CN105732470B - The high efficiency preparation method of 3- fluoro-indole-2-carbonyl compound - Google Patents
The high efficiency preparation method of 3- fluoro-indole-2-carbonyl compound Download PDFInfo
- Publication number
- CN105732470B CN105732470B CN201610173119.8A CN201610173119A CN105732470B CN 105732470 B CN105732470 B CN 105732470B CN 201610173119 A CN201610173119 A CN 201610173119A CN 105732470 B CN105732470 B CN 105732470B
- Authority
- CN
- China
- Prior art keywords
- indoles
- fluoro
- methanol
- hydrogen
- method described
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention discloses a kind of method efficiently synthesizing 3 fluoro indoles, 2 carbonyls.The method includes using 3 hydrogen indoles of fluoro reagent pair, 2 alcohol compound to carry out fluoro oxidation reaction, corresponding 3 fluoro indoles, 2 carbonyls is generated.The raw material of the present invention is easy to get, and reaction condition is mild, and reaction selectivity and yield are high.
Description
Technical field
The invention belongs to chemosynthesis technical fields, are related to a kind of preparation side of 3- fluoro-indole-2-carbonyl compound
Method carries out fluoro oxidation reaction to 3- hydrogen-indoles -2- alcohol compounds using fluoro reagent, generates corresponding 3- fluoro-Yin
Diindyl -2- carbonyls.
Background technology
Benzazole compounds are extremely important a kind of organic compounds.Such as indoles alkaloid is alkaloid super families
In one of greatest member (about 2000 members, Facchini, P.J.Annu.Rev.Plant Physiol.Plant
Mol.Biol.2001,52,29；Saxton,E.J.Nat.Prod.Rep.1997,14,559.).Fluorochemical is in drug, agriculture
With the application in terms of chemicals, biomedical imaging agent and material more and more extensive (M ü ller, K.；Faeh,C.；
Diederich,F.Science,2007,317,1881；Kirk,K.L.Org.Process Res.Dev.,2008,12,305；
Grushin,V.V.Acc.Chem.Res.,2010,43,160；Furuya,T.；Kuttruff,C.A.；Ritter,
T.Curr.Opin.Drug Discovery,2008,11,803；Furuya,T.；Kamlet,A.S.；Ritter,T.Nature,
2011,473,470；Campbell,M.G.；Ritter,T.Chem.Rev,2015,115,612；Lee,E.；Kamlet,A.S.；
Powers,D.C.；Neumann,C.N.；Boursalian,G.B.；Furuya,T.；Choi,D.C.；Hooker,J.M.；
Ritter,T.Science,2011,334,639).Fluorin radical is extremely important in pharmaceutical chemistry, because it can influence guideization
Close almost all of physicochemical property in object, including absorption,distribution,metabolism,excretion.With fluoro drug can be often improved for hydrogen
Bioactivity, and since carbon-fluorine bond is very strong, metabolic chemistry environment that more can be in receiving body.Many chemists are keen to thus
In the fluorine-containing derivant of synthetic drug.There are one about 40% agricultural chemicals and 20% drug contain on the market according to statistics
Or more fluorine atom (Thayer, A.M.Chem.Eng.News 2006,84, (23, June 5) 15), wherein comprising 3 pin
Sell before volume ten drug (Ainsworth, S.J.Chem.Eng.News, 2008,86, (48December 1) 15).But for
For many compounds, synthesizes its fluorine-containing derivant and be not easy to.Such as 3- fluoro-indoles -2- aldehyde compounds are a kind of non-
Often important organic synthesis intermediate, but traditional synthetic method is respectively necessary for the cumbersome and harsh mistakes such as experience oxidation and fluoro
Journey, and need the chemical reagent using high-risk, such as butyl lithium.Conventional method synthesizes 3- fluoro-indoles -2- aldehyde compounds
It is maximum the disadvantage is that, in crucial fluoro-reaction, only 33% yield, so gross production rate is less than 24% (Gurmit, G.；
Vibbha,O.PCT Int.Appl.,2008059238).Therefore develop it is a kind of efficiently, the mild new method of safety, reaction condition
It is to have very much research and application value to synthesize 3- fluoro-indole-2-carbonyl compound.
Invention content
In order to solve the problems in the existing technology, the present invention provides a kind of 3- fluoro-indole-2-carbonyl compounds
High-efficiency synthesis method.
