CN105859620A - 6-trichloromethyl phenanthridine compound and preparation method and application thereof - Google Patents
6-trichloromethyl phenanthridine compound and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
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Abstract
The invention relates to a 6-trichloromethyl phenanthridine compound and a preparation method thereof and application of synthesizing a phenanthridine derivative with the biological activity by the compound serving as an intermediate, and belongs to the field of synthesis of compounds. The 6-trichloromethyl phenanthridine compound is characterized in that the compound has the structure as shown in the general formula I which is shown in the description, wherein R<1> is selected from H or a halogen or C1-C5 alkyl groups or a cyano group or trifluoromethyl or C1-C4 ester groups or C1-C4 alkoxy groups or C1-C4 acyl groups, and R<2> is selected from H or C1-C5 alkyl groups or C1-C4 ester groups or a halogen or a cyano group or trifluoromethyl or C1-C4 alkoxy groups or C1-C4 acyl groups. The 6-trichloromethyl phenanthridine derivative can be conveniently synthesized into the phenanthridine derivative substituted with various functional groups such as methyl and carboxyl through a trichloromethyl group which is prone to derivatization, and rapid synthesis of the phenanthridine derivative with various structures is promoted.
Description
Technical field
The present invention relates to class 6-trichloromethyl phenanthridines compounds and preparation method thereof, and this compounds is as centre
Body synthesis has the application of bioactive phenanthridines analog derivative, belongs to compou nd synthesis field.
Background technology
Phenanthridines is a very important compound of class at organic chemistry and medicinal chemistry art.Because having extraordinary
Biological activity and pharmaceutically active, such as active anticancer, anti-tumor activity, antiviral activity, antifungal activity, spreading out of phenanthridines class
Biology appears widely in nature and (J.Am.Chem.Soc.2014,136,2583 in some medicines；
Bioorg.Med.Chem.Lett.2014,24,2712；Bioorg.Med.Chem.Lett.2013,23,6805；
Med.Res.Rev.2001,21,61；Med.Chem.2012,55,9693).Also have some phenanthridines to have photoelectric activity and
Occur in field of functional materials (J.Am.Chem.Soc.2008,130,7182；J.Phys.Chem.B.2005,109,8701).
Therefore synthesis phenanthridines compounds is significant.
In recent years, the method for intramolecular cyclization after many seminars pass in succession through the different cyanobiphenyls of 2-and free radical addition
Synthesize the phenanthridines with different substituents.Promote that phenylboronic acid compound generates corresponding to isonitrile cyclization by manganese salt
6 substituted phenanthridines report relatively early (Angew.Chem.Int.Ed., 2012,51,11,363 11366), such synthesis afterwards
Method causes to be paid close attention to widely, and a series of phenanthridines compounds can pass through to divide with suitable precursor and the different cyanobiphenyls of 2-
The method synthesis of sub-intramolecular cyclization.According to this strategy, the replacement that the phenanthridine derivatives needs of 6 different substituents are different to be synthesized
Based precursor, such as: carboxylic acid, amine, ester, aldehyde, hydrazine etc..At present, also lack and be readily synthesized various official by being prone to the group of derivatization
The method that can roll into a ball substituted phenanthridine derivatives, this is unfavorable for the phenanthridine derivatives of Fast back-projection algorithm various structures.
Trichloromethyl aromatic compound is important synthetic intermediate, can be further converted to trifluoromethyl
(CN102491906A), carboxyl or amide (Chem.Pharm.Bull.1975,23,3170-3177), dichloromethyl
(Tetrahedron 2014,70,4540-4546), thiazolinyl (Tetrahedron Lett.2004,45,3039-3042), virtue acyl
Base (Res.Chem.Intermed.2015,41,6433-6441), methyl (Chem.Pharm.Bull.1975,23,3170-
3177) substituted aromatic compound.Therefore, 6-trichloromethyl phenanthridines compounds can synthesize various 6 as intermediate
Substituted phenanthridine derivatives, such as: have DNA/RNA embed activity 6-methyl phenanthridines compounds (Chem.Commun.2005,
2561-2563), the phenanthridine derivatives (J.Chem.Soc.1950,311-317) of trypanocidal activity, or there is anti-tumor activity
Phenanthridine derivatives (Anti-Cancer Drug Design 1999,14 (3), 281-299).
