CN107827887B - Triazole methyl esters link volution compound with antibacterial activity and its preparation method and application - Google Patents
Triazole methyl esters link volution compound with antibacterial activity and its preparation method and application Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of, and the triazole methyl esters with antibacterial activity links volution compound and its preparation method and application, belongs to technical field of medicine synthesis.Technical solution of the present invention main points are as follows: a kind of triazole methyl esters link volution compound with antibacterial activity has the following structure:
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of triazole methyl esters link with antibacterial activity
Volution compound and its preparation method and application.
Background technique
Triazole compound has the structure of more five yuan of heteroaromatics of nitrogen, and structure is as a kind of important active structure list
Member shows a variety of important bioactivity, such as antibacterium, treating tuberculosis, antitumor, antiviral, anti-inflammatory and analgesia etc..It is long
It has been constantly subjected to the common concern of people since phase, is widely used in pesticide, medicine and chemical field.In pharmaceutical chemistry
In field, 1,2,3- triazole is introduced into the structure of modification of lead compound or drug candidate frequently as pharmacophoric group, from
And cause the raising or change of pharmacological activity.Such as 1H-1,2,3- triazole is synthesis beta-lactamase inhibitor Tazobactam Sodium
Important intermediate.Pharmacological Results show, Tazobactam Sodium than clinically common beta-lactamase inhibitory preparation Sulbactam and gram
The better inhibition bacterium beta-lactam enzyme effect of clavulanic acid tool (Chen Jian, wangdan etc., clinic skin section magazine, 2002,31 (8),
478-478).For another example, it has been found that use 1-H-1,2,3- triazole substituted oxazolidine ketone antibiotic linezolid (PUN-
100766) the obtained derivative of beautiful jade ring not only has fairly good anti-leather orchid scholar positive bacteria activity, but also to negative bacterium
Also there is good curative effect, to expand the antimicrobial spectrum of this kind of drug.
Spiro-compound is also a kind of important chemical intermediate, is widely used in medicine, pesticide, asymmetry catalysis, hair
The fields such as luminescent material, photochromic material and polymer binder.From the 60 to 70's of 20th century, naturally produced from nature
Isolated spiro-compound has good bioactivity in object, causes the concern of drug scholar and biologist.Spiral shell
Cycle compound molecular structure has following particularity, and molecular weight is small, and shared spatial volume is larger, and computer simulation show contains this
The molecule of class " drug template " has various physiological activity.In recent years, designing and synthesizing spiro-compound becomes organic
One hot spot in synthesis field.For example, the designs such as patent WO2007136605, Hamblett, which have synthesized, has histone deacetylase
Change the hydroximic acid spiro-compound of enzyme inhibition, this kind of compound can be lured with the selectivity of inhibition of histone deacetylase
It leads terminal differentiation and prevents the growth of chela natural disposition cell, there is significant antitumaous effect.Document (Bioorg., Med, Chem,
Lett.2008,18:3359-3363 Lippa etc. has synthesized indoline-pyrrole with AKT (protein kinase) inhibiting effect in)
Miazines spiro-compound is coughed up, tumour can be slowed down in the intracorporal speed of growth of machine.Patent WO2008144266, Flecher etc.
A series of azaindole spiro-compounds with HIF hydroxylation enzyme inhibition have been synthesized, hypoxia inducible factor hydroxyl can be inhibited
The activity for changing enzyme has important curative effect in treating anaemia relevant to cancer, but does not have treatment to red blood cell biotin
Effect.Many of plant is containing spirane structure and with the compound of physiological activity, such as vinblastine.Yao new life etc. is to stone beans
Orchid obtains a new spiro-compound after carrying out separation and Extraction, the compound can be considered in vitro be used for tumour and
In the treatment of the disease induced because nitric oxide excessively discharges in vivo.
We link 1,2,3- triazole ring and spirane structure, have synthesized a kind of novel triazole methyl esters chain
Connect volution compound.
