CN107857722A - A kind of novel processing step of spiral shell worm ethyl ester - Google Patents
A kind of novel processing step of spiral shell worm ethyl ester Download PDFInfo
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- CN107857722A CN107857722A CN201711165806.6A CN201711165806A CN107857722A CN 107857722 A CN107857722 A CN 107857722A CN 201711165806 A CN201711165806 A CN 201711165806A CN 107857722 A CN107857722 A CN 107857722A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
Abstract
The invention discloses a kind of novel processing step of spiral shell worm ethyl ester, belong to pesticide synthesis technical field.Technical scheme main points are：Issue raw annulation using the methoxycyclohexyl alkane of 1 amino 4 and formamide and carbon monoxide in catalyst action and obtain the methoxyl groups 1 of key intermediate cis 8,3 diaza spiros [4,5] last of the ten Heavenly stems 2,4 diketone, and then instead of in traditional route and prepare the methoxyl groups 1 of cis 8 using hypertoxic Cymag, 3 diaza spiros [4,5] last of the ten Heavenly stems 2, the method for 4 diketone, and W-response process are with operation is simple, the advantages that raw material is cheap and easy to get, and reaction efficiency is higher and repeated preferable.
Description
Technical field
The invention belongs to pesticide synthesis technical field, and in particular to a kind of novel processing step of spiral shell worm ethyl ester.
Background technology
With the fast development of social economy and the continuous improvement of living standards of the people, food-safety problem turns into people increasingly
Focus of attention.Therefore, in the development process of new varieties of pesticides, emphasize more to pay attention to the phase of environment while high activity
Capacitive, to ensure the safety of the mankind and non-target organism.Similar to insect conditioning agent and there is optically active loop coil class desinsection
Agent, it is exactly the environment friendly agricultural that people generally say.Contain one or more spirane structures in loop coil insecticides molecule, be the field
New lover, external Devoting Major Efforts To Developing now and use this insecticide and agricultural chemicals.And domestic also this knot of utilization not yet in effect at this stage
Structure, therefore Devoting Major Efforts To Developing is necessary with its synthesis route is explored.Two plane of a loops of spiro-compound mutually hang down
Directly, the general organic compound such as different head effect, spiral shell conjugation, spiral shell hyperconjugation may also does not possess for heterocyclic ring spiroring compounds
Special nature, under certain conditions, can be into asymmetric molecult or chiral molecular due to the presence of chiral axis；It is chiral
Loop coil is rigidly strong, is not easy racemization.It is unique containing the heteroatomic spiro-compound mechanism of action, the resistance to the action of a drug is not likely to produce, has been caused
The concern of common people.
Spiral shell worm ethyl ester is one and represents molecule in loop coil insecticides molecule.It is the tetronic acid class developed by Beyer Co., Ltd
Desinsection kills snail agent.Formulation is mainly 240g/L suspending agent.It is mainly used in cotton, vegetables and ornamental plant preventing and treating aleyrodid and leaf
Mite.The property of compound is that its ovum and adult to aleyrodid class and snail class is all effective, especially red to room temperature aleyrodid and cotton
Spider.With 100~150g/hm2Dosage be used for cotton, vegetables and ornamental plant, the very long lasting period can be kept；In grass
Good application prospect is also showed that on the orchard crops such as the certain kind of berries, apple and seeding corn and other crops.If it is worth noting that, it is to aleyrodid
Worm and deutonymph are especially effective, also there is high lethality to aleyrodid ovum.The incubation rate of ovum can be also reduced, it is very high except having to its adult
Outside preventive effect, its spawning rate can be also reduced.If it is coordinated to the deficiency for making up its early prevention and treatment with imidacloprid.Applying
On, really one " tolerance " very high kind, new construction introduce new capability for it.In the synthesis of current existing spiral shell worm ethyl ester
Using the Cymag to severe toxicity, Cymag not only has very strict requirement in building-up process to operating, and for
The processing of waste liquid is also very strict, it is necessary to enterprise puts into substantial amounts of fund in production equipment and waste liquor treatment equipment after production,
Therefore the route for finding the synthesis spiral shell worm ethyl ester that can substitute Cymag has very important realistic meaning.
