CN107721996A - A kind of preparation method and application of novel amino heterocyclic nitrogen compound - Google Patents
A kind of preparation method and application of novel amino heterocyclic nitrogen compound Download PDFInfo
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- VXNQEWXQYWAIBC-UHFFFAOYSA-N CC(CC1)(CCC1OC)C(NC(N)=O)=O Chemical compound CC(CC1)(CCC1OC)C(NC(N)=O)=O VXNQEWXQYWAIBC-UHFFFAOYSA-N 0.000 description 1
- SDMXLAZIFYYECU-UHFFFAOYSA-N COC(CC1)CCC1N Chemical compound COC(CC1)CCC1N SDMXLAZIFYYECU-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of preparation method and application of novel amino heterocyclic nitrogen compound, belong to applied chemistry technical field.Technical scheme main points are：A kind of novel amino heterocyclic nitrogen compound, there is following structure：
Description
Technical field
The invention belongs to applied chemistry technical field, and in particular to a kind of preparation side of novel amino heterocyclic nitrogen compound
Method and application.
Background technology
Nitrogen-containing heterocycle compound is due to extensive bioactivity and by attention, having developed many nitrogen heterocyclic rings
Bactericide, herbicide, insecticide and the medical of class, such compound have turned into the study hotspot of agrochemicals and medicine,
Have broad application prospects.Oxazole ring is a kind of five yuan of important nitrogen oxa- rings, is widely present in natural products molecule, due to
It easily forms hydrogen bond and metallic ion coordination and hydrophobic effect, pi-pi accumulation, electrostatic interaction etc. occurs, because of Ci oxazole class chemical combination
A variety of non-covalent interactions can occur for thing, show good desinsection, weeding, antibacterial, enzyme inhibitor isoreactivity, have developed
More than 10 individual agricultural chemicals and medical kind, such as herbicide isoxadifen, clinical antibacterials Linezolid and VIRGINIAMYCIN.By
The compound of Yu Han oxazole rings have the advantages that it is less toxic to human body, efficient, the synthesis of such compound with bioactivity research still
It is so the focus of current agricultural chemicals and medical research.
Equally, nitrogen-containing hetero spiro-compound is due to that with different head effect, can form chiral axis, under certain conditions,
Can be into asymmetric molecult or chiral molecular, chiral spiro is rigidly strong, is not easy racemization, makees containing heteroatomic spiro-compound
It is unique with mechanism, it is not likely to produce the resistance to the action of a drug, the miscellaneous spiro-compound conduct of external many nitrogenous chiralitys of the present Devoting Major Efforts To Developing of major company
New insecticide and agricultural chemicals.
It is of the present invention that oxazole ring and chiral nitrogen-containing hetero loop coil are linked together, it is prepared for a kind of amino with new structure
Nitrogen heterocyclic, and to carrying out insecticidal activity application.
The content of the invention
Present invention solves the technical problem that there is provided one kind, operation is simple, raw material is cheap and easy to get, reaction efficiency is high
And the preparation method and application of reproducible novel amino heterocyclic nitrogen compound.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of novel amino heterocyclic nitrogen compound
Preparation method and application, it is characterised in that its molecular structure is：
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of novel amino heterocyclic nitrogen compound
Preparation method, it is characterised in that concretely comprise the following steps：
A, paraphenetidine is hydrogenated reduction and obtains 1- amino-4-methoxyl hexamethylenes；
B, 1- amino-4-methoxyls hexamethylene issues raw annulation in catalyst action with formamide and carbon monoxide and obtained
To cis-8- methoxyl group -1,3- diaza spiros [4,5]-decyl- 2,4- diketone；
C, cis-8- methoxyl groups -1,3- diaza spiros [4,5]-decyl- 2,4- diketone hydrolyzes to obtain cis- in the basic conditions
4- methoxyl group -1- aminocyclohexyl formic acid；
D, cis-4- methoxyl groups -1- aminocyclohexyls formic acid obtains compound cis-4- methoxies with methanol generation esterification
Base -1- aminocyclohexyl methyl formates；
E, acrylic acid and urea react to obtain 2- An Ji oxazole -4- acetic acid；
F, cis-4- methoxyl groups -1- aminocyclohexyls methyl formate and 2- An Ji oxazole -4- acetic acid are in sodium acid carbonate and alkali
Property the lower reaction of zeolite molecular sieve catalyst effect obtain cis-3- (2- An Ji oxazolyls) -8- methoxyl group -2- oxo -1- azaspiros
Ring [4,5] decyl- 3- alkene -4- alcohol；
G, cis-3- (2- An Ji oxazolyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol with
Ethyl chloroformate reacts to obtain compound
Further limit, step A detailed process：Absolute ethyl alcohol, paraphenetidine, thunder Buddhist nun are added into autoclave
Nickel, logical nitrogen displacement reaction gas reactor is multiple, then is replaced repeatedly with hydrogen, is passed through 1.0Mpa every time；Replacement completion, lead to hydrogen
To 1.5Mpa, stirring is opened, is warming up to 120~130 DEG C, start to consume hydrogen, when being down to 0.5Mpa, hydrogen make-up to 2.5Mpa,
And 2.0~2.5Mpa is kept, when confirming no longer to consume hydrogen after reaction a period of time, controlled in sampling, when p-aminophenyl first in reaction solution
Reaction terminates when ether content is less than 1%, is cooled to 30 DEG C, filters out catalyst, filtrate steaming removal solvent, it is 1- that decompression, which steams product,
Amino-4-methoxyl hexamethylene.
