CN105085564B - A kind of synthetic method of pesticide Silthiopham - Google Patents
A kind of synthetic method of pesticide Silthiopham Download PDFInfo
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Abstract
The invention belongs to technical field of organic synthesis; to solve the problems, such as that there are exchange reaction yield is low in current pesticide Silthiopham synthesis technology; the present invention provides a kind of synthetic method of pesticide Silthiopham; (1) under inert gas protection; using trimethyl silicane ethyl-acetylene as raw material, react to obtain trimethyl silicon substrate Methyl propiolate with methylchloroformate under organic base effect；(2) trimethyl silicon substrate Methyl propiolate reacts to obtain 4,5- dimethyl -2-(trimethyl silicon substrate with 3- sulfydryl -2- butanone under base catalyst effect) thiophene -3- methyl formate；(3) 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate reacts to obtain final product pesticide Silthiopham under the action of catalyst with allyl amine.Raw material used in this method is cheap and easy to get, and route is succinct, and total recovery is higher, and avoid using alpha..alpha.-dimethylethyl nitrite (t- BuONO) with the serious reagent of environmental pollutions such as thionyl chloride.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of pesticide Silthiopham efficiently synthesizes technique.
Background technique
Take-all (Gaeumammomyces gramini) is one of serious plant disease of wheat, Silthiopham
(Silthiopham) the having to the microbial take-all of wheat total eclipse in official listing in 1999 that be Monsanto Chemicals
The seed treatment of special efficacy.But the Silthiopham synthetic method being currently known, there is reaction step more and is related to a variety of severe toxicity
The use of object and the serious reagent of environmental pollution, it is at high cost the disadvantages of.Hence it is imperative that developing a kind of high efficiency, low cost
Silthiopham synthetic method.
United States Patent (USP) US 5,486,621 reports Silthiopham N- allyl -4,5- dimethyl -2-(trimethyl for the first time
Silicon substrate) thiophene -3- formamide it is fully synthetic, they obtain 2- ammonia using 2- butanone, cyan-acetic ester and sulphur single step reaction
Then base thiophene reacts to obtain Silthiopham using several steps, this method total recovery is relatively low (about 2%), and further relates to height
Toxic agent alpha..alpha.-dimethylethyl nitrite (t- BuONO) and thionyl chloride use, great pressure is caused to environment and health.
Afterwards by continuing to optimize and improving (WO 9962915), it is using 3- sulfydryl -2- butanone and trimethyl silane substitution propine amide
One step of raw material (containing simple dehydration) obtains final product, and yield is higher, but key intermediate trimethyl silicon substrate alkynes
Amide is difficult to be synthetically prepared in high yield.The journey of nearest Henan agricultural university unravels silk south et al. and reports (CN 103044479A) one kind newly
The synthetic method of the Silthiopham of type, they have obtained 3-(trimethyl from Methyl propiolate and trim,ethylchlorosilane synthesis
Silicon substrate) Methyl propiolate, then cyclization dehydration is carried out with 3- sulfydryl -2- butanone, it finally swaps and reacts with allyl amine
Final product Silthiopham is obtained.This method relative to having reported that process route is simple, and avoid high toxicity reagent (t-
BuONO use), but some fatal defects still have, such as final step 4,5- dimethyl -2-(trimethyl silicane
Base) thiophene -3- methyl formate and allyl amine exchange reaction yield it is extremely low, even if in the reflux condition that pure allyl amine is solvent
20 hours yields are reacted under part also 10% hereinafter, therefore there is an urgent need to develop a kind of synthesis technology of green high-efficient.
Summary of the invention
To solve the problems, such as in current pesticide Silthiopham synthesis technology that there are exchange reaction yield is low, the present invention provides one
The synthetic method of pesticide Silthiopham is planted, raw material used in this method is cheap and easy to get, and route is succinct, and total recovery is higher, and
Avoid using alpha..alpha.-dimethylethyl nitrite (t- BuONO) with the serious reagent of environmental pollutions such as thionyl chloride.
What the invention is realized by the following technical scheme: a kind of synthetic method of pesticide Silthiopham is following steps:
(1) under inert gas protection, using trimethyl silicane ethyl-acetylene as raw material, organic base effect under with methylchloroformate
Reaction obtains trimethyl silicon substrate Methyl propiolate；
The organic base is a kind of in metal alkyl lithiumation object, amido lithiumation object, organic base and trimethyl silicon substrate second
The molar ratio of alkynes is 1.0 ~ 1.5:1.Preferably, metal alkyl lithiumation object is selected from butyl lithium, lithium methide, phenyl lithium, tert-butyl
It is a kind of in lithium, lithium diisopropyl amido.More preferably butyl lithium.