The content of the invention
Present invention solves the technical problem that there is provided it is a kind of operation is simple, raw material is cheap and easy to get, reaction efficiency is high,
The novel processing step of the spiral shell worm ethyl ester of reproducible and unused Cymag.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of novel processing step of spiral shell worm ethyl ester,
It is characterized in that concretely comprise the following steps：
A, paraphenetidine obtains 1- amino-4-methoxyl hexamethylenes by hydrogenating reduction；
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, cis-4- methoxyl groups -1- aminocyclohexyls methyl formate and 2,5- dimethyl benzene chloroacetic chlorides are in sodium acid carbonate and alkali
Property zeolite molecular sieve catalyst effect is lower substitution reaction occurs obtains cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl group -2- oxygen
Generation -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；
F, cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl group -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol
React to obtain compound spiral shell worm ethyl ester with ethyl chloroformate.
Further limit, step A detailed process：Absolute ethyl alcohol, paraphenetidine, thunder Buddhist nun are added into autoclave
Nickel, seal kettle cover；Logical nitrogen displacement reaction gas reactor is multiple, then is replaced repeatedly with hydrogen, is passed through 1.0Mpa every time；Displacement knot
Beam, lead 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, hydrogen make-up
To 2.5Mpa, and keep 2.0~2.5Mpa, when reaction a period of time confirms no longer to consume hydrogen, controlled in sampling, when in reaction solution to ammonia
Reaction terminates when base methyl phenyl ethers anisole content is less than 1%, is cooled to 30 DEG C, filters out catalyst Raney's nickel, filtrate steaming removal solvent, decompression
It is 1- amino-4-methoxyl hexamethylenes to steam product.
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 a period of time, when 1- amino-4-methoxyls cyclohexane content is small in reaction solution
Reacting and terminate when 2%, be cooled to 25~30 DEG C, watery hydrochloric acid is added dropwise into reaction solution, 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, preferably rhodium C catalyst.
Further limit, step C detailed process：Water is added into four-hole bottle, 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, at 95 DEG C -100
DEG C reaction a period of time；Sampling monitoring, when cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone in reaction solution
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 and activated carbon are added into system, is warming up to 80 DEG C of stirring a period of times；It is residue to filter out solid while hot, filter
Liquid heating concentrates, and concentrates water unnecessary in system under vacuum condition, and when steaming to thick-pasty, distillation terminates to add toluene normal pressure
Divide water, after moisture is most, be cooled to less than 30 DEG C；Centrifugal filtration, solid drying, which is weighed, produces cis-4- methoxyl group -1- amino rings
Hexyl formic acid；Described alkali compounds is barium hydroxide, calcium hydroxide, magnesium hydroxide, preferably barium hydroxide；Alkali compounds
Inventory mol ratio with cis-8- methoxyl group -1,3- diaza spiros [4,5]-decyl- 2,4- diketone is 3~5:1, preferably 4:1.
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 (excessive 1.2mol) thionyl chloride 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 back flow reaction, sampling detection；
Detect after reaction raw materials surplus area percentage composition is less than 1% and stop reaction；Solvent removed by vacuum methanol, steam to thick,
Stop heating；Add hexamethylene, atmospheric pressure reflux separates remaining methanol in system (water knockout drum lower floor is methanol)；When can't see
There is methanol to stop reacting when separating, opening cooling water temperature to less than 30 DEG C filterings, filtrate recycle to hexamethylene band methanol process,
Solid is weighed, and obtains cis-4- methoxyl group -1- aminocyclohexyl methyl formates.