But, by the method for 2-different cyanobiphenyls intramolecular cyclization synthesize phenanthridines compounds need functional group precursor,
Coupling between the conditions such as initiator, reaction temperature, solvent, difficulty is relatively big, there is presently no a kind of blanket method.Cause
This, also do not have the report of 6-trichloromethyl phenanthridines compounds.
Summary of the invention
It is an object of the invention to provide class 6-trichloromethyl phenanthridine derivatives and preparation method thereof.This compounds is permissible
As intermediate, for synthesis, there is bioactive phenanthridine derivatives.
One class 6-trichloromethyl phenanthridines compounds, this compounds has a structure as shown in following formula I:
Wherein,
R1Selected from H, halogen, C1～C5 alkyl, cyano group, trifluoromethyl, C1～C4 ester group, C1～C4 alkoxyl, C1～C4
Acyl group；
R2Selected from H, C1～C5 alkyl, C1～C4 ester group, halogen, cyano group, trifluoromethyl, C1～C4 alkoxyl, C1～C4
Acyl group.
Term used herein " alkyl " includes straight chained alkyl and branched alkyl.As mentioned by single alkyl such as " propyl group ",
The most only refer in particular to straight chained alkyl, as mentioned by single branched alkyl such as " isopropyl ", the most only refer in particular to branched alkyl.Such as, C1～C5 alkane
Base is straight or branched alkyl group, such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, different
Amyl group, tertiary pentyl.
Term used herein " halogen " includes fluorine, chlorine, bromine, iodine.
C1～C4 ester group specifically described herein is the group with following structure :-COOR, and wherein, R is C1～C3 alkyl.
C1～C4 acyl group specifically described herein is the group with following structure :-COR, and wherein, R is C1～C3 alkyl.
C1～C4 alkoxyl specifically described herein is the group with following structure :-O-M2, wherein, M2For C1～C4 alkyl,
Such as methoxyl group, ethyoxyl, propoxyl group, butoxy.
In formula I of the present invention, R1Replace for 1-, 2-, 3-or 4-position；R2Replace for 7-, 8-, 9-or 10-position.
6-trichloromethyl phenanthridines compounds of the present invention, the most described R1For methyl, ethyl, isopropyl, tertiary fourth
Base ,-COOCH3、-COOC2H5、-COOCH(CH3)2, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, formoxyl, acetyl group.
6-trichloromethyl phenanthridines compounds of the present invention, the most described R2For methyl, ethyl, isopropyl, tertiary fourth
Base ,-COOCH3、-COOC2H5、-COOCH(CH3)2, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, formoxyl, acetyl group.
It is a further object of the present invention to provide the preparation method of above-mentioned 6-trichloromethyl phenanthridines compounds.This preparation method
With cheap, commercially available radical initiator directly as initiator, with 2-isonitrile base biphenyl compound as raw material, efficient, simple
Just, the economic substituted phenanthridine derivatives of synthesis trichloromethyl.
With 2-isonitrile base biphenyl compound (II) and carbon tetrachloride as raw material, under the effect of initiator, react
Obtain described 6-trichloromethyl phenanthridine derivatives, particularly as follows:
With the compound with structure shown in formula II and carbon tetrachloride as raw material, under the effect of initiator, 50 DEG C～
110 DEG C of reactions 6～24h, obtain described 6-trichloromethyl phenanthridine derivatives:
Wherein,
R1Selected from H, halogen, C1～C5 alkyl, cyano group, trifluoromethyl, C1～C4 ester group, C1～C4 alkoxyl, C1～C4
Acyl group；
R2Selected from H, C1～C5 alkyl, C1～C4 ester group, halogen, cyano group, trifluoromethyl, C1～C4 alkoxyl, C1～C4
Acyl group.
In all technical schemes of preparation method of 6-trichloromethyl phenanthridines compounds of the present invention, the most described R1For
Methyl, ethyl, isopropyl, the tert-butyl group ,-COOCH3、-COOC2H5、-COOCH(CH3)2, methoxyl group, ethyoxyl, isopropoxy, uncle
Butoxy, formoxyl, acetyl group.