Chloro-carbonic acid esters and the molar ratio of trimethyl silicane ethyl-acetylene are 1.1 ~ 1.5:1.Preferably, chloro-carbonic acid esters are selected from
Methylchloroformate, it is a kind of in ethyl chloroformate.
Preferably, the effect in tetrahydrofuran (THF) with organic base at -50 ~ -78 DEG C of trimethyl silicane ethyl-acetylene,
It is warmed to room temperature again and with ether extraction, dry and column chromatographic purifying obtains trimethyl after being quenched with chloro-carbonic acid ester reaction, ammonium chloride
Silicon substrate Methyl propiolate.
(2) trimethyl silicon substrate Methyl propiolate reacts to obtain 4,5- bis- with 3- sulfydryl -2- butanone under base catalyst effect
Methyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate；
The base catalyst is selected from the carbonate of alkali metal, alkali alcoholate, one of organic amine compound
Or it is several, base catalyst and trimethyl silicon substrate Methyl propiolate mole are 0.1 ~ 1.5:1.It is preferred that base catalyst is sodium methoxide,
Sodium ethoxide, sodium carbonate, it is a kind of in potassium carbonate.
Preferably, the molar ratio of 3- sulfydryl -2- butanone and trimethyl silicon substrate Methyl propiolate is 1.0 ~ 5.0:1.
Preferably, under inert gas protection by trimethyl silicon substrate Methyl propiolate and 3- sulfydryl -2- butanone, base catalysis
Under agent effect, back flow reaction 5 ~ for 24 hours, is down to room temperature in a solvent, washes, dry simultaneously to obtain 4,5- diformazan through column chromatographic purifying
Base -2-(trimethyl silicon substrate) thiophene -3- methyl formate.
(3) 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate under the action of catalyst with allyl amine
Reaction obtains final product pesticide Silthiopham.
The catalyst is selected from tri- azabicyclic of 1,5,7- [4.4.0] decyl- 5- alkene, four zirconium tert-butoxides, four isopropyl of metatitanic acid
Ester, aluminum isopropylate, indium bromide and zinc chloride, catalyst and 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- formic acid first
The molar ratio of ester is 0.1 ~ 1:1, preferred catalyst 1,5, tri- azabicyclic of 7- [4.4.0] decyl- 5- alkene (TBD).
4,5- dimethyl -2-(trimethyl the silicon substrate) molar ratio of thiophene -3- methyl formate and allyl amine is 1:1
~10。
Preferably, under inert gas protection, by 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate
Under the action of catalyst with allyl amine, heating reflux reaction is down to room temperature in solvent-free or solvent after 12 ~ 72 hours, decompression
Solvent and extra allyl amine are boiled off, residue, which is added n-hexane and is heated to reflux rear low temperature crystallization, obtains pesticide silicon thiophene bacterium
Amine.Preferred reaction time is 12~48h.
Solvent described in above-mentioned steps is selected from toluene, halogenated hydrocarbons, aromatic hydrocarbon, and alcohols is a kind of in polar non-solute
Or it is several, step (2) preferred solvent is diethoxymethane, and the preferred solvent of step (3) is toluene.
Above-mentioned room temperature is 23 DEG C ± 3 DEG C.Inert gas is preferably nitrogen, argon gas.
The present invention i.e. from cheap raw material trimethyl silicane ethyl-acetylene, byn-BuLi acts on lower and methylchloroformate
Reaction is converted into trimethyl silicon substrate Methyl propiolate, then carries out ring closure reaction with 3- sulfydryl -2- butanone and obtains 4,5- dimethyl -
2-(trimethyl silicon substrate) thiophene -3- methyl formate, finally reacts with allyl amine under the activation of catalyst and is converted into finished product
Pesticide Silthiopham.Reaction equation is as follows:
Compared with prior art, the beneficial effects of the present invention are: raw material used in this method is cheap and easy to get, route letter
Clean, yield is higher, and avoid using alpha..alpha.-dimethylethyl nitrite (t- BuONO) with the serious examination of environmental pollutions such as thionyl chloride
Agent is suitble to large-scale production.
