CN110105266A - Synthetic method of one species specificity for the small molecule, anti-tumor drug of CYP2J2 - Google Patents
Synthetic method of one species specificity for the small molecule, anti-tumor drug of CYP2J2 Download PDFInfo
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- CN110105266A CN110105266A CN201810102528.8A CN201810102528A CN110105266A CN 110105266 A CN110105266 A CN 110105266A CN 201810102528 A CN201810102528 A CN 201810102528A CN 110105266 A CN110105266 A CN 110105266A
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- diphenyl
- piperidyl
- butanone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Abstract
The invention discloses a species specificity for the synthetic method of the small molecule, anti-tumor drug of CYP2J2, this method is that Suzuki coupling reaction is occurred for compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone and vinyl boron compound, obtains compound 1- (4- ethenylphenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone；Then it, then by it with HCl reacts, to obtain small molecule, anti-tumor drug 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride that specificity is directed to CYP2J2.The present invention is by improving synthetic method integral process flow design, using Suzuki coupling reaction, and the condition and parameter of each reaction step are improved, it can effectively solve the problem that existing synthetic method low efficiency, low yield, can not largely synthesize, or need to require the problems such as harsh using severe toxicity and expensive organotin reagent, reaction condition.
Description
Technical field
The invention belongs to organic chemical synthesis application fields, more particularly, to a species specificity for the small of CYP2J2
The synthetic method of molecule antineoplastic medicament, the utilization of the synthetic method more particularly to Suzuki coupling reaction.
Background technique
Inventor discloses small molecule, anti-tumor drug 1- (the 4- second that specificity is directed to CYP2J2 in CN101219142A
Alkenyl phenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride (III) preparation method and pharmaceutical use,
The drug can be used in the research of anti-tumor disease.
Preparation method disclosed in patent CN101219142A is using vinyl benzene as starting material, by Fu Ke acyl group
Change reaction, substitution reaction and salt-forming reaction obtain target 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidines
Base) -1- butanone hydrochloride.Wherein committed step is the friedel-crafts acylation of styrene and acyl chlorides, but the reaction efficiency pole
It is low, cause yield in the synthetic route not high, it is difficult to be applied to a large amount of synthesis, theoretically analyze, styryl structures are carrying out
When friedel-crafts acylation, vinyl can be passivated benzene ring structure, lead to acylated difficulty.Subsequent inventor team develops again utilizes ethylene
Base tin reagent and halogeno-benzene coupling construct method (the Journal of Pharmacology of target compound III and the like
And Experimental Therapetics, 2009,908-918), this method can quickly replace the vinyl on phenyl ring
To synthesize various analogs, but organotin reagent severe toxicity and expensive, thus this route preparation cost is high, does not meet green
The theory of chemistry.In addition, also have document (Archives of Biochemistry and Biophysics 464,2007,
155-168) vinyl is introduced into phenyl ring using elimination reaction, but its strong alkaline condition may cause in substrate other groups not
Tolerance, therefore the not applicable synthesis with the target compound.
Summary of the invention
Aiming at the above defects or improvement requirements of the prior art, the purpose of the present invention is to provide a species specificity to be directed to
The synthetic method of the small molecule, anti-tumor drug of CYP2J2 can synthesize to obtain the small molecule, anti-tumor that specificity is directed to CYP2J2
Drug 1- (4- ethenylphenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride, wherein passing through pairing
It is improved at method integral process flow design, using Suzuki coupling reaction, and to each reaction step, (especially Suzuki is even
Connection reaction step) condition and parameter (types and proportion of such as reaction raw materials) improve, compared with prior art can
Effectively solve 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride synthetic method effect
Rate is low, low yield, can not largely synthesize, or needs to require using severe toxicity and expensive organotin reagent, reaction condition severe
The problem carved etc., the present invention without using the such violent in toxicity of vinyltributyltin, can efficient synthesis target product, synthesis
Reaction condition is mild, and yield is high, and production cost is low, is specificity for a large amount of synthesis of the small molecule, anti-tumor drug of CYP2J2
Provide possibility.
To achieve the above object, it is proposed, according to the invention, provide the small molecule anti-cancer drug that a species specificity is directed to CYP2J2
The synthetic method of object, which is characterized in that this method is by compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1-
Piperidyl) Suzuki coupling reaction occurs for -1- butanone and vinyl boron compound, obtain compound 1- (4- ethenylphenyl) -4-
(4- (diphenyl methylol) -1- piperidyl) -1- butanone；Then, then by compound 1- (4- ethenylphenyl) -4- (4- (two
Phenyl methylol) -1- piperidyl) -1- butanone is reacted with HCl, to obtain the small molecule, anti-tumor that specificity is directed to CYP2J2
Drug 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride.
