CN102603526B - Synthetic method of 3,13-dimethyl pentadecylic acid (S)-2'-methyl-3'-tetranitrate - Google Patents
Synthetic method of 3,13-dimethyl pentadecylic acid (S)-2'-methyl-3'-tetranitrate Download PDFInfo
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Abstract
The invention discloses a synthetic method of 3,13-dimethyl pentadecylic acid (S)-2'-methyl-3'-tetranitrate. In the method, cheap and readily-available organic raw materials such as 2-bromobutane, 4-hydroxy-2-butanone, 1,9-nonanediol and the like are adopted for synthesizing 3,13-dimethyl pentadecylic acid (S)-2'-methyl-3'-tetranitrate serving as a major component of a clania variegate sex pheromone by using a practicable synthetic route. The method is a novel synthetic method. Due to the adoption of the method, the defect of difficulty in obtaining raw materials in the conventional synthesis technology is overcome, the product purity is high, and the yield is high. The synthetic method plays an important role in biologically preventing and controlling clania variegate.
Description
Technical field
The invention belongs to chemosynthesis technical field, the synthetic method that relates to Clania variegata Snellen telergone main component, be specifically related to a kind of Clania variegata Snellen telergone main component 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-novel synthesis of amylalcohol ester.
Background technology
Clania variegata Snellen, have another name called psychid, the moth of avoiding creditors, and is commonly called as the cloth basket worm, belongs to lepidopteran, Bagworm moths.Be distributed in subtropical and tropical zones, in states such as Japan, India, Malaysia and Sri Lanka, distribution all arranged, in North China, East China, Central China, southwest, the Northwest of China, extensive distribution is also all arranged.The Clania variegata Snellen feeding habits are assorted, and host plant has kind more than 600, the heaviest with the Rosaceae, pulse family, Salicaceae, Juglandaceae and Platanaceae hazard of plant, is one of common insect of fruit tree and forest, simultaneously also very harmful to farm crop.In 1 generation, occur usually every year.Adult survives the winter in protecting capsule.Pupate May in next year, late May mate and oviposit, approximately through 3 weeks the hatching, early November starts to survive the winter.Larval stage 310～340d.The mating in protecting capsule of male moth, land death after female worm lays eggs.1000～5000 of egg laying amounts.Larva weaves silk, and by wind-force, spreads, and phototaxis is arranged, and in 7～September, causes harm seriously.The many lower floors at tree crown of Clania variegata Snellen, carry out long-distance communications by taking worm nursery stock long distance transportation.
To the method for preventing and treating of Clania variegata Snellen, mainly contain several as follows at present: manually pluck the insect pest that the means such as bag method, protection natural enemy method, the chemical prevention method and biological control are carried out the Control and prevention Clania variegata Snellen.Manually pluck the bag method and exist and to waste time and energy and the shortcoming such as poor effect, can not utterly destroy; The natural enemy of Clania variegata Snellen is azurewinged magpie, white face titmouse etc., adopts protection Clania variegata Snellen natural enemy also can only control to a certain extent the harm of Clania variegata Snellen, does not have the effect of controlling fully; Biological control is imperial Clania variegata Snellen baculovirus, muscardine and colonizes in the controls such as dibrachys cavus in fly larva and pupa, and effect is still not good.The main method adopted at present is still the chemical prevention method, sprays exactly the 90% Trichlorphon aqueous solution or 80% DDT EC 1000-1500 doubly about early July or 2.5% deltamethrin milk oil 5000-10000 times of liquid control Clania variegata Snellen low instar larvae.Yet the havoc eubiosis and environmental pollution are understood in the use of chemical pesticide on the one hand, also can kill the Clania variegata Snellen natural enemy simultaneously, further cause the harm of less important property insect.In addition, Clania variegata Snellen is except the breeding season short, and the most of the time all lives in thick bag, by chemicals, is difficult to prove effective.
In modern biological prevention, by insect pheromone, for the prevention and control of plant diseases, pest control, be one of domestic and international priority fields of study, there is important theory and practical value.Due to insect pheromone have trace, colleges and universities, pollution-free, become the hot issue of our times various countries entomologist research with the characteristics such as agricultural chemicals compatibility.But as utilize insect sex pheromone monitoring and prediction insect population, thereby can disturb the adult mating that population density of future generation is sharply descended, can be used for the mass trapping insect, can be combined with agricultural chemicals or biological pesticide, improve the utilising efficiency of agricultural chemicals etc.Therefore, research Clania variegata Snellen sex pheromone, and be applied to disease control, will have great importance.
