CN102167681B - Method for preparing insect repellant icaridin - Google Patents
Method for preparing insect repellant icaridin Download PDFInfo
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- CN102167681B CN102167681B CN2011100508763A CN201110050876A CN102167681B CN 102167681 B CN102167681 B CN 102167681B CN 2011100508763 A CN2011100508763 A CN 2011100508763A CN 201110050876 A CN201110050876 A CN 201110050876A CN 102167681 B CN102167681 B CN 102167681B
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Abstract
The invention discloses a method for preparing an insect repellant icaridin, which comprises the following three steps of: performing low pressure catalytic hydrogenation reduction to convert 2-pyridineethanol into 2-piperidineethanol by taking active nickel as a catalyst; reacting a raw material of isobutanol with chloroform chloroformate or triphosgene under the catalysis of organic base to obtain sec-butyl alcohol chloroformate; and performing one-step condensation on the obtained sec-butyl alcohol chloroformate and the 2-piperidineethanol in a specified organic solvent to obtain crude icaridin, and rectifying to obtain the finished product with the purity of more than or equal to 97 percent. The method is easy to operate, and has a few side reactions, small three-waste amount and high yield.
Description
Technical field
The present invention relates to a kind of preparation method of wormer, be specifically related to the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate.
Background technology
Wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate (Icaridin) is also claimed hydroxyl piperazine ester, chemical name be 2-(2-hydroxyethyl) piperidines-1-sec-butyl carboxylate (CAS number: 119515-38-7), its structural formula is following:
The World Health Organization (WHO) made at following 5 to Ai Karuiding and estimated suggestions February calendar year 2001: 1, the Ai Karuiding character that has good security and meet makeup requires (cosmetics properties); Its folk prescription or compound preparation can not comprise that plastics, coating, metal finishing paper tinsel and paint etc. cause damage to common family package material; 2, Ai Karuiding under normal temperature and usual conditions, demonstrates remarkable kill effect to many mosquitoes of infecting malaria through test, and its effectiveness is superior to the DEET (mosquito-repellent liquid, chemical name N, N-diethylammonium-3-methyl benzamide) of standard; 3, the usage quantity of manufacturer's suggestion on skin is 0.3mg/cm
2, to hold more than 95% and imitated 6～7 hours, its efficiency time is recommended the anophelifuge as prevention of malaria significantly greater than DEET; 4, distant view is recommended the useful chemical of Ai Karuiding as mosquito-proof net, mosquito prevent suit and other materials; 5, Ai Karuiding is to human body safety and effective insecticidal agent.
Ai Karuiding is developed at the end of the nineties by Bayer (Bayer) company the earliest; Bayer discloses the method that is prepared as follows of Ai Karuiding in the U.S. Pat 4900834 of application in 1988: 2-(2-hydroxyethyl) piperidines (is had another name called 2-piperidines ethanol; Also have and claim 2-ethanol piperidines; CAS number: 1484-84-0) be dissolved in the THF, then under-20 ℃ temperature, add sec-butyl chloroformate with triethylamine; Said mixture extracts with methylene dichloride/water mixed liquid after 24 hours 20 ℃ of stirrings, and organic phase is used dried over mgso, and solvent steams in a vacuum and removes, residuum rectifying; Productive rate 49%.But this method is very harsh for the adding condition of sec-butyl chloroformate, and especially the productive rate of this method is very low.
Bayer (Bayer) is again in application U.S. Pat 5304650 in 1992; The another kind of preparation method of Ai Karuiding is disclosed: in reactor drum; With 2-piperidines dissolve with ethanol in 60 ℃ water; Add 45% highly basic sodium hydroxide solution, and then to wherein adding sec-butyl chloroformate and keep 60 ℃ of temperature, said mixture was 80 ℃ of following stirring reactions 40 minutes; Question response device internal temperature is reduced to 25 ℃, removes water layer, and organic phase is used methylcyclohexane extraction, uses 1N vitriolization 4 times until neutrality again, steams then and removes methylcyclohexane, and underpressure distillation obtains Ai Karuiding.
Chinese patent document CN101323588A (application number 200810123025) discloses a kind of preparation method of sterilant hydroxyl piperazine ester; 2-ethanol piperidines is dissolved in the non-polar solvent; Control reaction temperature is at 40 ℃～80 ℃; Drip chloroformic acid sec-butyl alcohol ester and concentration simultaneously and be 1～20% alkaline solution, 1～6 hour dropping time of control, add and continue stirring reaction and finished in 1 hour; Leave standstill branch vibration layer, the organic phase dilute acid wash, wash twice again after, decompression and solvent recovery obtains the bullion of Ai Karuiding, bullion again under vacuum 140 ℃～150 ℃ distill and obtain finished product, the purity of finished product is 93～94%.