Summary of the invention
The technical problem to be solved by the present invention is to provide one kind, operation is simple, raw material is cheap and easy to get, compound structure
Novelty, insecticidal activity is good, reaction efficiency is high and a kind of reproducible triazole methyl esters with antibacterial activity links loop coil
Class compound and its preparation method and application.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of triazole first with antibacterial activity
Ester links volution compound, it is characterised in that the molecular structure of the compound are as follows:
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of triazole first with antibacterial activity
The preparation method of ester link volution compound, it is characterised in that specific steps are as follows:
A, the chloro- 5- fluorine pyridine of 2,3- bis-, which reacts with ammonia water, generates the fluoro- 3- aminopyridine of the chloro- 5- of 2-；Again by H2O2Oxidation obtains
The fluoro- 3- nitropyridine of the chloro- 5- of 2-；Again with NaN3It is reduced after reaction, obtains 2- amino-5-fluorine -3- nitropyridine；Last 2- ammonia
The fluoro- 3- nitropyridine of base -5- sloughs nitro and obtains 2- amino-5-fluorine-pyridine；
B, 2- amino-5-fluorine-pyridine obtains 2- amino-5-fluorine-piperidines by hydrogenating reduction；
C, 2- amino-5-fluorine-piperidines reacts annulation with formamide and carbon monoxide under the action of catalyst and obtains
Fluoro- -1,3,6- the thriazaspiro [4,5] of (5S) -8--decyl- 2,4- diketone；
D, the fluoro- 1,3,6- thriazaspiro [4,5] of (5S) -8--decyl- 2,4- diketone hydrolyzes obtain (2R)-under alkaline condition
2- amino-5-fluorine-piperidines -2- formic acid；
E, (2R) -2- amino-5-fluorine-piperidines -2- formic acid and methanol generation esterification obtain (2R) -2- amino-5-fluorine -
Piperidines -2- methyl formate；Acrylic acid and formamide obtain oxazole acetic acid；
F, (2R) -2- amino-5-fluorine-piperidines -2- methyl formate and oxazole acetic acid occur after substitution reaction in alkaline condition
Under self-condensation occur again obtain fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] the decyl- 3- alkene -2- ketone of (5R) -3- oxazole -8-；
G, fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] the decyl- 3- alkene -2- ketone of (5R) -3- oxazole -8- and phosgene and nitrine
Change sodium to react to obtainOccur again with Methyl propiolate anti-
It should obtain
It further limits, the detailed process of step A: the chloro- 5- fluorine pyridine of 2,3- bis- being added in ammonium hydroxide, if temperature is
180 DEG C, reaction under high pressure 52h, TLC detect raw material fully reacting, rotate solvent, column chromatographs to obtain the fluoro- 3- amino pyrrole of the chloro- 5- of 2-
Pyridine；The fluoro- 3- aminopyridine of the chloro- 5- of 2- is placed in the round-bottomed flask for being dissolved in acetonitrile, water buffer solution (0.6M is sequentially added
K2CO3-4×10-4M EDETATE DISODIUM), acetonitrile and 30%H2O2Reaction mixture is stirred at room temperature 1 hour aqueous solution,
Mixture is extracted with ethyl acetate, and merges organic layer, uses anhydrous Na2SO4It is dry, solvent is removed under vacuum, and passes through short silica gel
Plug is separated by filtration the fluoro- 3- nitropyridine of the chloro- 5- of product 2- of enough purity；To the fluoro- 3- nitropyridine of the chloro- 5- of 2- in DMSO/
H2L-PROLINE, Na are added in solution in O (mass ratio 9:1)2CO3, NaN3, sodium ascorbate and CuSO4·5H2O；It will mix
It closes object to stir 24 hours at 70 DEG C of oil bath, then pour the mixture into ice water；Solid product is filtered and is crystallized and obtains 2-
Amino-5-fluorine -3- nitropyridine；Aqueous sulfuric acid is added in 2- amino-5-fluorine -3- nitropyridine, adds a certain amount of chlorine
Acetic acid is heated to 120 DEG C, after TLC monitors raw material fully reacting, and reaction solution is extracted with dichloromethane, then molten with sodium carbonate saturation
It is 7~8 that liquid, which adjusts organic phase pH, and concentration organic phase obtains 2- amino-5-fluorine-pyridine；The wherein fluoro- 3- nitre of the chloro- 5- of 2-
Yl pyridines and L-PROLINE, Na2CO3, NaN3, sodium ascorbate, CuSO4·5H2The inventory molar ratio of O is 1:7:7:10:5:
7。
It further limits, the detailed process of step B: dehydrated alcohol, 2- amino-5-fluorine-pyridine, thunder being added into autoclave
Buddhist nun's nickel, seals kettle cover；Gas is multiple in logical nitrogen replacement reaction kettle, then is replaced repeatedly with hydrogen, is passed through 1.0Mpa every time；Displacement
Terminate, leads to hydrogen to 1.5Mpa, open stirring, be warming up to 120~130 DEG C, start to consume hydrogen, when being down to 0.5Mpa, supplement hydrogen
Gas keeps 2.0~2.5Mpa to 2.5Mpa, the confirmation of reaction a period of time no longer consumption hydrogen when, control in sampling, when starting material left is small
Reacting when 1% terminates, and is cooled to 30 DEG C, filters out catalyst, filtrate steaming removal solvent, it is 2- amino -5- that decompression, which steams product,
Fluoro-piperidine.
It further limits, the detailed process of step C: water being added into autoclave, open stirring, formamide is added,
2- amino-5-fluorine-piperidines is added after stirring, adds catalyst, CO is passed through into reaction kettle, reach pressure in kettle
0.2MPa is warming up to 50 DEG C of reaction a period of times, and less than 2%, reaction terminates middle control raw material, 25~30 DEG C is cooled to, to reaction
Dilute hydrochloric acid is added dropwise in liquid, adjusting pH is 5~6, has solid precipitation, filters out product, and filter cake shuffles once, (5S) -8- fluoro- 1 is obtained,
3,6- thriazaspiro [4,5]-decyl- 2,4- diketone；The catalyst is rhodium C catalyst, rhodium aluminium oxide catalyst or levulinic
Ketone triphenylphosphine rhodium carbonyl.
It further limits, the detailed process of step D: water being added into reaction flask, 40 DEG C or so are heated under stirring, hydrogen
Barium monoxide is put into four-hole bottle, stirring and dissolving；(5S) -8- fluoro- 1,3,6- thriazaspiros [4,5]-decyl- 2 is added, 4- diketone adds
Heat was to back flow reaction 5 hours；Sampling monitoring, stops reaction after starting material left amount area percentage composition is less than 2%, and reaction is completed
Afterwards, cool down 60 DEG C or so, the concentrated sulfuric acid is slowly added dropwise into four-hole bottle, adjust pH value 3 or so；10min repetition measurement pH value is stirred, is stablized
Water and active carbon is added in backward system, is warming up to 80 DEG C and stirs 60 minutes；Filtering out solid while hot is residue, and filtrate heating is dense
Contracting, water extra in system is fallen in concentration under vacuum condition, and when steaming to thick-pasty, distillation terminates that toluene is added, (for dehydration
Toluene can be reuse 3 times, and when each reuse adds one barrel of new toluene) normal pressure divides water, after moisture to the greatest extent after, be cooled to 30 DEG C or less；From
Heart filtering, solid drying are weighed up to (2R) -2- amino-5-fluorine-piperidines -2- formic acid.
