CN106279105A - Compound that a kind of anti-tumor drugs targeting F16 synthesizes with chlorambucil and preparation method thereof - Google Patents
Compound that a kind of anti-tumor drugs targeting F16 synthesizes with chlorambucil and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of anti-tumor drugs targeting F16 and the compound of chlorambucil synthesis and the synthesis path of this compound and preparation method.This compound, with mitochondrion for target treatment cancer, overcomes cancer therapy drug selectivity low and the problem of Multidrug resistance, reaches to be removed the effect of cancerous cell by apoptotic approach.
Description
[technical field]
The present invention relates to a kind of antineoplastic agent compounds, particularly relate to a kind of anti-tumor drugs targeting F16
Compound with chlorambucil and preparation method thereof.
[background technology]
Cancer is a big pertinacious disease of serious harm human health, has become and has been only second to the of cardiovascular diseases
Two big killers, so seeking antitumor medicine and its mechanism of action of research, significant.
Mitochondrion is intracellular important organelle, plays key player in cellular process,
It is life entity " energy plants ", take part in energy and produce the multiple metabolism such as apoptosis, cell carcinogenesis
Journey.Structure of mitochondria and the change of function, not only can the growth of interference cell, metabolism and breeding,
Also can cause apoptosis.Therefore, the research and development of the new type antineoplastic medicine with mitochondrion as target spot, become
It it is a big study hotspot.
F16 is a kind of very hydrophobic of discovered in recent years, DLC (delocalize lipid cationic)
Medicine, F16 is to be formed by connecting by one indole ring of one pyridine ring copper by vinyl, the following institute of its structure
Show:
F16 effectively can recover the cycle by extended line plastochondria, reduces mitochondrion maximum quantity of heat production and mitochondria activity
Convalescent period speed constant, F16 is by opening tongue conversion duct for mitochondrial mechanism of action, broken
Bad mitochondrion proton motive force, thus interfering line plastochondria metabolic heat production.
But, generally there is selection in the medical compounds being target treatment cancer with mitochondrion more at present
Property low and Multidrug resistance problem, to this end, develop a kind of derivative type antineoplastic agent materialization based on F16
Compound becomes necessary.
[summary of the invention]
The features and advantages of the present invention are partly stated, or can show from this description
And be clear to, or can learn by putting into practice the present invention.
For overcoming problem of the prior art, the present invention provides a kind of anti-tumor drugs targeting F16 and benzene fourth
Compound of acid chlormethine synthesis and preparation method thereof, with mitochondrion for target treatment cancer, overcomes anticancer
The low problem with Multidrug resistance of drug selectivity, reaches to remove cancerous cell by apoptotic approach
Effect.
To achieve the above object of the invention, the present invention proposes following technical scheme:
The compound of anti-tumor drugs targeting F16 and chlorambucil, has a formula I:
Wherein, Y is NH, O, S；A, B, C, D, E are hydrogen-based that is identical or that differ, halogen
Base, alkyl, haloform base, alkylamino, ether or mercapto ether, n=0,1～18.
The compound of the formula I that the present invention provides, its alkyl is-R, and alkylamino is-NH-R, and ether is
-O-R, mercapto ether is-S-R；Wherein, R=CH3(CH2)m, m=0,1～10.
The present invention also provides for a kind of method preparing above-mentioned generalformula-compound, comprises the following steps:
S1, take compound α,
React with 4-picoline and obtain compound β:
Wherein X is halogen, n=0,1～18
S2, compound β protect through Bis(tert-butoxycarbonyl)oxide and obtain compound γ:
S3, compound γ warp and compound δ:
React under piperidines effect and obtain compound ε:
Wherein, Y is NH, O, S；A, B, C, D, E are hydrogen-based, halogen, alkyl, haloform
Base, alkylamino, ether or mercapto ether
S4, compound ε obtain compound η through hydrochloric acid deprotection:
S5, compound η warp and compound θ:
Condensation reaction obtains the compound of formula I.
In above-mentioned preparation method, in step sl, compound α and 4-picoline are at absolute alcohol or ether
In solvent, heating reflux reaction, after reaction completely, cooling reaction system to room temperature, filters, uses
State solvent washing；Described absolute alcohol or ether solvents are absolute methanol, dehydrated alcohol or absolute ether.