China arises from the seventies in last century to the research of Clania variegata Snellen, and research finds that Clania variegata Snellen is by chest glandular secretion sex pheromone, has studied ultrastructure, the type of body of gland, the physiological Mechanism of release property pheromone etc. in great detail.But to the structural research of Clania variegata Snellen sex pheromone until just have breakthrough in 2006.The modern analytical techniques such as employing high performance liquid chromatography such as Canada scientist Gries and Zhao Boguang find that the Clania variegata Snellen sex pheromone has two compounds, one of them main component identify by analysis show be 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester.Find 3 by the field test to its isomer, 13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-(S)-2 in the amylalcohol ester '-methyl-3 '-three-dimensional arrangement of amylalcohol has conclusive impact to the biological activity of ester, and the isomer structure of acid moieties is on the not impact of activity of ester.
About 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-amylalcohol ester synthetic, understatement road very at present, (the J.Chem.Ecol. such as Gries at first, 2006,32,1673-1685) take 2-n-butyl bromide, the bromo-2-undecylene of 11-etc. is raw material, success is synthetic obtains 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester, but yield is on the low side, and the bromo-2-undecylene of 11-of one of raw material is difficult to obtain, cost is high, and concrete reaction formula is as follows:
(the CN101157613A such as Wei Bangguo, 2008) adopt butyryl chloride, the bromo-1-heptanol of 7-, (S)-4-benzyl-2-oxazoline ketone, (R)-4-sec.-propyl-2-oxazoline 4-benzyloxy-butyramide etc. to synthesize 3 for raw material, 13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-four isomer of amylalcohol ester, but its stereoselectivity e, e% is report not.And raw material also is difficult to buy, synthetic route reaches more than 17 steps, and synthetic cost compare is high.
Summary of the invention
Goal of the invention: for the deficiencies in the prior art, the purpose of this invention is to provide a kind of 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, to utilize raw material cheap and easy to get to synthesize (S)-1-methyl-2-first propyl group-3,13-dimethyl pentadecane acid esters, for the biological control of Clania variegata Snellen provides cheap product.
Technical scheme: in order to realize the foregoing invention purpose, the technical solution used in the present invention is as follows:
A kind of 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, comprise the following steps:
(1) with the anhydrous THF solution of 1,9-, bis-bromononanes and grignard reagent sec-butyl bromination magnesium for raw material, take tetrachloro ketone acid lithium-tetrahydrofuran solution and N-Methyl pyrrolidone as catalyzer, reaction makes the bromo-dodecane of 3-methyl isophthalic acid 2-;
(2) the bromo-dodecane of 3-methyl isophthalic acid 2-and the triphenylphosphine that prepared by step (1) are raw material, and anhydrous THF is solvent, and heating reflux reaction makes 10-methyl-dodecyl triphenyl bromide phosphine;
(3) take 10-methyl-dodecyl triphenyl bromide phosphine as raw material prepares Wittig reagent, in the THF of 4-benzyloxy-2-butanone solution, drip Wittig reagent, reaction makes 3,13-dimethyl-3-, ten pentaene base benzylic ethers;
(4) with 3,13-dimethyl-3-, ten pentaene base benzylic ethers for raw material, under Pd-C catalysis, pass into H
2Reaction makes 3,13-dimethyl-1-pentadecylic alcohol; For raw material, add the Jones reagent react with 3,13-dimethyl-1-pentadecylic alcohol, make 3,13-dimethyl pentadecylic acid;
(5) with 3,13-dimethyl pentadecylic acid and SOCl
2For raw material, reaction makes the acyl chlorides intermediate; In the mixed solution of normal hexane, (S)-2-methyl-3-amylalcohol and pyridine, drip the acyl chlorides intermediate, reaction obtain 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester.
In step (1), 1,9-, bis-bromononanes prepare gained by following methods: in reaction vessel, add 1,9-nonanediol and part Hydrogen bromide, stir fully and dissolve, and is warming up to 40 ℃, drip the vitriol oil to finishing, add the residual hydrogen bromic acid, slowly be warming up to back flow reaction, gas-chromatography is followed the tracks of the detection reaction process to finishing, use n-hexane extraction, organic phase is used respectively saturated NaHCO
3Solution, saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, filter also rotary evaporation and obtain light yellow liquid 1,9-bis-bromononanes after concentrating.