It further limits, (2R) -2- amino-5-fluorine-piperidines -2- formic acid and the methanol of step E occurs esterification and obtains
(2R) -2- amino-5-fluorine-piperidines -2- methyl formate detailed process: methanol is added into reaction flask, is added with stirring (2R) -2-
Amino-5-fluorine-piperidines -2- formic acid stirs 10 minutes；It is slowly added dropwise (excessive 1.2mol) thionyl chloride, time for adding is about 2~
3 hours；Process control kettle temperature is added dropwise less than 60 DEG C, is suitable with micro- reflux visible on condenser；It is added dropwise, is warming up to reflux
Reaction 10 hours, sample detection；Stop reaction after reaction raw materials surplus area percentage composition is detected less than 1%；Vacuum removal
Solvent methanol is steamed to thick, stopping heating；Hexamethylene is added into reaction flask, atmospheric pressure reflux separates remaining first in system
Alcohol (water segregator lower layer is methanol)；When can't see methanol and separate, stop reaction；Open cooling water temperature to 30 DEG C hereinafter,
Filter (2R) -2- amino-5-fluorine-piperidines -2- methyl formate.
It further limits, the detailed process of step F: DMF being added into reaction flask, is added with stirring (2R) -2- amino -5-
Fluoro-piperidine -2- methyl formate is slow added into sodium bicarbonate, can release great amount of carbon dioxide in adition process, and control is needed to add
Enter speed, after (when 30% or so of total carbonic acid hydrogen sodium amount is added, can accelerate that speed is added, do not have foam evolution) adds
Stirring 30 minutes；Ethyl acetate is added, is put into ice-water bath, reaction solution is cooled to 0 DEG C；Start that oxazole acetic acid, control is added dropwise
0~5 DEG C of temperature, rate of addition is controlled with temperature；After being added dropwise, 0~5 DEG C is stirred to react 5 hours, sampling monitoring react into
Journey, when starting material left is less than 2%, reaction terminates；Basic zeolite molecular sieve KF/Al is added2O3, open stirring；And it is passed through nitrogen
There is bubble to emerge to bubbler, 20~30 DEG C of kettle temperature of control and nitrogen protection are stirred to react 2 hours, sample detection in this temperature,
Raw material area percentage content less than 0.5% after stop reaction；Vacuum is opened to -0.1Mpa, 80~90 DEG C of kettle temperature, is removed under decompression
Neat solvent waits steaming to thick-pasty, after being cooled to 40 DEG C, opens nitrogen protection, and water is added dropwise into system and (notices that phenomenon becomes in kettle
Change and temperature change) after completion of dropwise addition, stir 15min, remaining water is added at one time after stablizing, being slow added into concentration is
6% NaOH solution stirs 20min after being added, and filters out KF/Al2O3(reusable), static layering, upper layer floccule point
Fall to discard, lower aqueous layer retains, and hydrochloric acid acidification is added dropwise, and (acid adding speed needs to control, and too fast addition speed can be such that product is precipitated
Moment package impurity and form lump) there are in kettle a large amount of solids to be precipitated, when pH value reaches 3~4, continue after stirring a period of time
It filters out solid product and obtains fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] the decyl- 3- alkene -2- ketone of (5R) -3- oxazole -8-.
It further limits, the detailed process of step G: water being added into reaction flask, adds dry (5R) -3- oxazole -
Fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] decyl- 3- alkene -2- ketone of 8- and sodium azide, reaction temperature are set as -5 DEG C, slowly drip
Liquid feeding state phosgene controls rate of addition, and reaction temperature is made to be no more than 0 DEG C, is slowly increased to room temperature after stirring 1h after dripping, and continues
1h is stirred, TLC monitors raw material fully reacting, and it is neutral for adjusting reaction solution pH with saturated sodium bicarbonate solution, then uses methylene chloride
Reaction solution is extracted, is concentrated to get after merging organic phase?It is added anti-
It answers in bottle, water adds a certain amount of catalyst as solvent, Methyl propiolate is added into reaction flask, at room temperature
5h is reacted, after TLC monitors raw material fully reacting, reaction solution is extracted with ethyl acetate, is concentrated to get compound after merging organic phaseThe catalyst is positive triphenylphosphine cuprous complex.
A kind of synthetic route of triazole methyl esters link volution compound with antibacterial activity of the present invention
Are as follows:
Operation is simple, raw material is cheap and easy to get, reaction efficiency is high and reproducible for present invention kind.