Detailed description of the invention
Fig. 1 is 1 gained pesticide Silthiopham of embodiment1H NMR spectra；
Fig. 2 is 1 gained pesticide Silthiopham of embodiment13C NMR spectra.
Specific embodiment
Below by embodiment, invention is further described in detail.
Embodiment 1
(1) preparation of trimethyl silicon substrate Methyl propiolate:
Under nitrogen protection, trimethyl silicane ethyl-acetylene (5.6 mL, 40.0 mmol) are added in dry THF, be cooled to-
78 DEG C, n-BuLi (27.6 mL, 44.0 mmol) are slowly added into system, and stirring 30 minutes at this temperature, so
After be warmed to room temperature, and methylchloroformate (3.4 mL, 44.0 mmol) are added, are followed by stirring for reaction 2.5 hours.Reaction is mixed
It closes object and pours into ammonium chloride solution to quench the reaction, and ether extraction is added, organic phase water and brine It and with anhydrous sulphur
Sour sodium is dry.It is removed in vacuum solvent, gained crude product obtains yellow oil product three with column chromatographic purifying (5% EtOAc/PE)
Methylsilyl Methyl propiolate 5.9 g (yield: 95.0%).
(2) 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate preparation:
Under nitrogen protection, by trimethyl silicon substrate Methyl propiolate (3 g, 19.2mmol) and 3- sulfydryl -2- butanone (2.4
G, 23.0 mol) it is added in dry toluene, sodium methoxide (1.0 g, 19.2 mmol) then are added, reaction system heats back
Reaction system is down to room temperature by stream reaction 10 hours, distillation water washing is added, and (2 × 20 ml) is extracted with ethyl acetate, has
Machine is mutually dry with anhydrous sodium sulfate, solvent is removed in vacuum, gained crude product column chromatographic purifying obtains yellow oil product 4,5-
Dimethyl -2-(trimethyl silicon substrate) 4.1 g (yield: 88.3%) of thiophene -3- methyl formate.
(3) preparation of final product pesticide Silthiopham:
Under nitrogen protection, 4,5- dimethyl -2-(trimethyl silicon substrate is added into reaction flask) thiophene -3- methyl formate (1.0
G, 4.1 mmol) and allyl amine (1.2 g, 20.5 mmol), add tri- azabicyclic of 1,5,7- of catalyst
[4.4.0] decyl- 5- alkene (TBD, 0.17 g, 1.2 mmol), reaction mixture is heated to reflux after 48h and is down to room temperature, vacuum
Extra allyl amine is pumped, residue is added n-hexane and is heated to reflux 2h, and reaction system is cooling, and yellow solid, mistake is precipitated
0.68 g (yield: 62.3%) of yellow powder pesticide Silthiopham is dried to obtain after filter.
1H-NMR (CDCl3, 400MHz), δ =5.89-5.94 (m, 1H), 5.68 (br, s, 1H), 5.27
(d, J= 16.8 Hz, 1H), 5.20 (d, J=10.0 Hz, 1H), 4.06 (t, J= 5.6 Hz, 2H), 2.34
(s, 3H). 2.16 (s, 3H), 0.31 (s, 9H). 13C-NMR (CDCl3, 100MHz), δ =167.0, 144.7,
138.5, 134.6, 133.0, 132.3, 116.4, 41.6, 12.5, 11.9, -0.6。
Gained pesticide Silthiopham1H NMR spectra as shown in Figure 1,13C NMR spectra is as shown in Figure 2.
Embodiment 2
(1) preparation of trimethyl silicon substrate Methyl propiolate:
Under nitrogen protection, trimethyl silicane ethyl-acetylene (5.6 mL, 40.0 mmol) are added in dry tetrahydrofuran,
It is cooled to -50 DEG C, lithium methide (37.6 mL, 60.0 mmol) is slowly added into system, and stirs 30 minutes at this temperature,
Then it is warmed to room temperature, and methylchloroformate (4.0 mL, 52.0 mmol) is added, be followed by stirring for reaction 2.5 hours.It will reaction
Mixture pours into ammonium chloride solution to quench the reaction, and ether extraction is added, organic phase water and brine It and with anhydrous
Sodium sulphate is dry.It is removed in vacuum solvent, gained crude product obtains yellow oil product with column chromatographic purifying (5% EtOAc/PE)
5.8 g (yield: 93.0%) of trimethyl silicon substrate Methyl propiolate.