In step (1), grignard reagent sec-butyl bromination magnesium prepares gained by following methods: in reaction vessel, add magnesium chips and the part anhydrous tetrahydro furan crossed through 5% dilute hydrochloric acid and Ethanol Treatment, stir and also first add part 2-n-butyl bromide, add thermal booster reaction, slowly splashing into remaining 2-n-butyl bromide and tetrahydrofuran (THF) mixed solution, finish, back flow reaction, to reacting completely, obtains the tetrahydrofuran solution of sec-butyl bromination magnesium.
In step (1), under nitrogen protection, add the tetrachloro ketone acid lithium of 0.1mol/L-tetrahydrofuran solution 5.3mL and 6.8mL N-Methyl pyrrolidone in reactor, drip 17.5mmol1 under room temperature, the anhydrous THF solution of 9-bis-bromononanes (concentration is 0.4g/mL), dropwise, continue stirring reaction 1h under room temperature; Then slowly add grignard reagent sec-butyl bromination magnesium 45mL, finish, continue reaction 3h under room temperature, with gas-chromatography, follow the tracks of the detection reaction process; Reaction is used solvent extraction after finishing, and extraction liquid uses respectively saturated NH4Cl solution, saturated common salt water washing to neutral, and after anhydrous Na 2SO4 drying, rotary evaporation reclaims solvent, and crude product is further purified through column chromatography, obtains the bromo-dodecane of 3-methyl isophthalic acid 2-.
In step (2), in reactor, add anhydrous THF, triphenylphosphine and the bromo-dodecane of 3-methyl isophthalic acid 2-, reflux 12h, steam THF, then wash with anhydrous diethyl ether, until residual without triphenylphosphine, obtain light yellow paste 10-methyl-dodecyl triphenyl bromide phosphine.
In step (3), prepared by following methods by 4-benzyloxy-2-butanone: in reactor, add 4-hydroxy-2-butanone, ethylene glycol, citric acid and toluene, heating reflux reaction is to finishing; After reaction finishes, rotary evaporation reclaims band aqua and unreacted ethylene glycol, and underpressure distillation, collect 106-108 ℃ of cut and obtain 4-hydroxy-2-butanone condensed ethandiol; Under nitrogen protection, use petroleum ether NaH, decompressing and extracting, add anhydrous tetrahydro furan, drips 4-hydroxy-2-butanone condensed ethandiol, dropwises stirring reaction 1h; Drip the tetrahydrofuran solution of cylite, heating reflux reaction, follow the tracks of the detection reaction process with gas-chromatography; Reaction is used n-hexane extraction after finishing, and organic phase is used respectively saturated NH
4Cl solution, saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, rotary evaporation reclaims solvent, obtains 4-benzyloxy-2-butanone ethylene ketal; In reaction vessel, add methyl alcohol, Glacial acetic acid and distilled water, drip 4-benzyloxy-2-butanone ethylene ketal, slowly heating systems starts back flow reaction, and reaction adds water after finishing, and with the hexanaphthene extraction, extraction liquid is used respectively saturated NaHCO
3Solution and saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, after filtering, rotary evaporation reclaims solvent, obtains light yellow oily liquid, through column chromatography, is further purified and obtains 4-benzyloxy-2-butanone.
In step (3), in reaction vessel, add anhydrous THF and n-Butyl Lithium, after being cooled to-70 ℃, add 10-methyl-dodecyl triphenyl bromide phosphine, stirring reaction 2h, make Wittig reagent; 4-benzyloxy-2-butanone is dissolved in THF, and splashes in Wittig reagent, at room temperature react 3h, then react 2h under 50 ℃; Reaction solution is poured in frozen water, regulated pH to 1-2, use n-hexane extraction 3 times, merge organic phase, extremely neutral with the saturated common salt water washing, anhydrous Na
2SO
4Drying, concentrated, through silica gel column chromatography, obtain 3,13-dimethyl-3-, ten pentaene base benzylic ethers.
In step (4), 3,13-dimethyl-3-, ten pentaene base benzylic ethers are dissolved in methyl alcohol, add the Pd-C catalyzer, pass into H
2, under 30 ℃, react 12h; Reaction solution boils off solvent after removing catalyzer after filtration, through column chromatography, obtains 3,13-dimethyl-1-pentadecylic alcohol; By acetone and 3,13-dimethyl-1-pentadecylic alcohol adds reaction vessel, and ice-water bath is cooling, after making system temperature be down to 0 ℃, add Jones reagent, slowly rise to room temperature and react 5h, then adding the Virahol termination reaction, after reaction solution is concentrated, add distilled water, use n-hexane extraction, extremely neutral with distilled water and saturated brine washing organic phase successively, anhydrous Na
2SO
4Drying, after concentrated rear concentrating, resistates separates through silicagel column, take n-hexane/ethyl acetate (50:1, v/v) as eluent, obtains 3,13-dimethyl pentadecylic acid.
