CN109206333A - A kind of synthetic method and application of the benzocainum monosubstituted derivative with antibacterial activity - Google Patents
A kind of synthetic method and application of the benzocainum monosubstituted derivative with antibacterial activity Download PDFInfo
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- CN109206333A CN109206333A CN201811201047.9A CN201811201047A CN109206333A CN 109206333 A CN109206333 A CN 109206333A CN 201811201047 A CN201811201047 A CN 201811201047A CN 109206333 A CN109206333 A CN 109206333A
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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Abstract
The preparation method of the invention discloses a kind of benzocainum monosubstituted derivative with antibacterial activity is configured to solution A the specific steps are a certain amount of benzocainum to be dissolved in n,N-Dimethylformamide；A certain amount of bromo compound and triethylamine are dissolved in n,N-Dimethylformamide, solution B is configured to；Solution A and solution B are pumped into the silicon carbide reactor device of certain reaction temperature with certain flow rate by tetrafluoro, material keeps certain residence time that substitution reaction occurs in microreactor, material after collecting reaction, obtained total overall reaction liquid is poured into water, reaction solution is extracted with chloroform, merge organic phase, obtains monosubstituted derivative through silica gel column chromatography separation (PE:EA=5:1) after concentration.Synthesis technology of the invention is more economical, environmentally friendly, efficient, convenient, and has good antibacterial action.
Description
Technical field
The invention belongs to the synthesis technical fields with antimicrobial active medicament, and in particular to a kind of benzene with antibacterial activity
Help the synthetic method and application of cacaine monosubstituted derivative.
Background technique
Micro passage reaction is a kind of novel, micromation pipeline reactor continuously flowed.It is micro- in reactor
Channel is fabricated by precision processing technology, and characteristic size is generally between 10 to 1000 microns.It can in micro passage reaction
With comprising numerous minitype channels, fluid can be combined in the reactor flowing with specific physical state, therefore can be with
Realize very high yield.Due to the micromation of characteristic dimension, heat transfer coefficient, mass-transfer performance significantly increase micro passage reaction, instead
The conversion ratio answered, selectivity are significantly improved, and in addition uniformly, reaction process is continuous controllable and peace for fluid flowing in reactor
Quan Xinggao, so as to solve to carry out organic synthesis in traditional tank reactor.
Benzocainum, the entitled 4-aminobenzoic acid ethyl ester of chemistry, chemical molecular formula C9H11NO2, it is important in medicine
Mesosome can be used as a kind of water-insoluble local anesthetic, there is analgesic, itching-relieving efficacies.It is mainly used for the surface of a wound, ulcer surface, mucous membrane
Surface and hemorrhoid narcotic analgesic and disease of itching, ointment also act as the analgesic of the lubrications such as nasopharyngeal catheter, interior prominent sight glass.Benzocainum is made
It is to work rapidly with feature, can produce analgesic effect within about 30 seconds or so, and to mucous membrane without permeability, toxicity is low, Bu Huiying
Ring cardiovascular system and nervous system.And benzocainum is a kind of fat-soluble stronger drug, is easy to the rouge of mucous membrane or skin
Layer combines, and is not easy to penetrate and enter and generate toxicity in human body.Its action principle is block nerves tip, with release pain with not
It is suitable.The anaesthetics such as the Orthocaine synthesized using benzocainum as precursor raw material and procaine, have that stability is good, works
Fastly, the advantages that long and Small side effects of holding time.Since benzocainum related preparations mainly act on the surface of a wound, ulcer surface, and this
A little positions easily breed a large amount of bacteriums, if carrying out structural modification to benzocainum, make it have certain antibacterial action, can have
Good application prospect.From different bromo derivatives substitution reaction occurs for present invention benzocainum, has obtained a series of knots
The novel benzocainum derivative of structure, and influence of the reaction condition to single substitution reaction is had studied, finally to obtained derivative
Preliminary biological activity test is carried out, part of compounds shows certain antibacterial activity to staphylococcus aureus.
