CN105461588A - Method for compounding metabolites 6 in ridomil - Google Patents
Method for compounding metabolites 6 in ridomil Download PDFInfo
- Publication number
- CN105461588A CN105461588A CN201510954228.9A CN201510954228A CN105461588A CN 105461588 A CN105461588 A CN 105461588A CN 201510954228 A CN201510954228 A CN 201510954228A CN 105461588 A CN105461588 A CN 105461588A
- Authority
- CN
- China
- Prior art keywords
- rieter
- bolites
- organic solvent
- meta
- mould
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for compounding metabolites 6 in ridomil, which comprises steps: 1) ridomil (I) is used as raw materials, are dissolved in an organic solvent, is added with a catalyst after cooling, is reacted to obtain a compound (II) after heating; 2) the compound (II) is further dissolved into the organic solvent, is added with an alkali liquor after cooling, is reacted after heating to obtain the metabolites 6 (III). The invention further provides the metabolites 6 prepared through the method for compounding the metabolites 6 in the ridomil and a purpose thereof. The method for compounding the metabolites 6 in the ridomil can obtain N (2, 6-dimethyl phenyl)-N-(hydroxyl acetyl) alanine with high purity and excellent yield, and has extremely cnsiderable application and market prospect.
Description
Technical field
The invention belongs to chemosynthesis technical field; relate to the synthetic method of the mould middle meta-bolites of a kind of Rieter; be specifically related to a kind of synthetic method to mould middle meta-bolites 6:N – (2,6-xylyl)-N-(glycolyl) L-Ala of Rieter.
Background technology
The new and effective systemic fungicide that Rieter mould (Ridomil) is first reported in 1977 for F.Scwinn, have another name called metaxanin, its performance is more stable, to the subject range extensive (1.0 ~ 9.0) of pH, to high-temperature and high light better tolerance.As the new and effective systemic fungicide of one, its mechanism of action is by acting on mycelium, archespore wall, to make its selective permeability, affect water mo(u)ld absorbing nutritive substance, make that mycelial cell is dead, spore loses germination, blocking its life history, now there are some researches prove that it has good prevention effect to the fish molds of fish body and fish-egg, powder as mould in compound Rieter---the concentration of splashing of " U.S. graceful " is 5 ~ 10g/m
3, dipping bath concentration is 20g/m
3time, effectively can prevent and treat the fish molds of fish-egg, fry and adult fish.
At present, domestic main use have 35% seed dressing, 25% wettable powder, 5% granule and 25% missible oil containing the mould formulation of Rieter, common mixture has 58% metalaxyl manganese-zinc wettable powder (Rieter mould+zinc manganese ethylenebisdithiocarbamate), 60% metalaxyl manganese-zinc wettable powder, 72% metalaxyl manganese-zinc wettable powder etc.
2002 pesticide residue joint conference (JMPR) establish the mould toxicology of Rieter, and establish the mould Acceptable Daily Intake of Rieter (ADI).Simultaneously, show after deliberation, the mould metabolism in animal body of Rieter mainly contains 16 kinds of meta-bolitess, wherein, according to the content detected in different animals, the meta-bolites of more (>0.1mg/kg) is metabolite 6,8,12,16.And wherein, metabolite 6 is N – (2,6-xylyl)-N-(glycolyl) L-Ala, at home and abroad there is no the correlative study that synthesis obtains this kind of mould main metabolites of Rieter at present.
Summary of the invention
The shortcoming of prior art in view of the above, the object of the present invention is to provide the synthetic method of the mould middle meta-bolites 6 of a kind of Rieter, for solving in prior art the problem of the method lacking the mould middle meta-bolites 6 of synthesis Rieter.
For achieving the above object and other relevant objects, first aspect present invention provides the synthetic method of the mould middle meta-bolites 6 of a kind of Rieter, comprises the following steps:
1) getting Rieter mould (I) is raw material, is dissolved in organic solvent, adds catalyzer after cooling, then reaction after heating up, and obtains compound (II);
2) compound (II) is dissolved in organic solvent again, after cooling, adds alkali lye, then reaction after heating up, obtain meta-bolites 6 (III);
Step 1) and step 2) reaction scheme as follows:
Wherein: described Rieter mould (I) is N – (2,6-xylyl)-2-methoxyl group aldehyde-base sec.-propyl methyl esters amine; Described compound (II) is N – (2,6-xylyl)-(2-hydroxy acyl) sec.-propyl methyl esters amine; Described meta-bolites 6 (III) is N – (2,6-xylyl)-N-(glycolyl) L-Ala.
Preferably, step 1) in, described organic solvent is selected from methylene dichloride, ethyl acetate, methyl tertiary butyl ether, any one in toluene.More preferably, described organic solvent is methylene dichloride (DCM).