Further limit, step E detailed process：Docking reaction：1st, dichloromethane, stirring are added into reaction bulb
Under add 2,5- dimethyl phenyl acetic acids from hand hole, stir 10 minutes；Thionyl chloride is added dropwise into reactor, process is added dropwise and keeps
Kettle temperature is less than 40 DEG C, and a large amount of sour gas, tail gas alkali liquor absorption are produced in course of reaction；Completion of dropwise addition is warming up to 50 DEG C of backflows
Reaction, sampling detection raw material area percentage composition stop reaction after being less than 0.5%；Normal pressure desolventizing dichloromethane, keep kettle temperature
No more than 60 DEG C, steamed under vacuum condition to not flow liquid, Liquid Residue is 2,5- dimethyl benzene chloroacetic chlorides in kettle, and bottling is stand-by, close
Close preservation；2nd, DMF is added into reaction bulb, stirs lower addition cis-4- methoxyl group -1- aminocyclohexyl methyl formates, Zhi Houhuan
It is slow to add sodium acid carbonate, great amount of carbon dioxide can be released, it is necessary to control addition speed in adition process, and 30 points are stirred after adding
Clock；Ethyl acetate is added, is put into ice-water bath, reaction solution is cooled to 0 DEG C；Start dropwise addition 2,5- dimethyl benzene chloroacetic chlorides, control
0~5 DEG C of temperature processed, rate of addition are controlled with temperature；After being added dropwise, 0~5 DEG C of stirring reaction 5 hours, sampling monitoring reaction
Process, when starting material left is less than 2%, reaction terminates；Basic zeolite molecular sieve is added, opens stirring；And nitrogen is passed through to drum
Bubbler has bubble to emerge.20~30 DEG C of kettle temperature is controlled, in this temperature stirring reaction 2 hours, sampling detection, raw material area percentage
Content stops reaction after being less than 0.5%；It is lower except neat solvent is waited to steam to viscous to -0.1Mpa, 80~90 DEG C of kettle temperature, decompression to open vacuum
Thick paste, after being cooled to 40 DEG C, nitrogen protection is opened, (adjustment nitrogen pressure 0.02Mpa) is added dropwise water into system and (starts 20g
Be slowly added dropwise, pay attention in kettle phenomenon change and temperature change) after completion of dropwise addition, stir 15min, it is stable after by remaining water once
Property add, stir 10min, be slow added into concentration be 6% NaOH solution add after stir 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 stir 30min, filter out solid product afterwards and obtain cis-3- (2,5- 3,5-dimethylphenyl) -8- methoxies
Base -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Described basic zeolite molecular sieve is KF/Al2O3。
Further limit, step F detailed process：Dichloromethane is added into reaction bulb；Add under stirring into bottle
Enter dry cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl group -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Stir
Triethylamine is slowly added to after mixing a period of time, there is slight exotherm phenomenon, addition finishes adjustment temperature to 20~25 DEG C；Chloromethane is added dropwise
Acetoacetic 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
Water and concentrated hydrochloric acid are added in reaction solution；Stratification after stirring 20 minutes；Release lower organic layer and middle floccule, upper strata are given up
Water is drained；Organic layer is washed with water once again, stirs 30 minutes, separates organic layer and intermediate layer, water layer discarded；Organic layer is normal
Pressure steams solvent, stops distillation when kettle temperature rises to 75 DEG C, petroleum ether is added into precipitation kettle, is warming up to 90 DEG C to complete molten insulation
Backflow 30 minutes；30 DEG C of filterings are cooled to 15~20 DEG C/h of speed, obtain product spiral shell worm ethyl ester.
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 is added into 1000mL autoclaves, paraphenetidine 100g, Raney's nickel 20g, seals kettle
Lid；Logical nitrogen is to 3.0Mpa, pressurize 30min, after ensureing that 30min does not fall pressure, is drained nitrogen by blow-down pipe, continues logical nitrogen
Displacement 2 times, hydrogen are replaced 2 times, are passed through 1.0Mpa every time；Replacement completion, lead 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, hydrogen make-up keeps 2.0-2.5Mpa to 2.5Mpa, and reaction 20 is small
When, when confirming no longer to consume hydrogen, controlled in sampling, react and terminate when paraphenetidine content is less than 1% in reaction solution, be cooled to
30 DEG C, filter out catalyst.Filtrate steaming removal solvent (- 0.1MPa, 90 DEG C), it is 1- amino-4-methoxyl rings that decompression, which steams product,
Hexane 100g, yield 95.6%, content 90%.