Further limit, step B detailed process：Water is added into autoclave, opens stirring, adds formamide,
After stirring a period of time, 1- amino-4-methoxyl hexamethylenes are added, catalyst is added, CO is passed through into reactor, make in kettle
Pressure reaches 0.2MPa, is warming up to 50 DEG C, insulation is for a period of time, middle to control 1- amino-4-methoxyl cyclohexane contents in reaction solution
Less than 2%, reaction terminates, and is cooled to 25~30 DEG C, and watery hydrochloric acid is added dropwise into reaction solution, and regulation pH is 5~6, there is solid precipitation,
Product is filtered out, filter cake shuffles once, obtains cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone；Described urges
Agent is rhodium C catalyst, rhodium aluminium oxide catalyst or acetylacetonatodicarrhodium rhodium.
Further limit, step C detailed process：Water is added into reaction bulb, 40 DEG C or so are heated under stirring, is added
Alkali compounds, stirring and dissolving；Add cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone, 95 DEG C~
100 DEG C of stirring reactions are for a period of time；Sampling monitoring, when cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2 in reaction solution,
4- diketone content stops reaction after being less than 2%, after the completion of reaction, cools 60 DEG C or so, the concentrated sulfuric acid is slowly added dropwise into four-hole bottle,
Adjust pH value 3 or so；Water is added into system, adds activated carbon, 80 DEG C is warming up to and stirs 60 minutes；Solid is filtered out while hot
For residue, filtrate heating concentration, when vacuum reaches -0.1Mpa, water unnecessary in system is fallen in 100 DEG C of concentrations of kettle temperature, steam to sticky
During pasty state, distillation terminates addition toluene normal pressure and divides water, after moisture is most, is cooled to less than 30 DEG C；Centrifugal filtration, solid drying claim
Cis-4- methoxyl group -1- aminocyclohexyl formic acid is produced again, and filtrate is that toluene is applied to dehydration；Described alkali compounds
For calcium hydroxide, magnesium hydroxide, preferably calcium hydroxide.
Further limit, step D detailed process：Add methanol into reaction bulb, stir it is lower add cis-4- methoxyl groups-
1- aminocyclohexyl formic acid, then thionyl chloride is slowly added dropwise, time for adding is about 2~3 hours；Process control kettle temperature is added dropwise to be less than
60 DEG C, be suitable with visible micro- backflow on condenser.It is added dropwise, is warming up to 64~67 DEG C of back flow reactions, sampling detection；Detection
Reaction raw materials surplus area percentage composition stops reaction after being less than 1%；Solvent removed by vacuum methanol, steam to thick, stopping
Heating；Add hexamethylene, atmospheric pressure reflux separates remaining methanol in system (water knockout drum lower floor is methanol)；When having can't see first
When alcohol separates, cooling water temperature is opened to less than 30 DEG C, filters to obtain cis-4- methoxyl group -1- aminocyclohexyl methyl formates；Institute
Cis-4- methoxyl groups -1- aminocyclohexyls the formic acid and the inventory mol ratio of thionyl chloride stated are 1:1.2.
Further limit, step E detailed process：Water and tween are added in reaction bulb, adds acrylic acid, is finally added
Enter catalyst, in 50 DEG C of reaction a period of times；After reaction terminates, water is evaporated in vacuo, adds ethanol and urea element, is heated to reflux；Instead
After should terminating, ethanol is spin-dried for, ethyl acetate dissolving is added, adds saturated aqueous common salt to extract, concentrate organic phase, column chromatography obtains 2- ammonia
Ji oxazole -4- acetic acid；Described catalyst behaviour dopamine-β hydroxylases.