The method that above-mentioned two kinds of 2-piperidines ethanol and chloroformic acid sec-butyl alcohol ester react under alkaline solution (like the aqueous solution of sodium hydroxide) catalysis; Test discovery through us; The very easily hydrolysis in highly basic of chloroformic acid sec-butyl alcohol ester, promptly the part of acyl chlorides can be reacted with liquid caustic soda earlier, therefore causes side reaction to increase; Impurity increases, and yield reduces; In addition, after finishing, reaction also need use organic solvent (the for example used methylcyclohexane of US5304650) to extract, complex operation not only, and, improved production cost because solvent is more expensive.Described 2-piperidines ethanol is generated by 2-(2-hydroxyethyl) pyridine hydrogenating reduction usually, and CAS number of said 2-(2-hydroxyethyl) pyridine is 103-74-2, and 2-(2-hydroxyethyl) pyridine is also referred to as 2-ethanol pyridine.
The reaction raw materials chloroformic acid sec-butyl alcohol ester that uses in above-mentioned two kinds of schemes is normally obtained by sec-butyl alcohol and phosgene reaction, but phosgene is a kind of hypertoxic gas, and transportation inconvenience requires now-making-now-using, and production preparation process is proposed higher requirement; If directly buy chloroformic acid sec-butyl alcohol ester,, increased preparation cost again because purchase price is higher.
Summary of the invention
It is gentle that technical problem to be solved by this invention provides a kind of reaction conditions, the preparation method of the Ai Karuiding that yield, purity are higher.
The technical scheme that realizes the object of the invention is a kind of preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate, may further comprise the steps:
1. 2-piperidines alcoholic acid preparation: under active nickel catalysis, 2-ethanol pyridine hydrogenating reduction is generated 2-piperidines ethanol.
2. the preparation of sec-butyl chloroformate: sec-butyl alcohol, organic solvent and organic alkali catalyst are added in the reaction flask; Temperature of charge is between 10 ℃～30 ℃ in the source material of adding chloroformic acid group and the maintenance bottle in reaction flask again, and the weight of said organic solvent is 1～10 times of sec-butyl alcohol weight; The source material of described chloroformic acid group is superpalite or two (trichloromethyl) carbonic ether.
Stir down; The source material of chloroformic acid group is in reaction flask after the mixing dissolving; The interior temperature of control bottle is 30 ℃～40 ℃, thereby the reaction of sec-butyl chloroformate takes place to generate, and keeps the interior temperature of bottle between 30 ℃～40 ℃; Stirring reaction is stopped reaction after 3～5 hours, perhaps stirring reaction after 3～5 hours again back flow reaction 0.5～2 hour make and react completely.
After liquid material behind the question response is cooled to room temperature; Successively with pure water and saturated common salt water washing; Leave standstill and layering, extract stratified organic phase, the organic phase of being extracted is carried out drying with the siccative anhydrous magnesium sulfate; Remove by filter siccative then, the purification thing that gained filtrating will obtain after directly perhaps will purifying to filtrating as the raw material of next step reaction is as the raw material of next step reaction; Described filtrating is the organic solvent system of sec-butyl chloroformate; Described purification thing is liquid sec-butyl chloroformate;
3. Ai Karuiding's is synthetic: in reaction kettle, add the 2-piperidines ethanol that 1. organic solvent, organic alkali catalyst and step obtain, stir and make solid complete molten and mixing of materials is even down; With above-mentioned temperature of charge reduce to 0 ℃ or be lower than 0 ℃ after, drip the filtrating or the liquid sec-butyl chloroformate that 2. obtain according to step, the control reactor temperature is between 0 ℃～20 ℃ in the dropping process; The mol ratio of above-mentioned sec-butyl chloroformate, 2-piperidines ethanol, organic alkali catalyst and organic solvent is 1: (1～1.1): (1～1.2): (2～10);
Stirring down, reactor temperature rises between 10 ℃ to 40 ℃; Thereby make sec-butyl chloroformate and 2-piperidines ethanol that the reaction of Ai Karuiding take place to generate; Keep temperature in the kettle between 10 ℃～40 ℃; Get in the reaction process that liquid detects in the still, stopped reaction when treating remaining sec-butyl chloroformate less than the 2wt% that adds total amount;
The post reaction mixture material with pure water and saturated common salt water washing, leaves standstill successively, extracts the organic phase that is positioned at lower floor, and the gained organic phase is removed siccative with the anhydrous sodium sulfate drying after-filtration, steams the organic solvent that removes in the gained filtrating; At last remaining organism underpressure distillation is obtained Ai Karuiding.
Above-mentioned steps 3. in, when Ai Karuiding synthesized, organic alkali catalyst was a 2-piperidines ethanol, stirred to make solid molten entirely down; The mol ratio of sec-butyl chloroformate, 2-piperidines ethanol, organic alkali catalyst and organic solvent is 1: (1～1.1): (1～1.1): (2～10).
Above-mentioned steps 3. in, used organic alkali catalyst can also be triethylamine, pyridine or Trimethylamine 99.
Above-mentioned steps 2. in, preparation is during sec-butyl chloroformate, used organic solvent is methylene dichloride, trichloromethane, benzene, toluene or THF; Used organic alkali catalyst is triethylamine, pyridine, Trimethylamine 99, piperidines or 2-monoethanolamine; Step 3. in, during Ai Karuiding synthetic, used organic solvent is methylene dichloride, trichloromethane, benzene, toluene, THF, normal hexane, hexanaphthene or methylcyclohexane.