In step (5), in reaction vessel, add toluene, 3,13-dimethyl pentadecylic acid and SOCl
2, the oil bath heating is reacted 3h under 80 ℃, and air distillation obtains the acyl chlorides intermediate; Add normal hexane, (S)-2-methyl-3-amylalcohol in reaction vessel, and, after dripping pyridine, ice bath is cooled to 0-5 ℃, drips the acyl chlorides intermediate, reaction 1h; Reaction solution is with after the normal hexane dilution, extremely neutral with the saturated brine washing, the organic phase anhydrous Na
2SO
4Drying, then through silicagel column separate obtain 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester.
Beneficial effect: compared with prior art, of the present invention 3, 13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is a kind of new synthetic method, adopt the 2-n-butyl bromide, 4-hydroxy-2-butanone and 1, the organic raw material cheap and easy to get such as 9-nonanediol, adopt the main component 3 of the synthetic Clania variegata Snellen telergone of practicable synthetic route, 13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester, overcome the unobtainable defect of existing synthetic technology Raw, product purity is high, yield is high, biological control to Clania variegata Snellen has great importance.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further.
In following examples, adopt GC to carry out quantitative analysis, instrument is the Agilent6890N gas chromatograph, adopt flame ionization ditector, analysis condition is as follows: adopt DB-5 quartz capillary column (30m * 0.25mm id) to do carrier gas with nitrogen, column head pressure is 100kPa; Splitting ratio is 50:1; 250 ℃ of vaporizer temperature, 260 ℃ of detector temperatures; 50～260 ℃ of column temperatures, adopt temperature-programmed mode: 10 ℃/min between 50 ℃ to 250 ℃; Adopt area normalization method to carry out quantitative analysis.Adopt silica gel column chromatography to carry out purifying to each intermediate and product, used silica gel is silica gel for chromatography, and granular size is the 200-300 order.
Embodiment 1
In the four-hole boiling flask that reflux condensing tube, agitator, thermometer, constant pressure funnel are housed, first add 1,9-nonanediol 10.0g(62.40mmol) and a small amount of Hydrogen bromide (the HBr47% aqueous solution) 13.2g, under room temperature, fully stir, both are fully dissolved; Then be warming up to 40 ℃, slowly add 98% vitriol oil 7.49g with dropping funnel, work as H
2SO
4After adding, remaining 30g Hydrogen bromide is slowly heated up disposable adding in reactor again, be controlled at the 1.5h left and right and reach backflow, with gas-chromatography, follow the tracks of the detection reaction process.Reaction is used n-hexane extraction after finishing, and organic phase is used respectively saturated NaHCO
3Solution, saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, filter also rotary evaporation and obtain light yellow liquid 1 after concentrating, and 9-bis-bromononanes (compound 1) 16.60g, analyze through GC, and purity is 99.0%, yield 95.0%.Concrete reaction formula is as follows:
Be furnished with agitator, constant pressure funnel and be furnished with CaCl
2In the 100mL there-necked flask of the reflux condensing tube of drying tube, add respectively and soak through 5% dilute hydrochloric acid the magnesium chips 2.90g(0.12mol that deoxidation layer and washing with alcohol drying treatment are crossed), and the 10mL anhydrous tetrahydro furan; The 15.07g2-n-butyl bromide is dissolved in to the 25mL tetrahydrofuran (THF), is made into the tetrahydrofuran solution of 2-n-butyl bromide; Under agitation first add 5mL2-n-butyl bromide tetrahydrofuran solution, adopt the hair dryer heating, solution becomes muddy in a moment, shows that reaction causes; Remaining 2-n-butyl bromide tetrahydrofuran solution is slowly splashed in reaction flask, drip speed and steadily seethe with excitement and be advisable to maintain reaction solution.Finish, the about 0.5h of electric mantle reflux, make to react completely, and obtains the tetrahydrofuran solution of sec-butyl bromination magnesium (compound 2).