Further limit, step F detailed process：Add DMF into reaction bulb, stir it is lower add cis-4- methoxyl groups-
1- aminocyclohexyl methyl formates, sodium acid carbonate is slow added into, great amount of carbon dioxide can be released, it is necessary to control in adition process
Speed (when adding 30% or so of total carbonic acid hydrogen sodium amount, can accelerate to add speed, do not have foam effusion) is added, is added
Stir 30 minutes afterwards；Ethyl acetate is added, is put into ice-water bath, reaction solution is cooled to 0 DEG C；Start to be added dropwise 2- An Ji oxazoles-
4- acetic acid, controls 0~5 DEG C of temperature, and rate of addition is controlled with temperature；After being added dropwise, 0~5 DEG C of stirring reaction for a period of time,
Sampling monitoring reaction process, when content is less than 2% to cis-4- methoxyl group -1- aminocyclohexyl methyl formates in reaction solution,
Reaction terminates；Basic zeolite molecular sieve is added, opens stirring；And being passed through nitrogen to bubbler has bubble to emerge；Control kettle temperature 20
~30 DEG C, stop reaction after this temperature stirring reaction 3h；It is cleared under decompression to -0.1Mpa, 80~90 DEG C of kettle temperature to open vacuum
Solvent is waited to steam to thick-pasty, after being cooled to 40 DEG C, opens nitrogen protection, (adjustment nitrogen pressure 0.02Mpa) drips into system
Add water, after completion of dropwise addition, remaining water is disposably added after stirring is stable, is slow added into the NaOH solution that concentration is 6%
20min is stirred, filters out molecular sieve (repeatable to utilize), static layering, upper strata floccule point falls to discard, and lower aqueous layer retains,
Hydrochloric acid acidifying is added dropwise, (acid adding speed needs to control, and the moment that too fast addition speed can separate out product wraps up impurity and formed hard
Block) there are in kettle a large amount of solids to separate out, when pH value reaches 3~4, continue to filter out solid product cis-3- after stirring a period of time
(2- An Ji oxazolyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Described basic zeolite molecule
Sieve as KF/Al2O3。
Further limit, step G detailed process：Dichloromethane is added into reaction bulb, is added under stirring into bottle
Enter dry cis-3- (2- An Ji oxazolyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Stirring
Triethylamine is slowly added to after a period of time, there is slight exotherm phenomenon, addition finishes adjustment temperature to 20~25 DEG C；Chloro-carbonic acid is added dropwise
Ethyl ester, controlled in being sampled after being reacted 1 hour at 20~30 DEG C after being added dropwise, react and terminate when starting material left is less than 1%；To anti-
Answer and water and concentrated hydrochloric acid are added in bottle；Stratification after stirring 20 minutes；Release lower organic layer and middle floccule, upper strata waste water
Drain；Organic layer is washed with water once again, stirs 30 minutes, separates organic layer and intermediate layer, water layer discarded；Organic layer normal pressure
Solvent is steamed, stops distillation when kettle temperature rises to 75 DEG C, petroleum ether is added into precipitation kettle, 90 DEG C is warming up to and is incubated back to entirely molten
Stream 30 minutes；30 DEG C of filterings are cooled to 15~20 DEG C/h of speed, the accessory substance of disubstituted Ethyl formate is removed, obtains product
The synthetic route of spiral shell worm ethyl ester of the present invention is：
Operation is simple, raw material is cheap and easy to get, reaction efficiency is high and reproducible for present invention kind.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
Absolute ethyl alcohol 400mL, paraphenetidine 123g (1mol), Raney's nickel 10g, envelope are added into 1000mL autoclaves
Good kettle cover, lead to nitrogen to 3.0Mpa, pressurize 30min, after ensureing that 30min does not fall pressure, drained nitrogen by blow-down pipe, continue to lead to
Nitrogen displacement 2 times, hydrogen are replaced 2 times, are passed through 1.0Mpa every time, replacement completion, are led to hydrogen to 1.5Mpa, open stirring, heating
To 120~130 DEG C, start to consume hydrogen, when being down to 0.5Mpa, hydrogen make-up to 2.5Mpa, and 2.0~2.5Mpa is kept, reaction
20 hours, when confirming no longer to consume hydrogen, controlled in sampling, react and terminate when starting material left is less than 1%, be cooled to 30 DEG C, filter out
Catalyst, filtrate steaming removal solvent (- 0.1MPa, 90 DEG C), it is 1- amino-4-methoxyl hexamethylene 125g that decompression, which steams product, is received
Rate 96.8%, content 90%.