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
The chloro- 5- fluorine pyridine 85g (0.5mol) of 2,3- bis- is added in ammonium hydroxide 200mL in a high pressure reaction kettle, if temperature
It is 180 DEG C, for 24 hours, TLC detects raw material fully reacting to reaction under high pressure, and revolving solvent obtains the fluoro- 3- aminopyridine 65g of the chloro- 5- of 2-；
The fluoro- 3- aminopyridine 65g (0.45mol) of the chloro- 5- of 2- is placed in the round-bottomed flask for being dissolved in acetonitrile 900mL, it is slow to sequentially add water
Rush solution 450mL (0.6M K2CO3-4×10-4M EDETATE DISODIUM), acetonitrile 350mL (3mol) and 30%H2O2Aqueous solution
290mL (3mol) is extracted after reaction mixture is stirred at room temperature 1 hour with ethyl acetate (3 × 300mL), is merged organic
Layer, uses anhydrous Na2SO4It is dry, solvent is removed under vacuum obtains the fluoro- 3- nitropyridine of the chloro- 5- of product 2- of enough purity
65g；To the fluoro- 3- nitropyridine 65g (0.35mol) of the chloro- 5- of 2- in DMSO/H2Solution in O (mass ratio 9:1,3500mL)
Middle addition L-PROLINE 230g (2mol), Na2CO3210g (2mol), NaN3230g (3.5mol), sodium ascorbate 350g
(1.75mol) and CuSO4·5H2O500g(2mol)；Mixture is stirred 24 hours at 70 DEG C of oil bath, then falls mixture
Enter in 5000mL ice water, solid product is filtered and crystallizes acquisition 2- amino-5-fluorine -3- nitropyridine 47g；By 2- amino -5-
Aqueous sulfuric acid is added in fluoro- 3- nitropyridine, adds a certain amount of monoxone, is heated to 120 DEG C, TLC monitors raw material reaction
After completely, reaction solution is extracted with dichloromethane, then adjusting organic phase pH with saturated solution of sodium carbonate is 7~8, concentration organic phase obtains
To 2- amino-5-fluorine-pyridine.
Embodiment 2
Dehydrated alcohol 2000mL, 2- amino-5-fluorine-pyridine 160g (1mol), Raney's nickel 16g, envelope are added into autoclave
Good kettle cover；Gas is multiple in logical nitrogen replacement reaction kettle, then is replaced repeatedly with hydrogen, is passed through 1.0Mpa every time；Replacement completion is led to
Hydrogen opens stirring, is warming up to 120~130 DEG C, start to consume hydrogen, when being down to 0.5Mpa, hydrogen make-up is extremely to 1.5Mpa
2.5Mpa and keep 2.0~2.5Mpa, the confirmation of reaction a period of time no longer consumption hydrogen when, control in sampling, when starting material left is less than
Reaction terminates when 1%, is cooled to 30 DEG C, filters out catalyst, filtrate steaming removal solvent, it is 2- amino-5-fluorine-that decompression, which steams product,
Piperidinyl-1 50g, yield 92%.
Embodiment 3
Water 1200mL is added into autoclave, opens stirring, addition concentration is 40% formamide solution 225g
(2mol) after stirring 10min, is added 2- amino-5-fluorine-piperidinyl-1 63g (1mol), rhodium C catalyst 7g is added, to reaction kettle
In be passed through CO, so that pressure in kettle is reached 0.2MPa, be warming up to 50 DEG C, keep the temperature 20h, less than 2%, reaction terminates middle control raw material, drops
Dilute hydrochloric acid is added dropwise into reaction solution to 25~30 DEG C for temperature, and adjusting pH is 5~6, has solid precipitation, filters out product, filter cake shuffles
Once, (5S) -8- fluoro- 1,3,6- thriazaspiros [4,5]-decyl- 2,4- diketone 210g, yield 90.5% are obtained；1HNMR(400MHz,
DMSO-d6) δ: 10.23-10.22 (m, 1H), 6.78 (s, 1H), 3.47 (d, J=4.0Hz, 1H), 3.07-3.06 (m, 2H),
1.99-1.98(m,2H),1.64-1.63(m,2H)。
Embodiment 4
Water 1200mL is added into autoclave, opens stirring, addition concentration is 40% formamide solution 225g
(2mol) after stirring 10min, is added 2- amino-5-fluorine-piperidinyl-1 63g (1mol), adds rhodium aluminium oxide catalyst 7g, to anti-
It answers and is passed through CO in kettle, pressure in kettle is made to reach 0.2MPa, be warming up to 50 DEG C, keep the temperature 20h, middle control raw material is less than 2%, reaction knot
Beam is cooled to 29 DEG C, and dilute hydrochloric acid is added dropwise into reaction solution, and adjusting pH is 5~6, there is solid precipitation, filters out product, and filter cake is mixed
It washes once, obtains (5S) -8- fluoro- 1,3,6- thriazaspiros [4,5]-decyl- 2,4- diketone 191g, yield 82%.
Embodiment 5
Water 1200mL is added into autoclave, opens stirring, addition concentration is 40% formamide solution 225g
(2mol) after stirring 10min, is added 2- amino-5-fluorine-piperidinyl-1 63g (1mol), adds acetylacetone,2,4-pentanedione triphenylphosphine carbonyl
Rhodium 7g, CO is passed through into reaction kettle, and pressure in kettle is made to reach 0.2MPa, is warming up to 50 DEG C, keeps the temperature 20h, and middle control raw material is less than
2%, reaction terminates, and is cooled to 27 DEG C, and dilute hydrochloric acid is added dropwise into reaction solution, and adjusting pH is 5~6, has solid precipitation, filtering is produced
Product, filter cake shuffle once, obtain (5S) -8- fluoro- 1,3,6- thriazaspiros [4,5]-decyl- 2,4- diketone 220g, yield 95%.