Embodiment 2
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 rhodium C catalyst 7g, led into reactor
Enter CO, pressure in kettle is reached 0.2MPa, be warming up to 50 DEG C, 20h is incubated, when 1- amino-4-methoxyls hexamethylene in reaction solution
Reaction terminates when 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, there is solid
Separate out, filter out product, filter cake shuffles once, obtains cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone dry products
155g, yield 78%
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
147g, yield 74%；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 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.Barium hydroxide 350g (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 DEG C -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 barium 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 83g, and yield 95%, 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.Barium hydroxide 260g (1.5mol)
Put into 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 DEG C -100 DEG C；Sampling monitoring, when cis-8- methoxyl groups in reaction solution-
1,3- 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, to
Concentrated sulfuric acid regulation pH value 3 or so is slowly added dropwise in four-hole bottle；Water 150g is added into system, adds activated carbon 25g, heating afterwards
Stirred 60 minutes to 80 DEG C；It is barium sulfate to filter out solid while hot, and filtrate heating concentrates, when vacuum reaches -0.1Mpa, kettle temperature
Water unnecessary in system is fallen in 100 DEG C of concentrations, and when steaming to thick-pasty, distillation terminates to add toluene 400g, (is used for the toluene being 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；Centrifuged
Filter, solid drying, which is weighed, produces cis-4- methoxyl group -1- aminocyclohexyl formic acid 78g, and yield 89%, filtrate is applied mechanically for toluene
To dehydration (barrelling preserves after can applying mechanically 3 times, 3 times, is further continued for applying mechanically after re-distillation).
Embodiment 7
Water 720g is added into 2000L four-hole bottles, 40 DEG C or so are heated under stirring.Barium hydroxide 430g (2.5mol)
Put into 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 DEG C -100 DEG C；Sampling monitoring, when cis-8- methoxyl groups in reaction solution-
1,3- 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, to
Concentrated sulfuric acid regulation pH value 3 or so is slowly added dropwise in four-hole bottle；Water 150g is added into system, adds activated carbon 25g, heating afterwards
Stirred 60 minutes to 80 DEG C；It is barium sulfate to filter out solid while hot, and filtrate heating concentrates, when vacuum reaches -0.095Mpa, kettle temperature
Water unnecessary in system is fallen in 100 DEG C of concentrations, and when steaming to thick-pasty, distillation terminates to add toluene 400g, (is used for the toluene being 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；Centrifuged
Filter, solid drying, which is weighed, produces cis-4- methoxyl group -1- aminocyclohexyl formic acid 81g, and yield 93%, filtrate is applied mechanically for toluene
To dehydration (barrelling preserves after can applying mechanically 3 times, 3 times, is further continued for applying mechanically after re-distillation).
Embodiment 8
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 9
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), 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 magnesium 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 59g, and yield 66%, 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 10
Methanol 320mL is added into 1000L four-hole bottles, stirs lower addition cis-4- methoxyl group -1- aminocyclohexyl formic acid
80g, stir 10 minutes；Thionyl chloride 66g 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 10 hours, sampling inspection
Survey；Detect after reaction raw materials surplus area percentage composition is less than 1% and stop reaction；Vacuum is opened to -0.08Mpa, 40-60 DEG C
Desolvation methanol, steam to thick, stopping heating；Hexamethylene 400mL is added into four-hole bottle, atmospheric pressure reflux is separated in system
Remaining methanol (water knockout drum lower floor is methanol)；Stop reaction when can't see methanol and separated, open cooling water temperature to 30
Below DEG C, filtering, filtrate recycle to hexamethylene band methanol process, solid is weighed, and obtains cis-4- methoxyl group -1- aminocyclohexyl first
Sour methyl esters 95g, yield 92%；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 11
Dichloromethane 630g is added into 2000ml four-hole bottles, 2,5- dimethyl benzene second is added from hand hole under stirring
Sour 485g, stir 10 minutes；Thionyl chloride 386g is added dropwise into reactor, process is added dropwise and keeps 40 DEG C of kettle temperature ＜, course of reaction
It is middle to produce a large amount of sour gas, tail gas alkali liquor absorption；Completion of dropwise addition is warming up to 50 DEG C of back flow reactions 8 hours, and sampling detection is former
Charge level accumulates percentage composition<Stop reaction after 0.5%；If reaction not exclusively continue be incubated 1h after sample again in control.Reaction is still not
The thionyl chloride that total amount 10% need to be added completely continues to react, until qualified.After reacting qualified, normal pressure desolventizing dichloromethane,
Keep kettle temperature to be no more than 60 DEG C, then vacuumize -0.08Mpa, steam to not flow liquid, Liquid Residue is 2,5- dimethyl benzene acetyl in kettle
Chlorine, bottling are stand-by；Closed preservation.