Embodiment 2
Water 1200mL is added into autoclave, opens stirring, adds the formamide 220g (2mol) that concentration is 40%,
After stirring 10min, 1- amino-4-methoxyl hexamethylene 130g (1mol) are added, rhodium C catalyst 7g are added, into reactor
CO is passed through, pressure in kettle is reached 0.2MPa, is warming up to 50 DEG C, is incubated 20h, middle control raw material ＜ 2%, reaction terminates, and is cooled to
25~30 DEG C, watery hydrochloric acid is added dropwise into reaction solution, regulation pH is 5~6, has solid precipitation, filters out product, filter cake shuffles one
It is secondary, obtain cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone dry product 169g, yield 84.5%；1HNMR
(400MHz,DMSO-d6)δ:10.14(s,1H),6.31(s,1H),3.75(s,3H),3.29-3.25(m,4H),2.44-2.41
(m,4H)。
Embodiment 3
Water 1200mL is added into autoclave, opens stirring, addition concentration is 40% formamide 220g (2mol), is stirred
After mixing 10min, 1- amino-4-methoxyl hexamethylene 130g (1mol) are added, rhodium aluminium oxide catalyst 7g are added, to reactor
In be passed through CO, pressure in kettle is reached 0.2MPa, be warming up to 50 DEG C, 20h is incubated, when 1- amino-4-methoxyls ring in reaction solution
Reaction terminates when hexane content is less than 2%, is cooled to 25~30 DEG C, watery hydrochloric acid is added dropwise into reaction solution, regulation pH is 5~6, is had
Solid separates out, and filters out product, filter cake shuffles once, obtains cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone
Dry product 147g, yield 74%.
Embodiment 4
Water 1200mL is added into autoclave, opens stirring, addition concentration is 40% formamide 220g (2mol), is stirred
After mixing 10min, 1- amino-4-methoxyl hexamethylene 130g (1mol) are added, add acetylacetonatodicarrhodium rhodium 7g,
CO is passed through into reactor, pressure in kettle is reached 0.2MPa, is warming up to 50 DEG C, 20h is incubated, as 1- amino -4- in reaction solution
Reaction terminates when methoxycyclohexyl alkane content is less than 2%, is cooled to 25~30 DEG C, and watery hydrochloric acid is added dropwise into reaction solution, adjusts pH
For 5~6, have solid precipitation, filter out product, filter cake shuffles once, obtain cis-8- methoxyl groups -1,3- diaza spiro [4,5] -
Decyl- 2,4- diketone dry product 137g, yield 69%.
Embodiment 5
Water 720g is added into 2000L four-hole bottles, 40 DEG C or so are heated under stirring, calcium hydroxide 150g (2mol) is thrown
Enter in four-hole bottle, stir 10 minutes, dissolving；Add cis-8- methoxyl group -1,3- diaza spiros [4,5]-decyl- 2,4- diketone 100g
(0.5mol), 95 DEG C are heated, reacted 45 hours at 95~100 DEG C；Sampling monitoring, when cis-8- methoxyl groups -1,3- in reaction solution
Diaza spiro [4,5]-decyl- 2,4- diketone content stops reaction after being less than 2%, after the completion of reaction, cools 60 DEG C or so, Xiang Sikou
Concentrated sulfuric acid regulation pH value 3 or so is slowly added dropwise in bottle；Water 150g is added into system, activated carbon 25g is added afterwards, is warming up to 80
DEG C stirring 60 minutes；It is calcium sulfate to filter out solid while hot, and filtrate heating concentrates, when vacuum reaches -0.095Mpa, kettle temperature 100
Unnecessary water in system is fallen in DEG C concentration, and when steaming to thick-pasty, distillation terminates to add toluene 400g, and (toluene for being used to be dehydrated can
Reuse 3 times, add one barrel of new toluene during each reuse) normal pressure divides water, after moisture to the greatest extent after, be cooled to less than 30 DEG C；Centrifugal filtration,
Solid drying, which is weighed, produces cis-4- methoxyl group -1- aminocyclohexyl formic acid 67g, and yield 75%, filtrate is applied to for toluene
Dehydration (barrelling preserves after can applying mechanically 3 times, 3 times, is further continued for applying mechanically after re-distillation).