Above-mentioned steps 2. in; During the preparation sec-butyl chloroformate; Used reaction flask is a three-necked bottle; TM, prolong and tap funnel are housed on the three-necked bottle, wherein the port of prolong through conduit successively through surge flask, fill that the back links to each other with the bleeding point of negative pressure pump in the reservoir of aqueous sodium hydroxide solution, above-mentioned three-necked bottle, surge flask, reservoir, vacuum pump and conduit form a closed system; When sec-butyl alcohol and superpalite or two (trichloromethyl) carbonate reaction, open negative pressure pump and bleed, in time the hydrogen chloride gas that produces in the three-necked bottle is taken away.
Above-mentioned steps 2. in, the purification thing that will obtain after will purifying to filtrating is as the raw material of next step reaction; Method of purification to filtrating is: steam earlier the solvent recuperation of removing in the filtrating and apply mechanically, again to remaining organism underpressure distillation, the cut of collecting 148-152 ℃/5mmHg is purity at 98%～99% sec-butyl chloroformate.
Above-mentioned steps 2. in, when the source material of chloroformic acid group was superpalite, the mol ratio of sec-butyl alcohol and superpalite was (2～2.2): 1, preferred molar ratio is 2:1; When the source material of chloroformic acid group was two (trichloromethyl) carbonic ether, sec-butyl alcohol was (3～3.3) with the mol ratio of two (trichloromethyl) carbonic ethers: 1, and preferred molar ratio is 3:1.
Above-mentioned steps 2. in, during successively with the liquid material behind pure water and the saturated aqueous common salt washing reaction, earlier with pure water washing 2～3 times, each consumption is 2～5 times of sec-butyl alcohol weight; Use the saturated common salt water washing again 1～2 time, each consumption is 2～4 times of sec-butyl alcohol weight; Above-mentioned steps 3. in, during successively with the mixture behind pure water and the saturated aqueous common salt washing reaction, earlier with pure water washing 2～3 times, each consumption is 0.5～2 times of weight of solvent; Use the saturated common salt water washing again 1～2 time, each consumption is 0.5～1.5 times of weight of solvent.
Above-mentioned steps 3. in, the post reaction mixture material with pure water and saturated common salt water washing, leaves standstill successively; After extracting organic phase; Remaining water is handled as follows: add sodium hydrate regulator solution pH=12～14 to aqueous phase, add dichloromethane extraction then 2～3 times, combining extraction liquid; Comprise methylene dichloride and 2-piperidines ethanol in the organic phase after the extraction, be used for feeding intake next time; Detect earlier 2-piperidines alcoholic acid content in the methylene dichloride before feeding intake next time, 2-piperidines alcoholic acid amount is complemented to 2～2.2 times of sec-butyl chloroformate weight after, add sec-butyl chloroformate and carry out the reaction of synthetic Ai Karuiding next time.
Above-mentioned steps is 3. during underpressure distillation, collects the cut of 140-152 ℃/5mmHg and obtains Ai Karuiding.
The present invention has positive effect: the reaction conditions of the synthetic Ai Karuiding of (1) the present invention is gentle, and the Ai Karuiding purity of preparation reaches more than 97%, and in one embodiment of the present of invention, productive rate can reach 87%.
Under organic base catalytic, react when (2) the present invention is synthetic, avoid with the mineral alkali problem of sec-butyl chloroformate hydrolysis and side reaction that brings thereof during reaction and in the aqueous solution of alkali as catalyzer.
(3) the present invention is when preparation chloroformic acid sec-butyl alcohol ester; Avoid the use of phosgene; And select for use liquid chlorine diphosgene or Solid Double (trichloromethyl) carbonic ether of comparison safety and sec-butyl alcohol to carry out acyl chloride reaction; Make general factory-prepared become possibility, the now-making-now-using requirement of reactant phosgene when this reaction does not have phosgene and sec-butyl alcohol reaction.
(4) the present invention's second step preparation chloroformic acid sec-butyl alcohol ester can use identical solvent with last synthetic Ai Karuiding; Therefore after chloroformic acid sec-butyl alcohol ester synthesizes; Remove catalyzer and other relative substance through washing; Can purify without underpressure distillation behind the dry filter then and directly get into last synthesizing, reduce the energy consumption and the solvent loss of process step and chloroformic acid sec-butyl alcohol ester purification process.
(5) in the building-up process of the present invention's second step chloroformic acid sec-butyl alcohol ester, the hydrogen chloride gas that produces is in time taken away, promoted reaction to carry out, accelerated reaction process to the direction that generates chloroformic acid sec-butyl alcohol ester with negative pressure pump.
When (6) the present invention synthesizes Ai Karuiding; Drop into excessive 2-piperidines ethanol, make 2-piperidines ethanol, and can reclaim excessive 2-piperidines ethanol as feeding intake next time not only as reactant but also as catalyzer; Feasible operation is more easy, and the reactant utilization ratio is high and product purity that obtain is higher.
Description of drawings
Fig. 1 is the preparation wiring diagram of Ai Karuiding of the present invention.
