CN107151247A - The preparation method of the adjoining fluorophenyl compound of piperidones chain with bioactivity - Google Patents
The preparation method of the adjoining fluorophenyl compound of piperidones chain with bioactivity Download PDFInfo
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- CN107151247A CN107151247A CN201710411140.1A CN201710411140A CN107151247A CN 107151247 A CN107151247 A CN 107151247A CN 201710411140 A CN201710411140 A CN 201710411140A CN 107151247 A CN107151247 A CN 107151247A
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- 0 CN(C(CCN(*)C1)=C1C(Cl)=C1)C1=O Chemical compound CN(C(CCN(*)C1)=C1C(Cl)=C1)C1=O 0.000 description 2
- NUHHRBMURWOZPI-VBKFSLOCSA-N CC(C)(C)OC(N(CC1)CC(/C(/c(cccc2)c2F)=C\C(C)=O)=C1NC)=O Chemical compound CC(C)(C)OC(N(CC1)CC(/C(/c(cccc2)c2F)=C\C(C)=O)=C1NC)=O NUHHRBMURWOZPI-VBKFSLOCSA-N 0.000 description 1
- WLDVFUGWZBUREX-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(Cl)=C2)=C1N(C)C2=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(Cl)=C2)=C1N(C)C2=O)=O WLDVFUGWZBUREX-UHFFFAOYSA-N 0.000 description 1
- FSKYXEJQZNSJMI-UHFFFAOYSA-N CN(CCc1nc(O)c2)Cc1c2O Chemical compound CN(CCc1nc(O)c2)Cc1c2O FSKYXEJQZNSJMI-UHFFFAOYSA-N 0.000 description 1
- KRGGGGSVCGEKSX-UHFFFAOYSA-N Oc1c(CNCC2)c2nc(O)c1 Chemical compound Oc1c(CNCC2)c2nc(O)c1 KRGGGGSVCGEKSX-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The invention discloses a kind of preparation method of the adjoining fluorophenyl compound of piperidones chain with bioactivity, belong to the synthesis technical field of medicine intermediate.Technical scheme main points are：
Description
Technical field
The invention belongs to pharmaceutical chemical synthesis technical field, and in particular to a kind of piperidones link with bioactivity
The preparation method of adjacent fluorophenyl compound
Background technology
Nitrogen-containing heterocycle compound is because it has good bioactivity and is given birth in the human health such as medicine and agricultural chemicals and agricultural
Played an important role in production.In recent years, effect of this kind of material in medicine and Agrochemicals is increasingly apparent, most of miscellaneous
The novel pesticide of ring class is to warm-blooded animal toxicity very little, and the toxicity to birds, fish is also very low, and this is the research and development of novel agrochemical medicine
There is provided extremely wide application prospect.Piperidine derivative is important agricultural chemicals and medicine intermediate, such as in pesticide industry
A kind of herbicides for use in paddy of entitled dimepiperate can be synthesized, it is a kind of selective non-hormone-type thiocarbamic acid class weeding
Agent, with very big development space；Can be used for synthetic hydrochloric acid acetyl Roxatidine in pharmaceuticals industry (is a kind of digestive system drug
Thing), Dipyridmole heart (being a kind of vascular diseases medicine) etc..Therefore, the new compound with piperidines group is explored for closing
The lead compounds such as Cheng Xin agricultural chemicals and medicine have important practical significance.This seminar has designed and synthesized a series of new
The adjoining fluorophenyl compound of piperidones chain, and related activity test has been carried out to it.
