CN108484506A - A kind of green synthesis method of two chlordantoin of medicine intermediate - Google Patents
A kind of green synthesis method of two chlordantoin of medicine intermediate Download PDFInfo
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- CN108484506A CN108484506A CN201810247946.6A CN201810247946A CN108484506A CN 108484506 A CN108484506 A CN 108484506A CN 201810247946 A CN201810247946 A CN 201810247946A CN 108484506 A CN108484506 A CN 108484506A
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- lanthanum
- chlordantoin
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/10—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of rare earths
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
- C07D233/82—Halogen atoms
Abstract
The invention discloses a kind of green synthesis methods of two chlordantoin of medicine intermediate, using ethyl acetate and tetrahydrofuran as organic media, 5, the nanoscale Ga/Al complex solid alkali that 5 Dimethyl Hydan, liquid chlorine and lanthanum are modified is that raw material passes through condensing reflux, magnetic agitation obtains two chlordantoin of medicine intermediate after microwave reactor processing；Nanoscale Ga/Al complex solids alkali that the present invention is modified using unique lanthanum carries out the synthesis of two chlordantoin of medicine intermediate, it is easy to operate, raw material relatively easily obtains, the nanoscale Ga/Al complex solid alkali being modified by the way that lanthanum is added, effectively raises reaction rate, reduces the generation of side reaction, in the synthesis process, be conducive to being smoothed out for reaction, so that reaction is carried out towards expected direction, convenient for obtaining two chlordantoin of target product medicine intermediate.
Description
Technical field
The present invention relates to a kind of green syt sides of two chlordantoin of pharmaceutical chemistry technical field more particularly to medicine intermediate
Method.
Background technology
Two chlordantoin full name are 1,3-, bis- chloro- 5,5- Dimethyl Hydan, acyl in bis- chloro- 5,5- dimethyl second of also known as 1,3-
Urea, chemical name 1, bis- chloro- 5,5- methyl -2,4- imidazolinediones of 3-.
Two chlordantoins have been applied to industrial cooling circulating water system, swimming pool and fountain water as new and effective disinfectant and have disappeared
Bacterium and algae removal are killed, aquaculture and livestock-raising and daily life disinfection etc. are additionally operable to.
Currently, chlorinating agent and oxidant as pharmaceutical-chemical intermediate synthesis, usually used has chlorine, protochloride
Sulfone, phosphorus chloride, chloramine (toluene-sodium-sulfonchloramide), sodium hypochlorite, sym-closene, N- chlorosuccinimides and N- chloro succinyls
Imines etc., the above available chlorine contents other in addition to sym-closene are below two chlordantoins, the change of these common products
Physical property is unstable, and some chance water explosive, peculiar smell is big, stronger to skin irritation.Current most common N- chloros fourth
Two kinds of products of imidodicarbonic diamide and N-chlorosuccinimide, chlorination reaction process is mild, and storage is stablized, but uses price than two
High more of chlordantoin.
According to reported in literature, the current preparation in relation to two chlordantoins is mostly to produce powdered manufacturing method using following raw materials according,
Including：
1. with 5,5- Dimethyl Hydan, sodium hypochlorite and hydrochloric acid prepare two chlordantoins
2. with 5, two chlordantoins prepared by 5- Dimethyl Hydan, sodium carbonate and chlorine, available chlorine content is between 68-70%.
3. with 5, two chlordantoins prepared by 5- Dimethyl Hydan, liquid caustic soda and chlorine, available chlorine content 67-69.5% it
Between.
In three of the above method, the sodium hypochlorite that first method uses is easy to decompose, and reaction efficiency is low, the production of production
Product content is low, has no industrialized production；Second method is because using sodium carbonate to easy to produce carbon dioxide gas during the reaction
Body, technical process be not easy to operate；The liquid caustic soda content that the third method uses is unstable, generally 30% or so, there is phase difference
2%, cause the content of two chlordantoins unstable, generally between effective chlorine 67-69%, liquid caustic soda contaminant overstandard, influences to produce sometimes
Product purity.Above-mentioned several two chlordantoins product processes products obtained therefrom purity are low, cannot meet as pharmaceutical-chemical intermediate
Therefore the requirement of synthesis develops a kind of high income, it is imperative to synthesize two chlordantoin of simple medicine intermediate.
Invention content
In view of the above existing problems in the prior art, the present invention provides a kind of green syts of two chlordantoin of medicine intermediate
Method.