Fig. 2 be embodiment 1 step 2. in the synoptic diagram that is connected of prolong and air extractor of three-necked bottle.
Fig. 3 is that the GC of the Ai Karuiding of embodiment 1 preparation analyzes collection of illustrative plates.
Fig. 4 is that the GC of the Ai Karuiding of embodiment 5 preparations analyzes collection of illustrative plates.
Embodiment
(embodiment 1)
Chemical reagent ltd buys used all reagent of present embodiment from Changzhou, and purity >=98% is not for further processing before the use.
See Fig. 1, the compound method of present embodiment specifically may further comprise the steps:
1. 2-piperidines alcoholic acid preparation:
In the 1L stainless steel autoclave that band stirs; Add 2-ethanol pyridine 100g, solvent toluene 400g and catalyzer Raney's nickel (SC-4100) 5g; The off-response still with the air in the nitrogen replacement reaction kettle three times, is used twice of gas in the hydrogen exchange reaction kettle again; Charging into hydrogen then makes the reaction pressure in the reaction kettle reach 4MPa; Stir down and slowly be warming up to 60 ℃; It is 2-piperidines alcoholic acid catalytic hydrogenation reaction that thereby one of resultant takes place; Continue stirring reaction after 6 hours, get a small amount of reaction solution detection in the reaction kettle, gc (GC) check and analysis show 1% stopped reaction of 2-ethanol pyridine content less than total content.
The question response temperature in the kettle is reduced to 30 ℃, and emptying hydrogen filters the post reaction mixture material to remove catalyzer; Underpressure distillation filtrating recovery toluene is applied mechanically then, and remaining solids then is a 2-piperidines ethanol, and the receipts amount is 100.1g; Product GC analyzes; Have only on the collection of illustrative plates one unimodal, product purity is about 99%, need not to handle directly to be used for next step reaction.
2. sec-butyl chloroformate (CAS number: preparation 17462-58-7):
In the present embodiment, chloroformic acid group source material is a superpalite.The chemical formula of superpalite is ClCO
2CCl
3, have another name called trichloromethylchloroformate, be colourless liquid with irritating smell, its unstable chemcial property, heating then becomes bimolecular phosgene.When trichloromethylchloroformate and sec-butyl alcohol reaction generate sec-butyl chloroformate, be to be decomposed into phosgene earlier, the phosgene of harsh one-tenth generates hydrogen chloride gas and sec-butyl chloroformate with the sec-butyl alcohol reaction immediately, and its reaction formula is following,
It is three-necked bottle that present embodiment prepares the used reaction flask of sec-butyl chloroformate, and TM, prolong and tap funnel are housed on the three-necked bottle; See Fig. 2, wherein prolong vertically is arranged on the three-necked bottle, the port of prolong through conduit successively through surge flask, link to each other with the bleeding point of negative pressure pump after filling the reservoir of 15% aqueous sodium hydroxide solution; Above-mentioned three-necked bottle, surge flask, reservoir, vacuum pump and conduit form a closed system.
Under good ventilation condition; Sec-butyl alcohol 112g (1.5mol), methylene chloride 500mL and catalyst of triethylamine 160g adding are equipped with in the 2L three-necked bottle of TM, prolong and tap funnel; Open magnetic stirring apparatus, stirring makes above-mentioned three kinds of mixing of materials even.
Keep the state of stirring, at room temperature (present embodiment is 15 ℃) drips superpalite 150g (0.75mol) in three-necked bottle, makes bottle interior temperature maintenance in the dropping process between 10 ℃～30 ℃.
After superpalite dropwises; Open water of condensation switch and negative pressure pump; Making pressure of the inside of a bottle is 720～740mmHg, and the interior temperature of control bottle is 30 ℃～38 ℃ under stirring (then needs to heat if envrionment temperature is lower than 38 ℃, if envrionment temperature does not then need heating at 30 ℃～38 ℃; If envrionment temperature then need make material be cooled to 30 ℃～38 ℃ through the chuck cooling with water coolant greater than 38 ℃); Thereby the reaction of hydrogen chloride gas and sec-butyl chloroformate takes place to generate, keep the interior temperature of bottle between 30 ℃～38 ℃, the hydrogen chloride gas that is wherein generated moves upward through prolong; Again through getting in the reservoir behind the surge flask, and with reservoir in aqueous sodium hydroxide solution generation neutralization reaction and be absorbed; Behind the stirring reaction 4 hours, the transformation efficiency of GC chlorine detection formic acid sec-butyl alcohol ester reaches 98%, closes negative pressure pump; Again three-necked bottle is heated organic solvent boiling in bottle; Organic steam rises to emits heat and becomes liquid again and under action of gravity, flow back in the three-necked bottle in the prolong; Thereby carry out (reaction under this kind state is called back flow reaction) under the situation that is reflected at the organic materials boiling reflux of generation sec-butyl chloroformate, continue back flow reaction feasible reacting completely half a hour.