In above-mentioned preparation method, in step s 2, compound β, oxolane, sodium carbonate are dissolved in
Water, is slowly added dropwise Bis(tert-butoxycarbonyl)oxide after being stirred at room temperature, react 4 hours at 25-30 DEG C；Filter,
Filtrate being spin-dried for, the dichloromethane being subsequently adding response magnitude volume is stirred with absolute alcohol or ether, then
Filter, be spin-dried for filtrate obtaining compound γ；Described absolute alcohol or ether solvents are absolute methanol, anhydrous second
Alcohol or absolute ether.
In above-mentioned preparation method, described dichloromethane is [8～15] with the volume ratio of absolute alcohol or ether: 1.
In above-mentioned preparation method, in step s3, by compound γ, compound δ, absolute alcohol or ether
Solvent, piperidines are warming up to 50 DEG C of reactions, after reaction completely, reaction system was spin-dried for post, then adds
The dichloromethane entering response magnitude volume is stirred with absolute alcohol or ether, refilters, filtrate is spin-dried for
To compound ε；Described absolute alcohol or ether solvents are absolute methanol, dehydrated alcohol or absolute ether.
In above-mentioned preparation method, described dichloromethane with the volume ratio of absolute alcohol or ether solvents is
[25～35]: 1.
In above-mentioned preparation method, in step s 4, adding methanol in compound ε, room temperature dropping is dense
Hydrochloric acid, room temperature reaction 2～7 hours, it is spin-dried for reaction system obtaining compound η.
In above-mentioned preparation method, in step s 5, by compound η, DMF,
DIPEA is stirred at room temperature, and is subsequently adding compound θ and 2-(7-azo benzo
Triazole)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, 20-25 DEG C of reaction, add in reaction system
Entering water, extract with dichloromethane, organic facies is washed with water washs, and is dried, concentrated post, prepares formula
I compound.
By reading description, those of ordinary skill in the art will be best understood these technical schemes
Feature and content.
[accompanying drawing explanation]
Below with reference to accompanying drawing and combine example and be specifically described the present invention, advantages of the present invention and reality
Existing mode will become apparent from, and wherein content shown in accompanying drawing is only used for explanation of the present invention, and
Do not constitute the restriction gone up in all senses to the present invention, in the accompanying drawings:
Fig. 1 is the synthesis path figure of generalformula-compound provided by the present invention.
It is that the present invention implements the suppression curve chart to cem cell of the compound obtained by shown in Fig. 2-1；
It is that the present invention implements the suppression curve chart to Romas cell of the compound obtained by shown in Fig. 2-2；
It is that the present invention implements the suppression curve chart to HepG2 cell of the compound obtained by shown in Fig. 2-3；
It is that the present invention implements the suppression curve chart to HeLa cell of the compound obtained by shown in Fig. 2-4；
It is that the present invention implements the suppression curve chart to L-O2 cell of the compound obtained by shown in Fig. 2-5；
Shown in Fig. 3-1 be the present invention implement compound obtained by mitochondrion location laser co-focusing show
Micro mirror figure；
It it is the mitochondrion location laser confocal microscope figure of control compounds shown in Fig. 3-2；
It it is the mitochondrion location laser confocal microscope figure of another control compounds shown in Fig. 3-3；
It it is the mitochondrion location laser confocal microscope figure of another control compounds shown in Fig. 3-4.
[detailed description of the invention]
The present invention provides a kind of anti-tumor drugs targeting F16 with formula I to synthesize with chlorambucil
Compound:
Wherein, Y is NH, O, S；A, B, C, D, E be identical or different hydrogen-based, halogen,
Alkyl, haloform base, alkylamino, ether or mercapto ether, n=0,1～18.
In the compound of the formula I that the present invention provides, its alkyl is-R, and alkylamino is-NH-R, ether
For-O-R, mercapto ether is-S-R；Wherein, R=CH3(CH2)m, m=0,1～10.
More specifically, in above-mentioned formula I: Y represents any one in NH, O, S；A、
B, C, D, E then represent X, R, YR, CX3、In any one；Wherein X represent hydrogen or
Any one in halogen, i.e. H, F, Cl, Br, I；R is alkyl CH3(CH2)m, m=0,1～
10。
Refer to Fig. 1, the present invention also provides for a kind of method preparing above-mentioned generalformula-compound, including with
Lower step:
S1, take compound α:React with 4-picoline and obtain compound β:
Wherein X is halogen, n=0,1～18；Compound α and 4-picoline are at absolute alcohol or ether solvents
In, heating reflux reaction, after reaction completely, cooling reaction system to room temperature, filter, then with a small amount of
Absolute alcohol or ether solvents washing.