Embodiment 12
DMF 700g is added into 3000mL four-hole bottles, stirs lower addition cis-4- methoxyl group -1- ammonia
Butylcyclohexyl methyl formate 164g, sodium acid carbonate 154g is slowly added to afterwards, great amount of carbon dioxide can be released in adition process, it is special
It is not that preceding 50g adition process foam is most obvious, it is necessary to control addition speed, is stirred 30 minutes after adding；Add ethyl acetate
1230g, it is put into ice-water bath, reaction solution is cooled to 0 DEG C；Start that phenyllacetyl chloride 103g is added dropwise, control 0~5 DEG C of temperature, be added dropwise
Speed is controlled with temperature；After being added dropwise, 0~5 DEG C of stirring reaction 5 hours, sampling monitoring reaction process, when starting material left is small
When 2%, reaction terminates；Add basic zeolite molecular sieve KF/Al2O3200g, open stirring；And it is passed through nitrogen to bubbler and has
Bubble is emerged.20~30 DEG C of kettle temperature and nitrogen protection are controlled, in this temperature stirring reaction 2 hours, sampling detection, raw material area hundred
Divide and stop reaction after being less than 0.5% than content；It is lower except neat solvent is waited to steam to -0.1Mpa, 80~90 DEG C of kettle temperature, decompression to open vacuum
To thick-pasty, after being cooled to 40 DEG C, nitrogen protection is opened, (adjustment nitrogen pressure 0.02Mpa) water 100g is added dropwise into system
After (starting 20g to be slowly added dropwise, pay attention to phenomenon change and temperature change in kettle) completion of dropwise addition, 15min is stirred, by residue after stablizing
Water disposably add, stir 10min, be slow added into 6%NaOH 480g add after stir 20min, filter out molecular sieve
(repeatable to utilize), static layering, upper strata floccule point falls to discard, and lower aqueous layer retains, and hydrochloric acid acidifying, (acid adding speed is added dropwise
Need to control, too fast addition speed can make the moment parcel impurity that product separates out 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 hydrochloric acid 230g, when pH stable is to 3, continues to stir 30min, afterwards mistake
Filter out solid product obtain cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl group -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -
4- alcohol 211g, yield 93.4%.
Embodiment 13
Dichloromethane 1350g is added into 2000ml four-hole bottles；Added under stirring into bottle dry cis-3- (2,
5- 3,5-dimethylphenyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol 260g；After stirring 10min slowly
Triethylamine 96g is added, there is slight exotherm phenomenon, addition finishes adjustment temperature to 20~25 DEG C；Ethyl chloroformate 98g, drop is added dropwise
About 0.5~1h between added-time, controlled in being sampled after being reacted 1 hour at 20~30 DEG C after being added dropwise, it is anti-when starting material left is less than 1%
It should terminate；520g water and 26g concentrated hydrochloric acids are added into reaction bulb；Stratification after stirring 20 minutes；Release lower organic layer and
Middle floccule, upper strata waste water are drained；Again by organic layer with 520g water washings once, stir 30 minutes, separate organic layer and in
Interbed, water layer discarded.Organic layer normal pressure steams solvent, stops distillation when kettle temperature rises to 75 DEG C, oil is added into precipitation kettle
Ether 900g, 90 DEG C are warming up to complete molten insulation backflow 30 minutes；30 DEG C of filterings are cooled to 15~20 DEG C/h of speed, obtain spiral shell
Worm ethyl ester 271g, (external standard content 90-93.7%) filtrate recovery petroleum ether, yield 85%；1HNMR(400MHz,DMSO-d6)δ:
7.11-7.09(m,3H),4.04(s,2H),3.36-3.34(m,3H),3.23-3.22(m,1H),2.31(s,3H),2.25-
2.22(m,5H),1.91(t,2H),1.82(d,2H),1.55(q,2H),1.12(s,3H)。
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 (7)
1. a kind of novel processing step of spiral shell worm ethyl ester, it is characterised in that concretely comprise the following steps：
A, paraphenetidine obtains 1- amino-4-methoxyl hexamethylenes by hydrogenating reduction；
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, cis-4- methoxyl groups -1- aminocyclohexyls methyl formate boils with 2,5- dimethyl benzenes chloroacetic chloride in sodium acid carbonate and alkalescence
The lower generation substitution reaction of stone molecular sieve catalyst effect obtains cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl group -2- oxos -1-
Azaspiro [4,5] decyl- 3- alkene -4- alcohol；
F, cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl groups -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol and chlorine
Ethyl formate reacts to obtain compound spiral shell worm ethyl ester.