Embodiment 6
Water 720g is added into 2000mL four-hole bottle, 40 DEG C or so are heated under stirring, barium hydroxide 340g (2mol)
It puts into four-hole bottle, stirs 10 minutes, dissolution；The fluoro- 1,3,6- thriazaspiro [4,5] of (5S) -8--decyl- 2,4- diketone is added
232g (1mol), is heated to back flow reaction 5 hours；Sampling monitoring stops after starting material left amount area percentage composition is less than 2%
Reaction cools down 60 DEG C or so after the reaction was completed, and the concentrated sulfuric acid is slowly added dropwise into four-hole bottle and adjusts reacting liquid pH value 3 or so；(sulphur
The additional amount of acid is subject to pH value) stirring 10min repetition measurement pH value, water 150g is added after stablizing into system, activity is added later
Charcoal 25g is warming up to 80 DEG C and stirs 60 minutes；Filtering out solid while hot is residue, filtrate heating concentration, when vacuum reaches-
Extra water in system is fallen in 0.1Mpa, 100 DEG C of kettle temperature concentrations, and when steaming to thick-pasty, distillation terminates that toluene 400g is added, and (uses
Can be reuse 3 times in the toluene of dehydration, when each reuse, adds one barrel of new toluene) normal pressure divides water, after moisture to the greatest extent after, be cooled to 30 DEG C
Below；Centrifugal filtration, solid drying are weighed up to (2R) -2- amino-5-fluorine-piperidines -2- formic acid 189g, yield 91%, filtrate
Dehydration (can apply 3 times, barrelling saves after 3 times, is further continued for applying after re-distillation) is applied to for toluene.
Embodiment 7
Methanol 320mL is added into 1000mL four-hole bottle, is added with stirring (2R) -2- amino-5-fluorine-piperidines -2- formic acid
105g (0.5mol) is stirred 10 minutes；It is slowly added dropwise thionyl chloride (0.6mol), time for adding is about 2-3 hours；Dropwise addition process
Kettle temperature is controlled less than 60 DEG C, is suitable with micro- reflux visible on condenser.It is added dropwise, is warming up to back flow reaction 10 hours, takes
Sample detection；Stop reaction after reaction raw materials surplus area percentage composition is detected less than 1%；Vacuum is opened to -0.08Mpa, 40
~60 DEG C of removing solvent methanols are steamed to thick, stopping heating；Hexamethylene 400ml is added into four-hole bottle, atmospheric pressure reflux separates
Remaining methanol in system (water segregator lower layer is methanol)；When can't see methanol and separate, stop reaction.Open cooling water drop
Temperature is to 30 DEG C hereinafter, filtering, filtrate recycle to hexamethylene band methanol process, solid weighing obtain (2R) -2- amino-5-fluorine-piperazine
Pyridine -2- methyl formate 99g, yield 92%；1HNMR(400MHz,DMSO-d6)δ:5.62(s,2H),4.11(s,3H),3.33(d,
J=4.0Hz, 1H), 3.19-3.18 (m, 2H), 2.45-2.44 (m, 2H), 1.78-1.77 (m, 2H).
Embodiment 8
Water 3000mL is added in reaction flask, tween 30mL is added, adds acrylic acid 36g (0.5mol), is eventually adding
People's dopamine-β hydroxylase (1g), 36 DEG C of reaction 1h.After reaction, it is spin-dried for water, ethyl alcohol 3000mL is added, adding concentration is
40% formyl amine aqueous solution 56g (0.5mol), back flow reaction 1h.After reaction, it is spin-dried for ethyl alcohol, ethyl acetate dissolution is added,
Add saturated salt solution to extract, organic phase is concentrated, column chromatographs to obtain oxazole acetic acid 62g, yield 88%.
Embodiment 9
N,N-Dimethylformamide 700g is added into 3000mL four-hole bottle, is added with stirring (2R) -2- amino-5-fluorine -
Piperidines -2- methyl formate 176g (1mol) is slowly added to sodium bicarbonate 168g later, can release a large amount of titanium dioxides in adition process
Carbon, especially preceding 50g adition process foam is most obvious, needs to control addition speed, (when 30% left side that total carbonic acid hydrogen sodium amount is added
When right, can accelerate be added speed, do not have foam evolution) add after stir 30 minutes；Ethyl acetate 1230g is added, is put into
In ice-water bath, reaction solution is cooled to 0 DEG C；Start that oxazole acetic acid 130g (1mol) is added dropwise, controls 0~5 DEG C of temperature, rate of addition
It is controlled with temperature；After being added dropwise, 0~5 DEG C is stirred to react 5 hours, sampling monitoring reaction process, when starting material left < 2%
When, reaction terminates；KF/Al is added2O3200g opens stirring；And being passed through nitrogen to bubbler has bubble to emerge.Control kettle temperature 20
~30 DEG C and nitrogen protection, are stirred to react 2 hours, sample detection, after raw material area percentage content is less than 0.5% in this temperature
Stop reaction；Vacuum is opened to -0.1Mpa, 80~90 DEG C of kettle temperature, decompression is lower except neat solvent waits steaming to thick-pasty, is cooled to 40
After DEG C, nitrogen protection is opened, (adjustment nitrogen pressure 0.02Mpa) water 100g is added dropwise into system and (starts 20g to be slowly added dropwise, infuse
Anticipate phenomenon variation and temperature change in kettle) after completion of dropwise addition, 15min is stirred, remaining water is added at one time after stablizing, is stirred
10min is slow added into after 6%NaOH 480g is added and stirs 20min, filters KF/Al2O3(reusable), static layering,
Upper layer floccule point falls to discard, and lower aqueous layer retains, and hydrochloric acid acidification is added dropwise, (acid adding speed needs to control, too fast addition speed meeting
Moment package impurity that product is precipitated and form lump) there are in kettle a large amount of solids to be precipitated, when pH value reaches 4, acidification terminates,
Hydrochloric acid 230g is taken around, when pH stable is to 3, continues to stir 30min, solid product is filtered out later and obtains (5R) -3- evil
Fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] decyl- 3- alkene -2- ketone 242g of azoles -8-, yield 95.6%.