The synthetic method of the present invention, including：In fluoro reagent, under the conditions of solvent and additive are existing, to 3- hydrogen-Yin
Diindyl -2- alcohol compounds carry out fluoro oxidation reaction, obtain corresponding 3- fluoro-indole-2-carbonyl compound, wherein：
The fluoro reagent is N+- F salt or N-F amides, wherein N are nitrogen；
The solvent be 1,2- dichloroethanes, glycol dibromide, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate,
Methyl acetate, butyl acetate, acetone, nitromethane, nitroethane, acetonitrile, toluene, ortho-xylene, meta-xylene, to diformazan
Benzene, benzene, chlorobenzene, nitrobenzene, pentane, n-hexane, normal heptane, normal octane, pentamethylene, hexamethylene, cycloheptane, cyclooctane, second
Ether, butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4- dioxane, t-butyl methyl ether, N,N-dimethylformamide, N, N-
Dimethylacetylamide, dimethyl sulfoxide (DMSO), methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, cyclopentanol, cyclohexanol,
The mixture of one or more of formic acid, acetic acid, acetic anhydride, trifluoroacetic acid and water.
The additive be sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, saleratus, caesium bicarbonate, sodium phosphate,
The mixture of one or more of potassium phosphate, dibastic sodium phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, or do not add
Any additive.
In synthetic method of the present invention, the fluoro reagent is N+- F salt or N-F amides, have following (I) or
(II) structure shown in：
R1, R2, R3, R4Can be identical or different, it is respectively and independently selected from hydrogen, alkyl, halogenated alkyl, alkoxy, benzene methoxy
It is base, acyloxy, acyl group, ester group, amide groups, alkyl monosubstituted amino, dialkyl amido, unsubstituted or substituted aryl, unsubstituted
Or substituted heteroaryl；Or R1, R2, R3, R4Between be combined with each other unsubstituted or substituted naphthenic base, not be collectively formed
Substitution or substituted Heterocyclylalkyl, unsubstituted or substituted benzo naphthenic base, unsubstituted or substituted benzheterocycle alkane
Base, unsubstituted or substituted aromatic ring, unsubstituted or substituted heteroaromatic；
Preferably, the fluoro reagent is fluoro- two (the tetrafluoro boron of Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane of 1- chloromethyls -4-
Acid) salt (fluorine reagent), N- fluoro double benzsulfamide, the fluoro- 2,4,6- trimethylpyridines trifluoro-methanyl sulfonates of 1-, the fluoro- 4- first of 1-
The mixture of one or more of two (tetrafluoro boric acid) salt of base -1,4- diazabicyclos [2.2.2] octane.
In synthetic method of the present invention, 3- hydrogen-indoles -2- alcohol compounds can have (III) institute
The compound for showing structure obtains 3- fluoro-indole-2-carbonyl compound shown in formula (IV)；
Corresponding reaction equation is：
Wherein：R1, R2, R3, R4, R5Can be identical or different, it is respectively and independently selected from hydrogen, halogen, hydroxyl, cyano, alkyl, halogen
Substituted alkyl, alkoxy, benzyloxy, acyloxy, acyl group, ester group, amide groups, alkyl monosubstituted amino, dialkyl amido, it is unsubstituted or
Substituted aryl, unsubstituted or substituted heteroaryl；Or R1, R2, R3, R4, R5Between be combined with each other to be collectively formed and do not take
It is generation or substituted naphthenic base, unsubstituted or substituted Heterocyclylalkyl, unsubstituted or substituted benzo naphthenic base, unsubstituted
Or substituted benzheterocycle alkyl, unsubstituted or substituted aromatic ring, unsubstituted or substituted heteroaromatic；
In synthetic method of the present invention, it is preferred that R1, R2, R3, R4, R5It is respectively and independently selected from hydrogen, halogen, hydroxyl, benzene
The alkyl-substituted alkyl monosubstituted amino of base, benzyl, amino, cyano, C1-5 or dialkyl amido, benzylamino, C1-14 alkyl, C1-
5 alkoxies, C1-5 aldehyde radicals, C1-5 cyano or C1-5 ester groups.
In the present invention, " aryl " refers to the group for the planar ring system for possessing conjugation, including it is unsubstituted or by
Substituted phenyl, fused ring aryl or heterocyclic aryl, wherein fused ring aryl refers to the merging of simple aromatic ring, and shares them and connect
Key, including but not limited to naphthalene；When there is non-carbon element in ring, such as when oxygen, nitrogen, sulphur, it is formed by aryl and is known as heterocycle virtue
Base, including but not limited to indoles, pyrroles, quinoline, furans, benzofuran, thiophene, benzothiophene, indazole, pyrazoles, imidazoles, azepine
Indoles, pyrimidine, purine, pyrazine etc.." alkyl " is preferably C1-14 alkyl, is more preferably C1-6 alkyl.