Embodiment 6
Water 720g is added into 2000L four-hole bottles, 40 DEG C or so are heated under stirring.Magnesium hydroxide 120g (2mol) is thrown
Enter in four-hole bottle, stir 10 minutes, dissolving；Add cis-8- methoxyl group -1,3- diaza spiros [4,5]-decyl- 2,4- diketone 100g
(0.5mol), it is heated to 95~100 DEG C and reacts 45 hours；Sampling monitoring, when cis-8- methoxyl groups -1,3- diaza in reaction solution
Spiral shell [4,5]-decyl- 2,4- diketone content stops reaction after being less than 2%, after the completion of reaction, cools 60 DEG C or so, delays into four-hole bottle
It is slow that concentrated sulfuric acid regulation pH value 3 or so is added dropwise；Water 150g is added into system, activated carbon 25g is added afterwards, is warming up to 80 DEG C of stirrings
60 minutes；It is magnesium sulfate to filter out solid while hot, and filtrate heating concentrates, when vacuum reaches 100 DEG C of -0.095Mpa, kettle temperature concentrations
Fall water unnecessary in system, when steaming to thick-pasty, distillation terminates to add toluene 400g, and (toluene for being used to be dehydrated can reuse 3
Secondary, add one barrel of new toluene during each reuse) normal pressure divides water, after moisture to the greatest extent after, be cooled to less than 30 DEG C；Centrifugal filtration, solid
Drying, which is weighed, produces cis-4- methoxyl group -1- aminocyclohexyl formic acid 59g, yield 66%, and filtrate is that toluene is applied to dehydration
Step (barrelling preserves after can applying mechanically 3 times, 3 times, is further continued for applying mechanically after re-distillation).
Embodiment 7
Methanol 320ml is added into 1000L four-hole bottles, stirs lower addition cis-4- methoxyl group -1- aminocyclohexyl formic acid
87g (0.5mol), stir 10 minutes；Thionyl chloride (0.6mol) is slowly added dropwise, time for adding is about 2-3 hours；Dropwise addition process
Control kettle temperature to be less than 60 DEG C, be suitable with visible micro- backflow on condenser.It is added dropwise, is warming up to 64~67 DEG C of back flow reactions 10
Hour, sampling detection；Detect after reaction raw materials surplus area percentage composition is less than 1% and stop reaction；Open vacuum to-
0.08Mpa, 40~60 DEG C of desolvation methanol, steam to thick, stopping heating；Hexamethylene 400ml is added into four-hole bottle, often
Push back flow point and go out remaining methanol in system (water knockout drum lower floor is methanol)；When can't see methanol and separate, stop.Open cold
But water is cooled to less than 30 DEG C, and filtering, filtrate recycle to hexamethylene band methanol process, solid is weighed, and obtains cis-4- methoxyl groups -1-
Aminocyclohexyl methyl formate 89g, yield 94.6%；1HNMR(400MHz,DMSO-d6)δ:5.11(s,2H),3.68(s,3H),
3.30 (s, 3H), 2.79 (s, 1H), 2.13-2.11 (m, 2H), 1.88-1.87 (m, 2H), 1.70-1.69 (m, 2H), 1.45-
1.44(m,2H)。
Embodiment 8
Water 300mL is added in reaction bulb, tween 3mL is added, adds acrylic acid 0.05mol, be eventually adding
DBH0.175mol, 60 degree of reaction 1h.After reaction terminates, water is spin-dried for, adds ethanol 300mL, adds urea 0.05mol, backflow is anti-
Answer 1h.After reaction terminates, ethanol is spin-dried for, ethyl acetate dissolving is added, adds saturated aqueous common salt to extract, concentrate organic phase, column chromatography
Obtain 2- An Ji oxazole -4- acetic acid 6.2g, yield 88%.