In all technical schemes of preparation method of 6-trichloromethyl phenanthridines compounds of the present invention, the most described R2For
Methyl, ethyl, isopropyl, the tert-butyl group ,-COOCH3、-COOC2H5、-COOCH(CH3)2, methoxyl group, ethyoxyl, isopropoxy, uncle
Butoxy, formoxyl, acetyl group.
Preferred described initiation in all technical schemes of preparation method of 6-trichloromethyl phenanthridines compounds of the present invention
Agent is that tert-butyl hydroperoxide (TBHP), cumyl peroxide (DCP), di-tert-butyl peroxide (DTBP), azo two are different
At least one in butyronitrile (AIBN), benzoyl peroxide (BPO).
In all technical schemes of preparation method of 6-trichloromethyl phenanthridines compounds of the present invention preferably described in have
The compound of structure shown in formula II is 1:0.6～1:2 with the ratio of the amount of the material of initiator, further, it is preferable to be 1:
1.2。
The preparation method of 6-trichloromethyl phenanthridines compounds of the present invention can be carried out under the conditions of alkalescence or non-alkaline.
When reacting in the basic conditions, add in reaction dissolvent with alkali compounds for raw material, wherein said alkali compounds
It is preferably at least one in sodium hydroxide, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium acetate, Feldalat NM.Of the present invention
In all technical schemes of preparation method of 6-trichloromethyl phenanthridines compounds preferably described in there is the change of structure shown in formula II
Compound is 1:0～1:2 (not comprising 0) with the ratio of the amount of the material of alkali compounds, further, it is preferable to be 1:2.
Carbon tetrachloride of the present invention is used as reactant and solvent, and its consumption meets reaction and requires, is preferably described
The ratio with the compound of structure shown in formula II and the amount of carbon tetrachloride is 1mmol:2～6mL.
The preparation method of 6-trichloromethyl phenanthridines compounds of the present invention is preferably back flow reaction, particularly as follows: will
Have during shown in formula II, the compound of structure, carbon tetrachloride and initiator are placed at the container with counterflow condition, in 50 DEG C
～110 DEG C of reactions 6～24h.
Further, described reaction is preferably carried out at reflux temperature～110 DEG C；Further, for easy to operate, this
Invent described reaction to carry out at a reflux temperature.
When described reaction temperature is higher than reflux temperature, reaction of the present invention is preferably carried out in pressure pipe.
Preparation method of the present invention also includes the step of post processing, particularly as follows: remove solvent, extract, wash, be dried and
The step of chromatography.
Further, the step of described post processing includes: removing solvent, profit is extracted with ethyl acetate organic facies, is associated with
Machine saturated sodium bicarbonate solution washs, organic facies anhydrous Na2SO4It is dried, obtains target compound by column chromatography.
It is yet another object of the invention to provide described 6-trichloromethyl phenanthridines compounds to spread out as intermediate synthesis phenanthridines
Application in biology, especially it has the application in bioactive phenanthridine derivatives as intermediate synthesis.
One class technical scheme is: a kind of using 6-trichloromethyl phenanthridines compounds as intermediate synthesis phenanthridine derivatives
Method, is to be placed under reductive condition by 6-trichloromethyl phenanthridines compounds, carries out dechlorination reaction, obtain 6-methyl phenanthridines and spread out
Biology, described 6-trichloromethyl phenanthridines class has a structure as shown in following formula I:
Wherein,
R1Selected from H, halogen, C1～C5 alkyl, cyano group, trifluoromethyl, C1～C4 ester group, C1～C4 alkoxyl, C1～C4
Acyl group；
R2Selected from H, C1～C5 alkyl, C1～C4 ester group, halogen, cyano group, trifluoromethyl, C1～C4 alkoxyl, C1～C4
Acyl group.