To achieve the goals above, the technical solution adopted by the present invention is：A kind of green of two chlordantoin of medicine intermediate
Synthetic method, using ethyl acetate and tetrahydrofuran as organic media, nanoscale that 5,5- Dimethyl Hydan, liquid chlorine and lanthanum are modified
Ga/Al complex solid alkali is raw material by condensing reflux, and magnetic agitation obtains medicine intermediate dichloro after microwave reactor processing
Glycolylurea.
Further, a kind of specific synthesis step of two chlordantoin of medicine intermediate is：
（1）, by 5,5- Dimethyl Hydan, natrium carbonicum calcinatum is added in the container of spherical condensation tube, magnetic agitation, and room temperature is anti-
It answers 6 hours；
（2）, to step（1）In sequentially add lanthanum modification nanoscale Ga/Al complex solids alkali, organic media ethyl acetate and four
The mixed liquor of hydrogen furans, after liquid chlorine is added dropwise with the speed of 60 drop per minute, while opening magnetic agitation, and heating 2 is carried out to it
Hour；
（3）, to step（2）Mixed liquor after heating is transferred in microwave reactor and handles 5 hours, after cool, take out
Filter, filter cake are washed with tetrahydrofuran, the nanoscale that filtrate is modified through rotary distillation recovery section ethyl acetate, tetrahydrofuran and lanthanum
Ga/Al complex solid alkali；
（4）, by step（3）It is slowly poured into pure water while residue filtrate is stirred continuously, product is made fully to be precipitated, suction filtration obtains
Crude product, recrystallized afterwards with ethyl alcohol and pure water, again with toluene secondary recrystallization finally obtains product medicine intermediate dichloro sea
Cause.
Further, the above-mentioned steps（2）Middle heating temperature is 80-120 DEG C.
Further, the specific synthetic method of the nanoscale Ga/Al complex solid alkali of the lanthanum modification is：
（1）, calcium nitrate and aluminum nitrate handled into 3h under ultrasonic wave, then 160 DEG C of purging 4h under helium atmosphere, after be transferred to
In beaker；
（2）, deionized water dissolving is added into beaker, while opening magnetic agitation, 100 DEG C of water-bath 2h；
（3）, to step（2）Middle addition kaolin, magnetic agitation reaction, heating water bath keep 3h to 80 DEG C, then carry out heat
Alkali process, handles 2h under 150 DEG C of hot-airs, is finally transferred in the sodium hydroxide solution that mass fraction is 5% and handles 6h；
（4）, to step（3）In treated that product is transferred in another beaker, be added dropwise neopelex, addition go from
Sub- water, magnetic stirring apparatus 3h, is finally transferred in reaction kettle, reacts 4h at 160kpa, 260 DEG C；
（5）, lanthanum nitrate is dissolved into deionized water, then infusion process is used to introduce lanthanum element, knot will be reacted in reaction kettle
Product after beam is immersed in lanthanum nitrate hexahydrate, magnetic agitation 8h；
（6）, after dipping, be washed with deionized to neutrality, then dry 110 DEG C of processing 4h in thermostatic drying chamber, after
Calcination processing in tube furnace.
The method of calcination processing is：
It is first than 1 in nitrogen and oxygen volume:1,0.4kpa, calcination processing 3h at 550 DEG C, then in ammonia and helium volume
Than 2:1,1.0kpa, 650 DEG C of processing 4h, finally obtain the nanoscale Ga/Al complex solid alkali of lanthanum modification.
Beneficial effects of the present invention are：
Nanoscale Ga/Al complex solids alkali that the present invention is modified using unique lanthanum carries out the conjunction of two chlordantoin of medicine intermediate
At easy to operate, raw material relatively easily obtains, the nanoscale Ga/Al complex solid alkali being modified by the way that lanthanum is added, effective to improve
Reaction rate, reduces the generation of side reaction, can be played in the synthesis process to reactant by processing such as magnetic agitations
Activation is conducive to being smoothed out for reaction, and reaction is made to be carried out towards expected direction, intermediate convenient for obtaining target product medicine
Two chlordantoin of body.
Specific implementation mode
Further non-limiting detailed description is done to technical solution of the present invention with reference to several preferred embodiments.