Preferably, step 1) in, described catalyzer is selected from boron tribromide, aluminum chloride, any one in pyridine hydrochloride, Hydrogen bromide and acetic acid mixed aqueous solution.More preferably, described catalyzer is boron tribromide.
Preferably, step 1) in, the ratio of the volume that the mould mole number added of described Rieter adds with organic solvent is 1:5-20 (mmol/ml).
More preferably, the ratio of volume that the mould mole number added of described Rieter adds with organic solvent is 1:5 (mmol/ml).
Preferably, step 1) in, described catalyzer adds as required.
More preferably, described catalyzer and the mould mol ratio added of Rieter are 1-2:1.Further preferably, described catalyzer and the mould mol ratio added of Rieter are 1.5:1.
Preferably, step 1) in, described cooling adopts the mixture cooling of dry ice and acetone.Described cooling is carried out in vacuum jacketed flask.
Preferably, step 1) in, the temperature after described cooling is-78 to 0 DEG C.More preferably, the temperature after described cooling is-40 DEG C.
Preferably, step 1) in, the temperature after described intensification is room temperature.More preferably, described room temperature is 25 DEG C.The mixture of described intensification dry ice and acetone to be cooled to after certain temperature nature, slowly raised temperature along with the volatilization of dry ice in vacuum jacketed flask.
Preferably, step 1) in, after described intensification, the reaction times is 1-24h.More preferably, after described intensification, the reaction times is 5h.
Preferably, described step 1) in reaction determine reaction end by tlc (TLC).
More preferably, described tlc (TLC) is by determining reaction end to the detection of reaction product.
Further preferably, the testing conditions of described TLC be adopt volume ratio be the methylene dichloride of 1:1 (V:V) with sherwood oil as developer, under the inspecting of UV-irradiation, make the point sample of reaction product disappear is reaction end.
Preferably, described step 1) in also to carry out purifying to compound (II) after completion of the reaction, comprise the steps:
A) adding alkali lye regulates the pH value of compound (II) to neutral (i.e. pH=7);
More preferably, described alkali lye is the saturated solution of alkali.
More preferably, the alkali in described alkali lye is selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, any one in triethylamine.Most preferably, described alkali is sodium bicarbonate.
B) add organic solvent vibration layering again, form aqueous phase and be separated with after organic phase;
More preferably, described layering is carried out in separating funnel.Described compound (II) be dissolved in organic phase.
C), after water intaking adopts organic solvent repeatedly to extract mutually, collection organic extract and described organic phase merge, and remove aqueous phase;
More preferably, described aqueous phase adopts the extraction times of organic solvent to be 2-4 time.
D) get step C) in merge after organic phase washing, dry, decolouring, placement is spent the night, and filters, obtains the compound after purifying (II).
More preferably, the organic phase after described merging will adopt water repeatedly to wash.Described washing is for removing impurity water-soluble in organic phase.Further preferably, described washing times is 2-3 time.
More preferably, described organic phase drying is that organic phase and siccative are at room temperature stirred drying.
Further preferably, described siccative is selected from any one in sodium carbonate, salt of wormwood, potassium hydroxide, anhydrous sodium sulphate, anhydrous magnesium sulfate.Most preferably, described siccative is anhydrous sodium sulphate.
Further preferably, the quality that adds of described siccative and step 1) in dissolves Rieter mould needed for the ratio of volume that adds of organic solvent be 0.03-0.1:1 (g/ml).
Most preferably, the quality that adds of described siccative and step 1) in dissolves Rieter mould needed for the ratio of volume that adds of organic solvent be 0.05:1 (g/ml).
Further preferably, described stirring time of drying is 1.5-2.5 hour.Most preferably, described stirring time of drying is 2 hours.
More preferably, described decolouring adopts discoloring agent to decolour.
Further preferably, described discoloring agent is gac.Described gac adopts the most frequently used medical neutral active charcoal.
Further preferably, the quality that adds of described discoloring agent and step 1) in dissolves Rieter mould needed for the ratio of volume that adds of organic solvent be 0.02-0.05:1 (g/ml).
More preferably, vacuum filtration is filtered into described in.
More preferably, after described vacuum filtration, filtration product organic solvent is carried out repeatedly drip washing.Filtrate organic solvent is reclaimed after described drip washing.
Further preferably, described drip washing number of times is 3 times.
More preferably, in above-claimed cpd (II) purifying, described organic solvent is selected from methylene dichloride, ethyl acetate, methyl tertiary butyl ether, any one in toluene.
Described step D) in the compound (II) that obtains after purifying be white solid.
Preferably, step 2) in, described organic solvent is methyl alcohol.Described compound (II) is dissolved into the transparent no suspended substance of solution completely in methyl alcohol.
Preferably, step 2) in, described alkali lye is the saturated solution of alkali.