As present invention further optimization, compound 1- (the 4- halogenophenyl) -4- (4- (diphenyl methylol) -
1- piperidyl) -1- butanone, there is the structure as shown in following formula (I):
Wherein, X Cl, Br or I；
The vinyl boron compound has the structure as shown in following formula (II):
Wherein,For BF3K、B(OH)2、B(OCH3)2Or
As present invention further optimization, the Suzuki coupling reaction is existed in catalyst, ligand, alkali and solvent
Under conditions of carry out；The Suzuki coupling reaction is specifically by 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- piperazine
Piperidinyl) -1- butanone and vinyl boron compound carry out being heated to reflux in solvent under the action of catalyst, ligand and alkali it is anti-
It answers.
As present invention further optimization, in the corresponding reaction raw materials of the Suzuki coupling reaction,
Compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- the piperidyl) -1- butanone is 1- (4-
Bromo phenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone, i.e., X is Br in the described formula (I)；
The dosage of the vinyl boron compound is 1-5 times of equivalent, which is preferably vinyl trifluoro
Potassium borate；
The dosage of the catalyst is 0.03-0.5 times of equivalent, which is the compound of Metal Palladium, preferably dichloro
Change palladium；
The dosage of the ligand is 0.09-1.5 times of equivalent, which is Phosphine ligands, preferably triphenylphosphine；
The dosage of the alkali is 2-10 times of equivalent, which is inorganic base or organic base, preferably cesium carbonate；
The solvent is preferably the mixed solvent of tetrahydrofuran and water.
Contemplated above technical scheme through the invention, compared with prior art, due to using Suzuki coupling reaction to make
For committed step, with compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone and ethylene
Base boron compound carries out Suzuki coupling reaction as key reaction raw material and generates compound 1- (4- ethenylphenyl) -4- (4- (two
Phenyl methylol) -1- piperidyl) -1- butanone, and by compound 1- (4- halogenophenyl) -4- (4- (diphenyl hydroxyl first
Base) -1- piperidyl) both -1- butanone and vinyl boron compound chemical structure and proportion dosage, other raw materials are (as being catalyzed
Agent, ligand, alkali, solvent) proportion dosage, the carry out such as reaction condition are preferred, can be further assured that specificity for CYP2J2
Small molecule, anti-tumor drug 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride is special
The yield of fixed synthetic method entirety.Synthetic method in the present invention is suitable for various vinyl boron compounds, including vinyl
Boric acid, vinyl borate, vinyl potassium trifluoborate etc., preferably vinyl potassium trifluoborate；Catalyst is various metals
The compound of palladium, preferably palladium chloride；Ligand is various Phosphine ligands, preferably triphenylphosphine；Alkali is various inorganic bases and organic
Alkali, preferably cesium carbonate；The mixed solvent of the solvent preferred tetrahydrofuran and water, the volume ratio of the two are unlimited.
The present invention passes through the amount for controlling various reaction raw materials, by compound 1- (4- halogenophenyl) -4- (4- (diphenyl hydroxyl
Methyl) -1- piperidyl) the dosage control of -1- butanone is 1 times of equivalent, the dosage of vinyl boron compound is 1-5 times of equivalent, is urged
The dosage of agent is 0.03-0.5 times of equivalent, and the dosage of ligand is 0.09-1.5 times of equivalent, and the dosage of alkali is 2-10 times of equivalent, is removed
It can ensure outside yield, on the other hand be also ensured compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -
1- piperidyl) -1- butanone raw material fully reacting, it is convenient for raw material compound 1- (4- halogenophenyl) -4- (4- (diphenyl hydroxyl first
Base) -1- piperidyl) -1- butanone and product Compound 1- (4- ethenylphenyl) -4- (4- (diphenyl methylol) -1- piperidines
Base) -1- butanone separation.Since halogenated raw material is suitable with the product polarity that vinyl replaces, it is difficult to separate, the present invention passes through
The proportion for controlling reaction raw materials, reacts halogenated raw material thoroughly, in order to the separation of target product；In addition, further to protect
Raw material fully reacting is demonstrate,proved, the reaction time can be extended to a certain extent.In addition, Suzuki coupling reaction requires strictly anaerobic,
It needs to carry out stringent deoxygenation operation to reaction system and solvent before reaction.
As it can be seen that compound 1- (4- ethenylphenyl) -4- (4- (diphenyl methylol) -1- piperidines provided by the invention
Base) -1- butanone hydrochloride synthetic method method, use Suzuki coupling reaction as committed step, reaction condition is mild, no ethylene
The such violent in toxicity of base tributyl tin, can efficient synthesis target product, have reaction condition mild, raw material and reaction reagent at
The advantages that this is cheap is suitble to large-scale industrial production.