In synthetic method of the present invention, it is furthermore preferred that the 3- hydrogen-indoles -2- alcohol compounds be selected from
Any one of lower compound：1- hydrogen-indoles -2- methanol, 1- Methvl-indole -2- methanol, 1- Ethyl-indole -2- methanol, 1-
Isopropyl-indoles -2- first, 1- (2- fluoro ethyls)-indoles -2- methanol, 1- (3- cyanopropyls)-indoles -2- methanol, 1- benzyls -
Indoles -2- methanol, 1- phenyl-indole -2- methanol, 1- propargyls-indoles -2- methanol, 1- allyls-indoles -2- methanol, 1-
(3- methyl-2-butenes)-indoles -2- methanol, 1- (2- methyl-allyls)-indoles -2- methanol, 1- (2- Phenyl-allyls) -
Indoles-2- methanol, 5- fluoro- 1- hydrogen-indoles-2- methanol, the bromo- 1- hydrogen of 5--indoles-2- methanol, 5- methyl-1-hydrogen-indoles-2- first
Alcohol, 1- (1- methyl-1s hydrogen-indoles) -2- amylalcohols, 1- (1- methyl-1s hydrogen-indoles) -2- butyl- 3- alkene -ol, (- 1 hydrogen-Yin of 1- benzyls
Diindyl) -2- phenyl methyl alcohol.
In synthetic method of the present invention, it is preferred that the fluoro oxidizing reaction temperature is -80 DEG C~200 DEG C, preferably
It is 25 DEG C.
In synthetic method of the present invention, it is preferred that the 3- hydrogen-indoles -2- alcohol compounds and fluoro reagent
Molar ratio is 1:0.1 to 1:10, preferably 1:2.5 or 1:3.2.
In synthetic method of the present invention, it is preferred that a concentration of the 0.001 of the 3- hydrogen-indoles -2- alcohol compounds
~10.0M, preferably 0.25M.
In synthetic method of the present invention, it is preferred that the 3- hydrogen-indoles -2- alcohol compounds and additive rub
That ratio 0~50, preferably 1:2.5 or 1:3.2.
In synthetic method of the present invention, it is preferred that the reaction time is 0.01~24 hour.
The method of the present invention, which has, compares wide applicability, can provide the fluoro- indole-2-carbonyl compounds of several 3-.Tool
Body, the preparation method of 1 compound of table, wherein R are set forth in detail in a specific embodiment of the present invention1, R2, R3, R4, R5Only table
Show the substituent group in the compound, it should be understood that in other examples, the position of substitution of above-mentioned substituent group can be with
It is arbitrary.
Table 1：The fluoro- indole-2-carbonyl compounds (embodiment 1-16) of 3-
Under the conditions of the present invention is existing for fluoro reagent, by carrying out fluoro oxidation to 3- hydrogen-indoles -2- alcohol compounds
Reaction, can obtain highly useful 3- fluoro-indole-2-carbonyl compound with very high activity and selectivity.Using this hair
Bright method can efficiently and safely synthesize a series of 3- fluoro-indole-2-carbonyl compounds.The raw material of the method is easy to get, instead
Mild condition is answered, reaction selectivity and yield are high, are with a wide range of applications.
Description of the drawings
Fig. 1 to Figure 16 describes the synthetic route (route 1) of 3- fluoro-indole-2-carbonyl compound 1-16 respectively, wherein：
Fig. 1 describes the synthesis (route 1-1) of compound 1；
Fig. 2 describes the synthesis (route 1-2) of compound 2；
Fig. 3 describes the synthesis (route 1-3) of compound 3；
Fig. 4 describes the synthesis (route 1-4) of compound 4；
Fig. 5 describes the synthesis (route 1-5) of compound 5；
Fig. 6 describes the synthesis (route 1-6) of compound 6；
Fig. 7 describes the synthesis (route 1-7) of compound 7；
Fig. 8 describes the synthesis (route 1-8) of compound 8；
Fig. 9 describes the synthesis (route 1-9) of compound 9；
Figure 10 describes the synthesis (route 1-10) of compound 10；
Figure 11 describes the synthesis (route 1-11) of compound 11；
Figure 12 describes the synthesis (route 1-12) of compound 12；
Figure 13 describes the synthesis (route 1-13) of compound 13；
Figure 14 describes the synthesis (route 1-14) of compound 14；
Figure 15 describes the synthesis (route 1-15) of compound 15；
Figure 16 describes the synthesis (route 1-16) of compound 16.
Specific implementation mode
It will be helpful to further understand the present invention by following embodiments, but be not intended to limit the content of present invention.The present invention
Preparation method can further with the preparation process of following representation compounds embody.
Embodiment 1：The fluoro- 1- hydrogen of 3--indoles -2- formaldehyde (compound 1, route 1-1)
It takes a 25mL round-bottomed flasks, 1- hydrogen-indoles -2- methanol 29.4mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- chlorine is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of methyl -4- are stirred at 25 DEG C
20 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- hydrogen of 3--indoles -2- formaldehyde 20mg, produces
Rate 61%.