Another kind of technical scheme is: one synthesizes phenanthridine derivatives using 6-trichloromethyl phenanthridines compounds as intermediate
Method, be that 6-trichloromethyl phenanthridines compounds is placed in acid condition, be hydrolyzed reaction, obtains carboxylic acid derivates,
Described 6-trichloromethyl phenanthridines class has a structure as shown in following formula I:
Wherein,
R1Selected from H, halogen, C1～C5 alkyl, cyano group, trifluoromethyl, C1～C4 ester group, C1～C4 alkoxyl, C1～C4
Acyl group；
R2Selected from H, C1～C5 alkyl, C1～C4 ester group, halogen, cyano group, trifluoromethyl, C1～C4 alkoxyl, C1～C4
Acyl group.
One exemplary technical scheme of the present invention is:
The preparation method of 6-methyl-8-methoxyl group phenanthridines, with 10%Pd/C (commercially available) as catalyst, by 8-methoxy
Base-6-trichloromethyl phenanthridines under room temperature normal pressure, hydrogenating reduction dechlorination, obtain 6-methyl-8-methoxyl group phenanthridines.
6-methylphenanthrene piperidine derivatives has good DNA/RNA and embeds activity (Chem.Commun.2005,2561-
2563)。
Another exemplary technical scheme of the present invention is:
The preparation method of phenanthridines-6-carboxylic acid, is placed in 6-trichloromethyl phenanthridines in sulphuric acid, hydrolyzes at 130 DEG C～150 DEG C,
Phenanthridines-6-the carboxylic acid obtained.
6-trichloromethyl phenanthridines hydrolyzes, and the phenanthridines-6-carboxylic acid obtained can be used for synthesizing and has the phenanthridines of anti-tumor activity and spread out
Biological (Anti-Cancer Drug Design 1999,14 (3), 281-299).
The invention have the benefit that and the invention provides class 6-trichloromethyl phenanthridine derivatives and preparation method thereof,
By being prone to the trichloromethyl group of derivatization, various functional group (such as: methyl, carboxyl) substituted phenanthridines can be readily synthesized
Derivant, this is conducive to the Fast back-projection algorithm of phenanthridine derivatives of various structures.
Detailed description of the invention
Following non-limiting example can make those of ordinary skill in the art that the present invention be more fully understood, but not with
Any mode limits the present invention.
Test method described in following embodiment, if no special instructions, is conventional method；Described reagent and material, as
Without specified otherwise, the most commercially obtain.
Table 1 below lists the concrete structure of substituent group in general structure (II).
Table 1
Table 2 list the present invention synthesis the structure of particular compound 1～17, physical property and1H NMR data, but this
Invention is not limited in these compounds.
Table 2
The preparation (compound 1) of embodiment 1 8-methoxyl group-6-trichloromethyl phenanthridines
In the 25mL Schlenk bottle of argon shield, 2-isonitrile base-4'-methoxyl group-1,1'-connection it is sequentially added under room temperature
Benzene (105mg, 0.50mmol), 2-isonitrile base-4'-methoxyl group-1, the BPO of the amount of 1'-biphenyl material 1.2 times (145.2mg,
0.6mmol), 2-isonitrile base-4'-methoxyl group-1, the AcONa (82.0mg, 1mmol) of the amount of 1'-biphenyl material 2 times, CCl4
(2mL), back flow reaction 16h.Post processing removes solvent by Rotary Evaporators, adds 20mL saturated aqueous common salt, uses acetic acid second
Ester extracts 3 times (using 20mL ethyl acetate) every time, merges the washing of organic facies saturated sodium bicarbonate solution and (uses for 2 times every time
30mL saturated sodium bicarbonate solution), organic facies anhydrous Na2SO4It is dried, obtains target compound by column chromatography, chromatographic column
Inserts is silica gel, and eluant is petroleum ether: ethyl acetate (10:1), separation yield 71%.
The preparation (compound 2) of embodiment 2 6-trichloromethyl phenanthridines
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 2-isonitrile of the amount of commaterial
Base-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 78%.
The preparation (compound 3) of embodiment 3 6-trichloromethyl phenanthridines-8-carboxylate methyl ester
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 2'-isonitrile of the amount of commaterial
Outside base-(1,1'-biphenyl)-4-carboxylate methyl ester, carry out by method similarly to Example 1, it is thus achieved that target compound separation yield
63%.
The preparation (compound 4) of embodiment 4 8-chloro-6-trichloromethyl phenanthridines
The chloro-2-of 4'-of the amount except changing the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 into commaterial
Isonitrile base-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 58%.