Embodiment 9
DMF 700g is added into 3000mL four-hole bottles, stirs lower addition cis-4- methoxyl group -1- ammonia
Butylcyclohexyl methyl formate 187g (1mol), sodium acid carbonate 168g (2mol) is slowly added to afterwards, can be released in adition process big
Carbon dioxide is measured, particularly preceding 50g adition process foam is most obvious, it is necessary to addition speed be controlled, (when addition total carbonic acid hydrogen sodium amount
30% or so when, can accelerate add speed, do not have foam effusion) add after stir 30 minutes；Add ethyl acetate
1230g, it is put into ice-water bath, reaction solution is cooled to 0 DEG C；Start that 2- An Ji oxazole -4- acetic acid 142g (1mol), control is added dropwise
0~5 DEG C of temperature, rate of addition are controlled with temperature；After being added dropwise, 0-5 DEG C of stirring reaction 5 hours, sampling monitoring react into
Journey, work as starting material left<When 2%, reaction terminates；Add basic zeolite molecular sieve KF/Al2O3200g, open stirring；And it is passed through nitrogen
Gas to bubbler has bubble to emerge.20-30 DEG C of kettle temperature and nitrogen protection are controlled, stops reaction within 3 hours in this temperature stirring reaction；
Vacuum is opened to -0.1Mpa, 80~90 DEG C of kettle temperature, decompression is lower except neat solvent is waited to steam to thick-pasty, after being cooled to 40 DEG C, opens
Nitrogen is protected, and (adjustment nitrogen pressure 0.02Mpa) water 100g is added dropwise into system and (starts 20g to be slowly added dropwise, pays attention to phenomenon in kettle
Change and temperature change) after completion of dropwise addition, 15min is stirred, disposably adds remaining water after stable, stirs 10min, then delay
Slow add after 6%NaOH480g is added stirs 20min, filters out molecular sieve (repeatable to utilize), static layering, upper strata floccule
Divide to fall to discard, lower aqueous layer retains, and hydrochloric acid acidifying is added dropwise, (acid adding speed needs to control, and too fast addition speed can separate out product
Moment parcel impurity and form lump) there are in kettle a large amount of solids to separate out, when pH value reaches 4, acidifying terminates, and takes around salt
Sour 230g, when pH stable is to 3, continues to stir 30min, filter out solid product and obtain cis-3- (2- An Ji oxazolyls) -8-
Methoxyl group -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol 260g；Yield 96%.
Embodiment 10
Dichloromethane 1100mL is added into 2000mL four-hole bottles；Dry cis-3- is added under stirring into bottle
(2- An Ji oxazolyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol 270g (1mol)；Stirring
Triethylamine 100g is slowly added to after 10min, there is slight exotherm phenomenon, addition finishes adjustment temperature to 20-25 DEG C；Chloro-carbonic acid is added dropwise
Ethyl ester 110g, time for adding about 0.5-1h, controlled in being sampled after being reacted 1 hour at 20-30 DEG C after being added dropwise, when starting material left is small
React and terminate when 1%；520g water and 26g concentrated hydrochloric acids are added into reaction bulb；Stratification after stirring 20 minutes；Release lower floor
Organic layer and middle floccule, upper strata waste water are drained；Again by organic layer with 520g water washings once, stir 30 minutes, separated
Machine layer and intermediate layer, water layer discarded, organic layer normal pressure steam solvent, stop distillation when kettle temperature rises to 75 DEG C, into precipitation kettle
Petroleum ether 900g is added, is warming up to 90 DEG C to complete molten insulation backflow 30 minutes；30 DEG C of mistakes are cooled to 15-20 DEG C/h of speed
Filter, is obtained271g, yield 85%；1HNMR(400MHz,DMSO-d6)δ:7.69(s,1H),
6.99(s,2H),3.42(s,1H),3.30-3.29(m,3H),2.27(s,2H),1.78-1.77(m,2H),1.61-1.60(m,
2H), 1.19-1.11 (m, 4H), 1.05-1.03 (m, 3H).
Embodiment 11
Insecticidal activity is tested
It is 1 to take 2.5mL volume ratios:The mixed solvent of 1 acetone-methanol is added separately to fill obtained by 4mgMeasuring cup in, stirring makes it fully dissolve, and adds 2.5mL and contains mass fraction for 0.2%
Tween 80 standing running water, obtain 800mg/L's after stirringSolution 5mL, enters
One step dilutes to obtain the solution of various concentrations.Sprayed using Airbrush spray-on processes.Observed day by day after the processing of peach aphid larva
Feeding and death condition, if test worm eats the feed of chemicals treatment to the greatest extent, untreated fresh feed is supplemented, survival is investigated after 120h
Borer population amount, calculate the death rate.
As seen from the above table, the target compound obtained by the present invention is in concentration to peach aphid larva killing effect
Reach spiral shell worm ethyl ester level during 10mg/L.