After reaction finishes, after reaction solution naturally cools to room temperature, add the 500mL pure water, stir, standing demix is told lower floor's organic phase, repeats aforesaid operations once; The gained organic phase is used 300mL saturated common salt water washing 1 time after with 500 * 2 mL pure water washed twice again; Use anhydrous sodium sulfate drying then, remove by filter siccative, the direct raw material of filtrating as next step reaction; Above-mentioned washing operation has been removed catalyzer and other relative substance, and said filtrating is the dichloromethane solution of sec-butyl chloroformate.
Filtrating is detected through gas chromatograph, and the content conversion of sec-butyl chloroformate wherein is 196g for output, productive rate 98%.
In the present embodiment, having abandoned phosgene during the sec-butyl alcohol chloride and select the reaction of superpalite and sec-butyl alcohol, is because phosgene has severe toxicity and requires now-making-now-using, makes strange land transportation or strange land use and hardly maybe; And superpalite is when the reaction beginning; Only trace resolves into phosgene, decompose and phosgene immediately with the sec-butyl alcohol reaction and be consumed, therefore make the reaction that superpalite resolves into phosgene constantly carry out to the direction that generates gas; Entire reaction course is easy to control; Therefore superpalite does not have the restriction of duration of service and region, and toxicity is lower than phosgene, has improved processing safety.
Because sec-butyl alcohol and superpalite have hydrogen chloride gas and produce in reaction process; According to the chemical reaction equilibrium principle; In time the hydrogen chloride gas in the reaction system is taken away, helped balance and move right, also just help the generation of sec-butyl chloroformate; Open negative pressure pump when therefore reacting and bleed, in time the hydrogen chloride gas that produces in the three-necked bottle is taken away, accelerated reaction process; And negative pressure pump is connected with three-necked bottle through the reservoir that fills sodium hydroxide solution again, makes the interior hydrogenchloride of extracting out of bottle react away with sodium hydroxide immediately, has solved the waste gas problem in the reaction process, reaches environmental requirement.
3. Ai Karuiding's is synthetic:
To add in the reaction kettle of 100L band stirring according to 2-piperidines ethanol 25.6kg, the methylene chloride 25L of step method preparation 1., be connected with chilled brine in the chuck of this reaction kettle; Open to stir solid is dissolved entirely and mixing of materials even, open chilled brine and make reactor temperature reduce to 0 ℃; Drip the dichloromethane solution 20L that contains sec-butyl chloroformate 14.0kg that obtains according to step method 2. this moment, and the control reactor temperature is no more than 10 ℃ in the dropping process.
Stir down reactor temperature and rise to room temperature (between 10 ℃ to 38 ℃ all can); Thereby the reaction of Ai Karuiding takes place to generate, keep temperature in the kettle between 10 ℃～38 ℃, continue stirring reaction after 3 hours; Get liquid detection in the still; Gc (GC) detects and shows that remaining sec-butyl chloroformate is lower than 1.8% of adding total amount, also is that the transformation efficiency of sec-butyl chloroformate has reached more than 98% stopped reaction.
The post reaction mixture material earlier with the pure water washed twice (2 * 25kg), add water 25kg when washing at every turn, leave standstill, extraction is positioned at the organic phase of lower floor then; Use the water washing of 20kg saturated common salt more once, leave standstill, extract the organic phase that is positioned at lower floor, the gained organic phase is removed siccative with 5kg anhydrous sodium sulfate drying after-filtration, steams the methylene chloride recovery set that removes in the gained filtrating and uses.
With remaining organism underpressure distillation, collect the cut of 148-152 ℃/5mmHg, De Aikaruiding 19.9kg, productive rate 87%, the purity of gas chromatographic detection gained Ai Karuiding is 98.39%.
The gas chromatographic detection condition:
Post type: CSKJ-70 (CS-70)
Post specification: 30mm*0.53mm*1.0 μ m
Sample size (μ L): 0.2
Detector: the FID temperature (℃): 250
Sampler: the shunting temperature (℃): 220
Column temperature: temperature programming
The 1st stage initial temperature (℃): 150; The initial temperature hold-time (min): 2
The 2nd stage initial temperature (℃): 150; Temperature rise rate (℃/min): 20; Final temperature (℃): 260; The eventually warm hold-time (min): 5
The product analysis collection of illustrative plates is seen Fig. 3, and determination data is seen like following table 1:
Table 1
After above-mentioned saturated aqueous common salt washing extraction organic phase, add 15% sodium hydrate regulator solution pH=12 in the remaining water; Add twice of dichloromethane extraction (20L * 2) to aqueous phase; Combining extraction liquid; Comprise methylene dichloride and 2-piperidines ethanol in the isolating organic phase in extraction back, can be used for feeding intake next time; Detect 2-piperidines alcoholic acid content in the methylene dichloride with GC earlier before feeding intake next time, after 2-piperidines alcoholic acid amount is supplied, add sec-butyl chloroformate and carry out the reaction of synthetic Ai Karuiding next time; Said 2-piperidines alcoholic acid amount is supplied and is meant 2-piperidines alcoholic acid amount is added to reaction 2～2.2 times of required sec-butyl chloroformate weight.