The preparation (compound 5) of embodiment 5 6-trichloromethyl-8-formoxyl phenanthridines
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 changes into the 1-of the amount of commaterial, (2'-is different
Itrile group-(1,1'-biphenyl)-4-base) outside ethyl ketone, carry out by method similarly to Example 1, it is thus achieved that target compound separation yield
54%.
The preparation (compound 6) of the embodiment 6 8-tert-butyl group-6-(trichloromethyl) phenanthridines
The tertiary fourth of 4'-of the amount except changing the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 into commaterial
Base-2-isonitrile base-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 85%.
The preparation (compound 7) of embodiment 7 8-fluoro-6-(trichloromethyl) phenanthridines
The fluoro-2-of 4'-of the amount except changing the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 into commaterial
Isonitrile base-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 73%.
The preparation (compound 8) of embodiment 8 6-(trichloromethyl) phenanthridines-8-formonitrile HCN
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 2'-isonitrile of the amount of commaterial
Outside base-(1,1'-biphenyl)-4-formonitrile HCN, carry out by method similarly to Example 1, it is thus achieved that target compound separation yield 61%.
The preparation of embodiment 9 7-methoxyl group-6-(trichloromethyl) phenanthridines and 9-methoxyl group-6-(trichloromethyl) phenanthridines (is changed
Compound 9)
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 2-isonitrile of the amount of commaterial
Base-3'-methoxyl group-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield
65%, 7-methoxyl group-6-(trichloromethyl) phenanthridines and 9-methoxyl group-6-(trichloromethyl) phenanthridines ratio are 5:3.
The preparation (compound 10) of embodiment 10 2-chloro-6-(trichloromethyl) phenanthridines
The chloro-2-of 5-of the amount except changing the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 into commaterial
Isonitrile base-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 65%.
The preparation (compound 11) of embodiment 11 2-fluoro-6-(trichloromethyl) phenanthridines-8-formonitrile HCN
The 5'-of the amount except changing the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 into commaterial is fluoro-
Outside 2'-isonitrile base-(1,1'-biphenyl)-4-formonitrile HCN, carry out by method similarly to Example 1, it is thus achieved that target compound separates to be received
Rate 54%.
The preparation (compound 12) of embodiment 12 1-(2-methyl-6-(trichloromethyl) phenanthridines-8-base) ethyl ketone
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 changes into the 1-of the amount of commaterial, (2'-is different
Itrile group-5'-methyl-(1,1'-biphenyl)-4-base) outside ethyl ketone, carry out by method similarly to Example 1, it is thus achieved that target compound
Separation yield 66%.
The preparation (compound 13) of embodiment 13 2-methyl-6-(trichloromethyl) phenanthridines
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 2-isonitrile of the amount of commaterial
Base-5-methyl isophthalic acid, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 58%.
The preparation (compound 14) of embodiment 14 6-(trichloromethyl) phenanthridines-2-formonitrile HCN
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 6-isonitrile of the amount of commaterial
Outside base-(1,1'-biphenyl)-3-formonitrile HCN, carry out by method similarly to Example 1, it is thus achieved that target compound separation yield 74%.
The preparation (compound 15) of the chloro-2-of embodiment 15 8-fluoro-6-(trichloromethyl) phenanthridines
The chloro-5-of 4'-of the amount except changing the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 into commaterial
Fluoro-2-isonitrile base-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield 76%.
The preparation (compound 16) of embodiment 16 6-(trichloromethyl)-3-(trifluoromethyl) phenanthridines
Except the 2-isonitrile base-4'-methoxyl group-1,1'-biphenyl in embodiment 1 being changed into the 2-isonitrile of the amount of commaterial
Base-4-Trifluoromethyl-1, outside 1'-biphenyl, is carried out by method similarly to Example 1, it is thus achieved that target compound separation yield
74%.