Summary of the invention
One kind that is simple the technical problem to be solved by the present invention is to provide a kind of synthesis technology and facilitating operation has antibacterial
The synthetic method and application of active benzocainum monosubstituted derivative, the part benzocainum derivative of synthesis is to golden yellow Portugal
Grape coccus shows certain antibacterial activity, therefore the compound can be applied to the drug that preparation treats or prevents bacterium.
The present invention adopts the following technical scheme that the benzocainum with antibacterial activity is disubstituted to solve above-mentioned technical problem
Derivative, it is characterised in that its structural formula are as follows:R is propinyl, methyl, to methylbenzyl, to benzyl chloride
Base, methylbenzyl.
The preparation method of benzocainum disubstituted derivative of the present invention with antibacterial activity, it is characterised in that tool
Body step are as follows:
A certain amount of benzocainum is dissolved in n,N-Dimethylformamide, solution A is configured to；A certain amount of bromo
It closes object and triethylamine is dissolved in n,N-Dimethylformamide, be configured to solution B；Solution A and solution B are passed through four with certain flow rate
Fluorine is pumped into the silicon carbide reactor device of certain reaction temperature, and material keeps certain residence time to replace in microreactor
Reaction, the material after collecting reaction, is poured into water obtained total overall reaction liquid, extracts reaction solution with chloroform, merges organic phase,
Disubstituted product N is obtained through silica gel column chromatography separation (PE:EA=5:1) after concentration, N- bis- is to methylbenzyl-to group-4 ethyl formate benzene
Amine；The inventory molar ratio of the benzocainum and bromo compound is 1:0.9~1.5；The reaction temperature be 20~
60℃；The residence time is 1~6min.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 22g (0.11mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and molten
Liquid B is pumped into the silicon carbide reactor device that reaction temperature is 40 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material is micro-
Substitution reaction occurs in reactor, and its residence time is 4min, the material after collecting reaction, obtained total overall reaction liquid
Be poured into water, with chloroform 300mL extract reaction solution 4 times, merge organic phase, after concentration through silica gel column chromatography separation (PE:EA=5:
1) mono-substituted products N- is obtained to methylbenzyl-to group-4 ethyl formate aniline 19g (0.072mol), yield 72%,1H NMR
(DMSO-d6) δ: 7.65 (d, J=6.0Hz, 2H), 7.22 (d, J=6.0Hz, 2H), 7.14 (d, J=6.0Hz, 2H), 7.06
(t, J=6.0Hz, J=6.0Hz, 1H), 6.59 (d, J=12.0Hz, 2H), 4.29 (d, J=6.0Hz, 2H), 4.19 (dd, J1
=12.0Hz, J2=6.0Hz, 2H), 2.27 (s, 2H), 1.25 (t, J1=6.0Hz, J2=6.0Hz, 3H)13C NMR
(151MHz,DMSO-d6)δ:166.28,153.10,136.67,136.32,131.30,129.39,127.60,116.69,
111.71,59.97,46.06,21.13,14.83.MS(ESI)m/z:270.4[M+H]+
Embodiment 2
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 16.6g (0.09mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and
Solution B is pumped into the silicon carbide reactor device that reaction temperature is 10 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material exists
Substitution reaction occurs in microreactor, and its residence time is 4min, the material after collecting reaction, obtained total overall reaction
Liquid is poured into water, and is extracted reaction solution 4 times with chloroform 300mL, and organic phase is merged, and separates (PE:EA=through silica gel column chromatography after concentration
Mono-substituted products N- 5:1) is obtained to methylbenzyl-to group-4 ethyl formate aniline 15.6g.
Embodiment 3
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 27.7g (0.15mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and
Solution B is pumped into the silicon carbide reactor device that reaction temperature is 40 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material exists
Substitution reaction occurs in microreactor, and its residence time is 4min, the material after collecting reaction, obtained total overall reaction
Liquid is poured into water, and is extracted reaction solution 4 times with chloroform 300mL, and organic phase is merged, and separates (PE:EA=through silica gel column chromatography after concentration
Mono-substituted products N- 5:1) is obtained to methylbenzyl-to group-4 ethyl formate aniline 10.8g.
