CN107445880B - A kind of trifluoromethyl modification AβThe synthetic method of -42 inhibitor structure analogs - Google Patents
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of trifluoromethyls to modify AβThe synthetic method of -42 inhibitor structure analogs.The following steps are included: catalyst, acetophenone oxime ester, 1 is added, 1,1- tri- fluoro- 3- phenylacetone, alkali and solvent are stirred to react 12~24 hours the synthetic method at 60~100 DEG C, and 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitrae-diketone are made；Then reactor is added in 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitrae-diketone, 4- (4- aminophenyl) butyric acid and solvent, is stirred to react at 70~100 DEG C 12~24 hours, obtain trifluoromethyl modification Aβ- 42 inhibitor structure analogs.Synthetic method step of the present invention is simple, and yield is high, the A of gained trifluoromethyl modificationβ- 42 inhibitor structure analogs will have very big application prospect in field of medicaments.
Description
Technical field
The invention belongs to medication chemistry synthesis technical fields, and in particular to a kind of trifluoromethyl modification Aβ- 42 inhibitor knots
The synthetic method of structure analog.
Background technique
Compound I is a kind of Aβ- 42 inhibitor (formula 1) have preferable activity for treatment alzheimer's disease
(W.S.Weiner,R.M.Slade,Y.I.Klimova,R.J.Walton,M.B.Anderson,WO 2007038684,
2007)。
Studies have shown that the film transmission of parent drug molecule would generally be significantly improved by introducing trifluoromethyl into drug molecule
Property, hydrophilic and hydrophobic and metabolic stability (K.Muller, C.Faeh, F.Diederich, Science 2007,317,1881；
S.Purser,P.R.Moore,S.Swallow,V.Gouverneur,Chem.Soc.Rev.2008, 37,320；
W.K.Hagmann,J.Med.Chem.2008,51,4359；T.Furuya,A.S.Kamlet,T. Ritter,Nature
2011,473,470).But because the blank of synthetic method technology, the conjunction of the analogue of trifluoromethyl modified compound I
At not being reported yet but.
Summary of the invention
In order to solve trifluoromethyl modified compound I analogue synthetic technology blank predicament, mesh of the invention
Be a kind of trifluoromethyl that structural formula is as shown in Equation 2 modification A is providedβThe synthetic method of -42 inhibitor structure analogs.
The object of the invention is achieved through the following technical solutions:
A kind of trifluoromethyl modification Aβ- 42 inhibitor structure analogs, structural formula are as shown in Equation 2:
Above-mentioned trifluoromethyl modifies AβThe synthetic method of -42 inhibitor structure analogs, including following two step: the first step is such as
Shown in formula 3；Second step is as shown in Equation 4:
First step reaction step is as follows:
In the reactor, catalyst, acetophenone oxime ester, 1,1,1- tri- fluoro- 3- phenylacetone, alkali and solvent, 60 is added
It is stirred to react at~100 DEG C 12~24 hours, is cooled to 25 DEG C after reaction, ethyl acetate extracts reaction solution, removes under reduced pressure
Solvent obtains crude product；Hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C, ethyl acetate extracts reaction solution, mentions through column chromatography
It is pure to obtain the fluoro- 1,3- diphenyl pentane -1,4- diketone of 5,5,5- tri-.
The first step reaction described in catalyst be preferably stannous chloride, cuprous bromide, cuprous iodide, copper chloride, copper bromide,
The mixing of one or more of copper acetate, copper sulphate, copper trifluoromethanesulfcomposite.
Acetophenone oxime ester described in first step reaction is preferably acetyl acetophenone oxime ester, and one in pivaloyl acetophenone oxime ester
Kind or two or more mixing.
Alkali described in first step reaction is preferably cesium carbonate, pivalic acid caesium, potassium carbonate, tert-butyl alcohol lithium, lithium carbonate and methanol
The mixing of one or more of sodium.
The molar ratio of catalyst described in first step reaction and acetophenone oxime ester is preferably 1:(10~20).
The molar ratio of acetophenone oxime ester described in first step reaction and the fluoro- 3- phenylacetone of 1,1,1- tri- is preferably 1:(1
~3).
The molar ratio of acetophenone oxime ester described in first step reaction and alkali is preferably 1:(1~3).
The concentration of hydrochloric acid described in first step reaction is preferably 0.5~4 mole every liter.