Gray solid, fusing point：141-142℃；1H NMR(CDCl3,300MHz):δ10.02(s,1H),8.99(s,1H),
7.73-7.16(m,4H)；13C NMR(CDCl3,75MHz):δ179.9,130.1,122.8,120.9,120.8,114.2；19F
NMR(CDCl3,282MHz):δ-160.1；MS(TOF)calcd for C9H6NOF[M+1]+:164.0512；found:
164.0513。
Embodiment 2：The fluoro- 1- Methvl-indoles -2- formaldehyde of 3- (compound 2, route 1-2)
A 25mL round-bottomed flasks are taken, 1- Methvl-indole -2- methanol 32.2mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of chloromethyl -4- are stirred at 25 DEG C
It mixes 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- Methvl-indoles -2- formaldehyde of 3-
24.9mg, yield 70%.
Gray solid, fusing point：76-77℃；1H NMR(CDCl3,300MHz):δ10.12(s,1H),7.74-7.17(m,
4H),4.094(m,3H)；13C NMR(CDCl3,75MHz):δ179.1,128.3,120.9,119.4,119.3,110.3,
31.5；19F NMR(CDCl3,282MHz):δ-160.8；MS(TOF)calcd for C10H8NOF[M+1]+:178.0668；
found:178.0676。
Embodiment 3：The fluoro- 1- Ethyl-indoles -2- formaldehyde of 3- (compound 3, route 1-3)
A 25mL round-bottomed flasks are taken, 1- Ethyl-indole -2- methanol 35.0mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of chloromethyl -4- are stirred at 25 DEG C
It mixes 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- Ethyl-indoles -2- formaldehyde of 3-
27.6mg, yield 72%.
1H NMR(CDCl3,300MHz):δ 10.11 (s, 1H), 7.74-7.15 (m, 4H), 4.58 (q, J=6.0Hz, 2H),
1.39 (d, J=12.0Hz, 3H)；13C NMR(CDCl3,75MHz):δ178.6,128.2,128.1,120.83,120.81,
119.5,119.4,110.3,110.2,39.7,15.5。
Embodiment 4：The fluoro- 1- isopropyls of 3--indoles -2- formaldehyde (compound 4, route 1-4)
A 25mL round-bottomed flasks are taken, 1- isopropyls-indoles -2- methanol 37.8mg, acetonitrile 8mL, potassium carbonate 34.5mg is added,
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 1- chloromethyls -4- are at 25 DEG C
Stirring 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- isopropyls of 3--indoles -2- formaldehyde
34mg, yield 83%.
Yellow solid, fusing point：69-70℃；1H NMR(CDCl3,300MHz):δ10.08(s,1H),7.74-7.10(m,
4H),5.68-5.50(m,1H),1.64(s,3H),1.60(s,3H)；13C NMR(CDCl3,75MHz):δ178.3,127.8,
120.6,119.5,112.7,48.2,21.4；19F NMR(CDCl3,282MHz):δ-160.7；MS(TOF)calcd for
C12H12NOF[M+1]+:205.0976；found:205.0981.
Embodiment 5：The fluoro- 1- of 3- (2- fluoro ethyls)-indoles -2- formaldehyde (compound 5, route 1-5)
It takes a 25mL round-bottomed flasks, 1- (2- fluoro ethyls)-indoles -2- methanol 38.6mg, acetonitrile 8mL, potassium carbonate is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 34.5mg, 1- chloromethyl -4- exist
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- of 3- (2- fluoro ethyls)-
Indoles -2- formaldehyde 34.4mg, yield 82%.
White solid, fusing point：80-81℃；1H NMR(CDCl3,300MHz):δ10.10(s,1H),7.74-7.18(m,
4H),4.86-4.65(m,4H)；13C NMR(CDCl3,75MHz):δ178.9,128.8,121.3,119.3,119.2,110.9,
84.5 (d, J=170.3Hz), 45.3 (d, J=21.0Hz)；19F NMR(CDCl3,282MHz):δ-159.8,-111.2；MS
(TOF)calcd for C11H9NOF[M+1]+:210.0770；found:210.0772.
Embodiment 6：The fluoro- 1- of 3- (3- cyanopropyls)-indoles -2- formaldehyde (compound 6, route 1-6)
It takes a 25mL round-bottomed flasks, 1- (3- cyanopropyls)-indoles -2- methanol 42.8mg, acetonitrile 8mL, potassium carbonate is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 34.5mg, 1- chloromethyl -4- exist
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- of 3- (3- chloropropyls)-
Indoles -2- formaldehyde 37mg, yield 80%.