S2, compound β protect through Bis(tert-butoxycarbonyl)oxide and obtain compound γ:
Specifically, compound β, oxolane, natrium carbonicum calcinatum are dissolved in water, after being stirred at room temperature slowly
Dropping Bis(tert-butoxycarbonyl)oxide, reacts 4 hours at 25-30 DEG C；Filter, filtrate is spin-dried for, then adds
The dichloromethane entering appropriate volume is stirred with absolute alcohol or ether solvents, refilters, filtrate is revolved again
Dry obtain compound γ；Wherein, dichloromethane is [8～15] with the volume ratio of absolute alcohol or ether solvents: 1.
S3, compound γ warp and compound δ:React under piperidines effect and obtain
Compound ε:
Specifically, compound γ, compound δ, absolute methanol, piperidines are warming up to 50 DEG C of reactions, instead
Should completely after, reaction system was spin-dried for post, the dichloromethane being subsequently adding appropriate volume enters with methanol
Row stirring, refilters, is spin-dried for filtrate obtaining compound ε again；Wherein, chloromethanes and the volume of methanol
Than being [25～35]: 1.
Wherein, Y is NH, O, S；A, B, C, D, E are hydrogen-based that is identical or that differ, halogen
Base, alkyl, haloform base, alkylamino, ether or mercapto ether.
S4, compound ε obtain compound η through hydrochloric acid deprotection:
Specifically, add methanol in compound ε, room temperature dropping concentrated hydrochloric acid, room temperature reaction 2 to 7 is little
Time, it is spin-dried for reaction system obtaining compound η.
S5, compound η warp and compound θ:
Condensation reaction, i.e. obtains the compound of formula I.Specifically, by compound η, N, N-dimethyl
Methanamide, DIPEA are stirred at room temperature, and are subsequently adding compound θ, 2-(7-diphenyl diimide
And triazole)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, 20-25 DEG C of reaction, in reaction system
Adding water, extract with dichloromethane, organic facies is washed with water washs, and is dried, and concentrated post obtains formula
The compound of I.
Below by specific embodiment, the method that preparation compound of Formula I is expanded on further:
Embodiment 1
First, take compound 1 (3-propantheline bromide hydrobromide) and react with 4-picoline, compound 1
Structure is as follows:
When being embodied as, reaction bulb is separately added into 4-picoline (2g), 3-bromine propylamine hydrobromic acid
Salt (1.0eq), absolute methanol (or dehydrated alcohol, absolute ether) 10ml, then heating reflux reaction
Overnight.Reaction is complete, cooling reaction system to room temperature, filters, and washs with a small amount of methanol, is dried
To white solid i.e. compound 2 (5.0g)；In the present embodiment, the structure of compound 2 is as follows:
And then, reaction bulb adds compound 2 (2.27g), oxolane 20ml, anhydrous carbon
Acid sodium (2.0eq) is dissolved in water 20ml, 30min is stirred at room temperature, is then slowly added dropwise two dimethyl dicarbonate fourths
Ester (1.1eq) is dissolved in oxolane 10ml, reacts 4 hours at 25-30 DEG C.Filter, filtrate is revolved
Dry, the dichloromethane being subsequently adding appropriate volume stirs with methanol (volume ratio 8:1～15:1, preferably 10:1)
Mixing a period of time, filter, filtrate is spin-dried for obtaining lightpink grease i.e. compound 3 (2.31g) again,
The structure of compound 3 is as follows:
Subsequently, compound 3 is reacted with compound 4 (indole-3-formaldehyde),
It concretely comprises the following steps: be separately added into compound 3 (2.31g), indole-3-formaldehyde in reaction bulb
(1.0eq), absolute methanol 50ml, be subsequently adding piperidines (0.9eq), be warming up to 50 DEG C and reacted
Night.Reaction system completely, was spin-dried for post, was subsequently adding dichloromethane and the first of appropriate volume by reaction
Alcohol (volume ratio 25:1～35:1, preferably 30:1) is stirred, and refilters, and is spin-dried for filtrate obtaining again
Peony half decorating film i.e. compound 5 (1.27g), the structure of compound 5 is as follows:
Followed by, reaction bulb adds compound 5 (1.27g), methanol 10ml, room temperature dropping is dense
Hydrochloric acid 5ml, room temperature reaction 5 hours, it is spin-dried for reaction system obtaining the peony half i.e. chemical combination of decorating film
Thing 6 (1.0g), the structure of compound 6 is as follows:
After again, compound 6 is reacted with compound 7 (chlorambucil),
It concretely comprises the following steps: add compound 6 (100mg), N, N-dimethyl formyl in reaction bulb
Amine 10ml, DIPEA (3.0eq), be stirred at room temperature 20min, be subsequently adding benzenebutanoic acid
Chlormethine (1.2eq), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (1.2eq),
20-25 DEG C of reaction overnight.In reaction system, add water 20ml, extract with dichloromethane 20ml × 3
Taking, organic facies is washed with water 20ml × 2 again, is dried, and concentrated post obtains 100mg yellow foam
The compound 8 that solid i.e. F16 synthesizes with chlorambucil, its structural formula is as follows:
Embodiment 2
The mode preparing compound 3 is in the same manner as in Example 1, does not repeats them here.