Solvent described in first step reaction is preferably toluene, benzene, dimethylbenzene, 1,2- dichloroethanes, tetrahydrofuran, diformazan
The mixing of one or more of base sulfoxide and acetonitrile.
Column Chromatographic purification described in first step reaction refers to volume ratio for (5~1000): 1 petroleum ether: acetic acid second
The mixed solvent of ester is the column Chromatographic purification of eluent.
Second step reaction step is as follows:
In the reactor, 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitrae-diketone, 4- (4- aminophenyl) butyric acid are added
And solvent, it is stirred to react at 70~100 DEG C 12~24 hours, is cooled to 20-30 DEG C after reaction, water, acetic acid is added
Ethyl ester extracts reaction solution, and evaporating solvent under reduced pressure obtains crude product, obtains trifluoromethyl modification A through column Chromatographic purificationβ- 42 inhibitor knots
Structure analog.
The fluoro- 1,3- diphenyl pentane -1,4- diketone of 5,5,5- tri- and 4- (4- aminophenyl) fourth described in second step reaction
The molar ratio of acid is preferably 1:(1~2).
Solvent described in second step reaction is preferably toluene, benzene, dimethylbenzene, 1,2- dichloroethanes, tetrahydrofuran, diformazan
The mixing of one or more of base sulfoxide and acetonitrile.
Column Chromatographic purification described in second step reaction refers to volume ratio for (5~1000): 1 petroleum ether: acetic acid second
The mixed solvent of ester is the column Chromatographic purification of eluent.
Compared with prior art, the present invention has the following advantages and beneficial effects:
The present invention solves the predicament of the analogue synthetic technology blank of trifluoromethyl modified compound I, the original
Expect simple and easy to get, the synthetic method step is simple, mild condition, and yield is high.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram of embodiment 8-13 products therefrom；
Fig. 2 is the carbon spectrogram of embodiment 8-13 products therefrom；
Fig. 3 is the fluorine spectrogram of embodiment 8-13 products therefrom.
Specific embodiment
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
Acetophenone oxime ester used in the embodiment of the present invention is synthesized by mode described in following documents: Iron-Catalyzed
Synthesis of 2H-Imidazoles from Oxime Acetates andVinyl Azides under Redox-
Neutral Conditions(Z.Zhu,X.Tang,J.Li,X.Li,W.Wu,G.Deng,H.Jiang, Org.Lett.2017,
19,1370-1373)。
Embodiment 1-7 is first step reaction step:
Embodiment 1
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.02 mM of stannous chloride, 0.2 mM of acetophenone is added
Acetophenone oxime ester, 0.4 mM 1,1,1- tri- fluoro- 3- phenylacetone, 0.2 mM of pivalic acid caesium and 4 milliliters of dimethyl sulfoxides,
It is stirred to react at 60 DEG C 12 hours, is cooled to 25 DEG C after reaction, 10 milliliters of water, 10 milliliters of ethyl acetate extractions are added
Reaction solution, evaporating solvent under reduced pressure obtain crude product.1 milliliter of 1 mole of every liter of hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C,
10 milliliters of ethyl acetate extraction reaction solutions are added, subtracts and obtains 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitraes-through column Chromatographic purification
Diketone.Yield is 76%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1: ethyl acetate mixed solvent.
Embodiment 2
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.02 mM of stannous chloride, 0.2 mM of acetophenone is added
Acetophenone oxime ester, 0.4 mM 1,1,1- tri- fluoro- 3- phenylacetone, 0.2 mM of pivalic acid caesium and 4 milliliters of dimethyl sulfoxides,
It is stirred to react at 100 DEG C 12 hours, is cooled to 25 DEG C after reaction, 10 milliliters of water, 10 milliliters of ethyl acetate extractions are added
Reaction solution, evaporating solvent under reduced pressure obtain crude product.1 milliliter of 1 mole of every liter of hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C,
10 milliliters of ethyl acetate extraction reaction solutions are added, subtracts and obtains 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitraes-through column Chromatographic purification
Diketone.Yield is 57%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1: ethyl acetate mixed solvent.