Preferably, step 2) in, described alkali lye is selected from sodium hydroxide solution, potassium hydroxide solution, aqua calcis, solution of potassium carbonate, any one in sodium carbonate solution.More preferably, described alkali lye is potassium hydroxide solution.Above-mentioned solution is the aqueous solution.
Preferably, the ratio of volume that the mould mole number added of described Rieter adds with organic solvent is 1:5-20 (mmol/ml).
More preferably, the ratio of volume that the mould mole number added of described Rieter adds with organic solvent is 1:5 (mmol/ml).
Preferably, the ratio of volume that the mould mole number added of described Rieter adds with alkali lye is 1:1-1.1 (mmol/ml).
More preferably, the ratio of volume that the mould mole number added of described Rieter adds with alkali lye is 1:1.05 (mmol/ml).Excellent
Selection of land, described cooling adopts ice-water bath cooling.
More preferably, the temperature after described ice-water bath cooling is 0-20 DEG C.Further preferably, the temperature after described ice-water bath cooling is 5 DEG C.
Preferably, ice-water bath is removed in described intensification, after being naturally warming up to room temperature, then adopts water-bath to heat.
More preferably, the temperature after described intensification is 30-40 DEG C.Further preferably, the temperature after described intensification is 35 DEG C.
Preferably, after described intensification, the reaction times is 1-24h.More preferably, after described intensification, the reaction times is 2h.
Preferably, described step 2) in reaction determine reaction end by tlc (TLC).
More preferably, described tlc (TLC) is by determining reaction end to the detection of reaction product.
Further preferably, the testing conditions of described TLC be adopt volume ratio be the ethyl acetate of 1:1 (V:V) with sherwood oil as developer, under the inspecting of UV-irradiation, make the point sample of reaction product disappear is reaction end.
Preferably, described step 2) in also to carry out purifying to meta-bolites 6 (III) after completion of the reaction, comprise the steps:
A) in meta-bolites 6 (III), add organic solvent vibration layering, form aqueous phase and be separated with after organic phase;
More preferably, described layering is carried out in separating funnel.Described meta-bolites 6 (III) is dissolved in organic phase.
B) water intaking adopts organic solvent repeatedly to extract mutually, after removing organic extract, then regulates the pH value of aqueous phase by acid solution;
More preferably, described aqueous phase adopts the extraction times of organic solvent to be 2-4 time.Described extraction is conventional extraction mode, and will be dissolved in unreacted and the Impurity removal of organic phase in aqueous phase, number of times is The more the better.
More preferably, described acid solution is aqueous hydrochloric acid.The concentration of described aqueous hydrochloric acid is preferably 3mol/L.
More preferably, the pH of described aqueous phase after acid solution regulates is 1.5-2.5.Further preferably, the pH of described aqueous phase after acid solution regulates is 2.
C) by step b) in aqueous phase again adopt organic solvent repeatedly to extract after, collect organic extract and described organic phase and merge, and remove aqueous phase;
More preferably, described aqueous phase adopts the extraction times of organic solvent to be 2-4 time again.
D) get step c) in merge after organic phase washing, dry, decolouring, placement is spent the night, and filters, obtains the meta-bolites after purifying 6.
More preferably, the organic phase after described merging will adopt water repeatedly to wash.Described washing is for removing impurity water-soluble in organic phase.Further preferably, described washing times is 2-3 time.
More preferably, described organic phase drying is that organic phase and siccative are at room temperature stirred drying.
Further preferably, described siccative is selected from any one in sodium carbonate, salt of wormwood, potassium hydroxide, anhydrous sodium sulphate, anhydrous magnesium sulfate.Most preferably, described siccative is anhydrous sodium sulphate.
Further preferably, the quality that adds of described siccative and step 2) in dissolves Rieter mould needed for the ratio of volume that adds of organic solvent be 0.03-0.1:1 (g/ml).
Most preferably, the quality that adds of described siccative and step 2) in dissolves Rieter mould needed for the ratio of volume that adds of organic solvent be 0.05:1 (g/ml).
Further preferably, described stirring time of drying is 1.5-2.5 hour.Most preferably, described stirring time of drying is 2 hours.
More preferably, described decolouring adopts discoloring agent to decolour.
Further preferably, described discoloring agent is gac.Described gac adopts the most frequently used medical neutral active charcoal.
Further preferably, the quality that adds of described discoloring agent and step 2) in dissolves Rieter mould needed for the ratio of volume that adds of organic solvent be 0.02-0.05:1 (g/ml).
More preferably, vacuum filtration is filtered into described in.
More preferably, after described vacuum filtration, filtration product organic solvent is carried out repeatedly drip washing.Filtrate organic solvent is reclaimed after described drip washing.
Further preferably, described drip washing number of times is 3 times.
More preferably, in above-mentioned meta-bolites 6 (III) purifying, described organic solvent is selected from methylene dichloride, ethyl acetate, methyl tertiary butyl ether, any one in toluene.