The content of the invention
Present invention solves the technical problem that there is provided, a kind of synthetic method is simple, and having for molecular structure novelty is antimycotic
The preparation method of the adjoining fluorophenyl compound of piperidones chain of activity.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of new adjoining fluorobenzene of piperidones chain
Compound preparation method, it is characterised in that concretely comprise the following steps：
A, N-Boc-4- piperidones and dimethyl carbonate react in the presence of potassium tert-butoxide obtains N-Boc-3- formic acid first
Ester -4- piperidones
B, N-Boc-3- methyl formate -4- piperidones are under ammonium acetate effect, and ketone carbonyl redox is changed into amino
Compound N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
C, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines and chloroformyl ethyl acetate take under TEA effects
Generation reaction obtains compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
D, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines occur in the presence of potassium tert-butoxide
Intramolecular cyclization obtains compoundThen the compound carries out intramolecular in acid condition
Hydrogen migration and carbonyl reduction obtain compound
E、Under strongly acidic conditions, ester group and Boc groups are sloughed in heating, obtain compound
F、Under POCl3 effect, hydroxyl is replaced by chlorine obtains compound
G、Chloro carbon-to-nitrogen double bon is changed into amido link under concentrated hydrochloric acid effect and obtain compound
H、In the basic conditions, Boc amido protectings are carried out and obtains compound
I、Under cesium carbonate effect compound is obtained with iodomethane reaction
J、React and generate with adjacent fluorobenzoic boric acid under potassium phosphate effect
K、Slough Boc groups and obtain compound
L、It is acylated and is obtained with demethylating reaction in alkalescence condition with carboxylic acid compound
Further limit, step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to
In the toluene of 10V volumes, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to
Room temperature, adds water and is quenched, and it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, is spin-dried for
Obtain yellow oil N-Boc-3- methyl formate -4- piperidones
Further limit, step B detailed process is：1eq N-Boc-3- methyl formate -4- piperidones is added to 10
In the methanol of times volume, 3eq ammonium acetate is added, reaction is stayed overnight, be spin-dried for methanol, add the water of 3 times of volumes, dichloromethane extraction
Anhydrous sodium sulfate drying is used after extracting reaction solution, red oily liquids N-Boc-3- methyl formate -4- amino -3- is obtained after being spin-dried for
Alkene-piperidines
Further limit, step C detailed process is：By 1eq N-Boc-3- methyl formate -4- amino -3- alkene-piperidines
In the DCM for being added to 8 times of volumes, 1.05eq TEA is added, 10 DEG C are cooled to, 1.05eq 4- chloromethane ethyl acetoacetic acid second is added dropwise
Ester, room temperature reaction is stayed overnight, and adds the DCM dilute reaction solutions of 8 times of volumes, twice, anhydrous sodium sulfate drying is spin-dried for both obtaining for washing
Red oil product N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
Further limit, step D detailed process is：1eq N-Boc-3- methyl formate -4- carbamyl acetic acid second
Ester -3- alkene-piperidines is added in the THF of 10 times of volumes, then is added portionwise 2.0eq t-BuOK, reaction temperature control less than
25 DEG C, frozen water is added after reaction 1h and is quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, filtering, and it is white that vacuum drying obtains class
Color solid product
Further limit, step E detailed process is：In 10eq 6mol/L HCl solution, it is added portionwise 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for reaction dissolvent, then washed with ether, is dried in vacuo
Obtain off-white powder
Further limit, step F detailed process is：To 5eq POCl3In be added portionwise 1.0eq's
100 DEG C are heated to, reaction is stayed overnight, are spin-dried for POCl3Obtain Red oil product
Further limit, step G detailed process is：It is added to the 1,4- dioxies six of 4 times of volumes
In ring, the concentrated hydrochloric acid of 4 times of volumes is added, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for adding the second of 10 times of volumes after solvent
Acetoacetic ester, is washed three times, is dried and is obtained brown solid after being spin-dried for
Further limit, step H detailed process is：1eq'sIt is added to the 1,4- of 10 times of volumes
In dioxane and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2O, reacts at room temperature 10h