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of novel amino heterocyclic nitrogen compound, it is characterised in that its structural formula is：
A kind of 2. preparation method of the novel amino heterocyclic nitrogen compound described in claim 1, it is characterised in that specific steps
For：
A, paraphenetidine is hydrogenated reduction and obtains 1- amino-4-methoxyl hexamethylenes；
B, 1- amino-4-methoxyls hexamethylene issues raw annulation in catalyst action with formamide and carbon monoxide and obtained
Cis-8- methoxyl group -1,3- diaza spiros [4,5]-decyl- 2,4- diketone；
C, cis-8- methoxyl groups -1,3- diaza spiros [4,5]-decyl- 2,4- diketone hydrolyzes to obtain cis-4- first in the basic conditions
Oxy-1-aminocyclohexyl formic acid；
D, cis-4- methoxyl groups -1- aminocyclohexyls formic acid and methanol occur esterification obtain compound cis-4- methoxyl groups -
1- aminocyclohexyl methyl formates；
E, acrylic acid and urea react to obtain 2- An Ji oxazole -4- acetic acid；
F, cis-4- methoxyl groups -1- aminocyclohexyls methyl formate boils with 2- An Ji oxazole -4- acetic acid in sodium acid carbonate and alkalescence
The lower reaction of stone molecular sieve catalyst effect obtains cis-3- (2- An Ji oxazolyls) -8- methoxyl group -2- oxo -1- azaspiros
[4,5] decyl- 3- alkene -4- alcohol；
G, cis-3- (2- An Ji oxazolyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol and chloromethane
Acetoacetic ester reacts to obtain compound
A kind of 3. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step A
Detailed process be：Absolute ethyl alcohol is added into autoclave, paraphenetidine, Raney's nickel, leads to gas in nitrogen displacement reactor
Body is multiple, then is replaced repeatedly with hydrogen, is passed through 1.0Mpa every time；Replacement completion, lead to hydrogen to 1.5Mpa, open stirring, heating
To 120~130 DEG C, start to consume hydrogen, when being down to 0.5Mpa, hydrogen make-up to 2.5Mpa, and 2.0~2.5Mpa is kept, reaction
When confirming no longer to consume hydrogen after a period of time, controlled in sampling, the reaction knot when paraphenetidine content is less than 1% in reaction solution
Beam, 30 DEG C are cooled to, filter out catalyst, filtrate steaming removal solvent, it is 1- amino-4-methoxyl hexamethylenes that decompression, which steams product,.
A kind of 4. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step B
Detailed process be：Water is added into autoclave, opens stirring, adds formamide, after stirring a period of time, adds 1- ammonia
Base -4- methoxycyclohexyl alkane, adds catalyst, CO is passed through into reactor, pressure in kettle is reached 0.2MPa, be warming up to 50
DEG C, for a period of time, 1- amino-4-methoxyls cyclohexane content is less than 2% in middle control reaction solution, and reaction terminates, and is cooled to for insulation
25~30 DEG C, watery hydrochloric acid is added dropwise into reaction solution, regulation pH is 5~6, has solid precipitation, filters out product, filter cake shuffles one
It is secondary, obtain cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone；Described catalyst is rhodium C catalyst, rhodium oxygen
Change Al catalysts or acetylacetonatodicarrhodium rhodium.
A kind of 5. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step C
Detailed process be：Water is added into reaction bulb, 40 DEG C or so are heated under stirring, adds alkali compounds, stirring and dissolving；Add
Enter cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone, in 95 DEG C~100 DEG C stirring reactions for a period of time；Take
Sample monitors, and when cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2 in reaction solution, 4- diketone content stops after being less than 2%
Reaction, after the completion of reaction, cool 60 DEG C or so, the concentrated sulfuric acid is slowly added dropwise into four-hole bottle, adjust pH value 3 or so；Into system
Water is added, adds activated carbon, 80 DEG C is warming up to and stirs 60 minutes；It is residue to filter out solid while hot, and filtrate heating concentrates, when
Vacuum reaches -0.1Mpa, water unnecessary in system is fallen in 100 DEG C of concentrations of kettle temperature, and when steaming to thick-pasty, distillation terminates to add toluene
Normal pressure divides water, after moisture is most, is cooled to less than 30 DEG C；Centrifugal filtration, solid drying, which is weighed, produces cis-4- methoxyl group -1- ammonia
Butylcyclohexyl formic acid, filtrate are that toluene is applied to dehydration；Described alkali compounds is calcium hydroxide, and magnesium hydroxide is excellent
Select calcium hydroxide.
A kind of 6. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step D
Detailed process be：Methanol is added into reaction bulb, stirs lower addition cis-4- methoxyl group -1- aminocyclohexyl formic acid, then delay
Slow that thionyl chloride is added dropwise, time for adding is about 2~3 hours；Process control kettle temperature is added dropwise and is less than 60 DEG C, with visible micro- on condenser
Flow back to be suitable.It is added dropwise, is warming up to 64~67 DEG C of back flow reactions, sampling detection；Detect reaction raw materials surplus area hundred
Content is divided to stop reaction after being less than 1%；Solvent removed by vacuum methanol, steam to thick, stopping heating；Hexamethylene is added, often
Push back flow point and go out remaining methanol in system (water knockout drum lower floor is methanol)；When can't see methanol and separate, cooling water is opened
Less than 30 DEG C are cooled to, filters to obtain cis-4- methoxyl group -1- aminocyclohexyl methyl formates；Described cis-4- methoxyl groups -1-
The inventory mol ratio of aminocyclohexyl formic acid and thionyl chloride is 1:1.2.