Grey grease,1H NMR(CDCl3,300MHz):δ10.08(s,1H),7.76-7.20(m,4H),4.63(t,J
=6.0Hz, 2H), 2.40 (t, J=6.0Hz, 2H), 2.21-2.16 (m, 2H)；13C NMR(CDCl3,75MHz):δ178.7,
129.0,121.4,119.7,119.0,114.3,110.1,43.1,26.4,14.6；19F NMR(CDCl3,282MHz):δ-
159.8；MS(TOF)calcd for C13H11N2OF[M+1]+:231.0966；found:231.0976.
Embodiment 7：The fluoro- 1- Benzyl-indols -2- formaldehyde of 3- (compound 7, route 1-7)
A 25mL round-bottomed flasks are taken, 1- Benzyl-indol -2- methanol 47.4mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of chloromethyl -4- are stirred at 25 DEG C
It mixes 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- Benzyl-indols -2- formaldehyde of 3-
43.2mg, yield 85%.
Gray solid, fusing point：81-82℃；1H NMR(CDCl3,300MHz):δ10.15(s,1H),7.79-7.14(m,
9H),5.77(s,2H)；13C NMR(CDCl3,75MHz):δ178.8,137.5,128.7,127.6,126.7,121.3,
119.5,111.0,110.9,47.9；19F NMR(CDCl3,282MHz):δ-160.5；MS(TOF)calcd for C16H12NOF
[M+1]+:254.0975；found:254.0971.
Embodiment 8：The fluoro- 1- propargyls of 3--indoles -2- formaldehyde (compound 8, route 1-8)
A 25mL round-bottomed flasks are taken, 1- propargyls-indoles -2- methanol 37mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of chloromethyl -4- are stirred at 25 DEG C
It mixes 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- propargyls of 3--indoles -2- formaldehyde
29.5mg, yield 73%.
Gray solid, fusing point：77-78℃；1H NMR(CDCl3,300MHz):δ10.12(s,1H),7.77-7.22(m,
4H), 5.39 (d, J=3.0Hz, 2H), 2.30 (t, J=3.0Hz, 1H)；13C NMR(CDCl3,75MHz):δ178.9,128.8,
124.8,121.6,119.6,110.8,72.8,33.9；19F NMR(CDCl3,282MHz):δ-160.1；MS(TOF)calcd
for C12H8NOF[M+1]+:202.0668；found:202.0676.
Embodiment 9：The fluoro- 1- allyls of 3--indoles -2- formaldehyde (compound 9, route 1-9)
A 25mL round-bottomed flasks are taken, 1- allyls-indoles -2- methanol 39mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of chloromethyl -4- are stirred at 25 DEG C
It mixes 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- allyls of 3--indoles -2- formaldehyde
33.5mg, yield 82%.
1H NMR(CDCl3,300MHz):δ10.10(s,1H),7.75-7.17(m,4H),6.03-5.91(m,1H),
5.15-5.12(m,3H),4.99-4.92(m,1H)；13C NMR(CDCl3,75MHz):δ178.7,133.6,128.4,121.0,
119.4,116.6,110.7,46.7；19F NMR(CDCl3,282MHz):δ-160.8.MS(TOF)calcd for C12H10NOF
[M+1]+:204.0769；found:204.0771.
Embodiment 10：The fluoro- 1- of 3- (3- methyl-2-butenes)-indoles -2- formaldehyde (compound 10, route 1-10)
It takes a 25mL round-bottomed flasks, 1- (3- methyl-2-butenes)-indoles -2- methanol 43mg, acetonitrile 8mL, potassium carbonate is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 34.5mg, 1- chloromethyl -4- exist
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- of 3- (3- methyl -2- fourths
Alkene)-indoles -2- formaldehyde 29.7mg, yield 64%.
Grey grease；1H NMR(CDCl3,300MHz):δ10.11(s,1H),7.57-6.84(m,4H),5.24-5.13
(m, 2H), 4.32 (d, J=6.0Hz, 1H), 1.84 (s, 3H), 1.76 (s, 3H)；13C NMR(CDCl3,75MHz):δ178.8,
138.3,133.4,124.7,123.7,116.8,110.2,38.3,25.6,18.2；19F NMR(CDCl3,282MHz):δ-
112.2；MS(TOF)calcd for C14H14NOF[M+1]+:232.1178；found:232.1169.
Embodiment 11：The fluoro- 1- of 3- (2- methyl-allyls)-indoles -2- formaldehyde (compound 11, route 1-11)
It takes a 25mL round-bottomed flasks, 1- (2- methyl-allyls)-indoles -2- methanol 40.2mg, acetonitrile 8mL, carbonic acid is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of potassium 34.5mg, 1- chloromethyl -4-
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- of 3- (2- methyl-alkene
Propyl)-indoles -2- formaldehyde 28.3mg, yield 65%.