In the present embodiment; Step 2. with the 3. used solvent phase of step with being methylene dichloride, so step 2. in, the filtrating behind the anhydrous sodium sulfate drying can not purified and directly get into the 3rd step condensation reaction; Reduce operation steps, running time and production cost, be fit to industrial applications; In addition, because 3. step drops into excessive 2-piperidines ethanol, make 2-piperidines ethanol not only as reactant but also as catalyzer; And excessive 2-piperidines ethanol can reclaim as feeding intake next time; Feasible operation is more easy, and the reactant utilization ratio is high, and the product purity that especially obtains more reaches more than 98%.
The used 2-piperidines ethanol of present embodiment also can directly be bought from market.
(embodiment 2)
All the other are identical with embodiment 1 for the compound method of present embodiment, and difference is:
Step 3. in, when synthetic Ai Karuiding, the amount of the methylene chloride that is added is 40L, the question response temperature in the kettle is reduced to 0 ℃, drips according to step method purified sec-butyl chloroformate 14.0kg 2.; The post reaction mixture material is through twice pure water washing and saturated common salt water washing, anhydrous sodium sulfate drying, filtration, a steaming desolventize methylene dichloride and underpressure distillation obtains Ai Karuiding 19.8kg, productive rate 86.5%, and the purity of Ai Karuiding is 98.8%.
Compare with embodiment 1, remake after present embodiment is purified sec-butyl chloroformate and be step reaction raw materials 3., make that the last Ai Karuiding purity that obtains is higher; Owing to also comprise available solvent when 3. step reacts in the used mixture that comprises sec-butyl chloroformate of embodiment 1; And the present embodiment step no longer comprises solvent after 2. purifying, so the amount of used solvent wants many than embodiment 1 during the 3. synthetic Ai Karuiding of present embodiment step.
(embodiment 3)
All the other are identical with embodiment 1 for the compound method of present embodiment, and difference is:
During preparation; Under good ventilation condition; Sec-butyl alcohol 112g (1.5mol), methylene chloride 500mL, catalyzer pyridine 118g and two (trichloromethyl) carbonic ether 150g (0.5mol) adding are equipped with in the 2L three-necked bottle of TM, prolong and tap funnel; Open magnetic stirring apparatus, temperature dissolves two (trichloromethyl) carbonic ethers of solid at (room temperature is more than 0 ℃) below 30 ℃ entirely in the control three-necked bottle, and solid dissolves the back entirely and keeps said temperature to continue to stir half a hour.
Open water of condensation switch and negative pressure pump; Stir that temperature is warming up to 37 ℃ in following bottle, thereby the reaction of hydrogen chloride gas and sec-butyl chloroformate takes place to generate, keep the interior temperature of bottle at 37 ℃ of stirring reactions after 4 hours; The transformation efficiency of GC chlorine detection formic acid sec-butyl alcohol ester reaches 98.2%, closes negative pressure pump; Again three-necked bottle is heated to organic solvent boiling, back flow reaction feasible reacting completely half a hour.
After question response liquid was cooled to room temperature, after reaction solution was used zero(ppm) water (500mL * 2) and saturated aqueous common salt (300mL * 1) washing successively, organic phase was removed siccative with the anhydrous magnesium sulfate drying after-filtration, the raw material that 3. filtrating directly reacted as step.
Filtrating is detected through gas chromatograph, and the content conversion of sec-butyl chloroformate wherein is 197g for output, productive rate 98.5%.
Present embodiment is selected two (trichloromethyl) carbonic ethers of solid phosgene and sec-butyl alcohol reaction for use, avoids the use of the phosgene of severe toxicity, has increased the security of operation.
(embodiment 4)
All the other are identical with embodiment 3 for the compound method of present embodiment, and difference is:
The method of step synthetic Ai Karuiding is 3. carried out according to the method for the step synthetic Ai Karuiding 3. of embodiment 2.
(embodiment 5)
All the other are identical with embodiment 2 for the compound method of present embodiment, and difference is:
Step 3. in; When synthesizing Ai Karuiding; In the 100L reaction kettle, add 2-piperidines ethanol 12.8kg, methylene chloride 40L and catalyzer pyridine 7.6kg; The question response temperature in the kettle is reduced to 0 ℃, drips to react according to heating up behind the embodiment 2 steps method purified sec-butyl chloroformate 14.0kg 2.; The post reaction mixture material through washing, dry, filter, steam desolventize and underpressure distillation after obtain Ai Karuiding 19.8kg, productive rate 86.5%.
Product GC analyzes collection of illustrative plates and sees Fig. 4, and the GC testing conditions is identical with embodiment 1, and product purity is 97.82%.
Though since 2-piperidines ethanol be self-control or purchase cost all than higher, so Ai Karuiding is when synthetic, other adds other organic alkali catalysts and reacts, other organic alkali catalysts can be any one in triethylamine, pyridine or the Trimethylamine 99.