Preferably, the water of above-mentioned use is pure water.
Second aspect present invention provides mould middle meta-bolites 6:N – (2,6-xylyl)-N-(glycolyl) L-Ala of a kind of Rieter obtained by above-mentioned synthetic method.
Third aspect present invention provides the purposes of the mould middle meta-bolites 6 of a kind of Rieter in sterilant, medicine.
Preferably, described sterilant is the reagent of killing aquatic animal wound water mo(u)ld.
Preferably, described medicine is the medicine of control saprolegniasis of aquatic animals.
As mentioned above, the synthetic method of the mould middle meta-bolites 6 of a kind of Rieter of the present invention, has following beneficial effect:
(1) synthetic method of the mould middle meta-bolites 6 of a kind of Rieter provided by the invention; effectively can synthesize the mould middle meta-bolites 6:N – (2 of Rieter; 6-xylyl)-N-(glycolyl) L-Ala, method is simple, and cost is lower.
(2) synthetic method of the mould middle meta-bolites 6 of a kind of Rieter provided by the invention, the purity of N – (2,6-xylyl)-N-(glycolyl) L-Ala of acquisition is higher, can be greater than 95%; Yield is better, can be greater than 80%.
(3) synthetic method of the mould middle meta-bolites 6 of a kind of Rieter provided by the invention; the N – (2 obtained; 6-xylyl)-N-(glycolyl) L-Ala, can be used in preparing the aspect such as sterilant, medicine, there are more considerable application and market outlook.
Accompanying drawing explanation
Fig. 1 is shown as the HNMR schematic diagram of N – in the present invention (2,6-xylyl)-N-(glycolyl) L-Ala.
Fig. 2 is shown as the HPLC schematic diagram of N – in the present invention (2,6-xylyl)-N-(glycolyl) L-Ala.
Embodiment
Set forth the present invention further below in conjunction with specific embodiment, should be understood that these embodiments are only not used in for illustration of the present invention and limit the scope of the invention.
Below by way of specific specific examples, embodiments of the present invention are described, those skilled in the art the content disclosed by this specification sheets can understand other advantages of the present invention and effect easily.The present invention can also be implemented or be applied by embodiments different in addition, and the every details in this specification sheets also can based on different viewpoints and application, carries out various modification or change not deviating under spirit of the present invention.
Notice, in the following example, the concrete processing unit that indicates or device all adopt conventional equipment in this area or device; All force value and scope all refer to relative pressure.The reagent used in following examples such as boron tribromide, dry ice, acetone, sodium bicarbonate, methyl alcohol, potassium hydroxide, hydrochloric acid, anhydrous sodium sulphate, methylene dichloride etc. are the reagent of this area routine use.The Rieter used in following examples is mould is metaxanin analytical standard product, is produced by Chemical Reagent Co., Ltd., Sinopharm Group.Chromatographic sheet (TLC), efficient liquid phase chromatographic analysis instrument (HPLC), hydrogen nuclear magnetic resonance spectrometer (HNMR) are the instrument that this area routine uses.
In addition should be understood that the one or more method stepss mentioned in the present invention do not repel and can also to there is additive method step or can also insert additive method step before and after described combination step between these steps clearly mentioned, except as otherwise noted; Will also be understood that, the relation that is connected between the one or more equipment/devices mentioned in the present invention is not repelled and can also to be there are other equipment/devices or can also insert other equipment/devices before and after described clustered aggregates/device between these two equipment/devices clearly mentioned, except as otherwise noted.And, except as otherwise noted, the numbering of various method steps is only the convenient tool differentiating various method steps, but not be ordering or the enforceable scope of restriction the present invention of restriction various method steps, the change of its relativeness or adjustment, when changing technology contents without essence, when being also considered as the enforceable category of the present invention.
Embodiment 1
The Rieter taking 2.79g10mmol is mould, is dissolved in 50mL methylene dichloride, is cooled to-40 degree left and right, drips the boron tribromide of 3.80g15mmol with the mixture of dry ice and acetone, dropwises slowly to rise to room temperature reaction 5 hours afterwards.Detect after above-mentioned reaction completes by TLC, pH is carefully regulated to arrive neutrality with saturated solution of sodium bicarbonate in the product, product adds 50mL methylene dichloride vibration layering in separating funnel, be layered as aqueous phase and organic phase, by aqueous phase 30mL dichloromethane extraction 3 times, the methylene dichloride that 3 times extract is merged in organic phase, and removes aqueous phase.Then, after merging after organic phase 50mL pure water 2 times, with 2.5g anhydrous sodium sulfate drying, 1g neutral active carbon decoloring, placement is spent the night, then after carrying out vacuum filtration, after filter cake methylene dichloride being carried out 3 drip washing in suction funnel, obtain white solid, and reclaim filtrate methylene dichloride.