Take compound 3 to react with compound 9 (6-fluoro indole-3-formaldehyde),
It concretely comprises the following steps: be separately added into compound 3 (1.0g), 6-fluoro indole-3-in reaction bulb
Formaldehyde (1.0eq), absolute methanol 30ml, be subsequently adding piperidines (0.9eq), is warming up to 50 DEG C instead
Overnight should react completely, reaction system be spin-dried for post, be subsequently adding the dichloromethane of appropriate volume
It is stirred with methanol (35:1), refilters, filtrate is spin-dried for obtains peony half decorating film again and i.e. changes
Compound 10 (0.7g), the structure of compound 10 is as follows:
Then, reaction bulb adds compound 10 (0.5g), methanol 5ml (or ethanol, ether),
Room temperature dropping concentrated hydrochloric acid 2.5ml, room temperature reaction 3 hours.Reaction system is spin-dried for obtains peony half solid
Shape thing i.e. compound 11 (0.4g), the structure of compound 11 is as follows:
Taking compound 11 to react with compound 7 (chlorambucil), it concretely comprises the following steps: in reaction
Compound 11 (100mg), N,N-dimethylformamide 10ml, N, N-diisopropyl second is added in Ping
Amine (3.0eq), is stirred at room temperature 20min, is subsequently adding chlorambucil (1.2eq), 2-(7-azo
BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (1.2eq), 20-25 DEG C of reaction overnight.
Adding water 20ml in reaction system, extract with dichloromethane 20ml × 3, organic facies is again with water 20
Ml × 2 are washed, and are dried, and concentrated post obtains 96mg yellow foamy solid i.e. F16 and benzenebutanoic acid nitrogen
The compound 12 of mustard synthesis, its structural formula is as follows:
Embodiment 3
The mode preparing compound 3 is in the same manner as in Example 1, does not repeats them here.
Take compound 3 to react with compound 13 (5-fluoro indole-3-formaldehyde),
It concretely comprises the following steps: be separately added into compound 3 (1.0g), 5-fluoro indole-3-in reaction bulb
Formaldehyde (1.0eq), absolute methanol 30ml, be subsequently adding piperidines (0.9eq), is warming up to 50 DEG C instead
Should be overnight.Reaction system completely, was spin-dried for post, was subsequently adding the dichloromethane of appropriate volume by reaction
It is stirred with methanol (25:1), refilters, filtrate is spin-dried for obtains peony half decorating film again and i.e. changes
Compound 14 (0.75g), the structure of compound 14 is as follows:
Subsequently, adding compound 14 (0.5g), methanol 5ml in reaction bulb, room temperature drips dense salt
Acid 2.5ml, room temperature reaction 3 hours, it is spin-dried for reaction system obtaining the peony half i.e. compound of decorating film
15 (0.42g), the structure of compound 15 is as follows:
Finally taking compound 15 to react with compound 7, it concretely comprises the following steps: additionization in reaction bulb
Compound 15 (100mg), DMF 10ml, DIPEA (3.0eq),
20min is stirred at room temperature, is subsequently adding chlorambucil (1.2eq), 2-(7-azo benzo three nitrogen
Azoles)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (1.2eq), 20-25 DEG C of reaction overnight.To reaction
Adding water 20ml in system, extract with dichloromethane 20ml × 3, organic facies is washed with water 20ml × 2 again
Washing, be dried, concentrated post obtains 100mg yellow foamy solid i.e. F16 and synthesizes with chlorambucil
Compound 16, its structural formula is as follows:
Embodiment 4
The mode preparing compound 3 is in the same manner as in Example 1, does not repeats them here.