The preparation (compound 17) of embodiment 17 1-(2-fluoro-6-(trichloromethyl) phenanthridines-8-base) ethyl ketone
Except the 2-isonitrile-4'-methoxyl group-1,1'-biphenyl in embodiment 1 changes into the 1-of the amount of commaterial, (5'-is fluoro-
2'-isonitrile-(1,1'-biphenyl)-4-base) outside ethyl ketone, carry out by method similarly to Example 1, it is thus achieved that target compound separates
Yield 60%.
The preparation (compound 1) of embodiment 18 8-methoxyl group-6-trichloromethyl phenanthridines
In addition to the AcONa in embodiment 1 is changed into the NaOH of the amount of commaterial, enter by method similarly to Example 1
OK, it is thus achieved that target compound proton magnetic yield 63% (with sym.-tetrachloroethane as internal standard).
The preparation (compound 1) of embodiment 19 8-methoxyl group-6-trichloromethyl phenanthridines
Except the AcONa in embodiment 1 being changed into the K of the amount of commaterial2CO3Outward, enter by method similarly to Example 1
OK, it is thus achieved that the proton magnetic yield 70% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 20 8-methoxyl group-6-trichloromethyl phenanthridines
Except the AcONa in embodiment 1 being changed into the NaHCO of the amount of commaterial3Outward, by method similarly to Example 1
Carry out, it is thus achieved that the proton magnetic yield 53% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 21 8-methoxyl group-6-trichloromethyl phenanthridines
In addition to the AcONa in embodiment 1 is changed into the MeONa of the amount of commaterial, enter by method similarly to Example 1
OK, it is thus achieved that the proton magnetic yield 67% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 22 8-methoxyl group-6-trichloromethyl phenanthridines
Except by the AcONa in embodiment 1 without in addition to, carry out by method similarly to Example 1, it is thus achieved that target chemical combination
The proton magnetic yield 64% (with 1,1,2,2-sym-tetrachloroethane as internal standard) of thing.
The preparation (compound 1) of embodiment 23 8-methoxyl group-6-trichloromethyl phenanthridines
In addition to the AcONa in embodiment 1 is changed into the t-BuOK of the amount of commaterial, by method similarly to Example 1
Carry out, it is thus achieved that the proton magnetic yield 69% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 24 8-methoxyl group-6-trichloromethyl phenanthridines
In addition to the AcONa in embodiment 1 is changed into the t-BuOK of the amount of commaterial, by method similarly to Example 1
Carry out, it is thus achieved that the proton magnetic yield 69% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 25 8-methoxyl group-6-trichloromethyl phenanthridines
In addition to the BPO in embodiment 1 is changed into the AIBN of the amount of commaterial, carry out by method similarly to Example 1,
Obtain the proton magnetic yield 60% (with 1,1,2,2-sym-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 26 8-methoxyl group-6-trichloromethyl phenanthridines
Except the BPO in embodiment 1 changes into the DTBP of the amount of commaterial, temperature is increased to outside 110 DEG C, presses and embodiment
1 same method is carried out, it is thus achieved that the proton magnetic yield 32% of target compound.
The preparation (compound 1) of embodiment 27 8-methoxyl group-6-trichloromethyl phenanthridines
Except the BPO in embodiment 1 changes into the DCP of the amount of commaterial, temperature is increased to outside 110 DEG C, presses and embodiment 1
Same method is carried out, it is thus achieved that the proton magnetic yield 45% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 28 8-methoxyl group-6-trichloromethyl phenanthridines
Except the ratio of the amount of the material of BPO with the 2-isonitrile-4'-methoxyl group-1,1'-biphenyl in embodiment 1 is changed by 1.2
It is outside 0.6, carries out by method similarly to Example 1, it is thus achieved that and the proton magnetic yield of target compound 69% (with 1,1,2,2-tetra-
Ethyl chloride is internal standard).
The preparation (compound 1) of embodiment 29 8-methoxyl group-6-trichloromethyl phenanthridines
Except the ratio of the amount of the material of BPO with the 2-isonitrile-4'-methoxyl group-1,1'-biphenyl in embodiment 1 is changed by 1.2
It is outside 2, carries out by method similarly to Example 1, it is thus achieved that and the proton magnetic yield of target compound 71% (with 1,1,2,2-tetrachloro
Ethane is internal standard).