Embodiment 1
It is prepared by the nanoscale Ga/Al complex solid alkali being modified to lanthanum
（1）, 3g calcium nitrate and 6g aluminum nitrates handled into 3h under ultrasonic wave, then 160 DEG C of purging 4h under helium atmosphere, rear to turn
It moves in beaker；
（2）, 100ml deionized water dissolvings are added into beaker, while opening magnetic agitation, 100 DEG C of water-bath 2h；
（3）, to step（2）Middle addition 8g kaolin, magnetic agitation reaction, heating water bath keep 3h to 80 DEG C, then carry out
Hot alkali treatment, handles 2h under 150 DEG C of hot-airs, is finally transferred in the sodium hydroxide solution that 200ml mass fractions are 5%
Manage 6h；
（4）, to step（3）In treated that product is transferred in another beaker, 0.01g neopelexes are added dropwise, add
Enter 80ml deionized waters, magnetic stirring apparatus 3h is finally transferred in reaction kettle, reacts 4h at 160kpa, 260 DEG C；
（5）, 1.5g lanthanum nitrates are dissolved into 40ml deionized waters, then infusion process is used to introduce lanthanum element, will be in reaction kettle
In product after reaction be immersed in lanthanum nitrate hexahydrate, magnetic agitation 8h；
（6）, after dipping, be washed with deionized to neutrality, then dry 110 DEG C of processing 4h in thermostatic drying chamber, after
Calcination processing in tube furnace.
Further, the method for the above-mentioned calcination processing is：
It is first than 1 in nitrogen and oxygen volume:1,0.4kpa, calcination processing 3h at 550 DEG C, then in ammonia and helium volume
Than 2:1,1.0kpa, 650 DEG C of processing 4h, finally obtain the nanoscale Ga/Al complex solid alkali of 4.76g lanthanums modification.
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1:0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.15 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.05g lanthanums are modified
Alkali.
（1）, by 7g5,5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums are added in the container of spherical condensation tube, magnetic force
Stirring reacts at room temperature 6 hours；
（2）, to step（1）In sequentially add 1.05g lanthanums modification nanoscale Ga/Al complex solids alkali, 30ml ethyl acetate and
The mixed liquor of 30ml tetrahydrofurans, after 21ml liquid chlorines are added dropwise with the speed of 60 drop per minute, while opening magnetic agitation, and to it
100 DEG C of heating is carried out to be kept for 2 hours；
（3）, to step（2）Mixed liquor after heating is transferred in microwave reactor and handles 5 hours, after cool, take out
Filter, filter cake are washed with tetrahydrofuran, the nanoscale that filtrate is modified through rotary distillation recovery section ethyl acetate, tetrahydrofuran and lanthanum
Ga/Al complex solid alkali；
（4）, by step（3）It is slowly poured into pure water while residue filtrate is stirred continuously, product is made fully to be precipitated, suction filtration obtains
Crude product, recrystallized afterwards with ethyl alcohol and pure water, again with toluene secondary recrystallization finally obtains product medicine intermediate dichloro sea
Cause.
Embodiment 2
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1.2:0.5 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum
It is 1 with the nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified:1:0.15 sample.30ml ethyl acetate, 36ml tetrahydrochysene furans
It mutters, 15ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solid alkali that 5- Dimethyl Hydan, 7g natrium carbonicum calcinatums, 1.05g lanthanums are modified.
Other raw materials are with operating procedure as embodiment 1.
Embodiment 3
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.13 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 0.91g lanthanums are modified
Alkali.Other raw materials are with operating procedure as embodiment 1.
Embodiment 4
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.11 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 0.77g lanthanums are modified
Alkali.Other raw materials are with operating procedure as embodiment 1.
Embodiment 5
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.1 sample.30ml ethyl acetate, 30ml tetrahydrofurans,
21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solid alkali that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 0.7g lanthanums are modified.Its
Its raw material is with operating procedure as embodiment 1.
Embodiment 6
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.08 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 0.56g lanthanums are modified
Alkali.Other raw materials are with operating procedure as embodiment 1.
Embodiment 7
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.06 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 0.42g lanthanums are modified
Alkali.Other raw materials are with operating procedure as embodiment 1.
Embodiment 8
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.18 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.26g lanthanums are modified
Alkali.Other raw materials are with operating procedure as embodiment 1.
Embodiment 9
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1：0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.2 sample.30ml ethyl acetate, 30ml tetrahydrofurans,
21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solid alkali that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.4g lanthanums are modified.Its
Its raw material is with operating procedure as embodiment 1.
Control group 1
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1:0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.15 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.05g lanthanums are modified
Alkali.Without ultrasonication, other raw materials are with operating procedure as embodiment 1.