(2) 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate preparation:
Under nitrogen protection, by trimethyl silicon substrate Methyl propiolate (3 g, 19.2mmol) and 3- sulfydryl -2- butanone (2.4
G, 23.0 mol) it is added in dry diethoxymethane, sodium methoxide (1.0 g, 19.2 mmol) then are added, reactant
It is heating reflux reaction 24 hours, reaction system is down to room temperature, distillation water washing is added, and be extracted with ethyl acetate (2 × 20
Ml), organic phase is dry with anhydrous sodium sulfate, solvent is removed in vacuum, gained crude product column chromatographic purifying obtains yellow oily
Product 4,5- dimethyl -2-(trimethyl silicon substrate) 4.0 g (yield: 86.0%) of thiophene -3- methyl formate.
(3) preparation of final product pesticide Silthiopham:
Under nitrogen protection, 4,5- dimethyl -2-(trimethyl silicon substrate is added into reaction flask) thiophene -3- methyl formate (1.0
G, 4.1 mmol), 15 mL toluene and allyl amine (0.24 g, 4.1 mmol) add the 1 of catalyst, 5,7- tri- nitrogen
Miscellaneous two ring [4.4.0] decyl- 5- alkene (TBD, 0.17 g, 1.2 mmol) cools down after reaction mixture is heated to reflux 48h, vacuum
It pumps solvent (toluene and extra allyl amine), residue is added n-hexane and is heated to reflux 2h, and reaction system is cooling, analysis
Yellow solid out is dried to obtain 0.55 g (yield: 50.4%) of yellow powder pesticide Silthiopham after filtering.
1H-NMR (CDCl3, 400MHz), δ =5.89-5.94 (m, 1H), 5.68 (br, s, 1H), 5.27
(d, J= 16.8 Hz, 1H), 5.20 (d, J=10.0 Hz, 1H), 4.06 (t, J= 5.6 Hz, 2H), 2.34
(s, 3H). 2.16 (s, 3H), 0.31 (s, 9H). 13C-NMR (CDCl3, 100MHz), δ =167.0, 144.7,
138.5, 134.6, 133.0, 132.3, 116.4, 41.6, 12.5, 11.9, -0.6。
Embodiment 3
(1) preparation of trimethyl silicon substrate Methyl propiolate:
Under nitrogen protection, trimethyl silicane ethyl-acetylene (5.6 mL, 40.0 mmol) are added in dry THF, be cooled to-
60 DEG C, phenyl lithium (26.7 mL, 40.0 mmol) are slowly added into system, and stirring 30 minutes at this temperature, then
It is warmed to room temperature, and methylchloroformate (4.7 mL, 60.0 mmol) is added, be followed by stirring for reaction 2.5 hours.Reaction is mixed
Object pours into ammonium chloride solution to quench the reaction, and ether extraction, organic phase water and brine It is added and uses anhydrous slufuric acid
Sodium is dry.It is removed in vacuum solvent, gained crude product obtains yellow oil product front three with column chromatographic purifying (5% EtOAc/PE)
5.7 g (yield: 92.0%) of base silicon substrate Methyl propiolate.
(2) 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate preparation:
Under nitrogen protection, by trimethyl silicon substrate Methyl propiolate (3 g, 19.2mmol) and 3- sulfydryl -2- butanone (2.4
G, 23.0 mol) it is added in dry toluene, sodium ethoxide (1.3 g, 19.2 mmol) then are added, reaction system heats back
Reaction system is down to room temperature by stream reaction 5 hours, distillation water washing is added, and (2 × 20 ml) is extracted with ethyl acetate, has
Machine is mutually dry with anhydrous sodium sulfate, solvent is removed in vacuum, gained crude product column chromatographic purifying obtains yellow oil product 4,5-
Dimethyl -2-(trimethyl silicon substrate) 3.9 g (yield: 83.8%) of thiophene -3- methyl formate.
(3) preparation of final product pesticide Silthiopham:
Under nitrogen protection, 4,5- dimethyl -2-(trimethyl silicon substrate is added into reaction flask) thiophene -3- methyl formate (1.0
G, 4.1 mmol), 15 mL toluene and allyl amine (1.8 g, 30.8 mmol) add four zirconium tert-butoxides of catalytic amount
(0.16 g, 0.41 mmol), reaction mixture is heated to reflux after 48h cooling, and vacuum pumps solvent (toluene and extra
Allyl amine), residue is added n-hexane and is heated to reflux 2h, and reaction system is cooling, and yellow solid is precipitated, dry after filtering
Obtain 0.62 g (yield: 56.8%) of yellow powder pesticide Silthiopham.