A kind of 2. novel processing step of spiral shell worm ethyl ester according to claim 1, it is characterised in that step A detailed process
For：Absolute ethyl alcohol is added into autoclave, paraphenetidine, Raney's nickel, seals kettle cover；Logical nitrogen displacement reaction gas reactor
Repeatedly, then with hydrogen replace repeatedly, be passed through 1.0Mpa every time；Replacement completion, lead 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, hydrogen make-up to 2.5Mpa, and 2.0~2.5Mpa is kept, reaction one
When the section time confirms no longer to consume hydrogen, controlled in sampling, react and terminate when paraphenetidine content is less than 1% in reaction solution, drop
Temperature filters out catalyst Raney's nickel, filtrate steaming removal solvent, it is 1- amino-4-methoxyl hexamethylenes that decompression, which steams product, to 30 DEG C.
A kind of 3. novel processing step of spiral shell worm ethyl ester according to claim 1, it is characterised in that step B detailed process
For：Water is added into autoclave, opens stirring, adds formamide, after stirring a period of time, adds 1- amino -4- methoxies
Butylcyclohexane, catalyst is added, CO is passed through into reactor, pressure in kettle is reached 0.2MPa, be warming up to 50 DEG C, insulation one
The section time, react and terminate when 1- amino-4-methoxyls cyclohexane content is less than 2% in reaction solution, be cooled to 25~30 DEG C, to
Watery hydrochloric acid is added dropwise in reaction solution, regulation pH is 5~6, has solid precipitation, filters out product, filter cake shuffles once, obtains cis-8- first
Oxy-1,3- diaza spiros [4,5]-decyl- 2,4- diketone；Described catalyst be rhodium C catalyst, rhodium aluminium oxide catalyst or
Acetylacetonatodicarrhodium rhodium, preferably rhodium C catalyst.
A kind of 4. novel processing step of spiral shell worm ethyl ester according to claim 1, it is characterised in that step C detailed process
For：Water is added into four-hole bottle, 40 DEG C or so are heated under stirring, adds alkali compounds, stirring and dissolving；Add cis-8- first
Oxy-1,3- diaza spiros [4,5]-decyl- 2,4- diketone, in 95~100 DEG C of reaction a period of times；Sampling monitoring, work as reaction solution
Middle cis-8- methoxyl groups -1,3- diaza spiro [4,5]-decyl- 2,4- diketone content stops reaction after being less than 2%, after the completion of reaction,
60 DEG C or so of cooling, the concentrated sulfuric acid is slowly added dropwise into four-hole bottle, adjusts pH value 3 or so；Water and activated carbon are added into system, is risen
Warm to 80 DEG C stirring a period of times；It is residue to filter out solid while hot, and filtrate heating concentrates, concentrates in system under vacuum condition
Unnecessary water, when steaming to thick-pasty, distillation terminates addition toluene normal pressure and divides water, after moisture is most, is cooled to less than 30 DEG C；From
The heart filters, and solid drying, which is weighed, produces cis-4- methoxyl group -1- aminocyclohexyl formic acid；Described alkali compounds is hydroxide
Barium, calcium hydroxide, preferably magnesium hydroxide, barium hydroxide；Alkali compounds and cis-8- methoxyl group -1,3- diaza spiros [4,5] -
The inventory mol ratio of decyl- 2,4- diketone is 3~5:1, preferably 4:1.
A kind of 5. novel processing step of spiral shell worm ethyl ester according to claim 1, it is characterised in that step D detailed process
For：Methanol is added into reaction bulb, stirs lower addition cis-4- methoxyl group -1- aminocyclohexyl formic acid, then be slowly added dropwise (excessive
1.2mol) thionyl chloride, time for adding are 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, be added dropwise, be warming up to back flow reaction, sampling detection；It is small to detect reaction raw materials surplus area percentage composition
Stop reaction after 1%；Solvent removed by vacuum methanol, steam to thick, stopping heating；Add hexamethylene, atmospheric pressure reflux point
Go out remaining methanol in system (water knockout drum lower floor is methanol)；Stop reaction when can't see methanol and separated, open cooling water
Less than 30 DEG C filterings are cooled to, filtrate recycle to hexamethylene band methanol process, solid is weighed, and obtains cis-4- methoxyl group -1- amino
Methyl cyclohexanecarboxylaand.