Control group 2
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1:0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.15 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.05g lanthanums are modified
Alkali.Without magnetic stirring apparatus, using mechanical agitation, other raw materials are with operating procedure as embodiment 1.
Control group 3
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1:0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.15 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.05g lanthanums are modified
Alkali.Without microwave treatment, other raw materials are with operating procedure as embodiment 1.
Control group 4
It prepared by two chlordantoin of medicine intermediate
It is 1 to take ethyl acetate, tetrahydrofuran and liquid chlorine volume ratio:1:0.7 sample, 5,5- Dimethyl Hydan, natrium carbonicum calcinatum with
The nanoscale Ga/Al complex solid alkali mass ratioes that lanthanum is modified are 1:1.2:0.15 sample.30ml ethyl acetate, 30ml tetrahydrochysene furans
It mutters, 21ml liquid chlorines, 7g5, the nanoscale Ga/Al complex solids that 5- Dimethyl Hydan, 8.4g natrium carbonicum calcinatums, 1.05g lanthanums are modified
Alkali.It is handled without toluene secondary recrystallization, other raw materials are with operating procedure as embodiment 1.
Control group 5
It prepared by two chlordantoin of medicine intermediate
It is added without the nanoscale Ga/Al complex solid alkali of lanthanum modification, other raw materials are with operating procedure as embodiment 1.
Control group 6
For other raw materials with operating procedure as embodiment 1, difference is the system for the nanoscale Ga/Al complex solid alkali that lanthanum is modified
It is standby：The preparation process for the nanoscale Ga/Al complex solid alkali that the lanthanum is modified is as follows：
（1）, 3g calcium nitrate and 6g aluminum nitrates handled into 3h under ultrasonic wave, then 160 DEG C of purging 4h under helium atmosphere, rear to turn
It moves in beaker；
（2）, 100ml deionized water dissolvings are added into beaker, while opening magnetic agitation, 100 DEG C of water-bath 2h；
（3）, to step（2）Middle addition 8g kaolin, magnetic agitation reaction, heating water bath keep 3h to 80 DEG C, then carry out
Hot alkali treatment, handles 2h under 150 DEG C of hot-airs, is finally transferred in the sodium hydroxide solution that 200ml mass fractions are 5%
Manage 6h；
（4）, to step（3）In treated that product is transferred in another beaker, 0.01g neopelexes are added dropwise, add
Enter 80ml deionized waters, magnetic stirring apparatus 3h is finally transferred in reaction kettle, reacts 4h at 160kpa, 260 DEG C；
（5）, 1.5g lanthanum nitrates are dissolved into 40ml deionized waters, then infusion process is used to introduce lanthanum element, will be in reaction kettle
In product after reaction be immersed in lanthanum nitrate hexahydrate, magnetic agitation 8h；
（6）, after dipping, be washed with deionized to neutrality, then dry 110 DEG C of processing 4h in thermostatic drying chamber, after
Calcination processing in tube furnace.
The method of the above-mentioned calcination processing is：
First in air, 0.4kpa, calcination processing 3h at 550 DEG C, the nanoscale Ga/Al for finally obtaining the modification of 4.76g lanthanums is compound
Solid base.
The purity and yield of experiment test product：
Liquid chromatogram：AcquityTM Ultra Performance Liquid Chromatography instruments, chromatographic column:PhenomenexSynergiMax-RP columns (150mm
× 2.0mm, 4 μm, aperture 8nm)；Mobile phase:A.10mmol/L ammonium acetate, B. acetonitriles；Gradient elution program:0.0~8.0min,
80%A~72%A；8.0~13.0min, 72%A~62%A；13.0~15.0min, 62%A~20%A；15.0~
18.0min 20%A；18.0~18.1min, 20%A~80%A；18.1~22.0min, 80%A；Flow velocity:0.5mL/min；
Sample size:5μL；Column temperature:25℃；Detection wavelength:350nm.Detect product component, calculated purity and yield.
Following table is the purity and yield result of two chlordantoin of medicine intermediate.
The experimental results showed that：The purity for two chlordantoin of medicine intermediate that embodiment 1,2 obtains is best with yield, illustrates this
Two kinds of proportionings in raw material, the production of the operation of technique most beneficial for target product；Product obtained is in purity under other techniques,
It is not especially desirable on yield.Comparative example 1, control group 1-6 is it can be found that without ultrasonication, without magnetic
Power stirs, and without microwave treatment, does not have to toluene secondary recrystallization, is added without the nanoscale Ga/Al complex solid alkali of lanthanum modification,
The purity and yield of two chlordantoin of medicine intermediate is not high.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention has appended power
Profit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent requirements of the claims
Variation is included within the present invention.Any label in claim should not be considered as and be limited the claims involved.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solution in each case study on implementation may also be suitably combined to form people in the art
The other embodiment that member is appreciated that.