Embodiment 10
Water 1000mL is added into reaction flask, adds dry fluoro- 4- hydroxyl -1, the 6- diaza of (5R) -3- oxazole -8-
Loop coil [4,5] decyl- 3- alkene -2- ketone 25g (0.1mol) and sodium azide 10g, reaction temperature are set as -5 DEG C, and liquid light is slowly added dropwise
Gas 20mL controls rate of addition, and reaction temperature is made to be no more than 0 DEG C, is slowly increased to room temperature after stirring 1h after dripping, continues to stir
1h, TLC monitor raw material fully reacting, and it is neutral for adjusting reaction solution pH with saturated sodium bicarbonate solution, then with methylene chloride 500mL
It extracts reaction solution three times, is concentrated to get after merging organic phase30g, yield 93.7%；1HNMR
(400MHz,DMSO-d6) δ: 8.22 (m, 1H), 7.97 (s, 1H), 7.63-7.62 (m, 1H), 3.46 (d, J=4.0Hz, 1H),
3.02-3.01(m,2H),1.79-1.77(m,2H),1.53-1.51(m,2H)。
Embodiment 11
In reaction flask,Reaction flask is added in 32g (0.1mol) and water 500mL, adds
Positive triphenylphosphine cuprous complex 3g, is eventually adding Methyl propiolate 16g (0.2mol), reacts 5h, TLC prison at room temperature
After controlling raw material fully reacting, filtering reacting liquid three times with ethyl acetate 300mL extraction filtrate is concentrated to get after merging organic phase
Compound32g, yield 80%；1HNMR(400MHz,DMSO-d6)δ:8.32-8.31(m,
1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.69-7.68 (m, 1H), 3.89 (s, 3H), 3.39 (d, J=4.0Hz, 1H),
3.06-3.05(m,2H),1.75-1.74(m,2H),1.63-1.62(m,2H)。
Embodiment 12
Biological activity determination
We select Escherichia coli (Gram-negative brevibacterium) and golden yellow glucose coccus (gram-positive bacteria) conduct
Antibacterial activity test object.It is to prepare fluid nutrient medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water first
100ml is placed in 250ml conical flask, is placed on electric furnace and is heated while stirring, it is to be mixed clarification it is uniform when, stop heating, by bottle
Mouthful successively sealed for use with gauze and brown paper) and solid medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar
2g, distilled water 100ml are placed in 250ml conical flask, are placed on electric furnace and are heated while stirring, it is to be mixed clarification it is uniform when, stop
Heating, bottleneck gauze and brown paper are successively sealed for use)；Then culture medium is carried out at sterilizing by high-pressure sterilizing pot
Reason.It is living to pipette 100 μ L with liquid-transfering gun after Escherichia coli and golden yellow glucose coccus actication of culture for the followed by preparation of bacterium solution
Bacterium solution after change is placed in sterilized 100ml distilled water and is uniformly mixed.It sterilizes finally by ultraviolet lamp to plate, so
Culture medium is quickly poured into plate while hot afterwards, thickness about 0.15cm is uniformly paved, and is stood, is allowed its slow solidification, puts after solidification
Enter to cultivate one day in 37 DEG C of incubator and does no Detection.
Synthesized target compound and control compound solution are respectively configured with DMF, is placed in volumetric flask stand-by.With beating
Hole device punches on filter paper, aperture 5mm, is immersed in the sample solution that concentration is 10mg/ml after then filter paper sterilizes
For use.
On superclean bench, alcolhol burner is lighted, takes the 10 diluted culture solutions of μ L to be added to solid culture base table with liquid-transfering gun
Face, and be coated with uniform.The garden filter paper impregnated is taken to be taped against media surface with aseptic nipper.Each plate puts 4, carries out 3
Secondary parallel laboratory test, wherein a piece of carry out blank control.The plate for being placed with tablet is placed in 37 DEG C of insulating boxs and is cultivated for 24 hours, observation
Phenomenon.It, can by measurement antibacterial circle diameter by occurring different size of transparent ring-inhibition zone on agar medium respectively
To find out the bacteriostatic activity size of each sample.
As seen from the above table, obtained target compound is much better than streptomycin sulphate to the inhibitory activity of Escherichia coli, right
The inhibiting effect of Staphylococcus aureus is weaker than streptomycin sulphate.