Grey grease；1H NMR(CDCl3,300MHz):δ10.10(s,1H),7.75-7.17(m,4H),5.08(s,
2H), 4.83 (d, J=6.0Hz, 1H), 4.44 (s, 1H), 1.72 (s, 3H)；13C NMR(CDCl3,75MHz):δ178.7,
155.3,141.1,136.9,128.3,121.1,119.3,111.1,49.9,19.9；19F NMR(CDCl3,282MHz):δ-
160.5；MS(TOF)calcd for C13H12NOF[M+1]+:218.0964；found:218.0969.
Embodiment 12：The fluoro- 1- of 3- (2- Phenyl-allyls)-indoles -2- formaldehyde (compound 12, route 1-12)
It takes a 25mL round-bottomed flasks, 1- (2- Phenyl-allyls)-indoles -2- methanol 52.6mg, acetonitrile 8mL, carbonic acid is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of potassium 34.5mg, 1- chloromethyl -4-
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- of 3- (2- phenyl-alkene
Propyl)-indoles -2- formaldehyde 45.9mg, yield 82%.
White solid, fusing point：77-78℃；1H NMR(CDCl3,300MHz):δ10.14(s,1H),7.77-7.18(m,
9H), 5.57 (t, J=3.0Hz, 2H), 5.29 (d, J=3.0Hz, 1H), 4.41 (s, 1H)；13C NMR(CDCl3,75MHz):δ
178.7,144.1,138.9,128.5,128.2,126.3,121.2,119.4,112.0,111.0,48.1；19F NMR
(CDCl3,282MHz):δ-160.5；MS(TOF)calcd for C18H14NOF[M+1]+:280.1138；found:
280.1146。
Embodiment 13：The fluoro- 1- phenyl-indoles -2- formaldehyde of 3- (compound 13, route 1-13)
A 25mL round-bottomed flasks are taken, 1- phenyl-indole -2- methanol 44.6mg, acetonitrile 8mL, potassium carbonate 34.5mg, 1- is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of chloromethyl -4- are stirred at 25 DEG C
It mixes 30 minutes.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- phenyl-indoles -2- formaldehyde of 3-
37.9mg, yield 79%.
1H NMR(CDCl3,300MHz):δ10.05(s,1H),7.82-7.16(m,9H)；13C NMR(CDCl3,75MHz):
δ178.2,142.0,137.9,129.4,128.6,128.5,127.9,121.8,119.3,111.6；19F NMR(CDCl3,
282MHz):δ-159.2；MS(TOF)calcd for C15H10NOF[M+1]+:240.0768；found:240.0764.
Embodiment 14：3,5- bis- fluoro- 1- hydrogen-indoles -2- formaldehyde (compound 14, route 1-14)
It takes a 25mL round-bottomed flasks, the fluoro- 1- hydrogen of 5--indoles -2- methanol 33.0mg, acetonitrile 8mL, potassium carbonate is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 34.5mg, 1- chloromethyl -4- exist
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains 3,5-, bis- fluoro- 1- hydrogen-indoles-
2- formaldehyde 24.0mg, yield 66%.
Gray solid, fusing point：199-200℃；1H NMR(CDCl3,300MHz):δ10.04(s,1H),8.81(s,1H),
7.39-7.18(m,3H)；13C NMR(CDCl3,75MHz):δ131.7,121.4,118.4,118.1,115.1,114.3,
103.9,103.6；19F NMR(CDCl3,282MHz):δ-160.8,-120.6；MS(TOF)calcd for C9H5NOF2[M+1
]+:182.0417；found:182.0422.
Embodiment 15：The fluoro- 1- hydrogen of the bromo- 3- of 5--indoles -2- formaldehyde (compound 15, route 1-15)
It takes a 25mL round-bottomed flasks, the bromo- 1- hydrogen of 5--indoles -2- methanol 45.0mg, acetonitrile 8mL, potassium carbonate is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 34.5mg, 1- chloromethyl -4- exist
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- hydrogen-Yin of the bromo- 3- of 5-
Diindyl -2- formaldehyde 32.4mg, yield 67%.
Yellow solid, fusing point：191-92℃；1H NMR(DMSO-d,300MHz):δ12.04(s,1H),9.99(s,1H),
7.94-7.36(m,3H)；13C NMR(DMSO-d,75MHz):δ179.6,133.7,133.6,130.8,128.4,121.2,
116.2,113.7；19F NMR(DMSO-d,282MHz):δ-162.6.MS(TOF)calcd for C9H5NOFBr[M+1]+:
241.9552；found:241.9544.