1H-NMR (CDCl3, 400MHz), δ =5.89-5.94 (m, 1H), 5.68 (br, s, 1H), 5.27
(d, J= 16.8 Hz, 1H), 5.20 (d, J=10.0 Hz, 1H), 4.06 (t, J= 5.6 Hz, 2H), 2.34
(s, 3H). 2.16 (s, 3H), 0.31 (s, 9H). 13C-NMR (CDCl3, 100MHz), δ =167.0, 144.7,
138.5, 134.6, 133.0, 132.3, 116.4, 41.6, 12.5, 11.9, -0.6。
Claims (9)
1. a kind of synthetic method of pesticide Silthiopham, which is characterized in that the synthetic method is following steps: (1) lazy
Property gas shield under, using trimethyl silicane ethyl-acetylene as raw material, organic base effect under react to obtain trimethyl with methylchloroformate
Silicon substrate Methyl propiolate；
(2) trimethyl silicon substrate Methyl propiolate reacts to obtain 4,5- dimethyl-with 3- sulfydryl -2- butanone under base catalyst effect
2-(trimethyl silicon substrate) thiophene -3- methyl formate；
(3) under inert gas protection, by 4,5- dimethyl -2-(trimethyl silicon substrate) thiophene -3- methyl formate and allyl amine
Under the action of catalyst, heating reflux reaction is down to room temperature after 12 ~ 72 hours, and vacuum pumps extra allyl amine, residue
N-hexane is added to crystallize to obtain pesticide Silthiopham,
The catalyst is selected from tri- azabicyclic of 1,5,7- [4.4.0] decyl- 5- alkene, four zirconium tert-butoxides, tetraisopropyl titanate, three
Aluminium isopropoxide, indium bromide and zinc chloride,
Reaction structure formula is as follows:
。
2. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that described in step (1)
Organic base it is a kind of in metal alkyl lithiumation object, amido lithiumation object, the molar ratio of organic base and trimethyl silicane ethyl-acetylene is
1.0 ~ 1.5:1.
3. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that chloro-carbonic acid esters and three
The molar ratio of methylsilyl acetylene is 1.1 ~ 1.5:1.
4. a kind of synthetic method of pesticide Silthiopham according to claim 1 or 2 or 3, which is characterized in that step (1)
Trimethyl silicane ethyl-acetylene acts at -50 ~ -78 DEG C with organic base in tetrahydrofuran, then at room temperature with chloro-carbonic acid esters
Reaction, ammonium chloride is extracted after being quenched with ether, dry and column chromatographic purifying obtains trimethyl silicon substrate Methyl propiolate.
5. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that described in step (2)
Base catalyst be selected from alkali metal carbonate, alkali alcoholate, one or more of organic amine compound, base catalysis
Agent and trimethyl silicon substrate Methyl propiolate mole are 0.1 ~ 1.5:1.
6. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that 3- mercapto in step (2)
The molar ratio of base -2- butanone and trimethyl silicon substrate Methyl propiolate is 1.0 ~ 5.0:1.
7. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that catalysis in step (3)
Agent and 4,5- dimethyl -2-(trimethyl silicon substrate) molar ratio of thiophene -3- methyl formate is 0.1 ~ 1:1.
8. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that described in step (3)
4,5- dimethyl -2-(trimethyl silicon substrate) molar ratio of thiophene -3- methyl formate and allyl amine is 1:1 ~ 10.
9. a kind of synthetic method of pesticide Silthiopham according to claim 1, which is characterized in that be added in step (3)
Solvent is reacted, and solvent is selected from toluene, halogenated hydrocarbons, aromatic hydrocarbon, and alcohols is one or more of in polar non-solute.
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Non-Patent Citations (3)
| Title |
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| "Novel one-pot synthesis of 5-alkynylporphyrins and their derivatisation to a butaiyne-linked benzoporphyrin dimer";Hiroko Yamada等;《Chem.Commun.》;20051106;第3863-3866页 |
| "Synthesis of Carbamates and Ureas Using Zr(IV)-Catalyzed Exchange Processes";Chong Han等;《Org. Lett.》;20070315;第9卷(第8期);第1517-1520页 |
| A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene(TBD) under solvent-free conditions";Cyrille Sabot等;《Tetrahedron Letters》;20070330;第48卷;第3863-3866页 |
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