Afterwards, filter, then wash with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution, dried, revolved
Reaction solution is obtained
Further limit, step I detailed process is：1.0eq'sIt is added to 10 times of volumes
DMF in, add 1.5eq Cs2CO3, 1.3eq KI, room temperature reaction stays overnight, and adds frozen water and reaction solution, acetic acid is quenched
Ethyl ester extractive reaction liquid, sodium chloride solution washing, dries, is spin-dried for, then is beaten with ether, filters, and it is solid that vacuum drying obtains white
Body
Further limit, step J detailed process is：By 1.0eq'sIt is added to 20 times of volumes
In THF, 3eq 1mol/L potassium phosphate and 1.2eq adjacent fluorobenzoic boric acid are added, 100 DEG C are heated to, reaction is stayed overnight, acetic acid
Ethyl ester is extracted, and is dried, is spin-dried for rear column chromatography for separation and obtains
Further limit, step K detailed process is：1.0eqBe added to 10 times of volumes methanol and
In the 12mol/L of 10 volumes HCl/1,4- dioxane, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
Further limit, step L detailed process is：In reaction bulb,It is added in DMF, then adds
Enter triethylamine and carboxylic acid compound, be heated to 70 DEG C, reaction a period of time, compound obtained with demethylation while being acylated
The adjoining fluorophenyl compound synthetic route of piperidones chain of the present invention with bioactivity is：
The present invention has synthesized a series of adjoining fluorophenyl compounds of piperidones chain simultaneously by being transformed piperidones molecule
Antifungal activity test has been carried out, it is found that such compound dialogue candidiasis has preferable inhibitory activity.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In reaction bulb, N-Boc-4- piperidones 20g (0.1mol) is added in toluene 200mL, carbonic acid two is added
Methyl esters 18g (0.2mol) and potassium tert-butoxide 22g (0.2mol), is heated to 70 DEG C of reaction 1h, is cooled to room temperature, the 100mL that adds water quenches
Go out, it is 7 to adjust reaction solution pH with 1mol/L HCl, ethyl acetate extraction, after anhydrous sodium sulfate drying, be spin-dried for obtaining yellow oil
Shape thing N-Boc-3- methyl formate -4- piperidones 24g；1HNMR(400MHz,CD3Cl)δ:3.81 (s, 1H), 3.71 (d, J=
8.4Hz, 1H), 3.68 (d, J=8.4Hz, 1H), 3.45 (s, 3H), 3.07-3.05 (m, 2H), 2.76-2.73 (m, 2H), 1.37
(s,9H).MS-ESI(m/z):258.3[M+H+]。
Embodiment 2
In reaction bulb, N-Boc-3- methyl formate -4- piperidones 25g (0.1mol) are added in methanol 300mL, then
Ammonium acetate 22g (0.3mol) is added, reaction is stayed overnight, TLC monitoring raw material reactions are complete, are spin-dried for methanol, water 900mL added, with two
Chloromethanes 300mL extractive reactions liquid three times, merges and anhydrous sodium sulfate drying is used after organic phase, red oily liquids is obtained after being spin-dried for
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 22g；1HNMR(400MHz,CD3Cl)δ:8.56(s,2H),3.93(s,
2H),3.77(s,3H),3.57-3.55(m,2H),2.16-2.13(m,2H),1.37(s,9H).MS-ESI(m/z):257.3[M
+H+]。
Embodiment 3
In reaction bulb, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines 26g (0.1mol) is added to dichloromethane
In alkane 200mL, TEA11g (0.11mol) is added, 10 DEG C are cooled to, 4- chloroformyl ethyl acetate 16g is slowly added dropwise
(0.105mol), room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, add dichloromethane 200mL dilute reaction solutions, water
Wash twice, anhydrous sodium sulfate drying, be spin-dried for both obtaining Red oil product N-Boc-3- methyl formate -4- carbamyl acetic acid second
Ester -3- alkene-piperidines 23g；1HNMR(400MHz,CD3Cl)δ:4.71(s,2H),3.93(s,2H),3.79(s,3H),3.57-
3.55(m,2H),3.53(s,2H),2.16-2.13(m,2H),1.37(s,9H),1.29(s,3H).MS-ESI(m/z):371.4
[M+H+]。
Embodiment 4
In reaction bulb, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines 37g (0.1mol)
It is added in THF400mL, then t-BuOK 23g (0.2mol) is added portionwise, reaction temperature control is reacted after 1h less than 25 DEG C
Add frozen water 300mL to be quenched, it is 3 to adjust reaction solution pH with 2mol/L HCl, and filtering, vacuum drying obtains off-white powder production
Product32g；1H NMR(400MHz,DMSO-d6)δ:11.51(s,1H),5.35(s,1H),
4.71 (s, 2H), 4.33 (d, J=4.0Hz, 2H), 3.66-3.62 (m, 2H), 3.25 (d, J=12.0Hz, 2H), 1.41-1.39
(m,9H),1.33-1.32(m,3H)。
Embodiment 5
In reaction bulb, the HCl solution 200mL in 6mol/L is added, then be added portionwise
34g (0.1mol), is heated to 100 DEG C, reaction is stayed overnight, and is spin-dried for reaction dissolvent, then is washed with ether, and vacuum drying obtains off-white color
Solid15g；1H NMR(400MHz,DMSO-d6)δ:11.47(s,1H),5.95(s,1H),5.41(s,
1H), 3.86-3.85 (m, 2H), 3.71 (d, J=12.0Hz, 2H), 3.11-3.09 (m, 2H), 1.90 (s, 1H).