Embodiment 3
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.02 mM of cuprous bromide, 0.2 mM of acetophenone is added
Acetophenone oxime ester, 0.4 mM 1,1,1- tri- fluoro- 3- phenylacetone, 0.2 mM of pivalic acid caesium and 4 milliliters of dimethyl sulfoxides,
It is stirred to react at 80 DEG C 12 hours, is cooled to 25 DEG C after reaction, 10 milliliters of water, 10 milliliters of ethyl acetate extractions are added
Reaction solution, evaporating solvent under reduced pressure obtain crude product.1 milliliter of 1 mole of every liter of hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C,
10 milliliters of ethyl acetate extraction reaction solutions are added, subtracts and obtains 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitraes-through column Chromatographic purification
Diketone.Yield is 61%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1: ethyl acetate mixed solvent.
Embodiment 4
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.02 mM of stannous chloride, 0.2 mM of pivaloyl is added
Acetophenone oxime ester, 0.6 mM of fluoro- 3- phenylacetone of 1,1,1- tri-, 0.2 mM of pivalic acid caesium and 4 milliliters of dimethyl Asias
Sulfone is stirred to react 12 hours at 80 DEG C, is cooled to 25 DEG C after reaction, and 10 milliliters of water, 10 milliliters of ethyl acetate extractions are added
It extracts reaction solution, evaporating solvent under reduced pressure obtains crude product.1 milliliter of 1 mole of every liter of hydrochloric acid is added in crude product, stirring 12 is small at 25 DEG C
When, 10 milliliters of ethyl acetate extraction reaction solutions are added, subtracts and obtains 5,5,5- tri- fluoro- 1,3- diphenyl pentanes-through column Chromatographic purification
1,4- diketone.Yield is 31%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1: ethyl acetate mixing is molten
Agent.
Embodiment 5
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.02 mM of stannous chloride, 0.2 mM of acetophenone is added
Acetophenone oxime ester, 0.2 mM 1,1,1- tri- fluoro- 3- phenylacetone, 0.2 mM of pivalic acid caesium and 4 milliliters of dimethyl sulfoxides,
It is stirred to react at 80 DEG C 12 hours, is cooled to 25 DEG C after reaction, 10 milliliters of water, 10 milliliters of ethyl acetate extractions are added
Reaction solution, evaporating solvent under reduced pressure obtain crude product.1 milliliter of 0.5 mole of every liter of hydrochloric acid is added in crude product, stirring 12 is small at 25 DEG C
When, 10 milliliters of ethyl acetate extraction reaction solutions are added, subtracts and obtains 5,5,5- tri- fluoro- 1,3- diphenyl pentanes-through column Chromatographic purification
1,4- diketone.Yield is 47%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1: ethyl acetate mixing is molten
Agent.
Embodiment 6
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.01 mM of stannous chloride, 0.2 mM of acetophenone is added
Acetophenone oxime ester, 0.4 mM 1,1,1- tri- fluoro- 3- phenylacetone, 0.2 mM of pivalic acid caesium and 4 milliliters of toluene, at 80 DEG C
Under be stirred to react 12 hours, be cooled to 25 DEG C after reaction, be added 10 milliliters of water, 10 milliliters of ethyl acetate extract reaction solutions,
Evaporating solvent under reduced pressure obtains crude product.1 milliliter of 4 moles of every liter of hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C, is added 10
Milliliter ethyl acetate extracts reaction solution, subtracts and obtains 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitrae-diketone through column Chromatographic purification.
Yield is 17%.Column chromatographic eluate used is the petroleum ether that volume ratio is 5:1: ethyl acetate mixed solvent.
Embodiment 7
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, 0.02 mM of stannous chloride, 0.2 mM of acetophenone is added
Acetophenone oxime ester, 0.4 mM 1,1,1- tri- fluoro- 3- phenylacetone, 0.6 mM of potassium carbonate and 4 milliliters of dimethyl sulfoxides, 80
It is stirred to react at DEG C 12 hours, is cooled to 25 DEG C after reaction, 10 milliliters of water, 10 milliliters of ethyl acetate extraction reactions are added
Liquid, evaporating solvent under reduced pressure obtain crude product.1 milliliter of 1 mole of every liter of hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C, is added
10 milliliters of ethyl acetate extract reaction solution, subtract and obtain 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitraes-two through column Chromatographic purification
Ketone.Yield is 47%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1: ethyl acetate mixed solvent.