Directly used by white solid 50mL dissolve with methanol to transparent, be then cooled to about 5 DEG C, drip the KOH aqueous solution of 10.5mL75mmol, dropwise and be heated to 35 DEG C of reactions 2 hours.After complete by TLC detection organic phase raw material reaction, product adds 50mL methylene dichloride vibration layering in separating funnel, be layered as aqueous phase and organic phase, collect aqueous phase, aqueous phase is with after 10mL dichloromethane extraction 3 times, aqueous phase concentrated hydrochloric acid regulates pH to 2, then uses 30mL dichloromethane extraction 3 times, is merged in organic phase by the methylene dichloride that 3 times extract.Then, after merging after organic phase 50mL pure water 2 times, with 2.5g anhydrous sodium sulfate drying, 1g neutral active carbon decoloring, placement is spent the night, after filter cake methylene dichloride being carried out 3 drip washing in suction funnel after carrying out vacuum filtration again, obtain 2.00g meta-bolites 6 sample 1#, reclaim filtrate methylene dichloride simultaneously.The molar yield of the meta-bolites 6 sample 1# obtained is 80.2%, and the calculation formula (i) of described molar yield is as follows.
Yield=(object product formation/key ingredient initial amount) × 100% (i)
In calculation formula (i), the molecular weight according to raw material calculates molar weight, and then in the theoretical amount calculating product according to the molecular weight of molar weight and product, actual amount is exactly yield divided by theoretical amount.
Embodiment 2
The meta-bolites 6 sample 1# obtained in embodiment 1 is carried out HNMR and HPLC respectively detect.
Wherein, as shown in Figure 1, being detected known by HNMR, is CH3 fat methyl hydrogen at 1.12-1.14ppm (d, 3H); At two methyl that 2.16ppm with 2.41ppm Wei not be connected with phenyl ring; It is the chemical displacement value of the methylene radical be connected with carbonyl with oxygen at 3.5-3.7ppm (dd, 2H); In the chemical shift that 4.57-4.59ppm (t, 1H) is the methyne be connected with methyl; In the chemical shift of fragrant district 7.11-7.17ppm (2H, dd) for two the symmetrical hydrogen in methyl ortho position on phenyl ring; Be position hydrogen chemical shifts between methyl on aromatic ring at 7.22-7.24 (d, 1H).According to above-mentioned HNMR detected result, judge experience according to general nuclear-magnetism purity, nuclear-magnetism spectrum is upper is less than less than 0.05 without obvious assorted peak or assorted peak hydrogen integral area, and we can judge that product purity is greater than 95%.Meanwhile, according to above-mentioned HNMR detected result, can verify that the product synthesized in the present invention is mould middle meta-bolites 6:N – (2,6-xylyl)-N-(glycolyl) L-Ala of Rieter.
As shown in Figure 2, detected known by HPLC, the purity adopting HPLC area normalization method to measure acquisition meta-bolites 6 sample 1# is 99.66%.
Embodiment 3
The Rieter taking 2.79g10mmol is mould, is dissolved in 100mL ethyl acetate, is cooled to-78 degree left and right, drips the boron tribromide of 20mmol with the mixture of dry ice and acetone, dropwises slowly to rise to room temperature reaction 24 hours afterwards.Detect after above-mentioned reaction completes by TLC, pH is carefully regulated to arrive neutrality by saturated solution of sodium carbonate in the product, product adds 50mL ethyl acetate vibration layering in separating funnel, be layered as aqueous phase and organic phase, by aqueous phase 30mL extraction into ethyl acetate 3 times, the ethyl acetate that 3 times extract is merged in organic phase, and removes aqueous phase.Then, after merging after organic phase 50mL pure water 3 times, with 3g anhydrous magnesium sulfate drying, 2.5g neutral active carbon decoloring, placement is spent the night, then after carrying out vacuum filtration, after filter cake ethyl acetate being carried out 3 drip washing in suction funnel, obtain white solid, and reclaim filtrate ethyl acetate.
Directly used by white solid 100mL dissolve with methanol to transparent, be then cooled to about 10 DEG C, drip the aqueous sodium hydroxide solution of 10mL75mmol, dropwise and be heated to 30 DEG C of reactions 5 hours.After complete by TLC detection organic phase raw material reaction, product adds 50mL ethyl acetate vibration layering in separating funnel, be layered as aqueous phase and organic phase, collect aqueous phase, aqueous phase is with after 10mL extraction into ethyl acetate 3 times, aqueous phase concentrated hydrochloric acid regulates pH to 2, then uses 30mL extraction into ethyl acetate 3 times, the ethyl acetate that 3 times extract is merged in organic phase.Then, after merging after organic phase 50mL pure water 2 times, with 3g anhydrous magnesium sulfate drying, 2.5g neutral active carbon decoloring, placement is spent the night, after carrying out vacuum filtration again, after filter cake ethyl acetate being carried out 3 drip washing in suction funnel, obtain 1.95g meta-bolites 6 sample 2#, reclaim filtrate ethyl acetate simultaneously.The molar yield of the meta-bolites 6 sample 2# obtained is 77.7%, and the calculation formula of described molar yield is with above-mentioned calculation formula (i).