Embodiment 6
In closed reaction bulb, it is added portionwise into POCl3 50g (0.5mol)16g
(0.1mol), is slowly heated to 100 DEG C, reaction is stayed overnight, and vacuum is spin-dried for POCl3 and obtains Red oil product16g；1H NMR(400MHz,DMSO-d6)δ:7.61 (s, 1H), 3.81 (s, 2H), 3.37 (d, J=
12.0Hz,2H),3.13-3.12(m,2H),1.87(s,1H)。
Embodiment 7
In the reaction bulb with thermometer and stirring,20g is added to 1,4- dioxane
In 100mL, concentrated hydrochloric acid 100mL is slow added into, 100 DEG C are heated to, back flow reaction 2 days is spin-dried for after solvent adding 10 times of volumes
Ethyl acetate, wash three times, dry be spin-dried for after obtain brown solid17g；1H NMR(400MHz,
CDCl3)δ:8.17 (s, 1H), 6.62 (s, 1H), 3.35 (s, 2H), 2.96 (d, J=12.0Hz, 2H), 2.07-2.05 (m,
2H).MS-ESI(m/z):185.6[M+H+]。
Embodiment 8
In reaction bulb,18g (0.1mol) is added to 1,4- dioxane 200mL and water 200mL
In, then sodium carbonate 30g (0.3mol) and (Boc) is added portionwise2After O 33g (0.15mol), room temperature reaction 10h, TLC monitoring is former
Material reaction is complete, filtering reacting liquid, then is washed with ethyl acetate 100mL after filter cake with ethyl acetate 200mL extractive reactions liquid three
It is secondary, then washed with sodium chloride solution, dry, rotation reaction solution is obtained20g；1H NMR(400MHz,DMSO-
d6)δ:6.61 (s, 1H), 3.93 (s, 2H), 3.54 (s, 3H), 3.57 (d, J=12.0Hz, 2H), 2.07-2.05 (m, 2H),
1.39(s,9H)。
Embodiment 9
In reaction solution,28g (0.1mol) is added in DMF 300mL, adds carbonic acid
Caesium 50g (0.15mol), KI 20g (0.13mol), room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, add frozen water
Reaction solution is quenched in 100mL, and ethyl acetate 200mL extractive reactions liquid three times, saturated nacl aqueous solution 200mL washing reaction liquids are done
It is dry, it is spin-dried for, then be beaten with ether, filter, vacuum drying obtains white solid26g；1H NMR
(400MHz,DMSO-d6)δ:6.61 (s, 1H), 3.94 (s, 2H), 3.54 (s, 3H), 3.55 (d, J=8.0Hz, 2H), 2.07-
2.05(m,2H),1.38(s,9H).MS-ESI(m/z):299.8[M+H+]。
Embodiment 10
, will in reaction solution30g (0.1mol) is added in anhydrous THF 500mL, is added
1mol/L potassium phosphate 70mL (0.3mol) and 2- fluorobenzoic boric acids 17g (0.12mol), is heated to 100 DEG C, reaction is stayed overnight, then use
Ethyl acetate 300mL extractive reactions liquid twice, merges organic relevant dry, is spin-dried for after organic phase obtaining through column chromatography for separation39g；1H NMR(400MHz,DMSO-d6)δ:7.47-7.41(m,4H),5.71(s,1H),3.96(s,
2H), 3.57 (s, 3H), 3.51 (d, J=12.0Hz, 2H), 2.11-2.10 (m, 2H), 1.39 (s, 9H).