Claims (5)
1. a kind of green synthesis method of two chlordantoin of medicine intermediate, its chemical name is 1,3-, bis- chloro- 5,5- dimethyl seas
Cause, bis- chloro- 5,5- dimethyl hydantoins of also known as 1,3-, structural formula are as follows：
,
It is characterized in that：Using ethyl acetate and tetrahydrofuran as organic media, what 5,5- Dimethyl Hydan, liquid chlorine and lanthanum were modified receives
Meter level Ga/Al complex solid alkali is raw material by condensing reflux, and magnetic agitation obtains medicine intermediate after microwave reactor processing
Two chlordantoins.
2. a kind of green synthesis method of two chlordantoin of medicine intermediate according to claim 1, it is characterised in that：It is described
A kind of specific synthesis step of two chlordantoin of medicine intermediate is：
（1）, by 5,5- Dimethyl Hydan, natrium carbonicum calcinatum is added in the container of spherical condensation tube, magnetic agitation, and room temperature is anti-
It answers 6 hours；
（2）, to step（1）In sequentially add lanthanum modification nanoscale Ga/Al complex solids alkali, organic media ethyl acetate and four
The mixed liquor of hydrogen furans, after liquid chlorine is added dropwise with the speed of 60 drop per minute, while opening magnetic agitation, and heating 2 is carried out to it
Hour；
（3）, to step（2）Mixed liquor after heating is transferred in microwave reactor and handles 5 hours, after cool, take out
Filter, filter cake are washed with tetrahydrofuran, the nanoscale that filtrate is modified through rotary distillation recovery section ethyl acetate, tetrahydrofuran and lanthanum
Ga/Al complex solid alkali；
（4）, by step（3）It is slowly poured into pure water while residue filtrate is stirred continuously, product is made fully to be precipitated, suction filtration obtains
Crude product, recrystallized afterwards with ethyl alcohol and pure water, again with toluene secondary recrystallization finally obtains product medicine intermediate dichloro sea
Cause.
3. a kind of green synthesis method of two chlordantoin of medicine intermediate according to claim 2, it is characterised in that：It is described
Step（2）Middle heating temperature is 80-120 DEG C.
4. a kind of green synthesis method of two chlordantoin of medicine intermediate according to claim 1 or claim 2, special
Sign is：The specific synthetic method for the nanoscale Ga/Al complex solid alkali that the lanthanum is modified is：
（1）, calcium nitrate and aluminum nitrate handled into 3h under ultrasonic wave, then 160 DEG C of purging 4h under helium atmosphere, after be transferred to
In beaker；
（2）, deionized water dissolving is added into beaker, while opening magnetic agitation, 100 DEG C of water-bath 2h；
（3）, to step（2）Middle addition kaolin, magnetic agitation reaction, heating water bath keep 3h to 80 DEG C, then carry out heat
Alkali process, handles 2h under 150 DEG C of hot-airs, is finally transferred in the sodium hydroxide solution that mass fraction is 5% and handles 6h；
（4）, to step（3）In treated that product is transferred in another beaker, be added dropwise neopelex, addition go from
Sub- water, magnetic stirring apparatus 3h, is finally transferred in reaction kettle, reacts 4h at 160kpa, 260 DEG C；
（5）, lanthanum nitrate is dissolved into deionized water, then infusion process is used to introduce lanthanum element, knot will be reacted in reaction kettle
Product after beam is immersed in lanthanum nitrate hexahydrate, magnetic agitation 8h；
（6）, after dipping, be washed with deionized to neutrality, then dry 110 DEG C of processing 4h in thermostatic drying chamber, after
Calcination processing in tube furnace.
5. the specific synthetic method for the nanoscale Ga/Al complex solid alkali that lanthanum according to claim 4 is modified, feature exist
In：The method of the calcination processing is：
It is first than 1 in nitrogen and oxygen volume:1,0.4kpa, calcination processing 3h at 550 DEG C, then in ammonia and helium volume
Than 2:1,1.0kpa, 650 DEG C of processing 4h, finally obtain the nanoscale Ga/Al complex solid alkali of lanthanum modification.
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