Embodiment 16：The fluoro- 1- hydrogen of 5- methyl -3--indoles -2- formaldehyde (compound 16, route 1-16)
It takes a 25mL round-bottomed flasks, the bromo- 1- hydrogen of 5--indoles -2- methanol 45.0mg, acetonitrile 8mL, potassium carbonate is added
Fluoro- two (tetrafluoro boric acid) salt (fluorine reagent) 177.1mg of 1,4- diazabicyclos [2.2.2] octane of 34.5mg, 1- chloromethyl -4- exist
It is stirred 30 minutes at 25 DEG C.Rotary evaporation removes solvent after reaction, and column chromatography for separation obtains the fluoro- 1- hydrogen-Yin of 5- methyl -3-
Diindyl -2- formaldehyde 27.1mg, yield 76%.
Gray solid, fusing point：167-168℃；1H NMR(CDCl3,300MHz):δ10.01(s,1H),8.96(s,1H),
7.50-7.23(m,3H),2.46(s,3H)；13C NMR(CDCl3,75MHz):δ178.4,134.0,130.9,120.3,
118.3,117.1,112.6,21.4；19F NMR(CDCl3,282MHz):δ-160.8；MS(TOF)calcd for MS(TOF)
calcd for C10H8NOF[M+1]+:178.0659；found:178.0656.
Some specific embodiments are described in detail herein, however this is intended only as saying goal of the invention example
It is bright, the range without limiting following claims.It should be appreciated that the different substitutions of concrete scheme described herein, change and
Modification is all without departing from the connotation and extension defined in the claims in the present invention, to belong to the application hair claimed
Bright range.
Claims (10)
1. a kind of preparation method of 3- fluoro-indole-2-carbonyl compound comprising：It is deposited in fluoro reagent, solvent, additive
Under the conditions, fluoro oxidation reaction is carried out to 3- hydrogen-indoles -2- alcohol compounds, obtains corresponding 3- fluoro-indoles -2-
Carbonyls, wherein：
The fluoro reagent be fluoro- two (tetrafluoro boric acid) salt of 1,4- diazabicyclos [2.2.2] octane of 1- chloromethyls -4- and/or
The fluoro- 4- methyl-1s of 1-, two (tetrafluoro boric acid) salt of 4- diazabicyclos [2.2.2] octane；
The solvent is 1,2- dichloroethanes, dichloromethane, ethyl acetate, acetone, acetonitrile, toluene, pentane, n-hexane, just
Heptane, pentamethylene, hexamethylene, ether, tetrahydrofuran, 1,4- dioxane, t-butyl methyl ether, N,N-dimethylformamide,
The mixture of one or more of dimethyl sulfoxide (DMSO), methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol and water；
The additive is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, saleratus, caesium bicarbonate
Mixture；
The 3- hydrogen-indoles -2- alcohol compounds have structure shown in formula (Ι Ι Ι)：
Wherein：The 3- hydrogen-the one kind of indoles -2- alcohol compounds in following compound：1- hydrogen-indoles -2- methanol, 1-
Methvl-indole -2- methanol, 1- Ethyl-indole -2- methanol, 1- isopropyls-indoles -2- methanol, 1- (2- fluoro ethyls)-indoles -2-
Methanol, 1- (3- cyanopropyls)-indoles -2- methanol, 1- Benzyl-indol -2- methanol, 1- phenyl-indole -2- methanol, 1- alkynes third
Base-indoles -2- methanol, 1- allyls-indoles -2- methanol, 1- (3- methyl-2-butenes)-indoles -2- methanol, 1- (2- methyl -
Allyl)-indoles -2- methanol, 1- (2- Phenyl-allyls)-indoles -2- methanol, the fluoro- 1- hydrogen of 5--indoles -2- methanol, 5- be bromo-
1- hydrogen-indoles-2- methanol, 5- methyl-1-hydrogen-indoles-2- methanol.
2. according to the method described in claim 1, the wherein described fluoro reagent is the fluoro- Isosorbide-5-Nitrae-diazabicyclos of 1- chloromethyls -4-
[2.2.2] octane two (tetrafluoro boric acid) salt.
3. according to the method described in claim 1, the wherein described solvent is acetonitrile.
4. according to the method described in claim 1, the temperature of the wherein described Replacement of Oxygen by Fluorineization reaction is -80 DEG C~200 DEG C.
5. according to the method described in claim 4, the wherein described reaction temperature is 25 DEG C.
6. according to the method described in claim 1, wherein described 3- fluoro-indoles -2- alcohol compounds and the fluoro reagent
Molar ratio be 1:0.1 to 1:10.
7. according to the method described in claim 6, the wherein described molar ratio is 1:2.5 or 1:3.2.
8. according to the method described in claim 1, a concentration of the 0.001 of wherein described 3- hydrogen-indoles -2- alcohol compounds~
10.0M。
9. according to the method described in claim 8, the wherein described a concentration of 0.25M.