Embodiment 11
, will in reaction bulb36g (0.1mol) is added to methanol 400mL's and 12mol/L
In HCl/1,4- dioxane 400mL, room temperature reaction is stayed overnight, and TLC monitoring raw material reactions are complete, are spin-dried for, ether washing concentrate,
Obtain22g；1H NMR(400MHz,DMSO-d6)δ:7.63-7.59(m,2H),7.19-7.17(m,2H),
5.71 (s, 1H), 3.93 (s, 2H), 3.55 (d, J=12.0Hz, 2H), 3.54 (s, 3H), 2.95-2.93 (m, 2H), 2.07-
2.05(m,2H)。
Embodiment 12
In reaction bulb,26g (0.1mol) is added in DMF, adds triethylamine 20g
(0.2mol) and benzoic acid 12g (0.1mol), is heated to after 70 DEG C, reaction 3h through the reaction of TLC monitoring raw materials completely, fall reaction solution
Enter in water, with chloroform 200mL extractive reactions liquid three times, be spin-dried for obtaining compound after merging organic phase
31g；1H NMR(400MHz,DMSO-d6)δ:8.11(s,1H),8.01-7.89(m,3H),7.70-7.66(m,2H),7.12-
7.09 (m, 2H), 7.02 (d, J=4.0Hz, 1H), 5.71 (s, 1H), 3.93 (s, 2H), 3.55 (d, J=12.0Hz, 2H),
2.07-2.05(m,2H)。
Embodiment 13
Biological activity determination
According to national standard GB15979-2002, when determining drug quality concentration for 0.1ml/L, target compound dialogue vacation silk
The bacteriostatic activity of saccharomycete and Candida glabrata reference culture.The false silk of compound dialogue by 0.1mg/L of mass concentration
Exemplified by the active testing process of saccharomycete and Candida glabrata, testing procedure is as follows：(1) laboratory sample 0.05mg is taken, plus
Enter 3mL DMSO and 2mL distilled water, be made into the sample solution that mass fraction is 10mg/L；(2) configuration of bacterium solution：Dipped with cotton swab
Appropriate candida albicans bacterium or Candida glabrata, are added in the standard test tube equipped with buffer solution and mix, with opacity tube
Contrast, turbidity suitable with opacity tube is required concentration；(3) laboratory sample pipe and the control containing same volume same solvent are taken
Each 1 pipe of liquid, autoclaving；(4) the μ L of bacteria suspension 100 in step (2) are removed with liquid-transfering gun respectively, are separately added into and are filled experiment sample
In product liquid and the test tube of control sample liquid, mix, act on 20min；(5) 0.5mL sample solutions are taken respectively, are added containing 4.5mL bufferings
In the test tube of solution, mixed with vortex mixer, take 3 dilution factors；(6) sample solution after 0.5mL dilutions is taken respectively, is placed in two
In material, specification identical sterile petri dish, the sterile sabouraud culture medium that about 15mL temperature is 40~50 DEG C is added wherein, gently
It is light to rotate culture dish, make culture medium thickness in culture dish uniform, after overturning flat board after culture medium solidifying, be placed in 37 DEG C of incubators
Middle culture 72h；(7) culture is finished, and takes out culture dish number bacterium colony number, calculates bacteriostasis rate.Such compound is found by experiment
On benzene ring substitution group, the false silk ferment of dialogue is generally better than to the inhibitory action of Candida glabrata when meta is electron-withdrawing substituent
The inhibitory action of female bacterium, when meta is electron substituent, the inhibitory action of dialogue candidiasis is generally better than to smooth vacation
The inhibitory action of silk saccharomycete.
Embodiment above describes general principle, principal character and the advantage of the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. the preparation method of the adjoining fluorophenyl compound of piperidones chain with bioactivity, it is characterised in that concretely comprise the following steps：
A, N-Boc-4- piperidones and dimethyl carbonate react in the presence of potassium tert-butoxide obtains N-Boc-3- methyl formates -4-
Piperidones；
B, N-Boc-3- methyl formate -4- piperidones are under ammonium acetate effect, and ketone carbonyl redox obtains compound into amino
N-Boc-3- methyl formate -4- amino -3- alkene-piperidines；
It is anti-that under TEA effects substitution occurs for C, N-Boc-3- methyl formate -4- amino -3- alkene-piperidines and chloroformyl ethyl acetate
Compound N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines should be obtained；
Molecule occurs in the presence of potassium tert-butoxide for D, N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines
Interior cyclization obtains compoundThen the compound carries out intramolecular hydrogen turn in acid condition
Move and carbonyl reduction obtains compound
E、Under strongly acidic conditions, ester group and Boc groups are sloughed in heating, obtain compound
F、Under POCl3 effect, hydroxyl is replaced by chlorine obtains compound
G、Chloro carbon-to-nitrogen double bon is changed into amido link under concentrated hydrochloric acid effect and obtain compound
H、In the basic conditions, Boc amido protectings are carried out and obtains compound
I、Under cesium carbonate effect compound is obtained with iodomethane reaction
J、React and generate with adjacent fluorobenzoic boric acid under potassium phosphate effect
K、Slough Boc groups and obtain compound
L、It is acylated and is obtained with demethylating reaction in alkalescence condition with carboxylic acid compound
2. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step A detailed process is：In reaction bulb, 1eq N-Boc-4- piperidones is added to the toluene of 10V volumes
In, 2eq dimethyl carbonate and 2eq potassium tert-butoxide are added, 70 DEG C of reaction 1h is heated to, is cooled to room temperature, adds water and be quenched,
It is 7 with 1mol/L hydrochloric acid regulation reaction solution pH, ethyl acetate is extracted, and after anhydrous sodium sulfate drying, is spin-dried for obtaining yellow oily
Thing N-Boc-3- methyl formate -4- piperidones；Step B detailed process is：By 1eq N-Boc-3- methyl formate -4- piperidines
Ketone is added in the methanol of 10 times of volumes, adds 3eq ammonium acetate, and reaction is stayed overnight, and is spin-dried for methanol, adds the water of 3 times of volumes,
Anhydrous sodium sulfate drying is used after dichloromethane extractive reaction liquid, obtained after being spin-dried for red oily liquids N-Boc-3- methyl formates-
4- amino -3- alkene-piperidines.
3. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step C detailed process is：1eq N-Boc-3- methyl formate -4- amino -3- alkene-piperidines is added to 8 times of volumes
DCM in, add 1.05eq TEA, be cooled to 10 DEG C, 1.05eq 4- chloroformyl ethyl acetate is added dropwise, reacted at room temperature
At night, the DCM dilute reaction solutions of 8 times of volumes are added, twice, anhydrous sodium sulfate drying is spin-dried for both obtaining Red oil product for washing
N-Boc-3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines；Step D detailed process is：1eq N-Boc-
3- methyl formate -4- carbamyl ethyl acetate -3- alkene-piperidines is added in the THF of 10 times of volumes, then 2.0eq is added portionwise
T-BuOK, reaction temperature control adds frozen water less than 25 DEG C, after reaction 1h and is quenched, and reaction solution is adjusted with 2mol/L HCl
PH is 3, and filtering, vacuum drying obtains off-white powder product
4. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step E detailed process is：In 10eq 6mol/L HCl solution, it is added portionwise 1.0eq's100 DEG C are heated to, reaction is stayed overnight, are spin-dried for reaction dissolvent, then washed with ether, is dried in vacuo
Obtain off-white powderTo 5eq POCl3In be added portionwise 1.0eq'sHeating
To 100 DEG C, reaction is stayed overnight, and is spin-dried for POCl3Obtain Red oil product
5. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step G detailed process is：In the Isosorbide-5-Nitrae-dioxane for being added to 4 times of volumes, 4 are added
The concentrated hydrochloric acid of times volume, is heated to 100 DEG C, back flow reaction 2 days is spin-dried for adding the ethyl acetate of 10 times of volumes, washing after solvent
Three times, dry and obtain brown solid after being spin-dried for1eq'sIt is added to 10 times of volumes
In Isosorbide-5-Nitrae-dioxane and the water of 10 times of volumes, then 3.0eq sodium carbonate and 1.5eq (Boc) is added portionwise2O, room temperature reaction
After 10h, filtering, then wash with ethyl acetate reaction solution is extracted with ethyl acetate after filter cake, then washed with sodium chloride solution, it is dry
Dry, rotation reaction solution is obtained
6. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, its feature exists
It is in step I detailed process：1.0eq'sIn the DMF for being added to 10 times of volumes, 1.5eq is added
Cs2CO3, 1.3eq KI, room temperature reaction stays overnight, and adds frozen water and reaction solution, ethyl acetate extractive reaction liquid, sodium chloride is quenched
Solution is washed, and is dried, is spin-dried for, then is beaten with ether, is filtered, and vacuum drying obtains white solid
7. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step J detailed process is：By 1.0eq'sIn the THF for being added to 20 times of volumes, add
3eq 1mol/L potassium phosphate and 1.2eq adjacent fluorobenzoic boric acid, are heated to 100 DEG C, reaction is stayed overnight, ethyl acetate extraction, do
It is dry, it is spin-dried for rear column chromatography for separation and obtains
8. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step K detailed process is：1.0eqIt is added to the methanol and 10 volumes of 10 times of volumes
In 12mol/L HCl/1,4- dioxane, room temperature reaction is stayed overnight, and is spin-dried for, ether washing, is obtained
9. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levy and be that step L detailed process is：In reaction bulb,It is added in DMF, adds triethylamine and carboxylic
Acid compound, is heated to 70 DEG C, reaction a period of time, compound is obtained with demethylation while being acylated
10. the preparation method of the piperidones chain adjoining fluorophenyl compound according to claim 1 with bioactivity, it is special
Levying the specific synthetic route being in preparation process is：
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