Embodiment 4
The meta-bolites 6 sample 2# obtained in embodiment 3 is carried out HNMR and HPLC respectively detect.
Wherein, as shown in Figure 1, being detected known by HNMR, is CH3 fat methyl hydrogen at 1.12-1.14ppm (d, 3H); At two methyl that 2.16ppm with 2.41ppm Wei not be connected with phenyl ring; It is the chemical displacement value of the methylene radical be connected with carbonyl with oxygen at 3.5-3.7ppm (dd, 2H); In the chemical shift that 4.57-4.59ppm (t, 1H) is the methyne be connected with methyl; In the chemical shift of fragrant district 7.11-7.17ppm (2H, dd) for two the symmetrical hydrogen in methyl ortho position on phenyl ring; Be position hydrogen chemical shifts between methyl on aromatic ring at 7.22-7.24 (d, 1H).According to above-mentioned HNMR detected result, judge experience according to general nuclear-magnetism purity, nuclear-magnetism spectrum is upper is less than less than 0.05 without obvious assorted peak or assorted peak hydrogen integral area, and we can judge that product purity is greater than 95%.Meanwhile, according to above-mentioned HNMR detected result, can verify that the product synthesized in the present invention is mould middle meta-bolites 6:N – (2,6-xylyl)-N-(glycolyl) L-Ala of Rieter.
Detected known by HPLC, the purity adopting HPLC area normalization method to measure acquisition meta-bolites 6 sample 2# is greater than 95%.
So the present invention effectively overcomes various shortcoming of the prior art and tool high industrial utilization.
Above-described embodiment is illustrative principle of the present invention and effect thereof only, but not for limiting the present invention.Any person skilled in the art scholar all without prejudice under spirit of the present invention and category, can modify above-described embodiment or changes.Therefore, such as have in art usually know the knowledgeable do not depart from complete under disclosed spirit and technological thought all equivalence modify or change, must be contained by claim of the present invention.
Claims (10)
1. a synthetic method for the mould middle meta-bolites 6 of Rieter, comprises the following steps:
1) getting Rieter mould (I) is raw material, is dissolved in organic solvent, adds catalyzer after cooling, then reaction after heating up, and obtains compound (II);
2) compound (II) is dissolved in organic solvent again, after cooling, adds alkali lye, then reaction after heating up, obtain meta-bolites 6 (III);
Step 1) and step 2) reaction scheme as follows:
Wherein: described Rieter mould (I) is N – (2,6-xylyl)-2-methoxyl group aldehyde-base sec.-propyl methyl esters amine; Described compound (II) is N – (2,6-xylyl)-(2-hydroxy acyl) sec.-propyl methyl esters amine; Described meta-bolites 6 (III) is N – (2,6-xylyl)-N-(glycolyl) L-Ala.
2. the synthetic method of the mould middle meta-bolites 6 of Rieter according to claim 1, is characterized in that, step 1) in, to comprise any one of following condition or multinomial:
A1) described organic solvent is selected from methylene dichloride, ethyl acetate, methyl tertiary butyl ether, any one in toluene;
A2) described catalyzer is selected from boron tribromide, aluminum chloride, any one in pyridine hydrochloride, Hydrogen bromide and acetic acid mixed aqueous solution;
A3) ratio of volume that the mould mole number added of described Rieter adds with organic solvent is 1:5-20;
A4) described catalyzer and the mould mol ratio added of Rieter are 1-2:1;
A5) described cooling adopts the mixture cooling of dry ice and acetone; Temperature after described cooling is-78 to 0 DEG C;
A6) temperature after described intensification is room temperature;
A7) after described intensification, the reaction times is 1-24h.
3. the synthetic method of the mould middle meta-bolites 6 of Rieter according to claim 1, is characterized in that, described step 1) in also to carry out purifying to compound (II) after completion of the reaction, comprise the steps:
A) adding alkali lye regulates the pH value of compound (II) to neutral;
B) add organic solvent vibration layering again, form aqueous phase and be separated with after organic phase;
C), after water intaking adopts organic solvent repeatedly to extract mutually, collection organic extract and described organic phase merge, and remove aqueous phase;
D) get step C) in merge after organic phase washing, dry, decolouring, placement is spent the night, and filters, obtains the compound after purifying (II).