Detailed description of the invention
Fig. 1 is that (reaction route shown in the first row can be according in figure for the synthetic route schematic diagram of synthetic method of the present invention
Method preparation in the prior art).
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.As long as in addition, technical characteristic involved in the various embodiments of the present invention described below
Not constituting a conflict with each other can be combined with each other.
Specificity is directed to small molecule, anti-tumor drug --- 1- (4- ethenylphenyl) -4- (4 of CYP2J2 in the present invention
(diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride synthetic route it is as follows:
Suzuki coupling reaction step and HCl including two steps, i.e., under catalyst, ligand, alkali and solvent condition
Under the conditions of conjunction salt-forming steps.
Synthesis 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidines provided by the invention introduced below
Base) -1- butanone hydrochloride crucial coupling step.Since Suzuki coupling reaction requires anaerobic stringent, implementation below
The reagents such as reaction system and solvent used by example need to carry out stringent deoxygenation operation before the reaction；Such as freeze-drying deoxygenation or
Inert gas repeatedly substitutes gas deoxygenation under water pump, and in addition solvent can also be used inert gas ultrasound to be bubbled deoxygenation.
Embodiment 1
The synthesis of 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone
By 500mg 1- (4- bromophenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone, 233mg vinyl
Three potassium fluoborates, 274mg triphenyl phosphorus, 1130mg cesium carbonate, 6.2mg PdCl2It sequentially adds in 15ml tube sealing, is protected in argon gas
Protect lower deoxygenation 2h, solvent THF:H2Solvent is added reaction system, seals tube sealing, set by O=9:1 deoxygenation 2h under ultrasound
It flows back in 85 DEG C of oil baths, reaction about 22h terminates reaction (can be in raw material, such as 1- (4- bromophenyl) -4- (4 (diphenyl hydroxyl first
Base) -1- piperidyl) -1- butanone raw material, run out of full-time termination reaction), water is added into reaction system and ethyl acetate carries out
Extraction, water phase ethyl acetate are stripped twice, merge organic phase, and saturation NaCl solution is washed, anhydrous Na2SO4It is filtered after drying,
400mg product, yield 90% are obtained through silicagel column column chromatography (DCM:MeOH=25:1-PE:EA=1:5) after vacuum concentration.1-
(4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone1H-NMR(400MHz,CD3OD),7.88(d,
2H, J=8.4Hz), 7.45 (m, 6H), 7.25 (t, 4H), 7.16 (t, 2H), 6.72 (dd, 1H, J=11.8,17.6Hz), 5.85
(d, 1H, J=17.6Hz), 5.38 (d, 1H, J=11.2Hz), 3.36 (d, 2H, J=11.6Hz), 3.07 (t, 2H, J=6.4,
6.8Hz),2.82(m,2H),2.51(m,3H),2.11(m,2H),1.6(m,2H),1.23(m,6H).
The synthesis of 1- (4- ethenylphenyl) -4- (4 (diphenyl methylol) -1- piperidyl) -1- butanone hydrochloride
It is vigorously mixed at room temperature for after 380mg product is mixed with ether, when being precipitated there is no white solid, filtering,
Crystal, which is washed, with glacial acetic acid ethyl ester obtains product 320mg, yield 77%.1- (4- ethenylphenyl) -4- (4 (diphenyl hydroxyl first
Base) -1- piperidyl) -1- butanone hydrochloride1H-NMR (400MHz, DMSO-d6), 9.78 (s, 1H), 7.94 (d, 2H, J=
8.4Hz), 7.62 (d, 2H, J=8.0Hz), 7.56-7.45 (m, 4H), 7.29 (t, 4H), 7.18-7.14 (m, 2H), 6.82
(dd, 1H, J=11.2,17.6Hz), 6.01 (d, 1H, J=17.6Hz), 5.43 (d, 1H, J=11.2Hz), 3.47 (d, 2H, J
=10.8Hz), 3.16 (t, 2H, J=6.8Hz), 3.06-2.82 (m, 5H), 2.05-1.95 (m, 2H), 1.83-1.73 (m,
2H),1.47-1.43(m,2H).
Fig. 1 show synthetic method synthetic route schematic diagram when X is bromine in formula (I), whereinSubstance can be prepared according to method in the prior art；Certainly, for X be chlorine or
The case where iodine, can also refer to method preparation in the prior art.For the dosage of reaction reagent, 1 times of vinyl borane reagent amount with
It is upper, when carrying out a small amount of milligram order reactions using excessive to 5 times amounts on reaction without influence, it is usable when quantitative response in progress
1 times of amount can be used to be attempted for 1.5 to 2 times of amounts, big quantitative response；The amount of the substance of catalyst palladium chloride and triphenylphosphine ligand
The ratio between be 1:3, similarly small quantitative response can be used 0.5 times of amount palladium chloride, 1.5 times of amount triphenylphosphine ligands guarantees react efficiently into
Row, a large amount of or middle quantitative response catalyst palladium chloride can be reduced to 0.03 times of amount, and corresponding triphenylphosphine ligand is 0.09 times of amount；
The used in amounts of alkali is no less than 2 times of amounts, and excessive alkali has no significant effect the reaction, and the too low meeting reaction system of alkali number can be led in acidity
It causes reaction efficiency to reduce or can not carry out, can be regulated and controled with specific reference to the size of reacting dose.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, not to
The limitation present invention, any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should all include
Within protection scope of the present invention.