A kind of 7. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step E
Detailed process be：Water and tween are added in reaction bulb, acrylic acid is added, is eventually adding catalyst, reacts one at 50 DEG C
The section time；After reaction terminates, water is evaporated in vacuo, adds ethanol and urea element, is heated to reflux；After reaction terminates, ethanol is spin-dried for, is added
Ethyl acetate dissolves, and adds saturated aqueous common salt to extract, and concentrates organic phase, and column chromatography obtains 2- An Ji oxazole -4- acetic acid；Described urges
Agent behaviour dopamine-β hydroxylases.
A kind of 8. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step F
Detailed process be：DMF is added into reaction bulb, stirs lower addition cis-4- methoxyl group -1- aminocyclohexyl methyl formates, then
Sodium acid carbonate is slowly added to, great amount of carbon dioxide can be released in adition process, it is necessary to control and add speed (when addition total carbonic acid hydrogen
Sodium amount 30% or so when, can accelerate add speed, do not have foam effusion), stirred 30 minutes after adding；Add acetic acid second
Ester, it is put into ice-water bath, reaction solution is cooled to 0 DEG C；Start that 2- An Ji oxazole -4- acetic acid is added dropwise, control 0~5 DEG C of temperature, drop
Acceleration is controlled with temperature；After being added dropwise, 0~5 DEG C of stirring reaction for a period of time, sampling monitoring reaction process, works as cis-
4- methoxyl group -1- aminocyclohexyl methyl formates in reaction solution content be less than 2% when, reaction terminates；Add basic zeolite point
Son sieve, opens stirring；And being passed through nitrogen to bubbler has bubble to emerge；20~30 DEG C of kettle temperature is controlled, in this temperature stirring reaction
Stop reaction after 3h；It is lower except neat solvent is waited to steam to thick-pasty, cooling to -0.1Mpa, 80~90 DEG C of kettle temperature, decompression to open vacuum
To after 40 DEG C, nitrogen protection is opened, (adjustment nitrogen pressure 0.02Mpa) water is added dropwise into system, is stirred after completion of dropwise addition stable
Remaining water is disposably added afterwards, the NaOH solution that concentration is 6% is slow added into and stirs 20min, filtering out molecular sieve (can
Recycling), static layering, upper strata floccule point falls to discard, and lower aqueous layer retains, and hydrochloric acid acidifying is added dropwise, (acid adding speed needs to control
System, too fast additions speed can make the moment parcel impurity that product separates out and form lump) there are a large amount of solids precipitations in kettle, work as pH
When value reaches 3~4, continue to filter out solid product cis-3- (2- An Ji oxazolyls) -8- methoxyl groups -2- after stirring a period of time
Oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Described basic zeolite molecular sieve is KF/Al2O3。
A kind of 9. preparation method of novel amino heterocyclic nitrogen compound according to claim 2, it is characterised in that step G
Detailed process be：Dichloromethane is added into reaction bulb, adds dry cis-3- (2- An Ji Evil under stirring into bottle
Oxazolyl) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Three second are slowly added to after stirring a period of time
Amine, there is slight exotherm phenomenon, and addition finishes adjustment temperature to 20~25 DEG C；Ethyl chloroformate is added dropwise, after being added dropwise 20~
30 DEG C reaction 1 hour after sample in control, when starting material left be less than 1% when reaction terminate；Water and concentrated hydrochloric acid are added into reaction bulb；
Stratification after stirring 20 minutes；Release lower organic layer and middle floccule, upper strata waste water are drained；Organic layer is washed with water again
Wash once, stir 30 minutes, separate organic layer and intermediate layer, water layer discarded；Organic layer normal pressure steams solvent, when kettle temperature rises to 75
DEG C when stop distillation, add petroleum ether into precipitation kettle, be warming up to 90 DEG C to complete molten insulation backflow 30 minutes；With 15~20 DEG C/
Hour, speed was cooled to 30 DEG C of filterings, and the accessory substance for removing disubstituted Ethyl formate obtains product
10. application of the novel amino heterocyclic nitrogen compound as claimed in claim 1 in insecticidal materials are prepared.
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