Embodiment 4
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 22g (0.11mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and molten
Liquid B is pumped into the silicon carbide reactor device that reaction temperature is 20 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material is micro-
Substitution reaction occurs in reactor, and its residence time is 4min, the material after collecting reaction, obtained total overall reaction liquid
Be poured into water, with chloroform 300mL extract reaction solution 4 times, merge organic phase, after concentration through silica gel column chromatography separation (PE:EA=5:
1) mono-substituted products N- is obtained to methylbenzyl-to group-4 ethyl formate aniline 10.3g.
Embodiment 5
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 22g (0.11mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and molten
Liquid B is pumped into the silicon carbide reactor device that reaction temperature is 60 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material is micro-
Substitution reaction occurs in reactor, and its residence time is 4min, the material after collecting reaction, obtained total overall reaction liquid
Be poured into water, with chloroform 300mL extract reaction solution 4 times, merge organic phase, after concentration through silica gel column chromatography separation (PE:EA=5:
1) mono-substituted products N- is obtained to methylbenzyl-to group-4 ethyl formate aniline 13.7g.
Embodiment 6
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 22g (0.11mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and molten
Liquid B is pumped into the silicon carbide reactor device that reaction temperature is 40 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material is micro-
Substitution reaction occurs in reactor, and its residence time is 1min, the material after collecting reaction, obtained total overall reaction liquid
Be poured into water, with chloroform 300mL extract reaction solution 4 times, merge organic phase, after concentration through silica gel column chromatography separation (PE:EA=5:
1) mono-substituted products N- is obtained to methylbenzyl-to group-4 ethyl formate aniline 6.1g.
Embodiment 7
Benzocainum 16.5g (0.1mol) is dissolved in n,N-Dimethylformamide 200mL, solution A is configured to；To first
Base benzyl bromine 22g (0.11mol) and triethylamine 20g (0.2mol) are dissolved in DMF 200mL, are configured to solution B；Solution A and molten
Liquid B is pumped into the silicon carbide reactor device that reaction temperature is 40 DEG C with identical flow velocity 10mL/min by tetrafluoro, and material is micro-
Substitution reaction occurs in reactor, and its residence time is 6min, the material after collecting reaction, obtained total overall reaction liquid
Be poured into water, with chloroform 300mL extract reaction solution 4 times, merge organic phase, after concentration through silica gel column chromatography separation (PE:EA=5:
1) mono-substituted products N- is obtained to methylbenzyl-to group-4 ethyl formate aniline 11g.
Antibacterial activity test
We select staphylococcus aureus conduct using the antibacterial activity of antibacterial around-France [13] measurement target compound
Antibacterial activity test object.It is to prepare fluid nutrient medium (containing peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water first
100ml) and solid medium (containing peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar 2g, distilled water 100ml), pass through
High-pressure sterilizing pot sterilizes to culture medium, and solid medium is placed on the plate after sterilizing.Secondly, golden yellow grape
After coccus actication of culture, 100 μ L bacterium solutions are pipetted, are uniformly mixed in the 100ml distilled water after being placed in sterilizing.With benzocainum and sulphur
As control compound, synthesized target compound and control compound are configured to concentration with DMF is sour streptomysin
The solution of 100mg/mL impregnates in the above solution after the circular filter paper that aperture is 5mm is sterilized.
On the super-clean bench, 10 μ L fluid nutrient mediums are pipetted and are added to solid culture primary surface, coating is uniform.It is taken with aseptic nipper
The circle filter paper impregnated out is taped against media surface.Each plate puts 4, carries out 3 parallel laboratory tests and 1 blank control.
It is put into 37 DEG C of insulating boxs and cultivates for 24 hours, phenomenon is observed, by occurring different size of transparent ring-on agar medium respectively
Inhibition zone can find out the bacteriostatic activity size of each sample by measuring antibacterial circle diameter.