A kind of 6. novel processing step of spiral shell worm ethyl ester according to claim 1, it is characterised in that step E detailed process
For：Docking reaction：1st, dichloromethane is added into reaction bulb, adds 2,5- dimethyl phenyl acetic acids under stirring from hand hole,
Stirring 10 minutes；Thionyl chloride is added dropwise into reactor, process is added dropwise and keeps kettle temperature to be less than 40 DEG C, is produced in course of reaction a large amount of
Sour gas, tail gas alkali liquor absorption；Completion of dropwise addition is warming up to 50 DEG C of back flow reactions, and sampling detection raw material area percentage composition is small
Stop reaction after 0.5%；Normal pressure desolventizing dichloromethane, keep kettle temperature to be no more than 60 DEG C, steamed under vacuum condition to not flow liquid,
Liquid Residue is 2,5- dimethyl benzene chloroacetic chlorides in kettle, stand-by, closed preservation of bottling；2nd, DMF is added into reaction bulb, under stirring
Cis-4- methoxyl group -1- aminocyclohexyl methyl formates are added, are slowly added to sodium acid carbonate afterwards, can be released in adition process big
Carbon dioxide is measured, it is necessary to control addition speed, is stirred 30 minutes after adding；Ethyl acetate is added, is put into ice-water bath, will react
Liquid is cooled to 0 DEG C；Start dropwise addition 2,5- dimethyl benzene chloroacetic chlorides control 0~5 DEG C of temperature, and rate of addition is controlled with temperature；Drop
After adding, 0~5 DEG C of stirring reaction 5 hours, sampling monitoring reaction process, when starting material left is less than 2%, reaction terminates；Add
Enter basic zeolite molecular sieve, open stirring；And being passed through nitrogen to bubbler has bubble to emerge.20~30 DEG C of kettle temperature is controlled, herein
Temperature stirring reaction 2 hours, sampling detection, raw material area percentage content stop reaction after being less than 0.5%；Open vacuum to-
0.1Mpa, 80~90 DEG C of kettle temperature, decompression is lower after being cooled to 40 DEG C, to open nitrogen protection except neat solvent is waited to steam to thick-pasty,
(adjustment nitrogen pressure 0.02Mpa) water is added dropwise into system and (starts 20g to be slowly added dropwise, notices that phenomenon change and temperature become in kettle
Change) after completion of dropwise addition, 15min is stirred, disposably adds remaining water after stable, stirs 10min, being slow added into concentration is
6% NaOH solution stirs 20min after adding, and filters out molecular sieve (repeatable to utilize), static layering, upper strata floccule point falls
Discard, lower aqueous layer retains, and hydrochloric acid acidifying is added dropwise, and (acid adding speed needs to control, and too fast addition speed can make the wink that product separates out
Between wrap up impurity and form lump) there are in kettle a large amount of solids to separate out, when pH value reaches 3~4, continue to stir 30min, afterwards mistake
Filter out solid product obtain cis-3- (2,5- 3,5-dimethylphenyls) -8- methoxyl group -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -
4- alcohol；Described basic zeolite molecular sieve is KF/Al2O3。
A kind of 7. novel processing step of spiral shell worm ethyl ester according to claim 1, it is characterised in that step F detailed process
For：Dichloromethane is added into reaction bulb, adds dry cis-3- (2,5- 3,5-dimethylphenyl) -8- under stirring into bottle
Methoxyl group -2- oxo -1- azaspiros [4,5] decyl- 3- alkene -4- alcohol；Triethylamine is slowly added to after stirring a period of time, is had slight
Exothermic phenomenon, addition finish adjustment temperature to 20~25 DEG C；Ethyl chloroformate is added dropwise, reacts 1 at 20~30 DEG C after being added dropwise
Controlled in being sampled after hour, react and terminate when starting material left is less than 1%；Water and concentrated hydrochloric acid are added into reaction solution；20 points of stirring
Stratification after clock；Release lower organic layer and middle floccule, upper strata waste water are drained；Organic layer is washed with water once again,
Stirring 30 minutes, separates organic layer and intermediate layer, water layer discarded；Organic layer normal pressure steams solvent, stops when kettle temperature rises to 75 DEG C
Only distill, petroleum ether is added into precipitation kettle, be warming up to 90 DEG C to complete molten insulation backflow 30 minutes；With 15~20 DEG C/h of speed
Degree is cooled to 30 DEG C of filterings, obtains product spiral shell worm ethyl ester.
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