Take compound 3 to react with compound 17 (5-methoxyindole-3-carboxaldehyde),
It concretely comprises the following steps: be separately added into compound 3 (1.0g), 5-methoxy-Indole in reaction bulb
-3-formaldehyde (1.0eq), absolute methanol 30ml, be subsequently adding piperidines (0.9eq), be warming up to 50 DEG C
Reaction is overnight.Reaction system completely, was spin-dried for post, was subsequently adding the dichloromethane of appropriate volume by reaction
Alkane is stirred with methanol (30:1), refilters, and is spin-dried for filtrate obtaining peony half decorating film i.e. again
Compound 18 (0.80g), the structure of compound 18 is as follows:
Subsequently, adding compound 18 (0.5g), methanol 5ml in reaction bulb, room temperature drips dense salt
Acid 2.5ml, room temperature reaction 3 hours, it is spin-dried for reaction system obtaining the peony half i.e. compound of decorating film
19 (0.45g), the structure of compound 19 is as follows:
Finally, taking compound 19 and react with compound 7, it concretely comprises the following steps: add in reaction bulb
Compound 19 (100mg), DMF 10ml, DIPEA (3.0eq),
20min is stirred at room temperature, is subsequently adding chlorambucil (1.2eq), 2-(7-azo benzo three nitrogen
Azoles)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (1.2eq), 20-25 DEG C of reaction overnight.To reaction
Adding water 20ml in system, extract with dichloromethane 20ml × 3, organic facies is washed with water 20ml × 2 again
Washing, be dried, it is that F16 closes with chlorambucil that concentrated post obtains 100mg yellow foamy solid
The compound 20 become, its structural formula is as follows:
Pharmaceutical properties is evaluated
1. extracorporeal anti-tumor Effect Evaluation
Extracorporeal anti-tumor Effect Evaluation is carried out for the compound 8 obtained by previous embodiment one.Mirror
Broad spectrum anticancer alkylating agent in chlorambucil, the present embodiment use CEM, Romas, HeLa and
HepG2 cell carries out evaluating drug effect to it, and LO2 liver cell carries out toxicity detection to it simultaneously.
Take the logarithm the cell of trophophase, according to the size of cell inoculate 4～40 × 103 on 96 orifice plates,
After 24 hours to be grown, abandon supernatant, then by following packet be administered: tumor cell set not dosing group and
Dosing group (concentration 2.5～160 μMs to tumor cell, concentration 50～800 μMs are to LO2 cell), F is
Compound 6, CBL is compound 7 (chlorambucil), and F+CBL is that F and CBL is isocyatic
Combination, FCBL is synthesis compound 8.Often group sets 4～6 multiple holes, cultivates 24 or 72 hours, abandons
Supernatant, adds 100 μ l MTT (tetrazolium) serum-free medium containing 0.5mg/ml and cultivates 4h,
Add 100 μ l DMSO (dimethyl sulfoxide), be positioned on micro-oscillating instrument vibration 10min, then be placed in
OD value is detected at 570nm in microplate reader.Normal cell system LO2 compares.Test counterpoise every time
Multiple 3 times.
Result shows, along with drug level increases, compares with corresponding not dosing matched group, cell proliferation
Activity declines respectively, illustrates that compound is concentration dependent suppression tumor cell propagation.And align
Often the proliferation activity of hepatic cell line L-O2 cell does not changes, and demonstrates that normal cell is had by this compound
There is low toxicity characteristic (such as table 1, Fig. 2-1 is to shown in Fig. 2-5).
The IC50 value (24h) of the different cell of table 1 and different compound IC50 ratio
2. mitochondrion location confirmation
The mitochondrion of compound 8 is carried out location confirmation.After Hela fishplate bar optics culture dish, by line
Plastochondria location reagent Mitotracker and compound 8 one pieces carry out hatching 1-2 hour with cell, laser
Laser Scanning Confocal Microscope (600X) is observed and is taken pictures, and red and green fluorescence carries out observing common location；Simultaneously
It is also carried out control compounds positioning accordingly, then observes under equal conditions and take pictures, the result obtained
As shown in Fig. 3-1 to 3-4.
Embodiment described above only have expressed the several embodiments of the present invention, its describe more concrete and
In detail, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that,
For the person of ordinary skill of the art, without departing from the inventive concept of the premise, it is also possible to
Making some deformation and improvement, these broadly fall into protection scope of the present invention.Therefore, patent of the present invention
Protection domain should be as the criterion with claims.