4. the synthetic method of the mould middle meta-bolites 6 of Rieter according to claim 3, is characterized in that, described compound (II) purifying to comprise any one of following condition or multinomial:
B1) in steps A) in, the alkali in described alkali lye is selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, any one in triethylamine;
B2) in step C) in, described aqueous phase adopts the extraction times of organic solvent to be 2-4 time;
B3) in step D) in, described organic phase drying is that organic phase and siccative are at room temperature stirred drying; Described siccative be selected from sodium carbonate, salt of wormwood, potassium hydroxide, anhydrous sodium sulphate, anhydrous magnesium sulfate any one;
B4) in step D) in, described decolouring adopts discoloring agent to decolour; Described discoloring agent is gac;
B5) in step D) in, described in be filtered into vacuum filtration; After described vacuum filtration, filtration product organic solvent is carried out repeatedly drip washing;
B6) in described compound (II) purifying, described organic solvent is selected from methylene dichloride, ethyl acetate, methyl tertiary butyl ether, any one in toluene.
5. the synthetic method of the mould middle meta-bolites 6 of Rieter according to claim 1, is characterized in that, step 2) in, to comprise any one of following condition or multinomial:
C1) described organic solvent is methyl alcohol;
C2) described alkali lye is selected from sodium hydroxide solution, potassium hydroxide solution, aqua calcis, solution of potassium carbonate, any one in sodium carbonate solution;
C3) ratio of volume that the mould mole number added of described Rieter adds with organic solvent is 1:5-20;
C4) ratio of volume that the mould mole number added of described Rieter adds with alkali lye is 1:1-1.1;
C5) described cooling adopts ice-water bath cooling; Temperature after described ice-water bath cooling is 0-20 DEG C;
C6) ice-water bath is removed in described intensification, after being naturally warming up to room temperature, then adopts water-bath to heat; Temperature after described intensification is 30-40 DEG C;
C7) after described intensification, the reaction times is 1-24h.
6. the synthetic method of the mould middle meta-bolites 6 of Rieter according to claim 1, is characterized in that, described step 2) in also to carry out purifying to meta-bolites 6 after completion of the reaction, comprise the steps:
A) in meta-bolites 6, add organic solvent vibration layering, form aqueous phase and be separated with after organic phase;
B) water intaking adopts organic solvent repeatedly to extract mutually, after removing organic extract, then regulates the pH value of aqueous phase by acid solution;
C) by step b) in aqueous phase again adopt organic solvent repeatedly to extract after, collect organic extract and described organic phase and merge, and remove aqueous phase;
D) get step c) in merge after organic phase washing, dry, decolouring, placement is spent the night, and filters, obtains the meta-bolites after purifying 6.
7. the synthetic method of the mould middle meta-bolites 6 of Rieter according to claim 6, is characterized in that, described meta-bolites 6 purifying to comprise any one of following condition or multinomial:
D1) in step b) in, described aqueous phase adopts the extraction times of organic solvent to be 2-4 time;
D2) in step b) in, described acid solution is aqueous hydrochloric acid; The pH of described aqueous phase after acid solution regulates is 1.5-2.5;
D3) in step c) in, described aqueous phase adopts the extraction times of organic solvent to be 2-4 time again;
D4) in steps d) in, described organic phase drying is that organic phase and siccative are at room temperature stirred drying; Described siccative be selected from sodium carbonate, salt of wormwood, potassium hydroxide, anhydrous sodium sulphate, anhydrous magnesium sulfate any one;
D5) in steps d) in, described decolouring adopts discoloring agent to decolour; Described discoloring agent is gac;
D6) in steps d) in, described in be filtered into vacuum filtration; After described vacuum filtration, filtration product organic solvent is carried out repeatedly drip washing;
D7) in described meta-bolites 6 purifying, described organic solvent is selected from methylene dichloride, ethyl acetate, methyl tertiary butyl ether, any one in toluene.
8. the mould middle meta-bolites 6 of Rieter, is obtained by the synthetic method of the arbitrary described mould middle meta-bolites 6 of Rieter of claim 1-7.
9. the purposes of the mould middle meta-bolites 6 of a kind of Rieter according to claim 8 in sterilant, medicine.