10. according to the method described in claim 1, the reaction time of the wherein described Replacement of Oxygen by Fluorineization reaction is 0.01~24 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610173119.8A CN105732470B (en) | 2016-03-23 | 2016-03-23 | The high efficiency preparation method of 3- fluoro-indole-2-carbonyl compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610173119.8A CN105732470B (en) | 2016-03-23 | 2016-03-23 | The high efficiency preparation method of 3- fluoro-indole-2-carbonyl compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105732470A CN105732470A (en) | 2016-07-06 |
| CN105732470B true CN105732470B (en) | 2018-07-31 |
Family
ID=56251380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610173119.8A Active CN105732470B (en) | 2016-03-23 | 2016-03-23 | The high efficiency preparation method of 3- fluoro-indole-2-carbonyl compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105732470B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098506A (en) * | 2014-07-15 | 2014-10-15 | 华东理工大学 | Preparation method and application of benzo[c] carbazole amide compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008059238A1 (en) * | 2006-11-17 | 2008-05-22 | Astrazeneca Ab | Benzenesulfonamide compounds as edg-1 antagonists useful in the treatment of cancer |
| US20080227823A1 (en) * | 2007-03-12 | 2008-09-18 | Hassan Pajouhesh | Amide derivatives as calcium channel blockers |
-
2016
- 2016-03-23 CN CN201610173119.8A patent/CN105732470B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098506A (en) * | 2014-07-15 | 2014-10-15 | 华东理工大学 | Preparation method and application of benzo[c] carbazole amide compound |
Non-Patent Citations (1)
| Title |
|---|
| Recent Advances in the Application of SelectfluorTM F-TEDA-BF4 as a Versatile Mediator or Catalyst in Organic Synthesis;Stojan Stavber;《Molecules》;20110729;第16卷;6432-6464 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105732470A (en) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Inamoto et al. | A copper-based catalytic system for carboxylation of terminal alkynes: synthesis of alkyl 2-alkynoates | |
| KR20120050953A (en) | Method for preparing sulfone or sulfoxide compound | |
| CN104520275B (en) | For preparation method and the intermediate product of integrase inhibitor | |
| CN102718712B (en) | Preparation method of 3-difluoro-methyl pyrazole-4-carboxylic acid and 3-trifluoro-methyl pyrazole-4-carboxylic acid | |
| KR102599163B1 (en) | Method for producing benzoylformic acid compounds and pyridazine compounds | |
| CN112573978B (en) | High-efficiency halogenation synthesis method of aryl halide | |
| Khalili et al. | KF/Al 2 O 3: an efficient solid heterogeneous base catalyst in one-pot synthesis of benzimidazoles and bis-benzimidazoles at room temperature | |
| CN107540598B (en) | Method for preparing N-difluoromethylthio phthalimide compound | |
| CN104649857B (en) | Trifluoromethyl-substituted azide, amine and heterocycle compounds and preparing methods thereof | |
| CN105732470B (en) | The high efficiency preparation method of 3- fluoro-indole-2-carbonyl compound | |
| Fan et al. | Generation of 1-(trifluoromethyl) isoquinolines via a copper-catalyzed reaction of isoquinoline-N-oxide with Togni reagent | |
| CN106928121B (en) | High-efficiency preparation method of 3-substituted-benzo five-membered heterocycle-2-carbonyl compound | |
| Zook et al. | A concise synthesis of the HIV-protease inhibitor nelfinavir via an unusual tetrahydrofuran rearrangement | |
| CN109415383A (en) | Prepare the method and its intermediate of eribulin | |
| JP6683693B2 (en) | Process for preparing halo-substituted benzene | |
| CN105384668B (en) | The method for being used to prepare ether compound | |
| JP5583118B2 (en) | Method for producing isothiazole derivative | |
| CN110183341A (en) | 1,2- dicarbapentaborane class compound and its synthetic method | |
| CN107383057A (en) | Imidazoles [4,5 e] thiophene [2,3 b] pyridine derivatives with the double fluorescent functionals of solid-liquid and preparation method thereof | |
| KR20180068417A (en) | N-sulfonyl amidine synthesis via three-component coupling reaction using heterogeneous copper catalyst | |
| WO2016095662A1 (en) | Method for preparing (2s,3r,4r)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-d-ribose-γ-lactone and intermediate thereof | |
| ES2760598T3 (en) | A process for the preparation of bis (chloromethyl) dichlorosilane and bis (chloromethyl) (aryl) chlorosilane | |
| CN105001042A (en) | Preparing method for benzenyl trifluoride class compound | |
| JPWO2009069311A1 (en) | Method for producing 3-mercaptoaniline compound | |
| KR101006737B1 (en) | Process for the preparation of 2-sulfonyliminoindoline using Cu catalyst |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |