synthetic method of α-F- β-NHAc- carbonyls according to claim 1, it is characterised in that reaction solution is after
The step of processing are as follows: water is added into reaction solution and organic extractant is extracted, liquid separation is organic layer and water layer, organic layer warp
After anhydrous sodium sulfate is dry, solvent is removed by being concentrated under reduced pressure, condensate residue is by pillar layer separation, with petroleum ether and acetic acid
Acetate mixed solvent collects the eluent containing target product, solvent is evaporated off and obtains target product to get formula (II) as eluant, eluent
Shown in α-F- β-NHAc- carbonyls.
7. the synthetic method of α-F- β-NHAc- carbonyls according to claim 6, it is characterised in that organic extraction
Taking agent is methylene chloride or ethyl acetate.
8. the synthetic method of α-F- β-NHAc- carbonyls according to claim 6, it is characterised in that the petroleum
The ratio of ether and ethyl acetate is 10~30:1.
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