(embodiment 6 to embodiment 13)
The rest part of the compound method of each corresponding embodiment is identical with embodiment 2; Difference is: step 2. in; During the preparation sec-butyl chloroformate, the purity (GC purity) of the output (abbreviation output) after used solvent, solvent load, catalyzer, catalyst levels and sec-butyl chloroformate are purified according to the method for embodiment 2, productive rate, gas chromatographic detection is listed following table 2 and table 3 in:
Table 2
Table 3
(embodiment 14)
All the other are identical with embodiment 5 for the compound method of present embodiment, and difference is:
Step 3. in, during synthetic Ai Karuiding, used catalyzer is a triethylamine, consumption 10.5kg; Reaction finishes to obtain Ai Karuiding 20.8kg after the underpressure distillation, and productive rate is 91%, detects through GC, and the purity of Ai Karuiding is 97.4%.
(embodiment 15)
All the other are identical with embodiment 10 for the compound method of present embodiment, and difference is:
Step 3. in, during synthetic Ai Karuiding, used solvent is a normal hexane, consumption 40L; Reaction finishes to obtain Ai Karuiding 19.8kg after the underpressure distillation, and productive rate is 86.5%, detects through GC, and the purity of Ai Karuiding is 97.8%.
(embodiment 16 to embodiment 26)
The rest part of embodiment 16 to embodiment 26 is identical with embodiment 2; Difference is: step 3. in; Basically according to the synthetic Ai Karuiding of step method 3. among the embodiment 5; Wherein, the consumption of sec-butyl chloroformate still is 14kg, and the purity of the output of used solvent, solvent load, catalyzer, catalyst levels and Ai Karuiding, productive rate, gas chromatographic detection (GC purity) is then listed following table 4 and table 5 in:
Table 4
Table 5
Claims (8)
1. the preparation method of a wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate is characterized in that may further comprise the steps:
1. 2-piperidines alcoholic acid preparation: under active nickel catalysis, 2-ethanol pyridine hydrogenating reduction is generated 2-piperidines ethanol;
2. the preparation of sec-butyl chloroformate: sec-butyl alcohol, organic solvent and organic alkali catalyst are added in the reaction flask; Temperature of charge is between 10 ℃～30 ℃ in the source material of adding chloroformic acid group and the maintenance bottle in reaction flask again, and the weight of said organic solvent is 1～10 times of sec-butyl alcohol weight; The source material of described chloroformic acid group is superpalite or two (trichloromethyl) carbonic ether; Said organic solvent is methylene dichloride, trichloromethane, benzene, toluene or THF, and said organic alkali catalyst is triethylamine, pyridine, Trimethylamine 99, piperidines or 2-monoethanolamine;
Stir down; The source material of chloroformic acid group is in reaction flask after the mixing dissolving; Temperature of charge is 30 ℃～40 ℃ in the control bottle, thereby the reaction of hydrogen chloride gas and sec-butyl chloroformate takes place to generate, and through the method for bleeding the hydrogen chloride gas that is generated is extracted out; Keep the interior temperature of charge of bottle between 30 ℃～40 ℃, stirring reaction is stopped reaction after 3～5 hours;
After liquid material behind the question response is cooled to room temperature; Successively with pure water and saturated common salt water washing; Leave standstill and layering, extract stratified organic phase, the organic phase of being extracted is carried out drying with the siccative anhydrous magnesium sulfate; Remove by filter siccative then, the purification thing that gained filtrating will obtain after directly perhaps will purifying to filtrating as the raw material of next step reaction is as the raw material of next step reaction; Described filtrating is the organic solvent system of sec-butyl chloroformate; Described purification thing is liquid sec-butyl chloroformate;
3. Ai Karuiding's is synthetic: in reaction kettle, add the 2-piperidines ethanol that 1. organic solvent, organic alkali catalyst and step obtain, stir and make solid complete molten and mixing of materials is even down; With above-mentioned temperature of charge reduce to 0 ℃ or be lower than 0 ℃ after, drip the filtrating or the liquid sec-butyl chloroformate that 2. obtain according to step, the control reactor temperature is between 0 ℃～20 ℃ in the dropping process; The mol ratio of above-mentioned sec-butyl chloroformate, 2-piperidines ethanol, organic alkali catalyst and organic solvent is 1: (1～1.1): (1～1.2): (2～10); Said organic solvent is methylene dichloride, trichloromethane, benzene, toluene, THF, normal hexane, hexanaphthene or methylcyclohexane, and said organic alkali catalyst is triethylamine, pyridine, Trimethylamine 99 or 2-piperidines ethanol;
Stirring down, reactor temperature rises between 10 ℃ to 40 ℃; Thereby make sec-butyl chloroformate and 2-piperidines ethanol that the reaction of Ai Karuiding take place to generate; Keep temperature in the kettle between 10 ℃～40 ℃; Get in the reaction process that liquid detects in the still, stopped reaction when treating remaining sec-butyl chloroformate less than the 2wt% that adds total amount;
The post reaction mixture material with pure water and saturated common salt water washing, leaves standstill successively, extracts the organic phase that is positioned at lower floor, and the gained organic phase is removed siccative with the anhydrous sodium sulfate drying after-filtration, steams the organic solvent that removes in the gained filtrating; At last remaining organism underpressure distillation is obtained Ai Karuiding.
2. the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate according to claim 1 is characterized in that: step 3. in, when Ai Karuiding synthesized, organic alkali catalyst was a 2-piperidines ethanol, stirred to make solid molten entirely down; The mol ratio of sec-butyl chloroformate, 2-piperidines ethanol, organic alkali catalyst and organic solvent is 1: (1～1.1): (1～1.1): (2～10).