The preparation (compound 1) of embodiment 30 8-methoxyl group-6-trichloromethyl phenanthridines
Except changing the reflux temperature in embodiment 1 into 90 DEG C, in sealing pipe outside reaction, press similarly to Example 1
Method is carried out, it is thus achieved that the proton magnetic yield 74% (with sym.-tetrachloroethane as internal standard) of target compound.
The preparation (compound 1) of embodiment 31 8-methoxyl group-6-trichloromethyl phenanthridines
In addition to changing the reflux temperature in embodiment 1 into 70 DEG C, carry out by method similarly to Example 1, it is thus achieved that mesh
The proton magnetic yield 69% (with 1,1,2,2-sym-tetrachloroethane as internal standard) of mark compound.
The preparation of application examples 1 8-methoxyl group-6-methyl phenanthridines
Under room temperature condition, in two mouthfuls of flasks of 50mL, add 8-methoxyl group-6-(trichloromethyl) phenanthridines 162mg
(0.5mmol), and acetonitrile 30mL, 10%Pd/C (Shanghai Ke Feng Industrial Co., Ltd., granularity > 200) 70mg, it is passed through hydrogen under room temperature
Gas, reacts 5h.Post processing removes solvent by Rotary Evaporators, adds 20mL saturated aqueous common salt, is extracted with ethyl acetate 3 times
(using 20mL ethyl acetate) every time, organic facies anhydrous Na2SO4It is dried, obtains target compound, chromatographic column by column chromatography
Inserts be silica gel, eluant is petroleum ether: ethyl acetate (5:1), obtains oily liquids, separation yield 65%.
Products therefrom1H NMR data:1H NMR (400MHz), δ 8.52 (d, J=8.8Hz, 1H, ArH), 8.44 (d, J=
8.0Hz, 1H, ArH), 8.08 (d, J=8.0Hz, 1H, ArH), 7.67 7.56 (m, 2H, ArH), 7.49 7.44 (m, 2H,
ArH),3.99(s,3H,OCH3),3.00(s,3H,CH3)。
The preparation of application examples 2 phenanthridines-6-carboxylic acid
In 10mL pressure pipe, add 6-trichloromethyl phenanthridines (59mg, 0.2mmol), concentrated sulphuric acid 2mL, be heated to 130 DEG C instead
Answer 5 hours.It is cooled to room temperature, is slowly added to water 0.5mL, then is warming up to 150 DEG C, react 16 hours.Cooling, add water 15mL, second
Acetoacetic ester extracts, and anhydrous sodium sulfate is dried, and concentrates, obtains phenanthridines-6-carboxylic acid 44mg, yield 99%.White solid, fusing point 157～
158℃；
Products therefrom1H NMR data:1H NMR(400MHz,CDCl3) δ 10.34 (br, 1H), 9.72 (d, J=8.4Hz,
1H), 8.75 8.55 (m, 2H), 8.20 (m, 1H), 7.95 (t, J=7.6 Hz, 1H), 7.82 (m, 3H).
Claims (10)
1. a class 6-trichloromethyl phenanthridines compounds, it is characterised in that: this compounds has to be tied as shown in following formula I
Structure:
Wherein,
R1Selected from H, halogen, C1～C5 alkyl, cyano group, trifluoromethyl, C1～C4 ester group, C1～C4 alkoxyl, C1～C4 acyl group；
R2Selected from H, C1～C5 alkyl, C1～C4 ester group, halogen, cyano group, trifluoromethyl, C1～C4 alkoxyl, C1～C4 acyl group.
Compound the most according to claim 1, it is characterised in that: described R1Selected from methyl, ethyl, isopropyl, the tert-butyl group ,-
COOCH3、-COOC2H5、-COOCH(CH3)2, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, formoxyl, acetyl group.
Compound the most according to claim 1, it is characterised in that: described R2Selected from methyl, ethyl, isopropyl, the tert-butyl group ,-
COOCH3、-COOC2H5、-COOCH(CH3)2, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, formoxyl, acetyl group.