Shown (shown in table 1) as In Vitro Bacteriostatic test result, target compound has one to staphylococcus aureus
Fixed antibacterial activity, and all compound fungistatic effect is better than benzocainum, in mono-substituted products, has aromatic ring substituents
Compound bacteriostatic activity due to non-aromatic cyclosubstituted product, product bacteriostatic activity on aromatic ring with electron-withdrawing group structure due to
The product of donor residues structure, wherein compound f reaches 56% to the inhibiting rate of staphylococcus aureus, we will be to effect
Mechanism is further studied.
The antibacterial activity of 1 target compound of table
Table 1 Antibacterial activities of the target compounds
Above-mentioned biological activity test shows that the compound has good inhibiting effect to staphylococcus aureus, therefore
It can further treat or prevent in antibacterials and be applied in preparation.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (1)
1. a kind of synthetic method of the benzocainum monosubstituted derivative with antibacterial activity, it is characterised in that benzocainum list takes
For derivative, it is characterised in that the derivant structure formula are as follows:R is propinyl, methyl, to methylbenzyl
Base, p-chlorobenzyl, methylbenzyl；
The specific steps of benzocainum monosubstituted derivative synthetic method are as follows:
A certain amount of benzocainum is dissolved in n,N-Dimethylformamide, solution A is configured to；A certain amount of bromo compound
It is dissolved in n,N-Dimethylformamide with triethylamine, is configured to solution B；Solution A and solution B are pumped with certain flow rate by tetrafluoro
It is sent into the silicon carbide reactor device of certain reaction temperature, material keeps certain residence time to occur to replace instead in microreactor
It answers, the material after collecting reaction is poured into water obtained total overall reaction liquid, extracts reaction solution with chloroform, merges organic phase, dense
Monosubstituted derivative is obtained through silica gel column chromatography separation (PE:EA=5:1) after contracting；The benzocainum and bromo compound
Inventory molar ratio is 1:0.9~1.5；The reaction temperature is 20~60 DEG C；The residence time is 1~6min.
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| CN201811201047.9A CN109206333A (en) | 2018-10-16 | 2018-10-16 | A kind of synthetic method and application of the benzocainum monosubstituted derivative with antibacterial activity |
| CN201910202447.XA CN109761831A (en) | 2018-10-16 | 2019-03-11 | A kind of synthetic method and application of the benzocainum monosubstituted derivative with antibacterial activity |
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| US4185115A (en) * | 1975-03-12 | 1980-01-22 | American Cyanamid Company | Antilipidemic para-[aryl(alkyl or alkenyl)amino]-benzoic acid derivatives |
| JPH0228582B2 (en) * | 1985-02-06 | 1990-06-25 | Tokuyama Soda Kk | DAI2KYUAMINKAGOBUTSUNOSEIZOHOHO |
| JPS63269128A (en) * | 1987-04-27 | 1988-11-07 | Mitsubishi Petrochem Co Ltd | Nonlinear optical material |
| DK2275395T3 (en) * | 2001-04-24 | 2017-02-20 | Massachusetts Inst Of Tech (Mit) | Copper-catalyzed provision of carbon-carbon compounds. |
| CA2354921A1 (en) * | 2001-05-24 | 2002-11-24 | Yasuo Konishi | Drug evolution: drug design at hot spots |
| CN100345853C (en) * | 2003-01-24 | 2007-10-31 | 田边制药株式会社 | Pyrazolopyrimidine compound and method for producing the same |
| FR2862966B1 (en) * | 2003-11-27 | 2008-02-01 | Merck Sante Sas | NITROSO DERIVATIVES OF DIPHENYLAMINE. |
| FR2862964B1 (en) * | 2003-11-27 | 2006-12-29 | Merck Sante Sas | DERIVATIVES OF DIPHENYLAMINE. |
| JP2006056884A (en) * | 2004-07-23 | 2006-03-02 | Tanabe Seiyaku Co Ltd | Medicinal composition |
| EP2033949B1 (en) * | 2007-09-04 | 2017-04-19 | Agfa Graphics N.V. | Radiation curable compositions for food applications |
| WO2015171527A1 (en) * | 2014-05-05 | 2015-11-12 | Global Blood Therapeutics, Inc. | Pyrazolopyridine pyrazolopyrimidine and related compounds |
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