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 (10)
1. a kind of triazole methyl esters with antibacterial activity links volution compound, it is characterised in that its structural formula are as follows:。
2. a kind of preparation side of the triazole methyl esters link volution compound described in claim 1 with antibacterial activity
Method, it is characterised in that specific steps are as follows:
A, the chloro- 5- fluorine pyridine of 2,3- bis-, which reacts with ammonia water, generates the fluoro- 3- aminopyridine of the chloro- 5- of 2-, then by H2O2Oxidation obtains 2-
The chloro- fluoro- 3- nitropyridine of 5-, then with NaN3It is reduced after reaction, obtains 2- amino-5-fluorine -3- nitropyridine, last 2- ammonia
The fluoro- 3- nitropyridine of base -5- sloughs nitro and obtains 2- amino-5-fluorine-pyridine；
B, 2- amino-5-fluorine-pyridine obtains 2- amino-5-fluorine-piperidines by hydrogenating reduction；
C, annulation occurs under the action of catalyst and obtains (5S) -8- for 2- amino-5-fluorine-piperidines and formamide and carbon monoxide
Fluoro- -1,3,6- thriazaspiro [4,5]-decyl- 2,4- diketone；
D, the fluoro- 1,3,6- thriazaspiro [4,5] of (5S) -8--decyl- 2,4- diketone hydrolyzes obtain (2R) -2- ammonia under alkaline condition
Base -5- fluoro-piperidine -2- formic acid；
E, (2R) -2- amino-5-fluorine-piperidines -2- formic acid and methanol generation esterification obtain (2R) -2- amino-5-fluorine-piperazine
Pyridine -2- methyl formate；Acrylic acid and formamide obtain oxazole acetic acid；
F, (2R) -2- amino-5-fluorine-piperidines -2- methyl formate and oxazole acetic acid occur after substitution reaction under alkaline condition again
Self-condensation occurs and obtains fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] the decyl- 3- alkene -2- ketone of (5R) -3- oxazole -8-；
G, fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] the decyl- 3- alkene -2- ketone of (5R) -3- oxazole -8- and phosgene and sodium azide
It reacts to obtain,It reacts to obtain with Methyl propiolate again。
3. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that the detailed process of step A are as follows: the chloro- 5- fluorine pyridine of 2,3- bis- is added in ammonium hydroxide, temperature is 180 DEG C, high
Pressure reaction 52h, TLC detect raw material fully reacting, rotate solvent, column chromatographs to obtain the fluoro- 3- aminopyridine of the chloro- 5- of 2-；2- is chloro-
The fluoro- 3- aminopyridine of 5- is placed in the round-bottomed flask for filling acetonitrile, sequentially adds 0.6M K2CO3 -4×10-4 M EDETATE SODIUM
Buffered saline solution, acetonitrile and 30%H2O2Reaction mixture is stirred at room temperature 1 hour aqueous solution, mixture acetic acid second
Ester extraction, merges organic layer, uses anhydrous Na2SO4It is dry, solvent is removed under vacuum, and product is separated by filtration by short silica gel plug
The fluoro- 3- nitropyridine of the chloro- 5- of 2-；To the DMSO/H of the fluoro- 3- nitropyridine of the chloro- 5- of 2-2In O solution be added L-PROLINE,
Na2CO3、NaN3, sodium ascorbate and CuSO4·5H2O, wherein solvent DMSO and H2The mass ratio of O is 9:1；By mixture in oil
It stirs 24 hours at 70 DEG C of bath, then pours the mixture into ice water；Solid product is filtered and is crystallized and obtains 2- amino -5-
Fluoro- 3- nitropyridine；Aqueous sulfuric acid is added in 2- amino-5-fluorine -3- nitropyridine, a certain amount of monoxone is added, adds
Heat is to 120 DEG C, after TLC monitors raw material fully reacting, reaction solution is extracted with dichloromethane, then have with saturated solution of sodium carbonate adjusting
Machine phase pH is 7 ~ 8, and concentration organic phase obtains 2- amino-5-fluorine-pyridine；The wherein fluoro- 3- nitropyridine of the chloro- 5- of 2- and L-
Proline, Na2CO3、NaN3, sodium ascorbate, CuSO4·5H2The inventory molar ratio of O is 1:7:7:10:5:7.
4. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that the detailed process of step B are as follows: dehydrated alcohol, 2- amino-5-fluorine-pyridine, thunder Buddhist nun are added into autoclave
Nickel seals kettle cover；Gas is multiple in logical nitrogen replacement reaction kettle, then is replaced repeatedly with hydrogen, is passed through 1.0MPa hydrogen every time；It sets
End is changed, leads to hydrogen to 1.5MPa, opens stirring, be warming up to 120 ~ 130 DEG C, start to consume hydrogen, when being down to 0.5MPa, supplement hydrogen
Gas keeps 2.0 ~ 2.5MPa to 2.5MPa, the confirmation of reaction a period of time no longer consumption hydrogen when, control in sampling, when starting material left is small
Reacting when 1% terminates, and is cooled to 30 DEG C, filters out catalyst, and solvent is evaporated off in filtrate decompression, obtains product 2- amino-5-fluorine-
Piperidines.
5. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that the detailed process of step C are as follows: water is added into autoclave, opens stirring, formamide, stirring is added
2- amino-5-fluorine-piperidines is added afterwards, adds catalyst, CO is passed through into reaction kettle, pressure in kettle is made to reach 0.2MPa, rises
To 50 DEG C of reaction a period of times, less than 2%, reaction terminates middle control raw material temperature, is cooled to 25 ~ 30 DEG C, dilute salt is added dropwise into reaction solution
Acid, adjusting pH is 5 ~ 6, has solid precipitation, filters out product, filter cake shuffles once, obtains (5S) -8- fluoro- 1,3,6- thriazaspiros
[4,5]-decyl- 2,4- diketone；The catalyst is rhodium C catalyst, rhodium aluminium oxide catalyst or acetylacetone,2,4-pentanedione triphenylphosphine carbonyl
Base rhodium.
6. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that the detailed process of step D are as follows: water is added into reaction flask, 40 DEG C are heated under stirring, barium hydroxide is thrown
Enter in four-hole bottle, stirring and dissolving；(5S) -8- fluoro- 1,3,6- thriazaspiros [4,5]-decyl- 2 is added, 4- diketone is heated to flowing back
Reaction 5 hours；Sample detection stops reaction after starting material left amount area percentage composition is less than 2%, after the reaction was completed, is cooled to
60 DEG C, the concentrated sulfuric acid is added dropwise into four-hole bottle, adjusts pH value to 3；10min repetition measurement pH value is stirred, water is added into system after stablizing
And active carbon, it is warming up to 80 DEG C and stirs 60 minutes；Solid residue is filtered out while hot, and filter vacuum heating concentration is steamed to sticky paste
Shape is added toluene normal pressure and divides water, after moisture is most, is cooled to 30 DEG C hereinafter, centrifugal filtration, solid drying are weighed up to (2R)-
2- amino-5-fluorine-piperidines -2- formic acid；Wherein, for dividing toluene reuse 3 times of water, when each reuse, adds one barrel of new toluene.
7. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that (the 2R) -2- amino-5-fluorine-piperidines -2- formic acid and methanol of step E occurs esterification and obtains (2R) -2-
Amino-5-fluorine-piperidines -2- methyl formate detailed process are as follows: methanol is added into reaction flask, is added with stirring (2R) -2- amino -
5- fluoro-piperidine -2- formic acid stirs 10 minutes；Excessive 1.2mol thionyl chloride is added dropwise, time for adding is 2 ~ 3 hours；It was added dropwise
Process control kettle temperature is suitable with micro- reflux visible on condenser less than 60 DEG C；It is added dropwise, is warming up to back flow reaction 10 hours,
Sample detection；Stop reaction after reaction raw materials surplus area percentage composition is detected less than 1%；Solvent removed by vacuum methanol steams extremely
It is thick, stop heating；Hexamethylene is added into reaction flask, atmospheric pressure reflux separates remaining methanol in system, water segregator lower layer
It is methanol；When can't see methanol and separate, stop reaction；Cooling water temperature is opened to 30 DEG C hereinafter, filtering (2R) -2- ammonia
Base -5- fluoro-piperidine -2- methyl formate.
8. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that the detailed process of step F are as follows: DMF is added into reaction flask, is added with stirring (2R) -2- amino-5-fluorine -
Piperidines -2- methyl formate adds sodium bicarbonate, can release carbon dioxide in adition process, need to control addition speed, when adding
It when entering 30% or so of total carbonic acid hydrogen sodium amount, can accelerate that speed is added, not have foam evolution, stirred 30 minutes after adding；Add
Enter ethyl acetate, be put into ice-water bath, reaction solution is cooled to 0 DEG C；Start that oxazole acetic acid is added dropwise, control 0 ~ 5 DEG C of temperature, is added dropwise
Speed is controlled with temperature；After being added dropwise, 0 ~ 5 DEG C is stirred to react 5 hours, sampling monitoring reaction process, when starting material left is small
When 2%, reaction terminates；Basic zeolite molecular sieve KF/Al is added2O3, open stirring；And being passed through nitrogen to bubbler has bubble to emit
Out, 20 ~ 30 DEG C of kettle temperature of control and nitrogen protection, are stirred to react 2 hours, sample detection, raw material area percentage contains in this temperature
Stop reaction after measuring less than 0.5%；Vacuum is opened to -0.1MPa, 80 ~ 90 DEG C of kettle temperature, evaporating solvent under reduced pressure, wait steam to sticky paste
Shape and when being cooled to 40 DEG C, opens nitrogen protection, water is added dropwise into system, pays attention to phenomenon variation and temperature change, dropwise addition in kettle
After, 15min is stirred, is added at one time remaining water after stablizing, is slow added into the NaOH solution that concentration is 6%, is added
After stir 20min, filter out KF/Al2O3Recycling, static layering, upper layer floccule point fall to discard, and lower aqueous layer retains, drop
Add hydrochloric acid to be acidified, there is solid precipitation in kettle, acid adding speed needs to control, the moment package that too fast addition speed can be such that product is precipitated
Impurity and form lump, when pH value reaches 3 ~ 4, continue to filter out solid product after stirring a period of time and obtain (5R) -3- oxazole -
Fluoro- 4- hydroxyl -1,6- diazaspiracyclic [4,5] the decyl- 3- alkene -2- ketone of 8-.
9. the preparation side of the triazole methyl esters link volution compound according to claim 2 with antibacterial activity
Method, it is characterised in that the detailed process of step G are as follows: water is added into reaction flask, it is fluoro- to add dry (5R) -3- oxazole -8-
4- hydroxyl -1,6- diazaspiracyclic [4,5] decyl- 3- alkene -2- ketone and sodium azide, reaction temperature are set as -5 DEG C, and liquid light is added dropwise
Gas controls rate of addition, and reaction temperature is made to be no more than 0 DEG C, is warmed to room temperature after stirring 1h after dripping, and continues to stir 1h, TLC inspection
Raw material fully reacting is surveyed, it is neutral for adjusting reaction solution pH with saturated sodium bicarbonate solution, then reaction solution is extracted with dichloromethane, and is closed
And it is concentrated to get after organic phase；It willIt is added in reaction flask, water is made
For solvent, a certain amount of catalyst is added, Methyl propiolate is added into reaction flask, reacts 5h, TLC prison at room temperature
After controlling raw material fully reacting, reaction solution is extracted with ethyl acetate, is concentrated to get compound after merging organic phase, the catalyst is positive triphenylphosphine cuprous complex.
10. a kind of triazole methyl esters link volution compound described in claim 1 with antibacterial activity is anti-in preparation
Application in staphylococcus aureus or anti-Escherichia coli drug.
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