4. the preparation method of the compound described in claim 1, it is characterised in that: to have the compound of structure shown in formula II
It is raw material with carbon tetrachloride, under the effect of initiator, 50 DEG C～110 DEG C reactions 6～24h, obtain described 6-trichloromethyl luxuriant and rich with fragrance
Piperidine derivatives:
Wherein,
R1Selected from H, halogen, C1～C5 alkyl, cyano group, trifluoromethyl, C1～C4 ester group, C1～C4 alkoxyl, C1～C4 acyl group；
R2Selected from H, C1～C5 alkyl, C1～C4 ester group, halogen, cyano group, trifluoromethyl, C1～C4 alkoxyl, C1～C4 acyl group；
Described initiator be tert-butyl hydroperoxide, cumyl peroxide, di-tert-butyl peroxide, azodiisobutyronitrile,
At least one in benzoyl peroxide；
The described ratio with the compound of structure shown in formula II and the amount of the material of initiator is 1:0.6～1:2.
Method the most according to claim 4, it is characterised in that: described reaction is carried out in the basic conditions, described alkalescence bar
Part is provided by alkali compounds, described alkali compounds be sodium hydroxide, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium acetate,
At least one in Feldalat NM, described in there is the ratio of the compound of structure shown in formula II and the amount of the material of alkali compounds be
1:0～1:2.
6. require described method according to right 4, it is characterised in that: described reaction temperature is reflux temperature～110 DEG C；Work as reaction
When temperature is higher than reflux temperature, described reaction seals in pressure pipe and carries out.
7. the application in synthesis phenanthridine derivatives of the compound described in claim 1, it is characterised in that: with described in claim 1
Compound, under reductive condition, carries out dechlorination reaction, obtains 6-methylphenanthrene piperidine derivatives.
8. the application in synthesis phenanthridine derivatives of the compound described in claim 1, it is characterised in that: with described in claim 1
Compound, in acid condition, be hydrolyzed reaction, obtains carboxylic acid derivates.
The preparation method of 9.6-methyl-8-methoxyl group phenanthridines, it is characterised in that: with 10%Pd/C as catalyst, by 8-methoxyl group-
6-trichloromethyl phenanthridines under room temperature normal pressure, hydrogenating reduction dechlorination, obtain 6-methyl-8-methoxyl group phenanthridines.
10. the preparation method of phenanthridines-6-carboxylic acid, it is characterised in that: 6-trichloromethyl phenanthridines is placed in sulphuric acid, 130 DEG C～150
Hydrolyze at DEG C, the phenanthridines-6-carboxylic acid obtained.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0431373A2 (en) * | 1989-11-17 | 1991-06-12 | Asahi Glass Company Ltd. | Processes for producing 5-fluorbenzoic acids and their intermediates |
| JP2001114741A (en) * | 1999-10-14 | 2001-04-24 | Ihara Nikkei Kagaku Kogyo Kk | Method for producing aromatic cyanobenzoic acid compound |
| CN102127014A (en) * | 2011-01-14 | 2011-07-20 | 浙江大学 | Azaphenanthrone compound and preparation method thereof |
-
2016
- 2016-05-05 CN CN201610294227.0A patent/CN105859620B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0431373A2 (en) * | 1989-11-17 | 1991-06-12 | Asahi Glass Company Ltd. | Processes for producing 5-fluorbenzoic acids and their intermediates |
| JP2001114741A (en) * | 1999-10-14 | 2001-04-24 | Ihara Nikkei Kagaku Kogyo Kk | Method for producing aromatic cyanobenzoic acid compound |
| CN102127014A (en) * | 2011-01-14 | 2011-07-20 | 浙江大学 | Azaphenanthrone compound and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| BANAVARA L. MYLARI,等: "A Sorbitol Dehydrogenase Inhibitor of Exceptional in Vivo Potency with a Long Duration of Action: 1-(R)-{4-[4-(4,6-Dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2-yl}ethanol", 《J. MED. CHEM.》 * |
| BO ZHANG，等: "6-Perfluoroalkylated Phenanthridines via Radical Perfluoroalkylation of Isonitriles", 《ORG. LETT.》 * |
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| CN108727397A (en) * | 2018-05-28 | 2018-11-02 | 潍坊医学院 | phenanthridine derivatives |
| CN108727397B (en) * | 2018-05-28 | 2020-02-21 | 潍坊医学院 | Phenanthridine derivatives |
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