Claims (10)
1. a compound for anti-tumor drugs targeting F16 and chlorambucil synthesis, has a formula I:
Wherein, Y is NH, O, S；A, B, C, D, E are hydrogen-based that is identical or that differ, halogen
Base, alkyl, haloform base, alkylamino, ether or mercapto ether, n=0,1～18.
Compound the most according to claim 1, it is characterised in that described alkyl is-R, described alkane ammonia
Base is-NH-R, and described ether is-O-R, and described mercapto ether is-S-R；Wherein, R=CH3(CH2)m,
M=0,1～10.
3. the method preparing compound of Formula I described in claim 1, comprises the following steps:
S1, take compound α,
React with 4-picoline and obtain compound β:
Wherein X is halogen, n=0,1～18；
S2, compound β protect through Bis(tert-butoxycarbonyl)oxide and obtain compound γ:
S3, compound γ warp and compound δ
React under piperidines effect and obtain compound ε:
Wherein, Y is NH, O, S；A, B, C, D, E be hydrogen-based, halogen, alkyl,
Haloform base, alkylamino, ether or mercapto ether:
S4, compound ε obtain compound η through hydrochloric acid deprotection:
S5, compound η warp and compound θ:
Condensation reaction i.e. prepares generalformula-compound.
Preparation method the most according to claim 3, it is characterised in that in step sl, compound α with
4-picoline is in absolute alcohol or ether solvents, and heating reflux reaction, after reaction completely, cooling is anti-
Answer system to room temperature, filter, then wash with above-mentioned solvent；Described absolute alcohol or ether solvents are anhydrous
Methanol, dehydrated alcohol or absolute ether.
Preparation method the most according to claim 3, it is characterised in that in step s 2, by compound β,
Oxolane, sodium carbonate are dissolved in water, are slowly added dropwise Bis(tert-butoxycarbonyl)oxide after being stirred at room temperature,
25-30 DEG C is reacted 4 hours；Filter, filtrate is spin-dried for, is subsequently adding the dichloromethane of response magnitude volume
Alkane is stirred with absolute alcohol or ether, refilters, and is spin-dried for filtrate obtaining compound γ；Described nothing
Water alcohol or ether solvents are absolute methanol, dehydrated alcohol or absolute ether.
Preparation method the most according to claim 5, it is characterised in that described dichloromethane and absolute alcohol or ether
Volume ratio be [8～15]: 1.
Preparation method the most according to claim 3, it is characterised in that in step s3, by compound γ,
Compound δ, absolute alcohol or ether solvents, piperidines are warming up to 50 DEG C of reactions, after reaction completely, and will be anti-
Answering system to be spin-dried for post, the dichloromethane being subsequently adding response magnitude volume stirs with absolute alcohol or ether
Mix, refilter, be spin-dried for filtrate obtaining compound ε；Described absolute alcohol or ether solvents are without water beetle
Alcohol, dehydrated alcohol or absolute ether.
Preparation method the most according to claim 7, it is characterised in that described dichloromethane and absolute alcohol or ether
The volume ratio of solvent is [25～35]: 1.
Preparation method the most according to claim 3, it is characterised in that in step s 4, at compound ε
Middle interpolation methanol, room temperature dropping concentrated hydrochloric acid, room temperature reaction 2～7 hours, reaction system is spin-dried for
To compound η.
Preparation method the most according to claim 3, it is characterised in that in step s 5, by compound η,
DMF, DIPEA are stirred at room temperature, and are subsequently adding chemical combination
Thing θ and 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester,
20-25 DEG C of reaction, adds water in reaction system, extracts with dichloromethane, and organic facies uses water again
Washing, is dried, concentrated post, prepares generalformula-compound.
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| JP2022522977A (en) * | 2019-01-15 | 2022-04-21 | ザ ボード オブ トラスティーズ オブ ザ リーランド スタンフォード ジュニア ユニバーシティー | Delocalized lipophilic cation compound and its usage |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2022522977A (en) * | 2019-01-15 | 2022-04-21 | ザ ボード オブ トラスティーズ オブ ザ リーランド スタンフォード ジュニア ユニバーシティー | Delocalized lipophilic cation compound and its usage |
| JP7227656B2 (en) | 2019-01-15 | 2023-02-22 | ザ ボード オブ トラスティーズ オブ ザ リーランド スタンフォード ジュニア ユニバーシティー | Delocalized lipophilic cationic compound and method of use thereof |
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