Embodiment 8-13 is second step reaction step:
Embodiment 8
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, it is added 0.2 mM 5,5,5- tri- fluoro- 1,3- diphenyl penta
Alkane-Isosorbide-5-Nitrae-diketone, 0.2 mM of 4- (4- aminophenyl) butyric acid, 2 milliliters of toluene, it is small that reaction system at 70 DEG C is stirred to react 12
When, stop heating and stirring, is cooled to room temperature.Ethyl acetate extracts reaction solution, and vacuum rotary steam removes solvent, then is chromatographed by column
It isolates and purifies, obtains target product, yield 31%.Column chromatographic eluate used is the petroleum ether that volume ratio is 1000:1:
Ethyl acetate mixed solvent.
Embodiment 9
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, it is added 0.2 mM 5,5,5- tri- fluoro- 1,3- diphenyl penta
Alkane-Isosorbide-5-Nitrae-diketone, 0.2 mM of 4- (4- aminophenyl) butyric acid, 2 milliliters of toluene, it is small that reaction system at 100 DEG C is stirred to react 12
When, stop heating and stirring, is cooled to room temperature.Ethyl acetate extracts reaction solution, and vacuum rotary steam removes solvent, then is chromatographed by column
It isolates and purifies, obtains target product, yield 41%.Column chromatographic eluate used is the petroleum ether that volume ratio is 10:1: second
Acetoacetic ester mixed solvent.
Embodiment 10
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, it is added 0.2 mM 5,5,5- tri- fluoro- 1,3- diphenyl penta
Alkane-Isosorbide-5-Nitrae-diketone, 0.2 mM of 4- (4- aminophenyl) butyric acid, 2 milliliters of toluene, it is small that reaction system at 100 DEG C is stirred to react 24
When, stop heating and stirring, is cooled to room temperature.Ethyl acetate extracts reaction solution, and vacuum rotary steam removes solvent, then is chromatographed by column
It isolates and purifies, obtains target product, yield 45%.Column chromatographic eluate used is the petroleum ether that volume ratio is 10:1: second
Acetoacetic ester mixed solvent.
Embodiment 11
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, it is added 0.2 mM 5,5,5- tri- fluoro- 1,3- diphenyl penta
Alkane-Isosorbide-5-Nitrae-diketone, 0.4 mM of 4- (4- aminophenyl) butyric acid, 2 milliliters of toluene, it is small that reaction system at 100 DEG C is stirred to react 24
When, stop heating and stirring, is cooled to room temperature.Ethyl acetate extracts reaction solution, and vacuum rotary steam removes solvent, then is chromatographed by column
It isolates and purifies, obtains target product, yield 60%.Column chromatographic eluate used is the petroleum ether that volume ratio is 10:1: second
Acetoacetic ester mixed solvent.
Embodiment 12
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, it is added 0.2 mM 5,5,5- tri- fluoro- 1,3- diphenyl penta
Alkane-Isosorbide-5-Nitrae-diketone, 0.4 mM of 4- (4- aminophenyl) butyric acid, 2 milliliters of acetonitriles, it is small that reaction system at 100 DEG C is stirred to react 24
When, stop heating and stirring, is cooled to room temperature.Ethyl acetate extracts reaction solution, and vacuum rotary steam removes solvent, then is chromatographed by column
It isolates and purifies, obtains target product, yield 32%.Column chromatographic eluate used is the petroleum ether that volume ratio is 10:1: second
Acetoacetic ester mixed solvent.
Embodiment 13
Equipped in 25 milliliters of reaction flasks of reflux condensing tube, it is added 0.2 mM 5,5,5- tri- fluoro- 1,3- diphenyl penta
Alkane-Isosorbide-5-Nitrae-diketone, 0.4 mM of 4- (4- aminophenyl) butyric acid, 2 milliliters of dimethylbenzene, reaction system are stirred to react 24 at 100 DEG C
Hour, stop heating and stirring, is cooled to room temperature.Ethyl acetate extracts reaction solution, and vacuum rotary steam removes solvent, then passes through column layer
Analysis isolates and purifies, and obtains target product, yield 55%.Column chromatographic eluate used is the petroleum ether that volume ratio is 5:1: second
Acetoacetic ester mixed solvent.