10. purposes according to claim 9, described sterilant is the reagent of killing aquatic animal wound water mo(u)ld; Described medicine is the medicine of control saprolegniasis of aquatic animals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510954228.9A CN105461588A (en) | 2015-12-17 | 2015-12-17 | Method for compounding metabolites 6 in ridomil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510954228.9A CN105461588A (en) | 2015-12-17 | 2015-12-17 | Method for compounding metabolites 6 in ridomil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105461588A true CN105461588A (en) | 2016-04-06 |
Family
ID=55599808
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510954228.9A Pending CN105461588A (en) | 2015-12-17 | 2015-12-17 | Method for compounding metabolites 6 in ridomil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105461588A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905181A (en) * | 2017-04-14 | 2017-06-30 | 上海海洋大学 | A kind of vertical synthetic method up to mould metabolite 16 |
| CN106946727A (en) * | 2017-04-12 | 2017-07-14 | 上海海洋大学 | A kind of vertical synthetic method up to mould metabolite 8 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142592A (en) * | 2013-02-01 | 2013-06-12 | 上海海洋大学 | Medicine for preventing fish saprolegniasis and application thereof |
| CN103536586A (en) * | 2013-09-26 | 2014-01-29 | 上海海洋大学 | Method for preventing and treating saprolegniasis of aquatic animals |
| CN104193699A (en) * | 2014-08-14 | 2014-12-10 | 嘉兴特科罗生物科技有限公司 | Small-molecule compound as well as synthesis method and application thereof |
| CN104997805A (en) * | 2015-07-31 | 2015-10-28 | 曹晓宏 | Dry powder preparation for preventing and treating aquatic animal saprolegniasis and application thereof |
-
2015
- 2015-12-17 CN CN201510954228.9A patent/CN105461588A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142592A (en) * | 2013-02-01 | 2013-06-12 | 上海海洋大学 | Medicine for preventing fish saprolegniasis and application thereof |
| CN103536586A (en) * | 2013-09-26 | 2014-01-29 | 上海海洋大学 | Method for preventing and treating saprolegniasis of aquatic animals |
| CN104193699A (en) * | 2014-08-14 | 2014-12-10 | 嘉兴特科罗生物科技有限公司 | Small-molecule compound as well as synthesis method and application thereof |
| CN104997805A (en) * | 2015-07-31 | 2015-10-28 | 曹晓宏 | Dry powder preparation for preventing and treating aquatic animal saprolegniasis and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| DAVID J. COLE等: "Metabolism of Metalaxyl in Cell Suspension Cultures of Lactuca sativa L. and Vitis vinifera L.", 《PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY》 * |
| W. J. OWEN等: "《Oxidative Degradation of Chlortoluron, Propiconazole, and Metalaxyl in Suspension Cultures of Various Crop Plants》", 《PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY》 * |
| 马宇恒: "《有机合成反应速查手册》", 31 December 2009 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946727A (en) * | 2017-04-12 | 2017-07-14 | 上海海洋大学 | A kind of vertical synthetic method up to mould metabolite 8 |
| CN106905181A (en) * | 2017-04-14 | 2017-06-30 | 上海海洋大学 | A kind of vertical synthetic method up to mould metabolite 16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103467380B (en) | Substituted phenyl pyrazole amide derivative and preparation method and application thereof | |
| CN105461588A (en) | Method for compounding metabolites 6 in ridomil | |
| CN109369449A (en) | A kind of method of synthesizing oxime ether | |
| CN102617450B (en) | Polymer material stabilizer and preparation method thereof | |
| CN104557975B (en) | The preparation method of everolimus intermediate and its degradation impurity | |
| CN102993032B (en) | Synthetic method of methoxamine hydrochloride | |
| CN101870682A (en) | Preparation method of 4-methylthiazolaldehyde-5 | |
| CN103980120B (en) | A kind of synthetic method of DL danshensu isopropyl ester | |
| CN104230681A (en) | Preparation method of 1,2,3-trimethoxy-5-allylbenzene | |
| CN102001979A (en) | Preparation method of 2-(2', 2'-difluoroethoxyl)-6-trifluoromethyl phenyl propyl sulfide | |
| CN101885707A (en) | Triazine derivative and preparation method thereof as well as new application as insecticide | |
| CN101148433B (en) | Method for synthesizing pentadecanol | |
| CN102795977A (en) | Synthesis method of (7Z,11Z,13E)-hexadecatrienal | |
| CN103087060B (en) | High activity paichongding isomer and preparation method thereof | |
| CN108358981A (en) | Two kinds of metabolites of aspirin eugenol ester and preparation method thereof | |
| CN101508704B (en) | Organic bismuth ion compound containing bridge nitrogen atom ligand, preparation and uses thereof | |
| CN106699605B (en) | A kind of methylation method of scheme for lacosamide intermediate | |
| CN107043396B (en) | A kind of preparation method of triacontanol | |
| CN107501316A (en) | LUMEFANTRINE isomers and preparation method thereof | |
| CN102050775B (en) | Anastrozole impurity alpha, alpha, alpha', alpha'-tetramethyl-5-(succinimide-1-methyl)-1,3-phenyl diacetonitrile and preparation method thereof | |
| CN112707798A (en) | Preparation method of liquid crystal compound containing citrus greening alcohol-based methoxy idene bridge connecting group | |
| CN107011202B (en) | A kind of vertical synthetic method up to mould metabolite 12 | |
| CN109824536A (en) | A kind of preparation method of Otilonium Bromide | |
| CN103539822B (en) | Synthesis method and application of cup-shaped metal cyclophane [Rh{9,10-di(2-(diphenylphosphino)ethyl)anthracene}-(CO)C1]3 | |
| CN103709092B (en) | The preparation method of Mitiglinide Calcium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned | ||
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20180921 |