3. the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate according to claim 1; It is characterized in that: step 2. in; During the preparation sec-butyl chloroformate, used reaction flask is a three-necked bottle, and TM, prolong and tap funnel are housed on the three-necked bottle; Wherein the port of prolong through conduit successively through surge flask, fill that the back links to each other with the bleeding point of negative pressure pump in the reservoir of aqueous sodium hydroxide solution, above-mentioned three-necked bottle, surge flask, reservoir, vacuum pump and conduit form a closed system; When the source material of sec-butyl alcohol and chloroformic acid group reacts, open negative pressure pump and bleed, in time the hydrogen chloride gas that produces in the three-necked bottle is taken away.
4. the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate according to claim 1 is characterized in that: step 2. in, the purification thing that will obtain after will purifying to filtrating is as the raw material of next step reaction; Method of purification to filtrating is: steam earlier the solvent recuperation of removing in the filtrating and apply mechanically, again to remaining organism underpressure distillation, the cut of collecting 148-152 ℃/5mmHg is purity at 98%～99% sec-butyl chloroformate.
5. the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate according to claim 1 is characterized in that: step 2. in, when the source material of chloroformic acid group was superpalite, the mol ratio of sec-butyl alcohol and superpalite was (2～2.2): 1; When the source material of chloroformic acid group was two (trichloromethyl) carbonic ether, sec-butyl alcohol was (3～3.3) with the mol ratio of two (trichloromethyl) carbonic ethers: 1.
6. the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate according to claim 1; It is characterized in that: step 2. in; During successively with the liquid material behind pure water and the saturated aqueous common salt washing reaction, earlier with pure water washing 2～3 times, each consumption is 2～5 times of sec-butyl alcohol weight; Use the saturated common salt water washing again 1～2 time, each consumption is 2～4 times of sec-butyl alcohol weight; Step 3. in, during successively with the mixture behind pure water and the saturated aqueous common salt washing reaction, earlier with pure water washing 2～3 times, each consumption is 0.5～2 times of weight of solvent; Use the saturated common salt water washing again 1～2 time, each consumption is 0.5～1.5 times of weight of solvent.
7. according to the preparation method of claim 1 or 6 described wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylates, it is characterized in that: step 3. in, the post reaction mixture material is successively with pure water and saturated common salt water washing; Leave standstill, after the extraction organic phase, remaining water is handled as follows: add sodium hydrate regulator solution pH=12～14 to aqueous phase; Add dichloromethane extraction then 2～3 times; Combining extraction liquid comprises methylene dichloride and 2-piperidines ethanol in the organic phase after the extraction, be used for feeding intake next time; Detect earlier 2-piperidines alcoholic acid content in the methylene dichloride before feeding intake next time, 2-piperidines alcoholic acid amount is complemented to 2～2.2 times of sec-butyl chloroformate weight after, add sec-butyl chloroformate and carry out the reaction of synthetic Ai Karuiding next time.
8. the preparation method of wormer sec-Butyl 2-(2-hydroxyethyl) piperidine-1-carboxylate according to claim 1 is characterized in that: step is 3. during underpressure distillation, collects the cut of 140-152 ℃/5mmHg and obtains Ai Karuiding.
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| CN108084027A (en) * | 2016-11-23 | 2018-05-29 | 利尔化学股份有限公司 | The preparation method of sec-butyl chloroformate |
| CN111689858B (en) * | 2020-06-24 | 2022-09-09 | 江苏蓝丰生物化工股份有限公司 | Method for preparing ethyl chloroformate |
| EP4141009A1 (en) | 2021-08-30 | 2023-03-01 | Saltigo GmbH | Method for the preparation of a mixture containing hydroxy-ethyl isobutyl piperidine carboxylate |
| CN113861027A (en) * | 2021-09-17 | 2021-12-31 | 爱斯特（成都）生物制药股份有限公司 | Method for continuous flow synthesis of chloroformate compound |
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| US5304650A (en) * | 1991-10-10 | 1994-04-19 | Bayer Aktiengesellschaft | Process for the preparation of alkyl N-(hydroxyalkyl)-carbamates |
| CN101323588A (en) * | 2008-07-14 | 2008-12-17 | 江苏七洲绿色化工股份有限公司 | Preparation of pesticide 2-(2-hydroxyethyl)-piperidine-1-carbonate-1-methyl isopropyl ester |
| CN101698658A (en) * | 2009-10-16 | 2010-04-28 | 厦门森美达生物技术有限公司 | Method for preparing wormer sec-Butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate |
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| CN101323588A (en) * | 2008-07-14 | 2008-12-17 | 江苏七洲绿色化工股份有限公司 | Preparation of pesticide 2-(2-hydroxyethyl)-piperidine-1-carbonate-1-methyl isopropyl ester |
| CN101698658A (en) * | 2009-10-16 | 2010-04-28 | 厦门森美达生物技术有限公司 | Method for preparing wormer sec-Butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate |
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