Hydrogen spectrogram, carbon spectrogram and the fluorine spectrogram of 8~13 products therefrom of embodiment are respectively as shown in Figure 1, Figure 2 and shown in Fig. 3；Its
Structural characterization data are as follows:
1H NMR(400MHz,CDCl3): δ=7.50 (d, J=7.2Hz, 2H), 7.40 (t, J=7.2Hz, 2H), 7.33
(t, J=7.2Hz, 1H), 7.22 (d, J=8.8Hz, 2H), 7.15-7.18 (m, 5H), 7.09-7.11 (m, 2H), 6.41 (s,
1H), 2.71 (t, J=7.6Hz, 2H), 2.36 (t, J=7.6Hz, 2H), 1.98 (quint, J=7.6Hz, 2H)；
13C NMR(100MHz,CDCl3): δ=179.0,141.7,138.3 (q,3JF-C=1.7Hz), 136.1,
135.0,131.6,129.3(q,3JF-C=1.4Hz), 129.1 (q,3JF-C=2.2Hz), 128.8,128.8,128.1,
128.0,127.4,127.1,121.6(q,1JF-C=267.4Hz), 118.7 (q,2JF-C=35.7Hz), 111.3,34.5,
33.0,25.9；
19F NMR(376MHz,CDCl3): δ=- 51.6 (s, 3F)；
IR(KBr):3041,2933,1708,1512,1457,1417,1362,1281,1207,1165,1100 (cm-1)；
HRMS-ESI(m/z):[M+Na]+Calcd.for C27H22F3NO2+Na,472.1495；found, 472.1496.
Infer that the structure of 8~13 products therefrom of embodiment is as shown in Equation 2 according to above data.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (9)
1. a kind of trifluoromethyl modifies AβThe synthetic method of -42 inhibitor structure analogs, which comprises the following steps:
(1) in the reactor, it is added catalyst, acetophenone oxime ester, 1,1,1- tri- fluoro- 3- phenylacetone, alkali and solvent, 60~
It is stirred to react at 100 DEG C 12~24 hours, is cooled to 25 DEG C after reaction, ethyl acetate extracts reaction solution, removes under reduced pressure molten
Agent obtains crude product；Hydrochloric acid is added in crude product, is stirred 12 hours at 25 DEG C, ethyl acetate extracts reaction solution, through column Chromatographic purification
Obtain the fluoro- 1,3- diphenyl pentane -1,4- diketone of 5,5,5- tri-；The catalyst is stannous chloride, cuprous bromide, iodate Asia
The mixing of one or more of copper, copper chloride, copper bromide, copper acetate, copper sulphate, copper trifluoromethanesulfcomposite；
(2) in the reactor, be added 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitrae-diketone, 4- (4- aminophenyl) butyric acid with
And solvent, it is stirred to react at 70~100 DEG C 12~24 hours, is cooled to room temperature after reaction, extract reaction solution, decompression is steamed
Except solvent obtains crude product, trifluoromethyl modification A is obtained through column Chromatographic purificationβ- 42 inhibitor structure analogs.
2. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that step (1) the acetophenone oxime ester is acetyl acetophenone oxime ester, one or both of pivaloyl acetophenone oxime ester
Mixing.
3. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that step (1) alkali is one of cesium carbonate, pivalic acid caesium, potassium carbonate, tert-butyl alcohol lithium, lithium carbonate and sodium methoxide
Or two or more mixing.
4. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that the molar ratio of step (1) catalyst and acetophenone oxime ester is 1:10~20；Acetophenone oxime ester and 1,1,1- tri-
The molar ratio of fluoro- 3- phenylacetone is 1:1~3；The molar ratio of acetophenone oxime ester and alkali is 1:1~3.
5. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that solvent described in step (1) is toluene, benzene, dimethylbenzene, 1,2- dichloroethanes, tetrahydrofuran, dimethyl sulfoxide and second
The mixing of one or more of nitrile；The concentration of the hydrochloric acid is 0.5~4 mole every liter.
6. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that column Chromatographic purification described in step (1) refers to the petroleum ether with volume ratio for 5~1000:1: the mixing of ethyl acetate
Solvent is the column Chromatographic purification of eluent.
7. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that step (2) described 5,5,5- tri- fluoro- 1,3- diphenyl pentane-Isosorbide-5-Nitrae-diketone rub with 4- (4- aminophenyl) butyric acid
You are than being 1:1~2.
8. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that solvent described in step (2) is one of toluene, benzene, dimethylbenzene, 1,2- dichloroethanes, tetrahydrofuran and acetonitrile
Or two or more mixing.
9. a kind of trifluoromethyl according to claim 1 modifies AβThe synthetic method of -42 inhibitor structure analogs, it is special
Sign is that column Chromatographic purification described in step (2) refers to the petroleum ether with volume ratio for 5~1000:1: the mixing of ethyl acetate
Solvent is the column Chromatographic purification of eluent.
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