Claims (4)
1. a species specificity for CYP2J2 small molecule, anti-tumor drug synthetic method, which is characterized in that this method be by
Compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone and vinyl boron compound occur
Suzuki coupling reaction obtains compound 1- (4- ethenylphenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone；
Then, then it is compound 1- (4- ethenylphenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone and HCl is anti-
It answers, to obtain small molecule, anti-tumor drug 1- (4- ethenylphenyl) -4- (4 (diphenyl hydroxyl first that specificity is directed to CYP2J2
Base) -1- piperidyl) -1- butanone hydrochloride.
2. synthetic method of the specificity for the small molecule, anti-tumor drug of CYP2J2 as described in claim 1, which is characterized in that
Compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- the piperidyl) -1- butanone has such as following formula (I) institute
Show structure:
Wherein, X Cl, Br or I；
The vinyl boron compound has the structure as shown in following formula (II):
Wherein,For BF3K、B(OH)2、B(OCH3)2Or
3. synthetic method of the specificity for the small molecule, anti-tumor drug of CYP2J2 as described in claim 1, which is characterized in that
The Suzuki coupling reaction carries out under the conditions of being existing for catalyst, ligand, alkali and the solvent；Suzuki coupling reaction tool
Body is to urge 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone and vinyl boron compound
Heating reflux reaction is carried out under the action of agent, ligand and alkali in solvent.
4. synthetic method of the specificity for the small molecule, anti-tumor drug of CYP2J2 as described in claim 1, which is characterized in that
In the corresponding reaction raw materials of the Suzuki coupling reaction,
Compound 1- (4- halogenophenyl) -4- (4- (diphenyl methylol) -1- the piperidyl) -1- butanone is 1- (4- bromo
Phenyl) -4- (4- (diphenyl methylol) -1- piperidyl) -1- butanone, i.e., X is Br in the described formula (I)；
The dosage of the vinyl boron compound is 1-5 times of equivalent, which is preferably three fluoboric acid of vinyl
Potassium；
The dosage of the catalyst is 0.03-0.5 times of equivalent, which is the compound of Metal Palladium, preferably palladium chloride；
The dosage of the ligand is 0.09-1.5 times of equivalent, which is Phosphine ligands, preferably triphenylphosphine；
The dosage of the alkali is 2-10 times of equivalent, which is inorganic base or organic base, preferably cesium carbonate；
The solvent is preferably the mixed solvent of tetrahydrofuran and water.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409176A (en) * | 2020-11-20 | 2021-02-26 | 惠泽化学科技(濮阳)有限公司 | Synthesis method of p-acetoxystyrene |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219142A (en) * | 2008-01-21 | 2008-07-16 | 汪道文 | Method for preparing small-molecule antineoplastic medicament with specificity for CYP2J2 and medical use thereof |
| WO2016201096A1 (en) * | 2015-06-10 | 2016-12-15 | Forum Pharmaceuticals, Inc. | Aminobenzisoxazole compounds as agonists of a7-nicotinic acetylcholine receptors |
-
2018
- 2018-02-01 CN CN201810102528.8A patent/CN110105266A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219142A (en) * | 2008-01-21 | 2008-07-16 | 汪道文 | Method for preparing small-molecule antineoplastic medicament with specificity for CYP2J2 and medical use thereof |
| WO2016201096A1 (en) * | 2015-06-10 | 2016-12-15 | Forum Pharmaceuticals, Inc. | Aminobenzisoxazole compounds as agonists of a7-nicotinic acetylcholine receptors |
Non-Patent Citations (2)
| Title |
|---|
| CHEN CHEN ET AL.: "Selective Inhibitors of CYP2J2 Related to Terfenadine Exhibit Strong Activity against Human Cancers in Vitro and in Vivo", 《THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 * |
| MARK BURGESS ET AL.: "Impact of Backbone Tether Length and Structure on the Electrochemical Performance of Viologen Redox Active Polymers", 《CHEM. MATER.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409176A (en) * | 2020-11-20 | 2021-02-26 | 惠泽化学科技(濮阳)有限公司 | Synthesis method of p-acetoxystyrene |
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Application publication date: 20190809 |