To being furnished with agitator, thermometer, constant pressure funnel and with anhydrous CaCl
2Pass into nitrogen in the 100mL four-hole boiling flask of the reflux condensing tube of drying tube, after the emptying of question response system Air, use the tetrachloro ketone acid lithium that the syringe implantation concentration is 0.1mol/L-tetrahydrofuran solution 5.3mL and 6.8mL N-Methyl pyrrolidone, drip 5.0g(17.5mmol under room temperature) anhydrous THF solution of two bromononanes, dropwise, continue stirring reaction 1h under room temperature.Then slowly add freshly prepd grignard reagent sec-butyl bromination magnesium (above-mentioned preparation) 45mL with syringe, finish, continue reaction 3h under room temperature, with gas-chromatography, follow the tracks of the detection reaction process.Reaction is used solvent extraction after finishing, and extraction liquid is used respectively saturated NH
4Cl solution, saturated common salt water washing are to neutral, through anhydrous Na
2SO
4After drying, rotary evaporation reclaims solvent, and crude product is further purified through column chromatography, obtains the bromo-dodecane of 3-methyl isophthalic acid 2-(compound 3) of 4.23g, and yield is 92.1%.Through the GC purity assay, be 100%.Concrete reaction formula is as follows:
In being furnished with the 100mL there-necked flask of agitator, thermometer, water trap and reflux condensing tube, add 5.00g(56.75mmol) 4-hydroxy-2-butanone, 4.23g(68.10mmol) ethylene glycol, 0.33g(1.70mmol) citric acid and 30mL toluene, be heated to reflux state, every the 0.5h sampling analysis, after reaction finishes, rotary evaporation reclaims band aqua and unreacted ethylene glycol, underpressure distillation, collect 106-108 ℃ of (2.53kPa) cut and obtain 4-hydroxy-2-butanone condensed ethandiol (compound 4), yield is 93.5%, through the GC purity assay, is 99.0%.Concrete reaction formula is as follows:
First with nitrogen purging, be furnished with the 100mL there-necked flask of agitator, thermometer, reflux condensing tube, then under nitrogen atmosphere, add 1.26g NaH, by dry petroleum ether 3 times, decompressing and extracting.Add the 10mL anhydrous tetrahydro furan, drip 2.44g4-hydroxy-2-butanone condensed ethandiol, dropwise, at room temperature continue stirring reaction 1h.Drip the tetrahydrofuran solution 20mL containing the 3.60g cylite, heating reflux reaction, follow the tracks of the detection reaction process with gas-chromatography.Reaction is used n-hexane extraction after finishing, and organic phase is used respectively saturated NH
4Cl solution, saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, rotary evaporation reclaims solvent, obtains 4-benzyloxy-2-butanone ethylene ketal (compound 5) crude product 4.56g, and yield is 97.8%.Concrete reaction formula is as follows:
Add 20mL methyl alcohol, 5mL Glacial acetic acid and 2mL distilled water in being furnished with the 100mL there-necked flask of agitator, thermometer, reflux condensing tube, dripping 4-benzyloxy-2-butanone ethylene ketal under room temperature, slowly improve Heating temperature to system and start to reflux.Reaction adds 20mL water after finishing, and with hexanaphthene extraction 3 times, extraction liquid is used respectively saturated NaHCO
3Solution and saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, after filtering, rotary evaporation reclaims solvent, obtains light yellow oily liquid 2.35g, through column chromatography, is further purified and obtains 4-benzyloxy-2-butanone (compound 6), and yield is 92.9%, and purity is 100%.Concrete reaction formula is as follows:
In being furnished with the 100mL there-necked flask of agitator, thermometer, reflux condensing tube, add the anhydrous THF of 25mL, 5.50g(0.021mol) triphenylphosphine and 2.63g(0.010mol) the bromo-dodecane of 3-methyl isophthalic acid 2-, reflux 12h, steam THF, with anhydrous diethyl ether, wash again, until residual without triphenylphosphine, obtain light yellow paste 10-methyl-dodecyl triphenyl bromide phosphine (compound 7) 4.86g, yield is 92.5%.Concrete reaction formula is as follows:
In being furnished with the 100mL there-necked flask of agitator, thermometer, reflux condensing tube, add 20mL THF and 2.5mol/L n-Butyl Lithium 4.0mL, after dry ice-acetone bath is cooled to-70 ℃, add 4.0g(7.61mmol) 10-methyl-dodecyl triphenyl bromide phosphine, stirring reaction 2h, make Wittig reagent.By 2.70g(0.015mol) 4-benzyloxy-2-butanone is dissolved in 10mL THF, and splashes in freshly prepd Wittig reagent, at room temperature reacts 3h, after react 2h again under 50 ℃.Reaction solution is poured in frozen water, regulated pH to 1-2, use n-hexane extraction 3 times, merge organic phase, extremely neutral with the saturated common salt water washing, anhydrous Na
2SO
4Drying, concentrated, through silica gel column chromatography, obtain 3,13-dimethyl-3-, ten pentaene base benzylic ether (compound 8) 2.17g, yield is 83.1%.Concrete reaction formula is as follows:
Get 3,13-dimethyl-3-, ten pentaene base benzylic ether 2.0g(5.81mmol) be dissolved in 20mL methyl alcohol, add 50mg Pd-C catalyzer, pass into H
2, under 30 ℃, react 12h.Reaction solution boils off solvent after removing catalyzer after filtration, through column chromatography, obtains 3,13-dimethyl-1-pentadecylic alcohol (compound 9) 1.43g, and yield is 95.8%, through GC, analyzes, and purity reaches 99.3%.Concrete reaction formula is as follows:
By 20mL acetone and 1.2g(4.69mmol) 3,13-dimethyl-1-pentadecylic alcohol adds in the 100mL there-necked flask of being furnished with agitator and thermometer, ice-water bath is cooling, after making system temperature be down to 0 ℃, add 5.3mL(2.67mol/L, 14.1mmol) Jones reagent, slowly rise to room temperature and react 5h, then add 5mL Virahol termination reaction, after reaction solution is concentrated, add 10mL distilled water, with 3 * 5mL n-hexane extraction, merge organic phase extremely neutral with distilled water and saturated brine washing successively, anhydrous Na
2SO
4Drying, after concentrated rear concentrating, resistates separates through silicagel column, take n-hexane/ethyl acetate (50:1, v/v) as eluent, obtains 1.19g3, and 13-dimethyl pentadecylic acid (compound 10), be colourless oil liquid, and yield is 93.8%, and purity is 98.5%.Concrete reaction formula is as follows:
Add solvent 20mL toluene, 1.0g(3.7mmol in being furnished with the 100mL there-necked flask of agitator, thermometer and reflux condensing tube) 3,13-dimethyl pentadecylic acid and 1mL(13.7mmol) SOCl
2, oil bath heating is reacted 3h under 80 ℃, reaction after finishing first air distillation remove unnecessary after, obtain the acyl chlorides intermediate.Add 20mL normal hexane, 0.75g(7.35mmol in another is furnished with the 100mL there-necked flask of agitator, thermometer) (S)-2-methyl-3-amylalcohol, and after dripping 3 pyridines, ice bath is cooled to 0-5 ℃, drips the acyl chlorides intermediate, reaction 1h.Reaction solution is with after the normal hexane dilution, extremely neutral with the saturated brine washing, the organic phase anhydrous Na
2SO
4Drying, then through silicagel column separate obtain 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-amylalcohol ester (compound 11) 1.25g, yield is 95.6%, through GC, analyzes, purity is 99.5%.Concrete reaction formula is as follows:
Claims (9)
1. one kind 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that, comprise the following steps:
(1) with the anhydrous THF solution of 1,9-, bis-bromononanes and grignard reagent sec-butyl bromination magnesium for raw material, take tetrachloro ketone acid lithium-tetrahydrofuran solution and N-Methyl pyrrolidone as catalyzer, reaction makes the bromo-dodecane of 3-methyl isophthalic acid 2-;
(2) take the bromo-dodecane of 3-methyl isophthalic acid 2-and triphenylphosphine prepared by step (1) is raw material, and anhydrous THF is solvent, and heating reflux reaction makes 10-methyl-dodecyl triphenyl bromide phosphine;
(3) take 10-methyl-dodecyl triphenyl bromide phosphine as raw material prepares Wittig reagent, in the THF of 4-benzyloxy-2-butanone solution, drip Wittig reagent, reaction makes 3,13-dimethyl-3-, ten pentaene base benzylic ethers;
(4) with 3,13-dimethyl-3-, ten pentaene base benzylic ethers for raw material, under Pd-C catalysis, pass into H
2Reaction makes 3,13-dimethyl-1-pentadecylic alcohol; For raw material, add the Jones reagent react with 3,13-dimethyl-1-pentadecylic alcohol, make 3,13-dimethyl pentadecylic acid;
(5) with 3,13-dimethyl pentadecylic acid and SOCl
2For raw material, reaction makes the acyl chlorides intermediate; In the mixed solution of normal hexane, (S)-2-methyl-3-amylalcohol and pyridine, drip the acyl chlorides intermediate, reaction obtain 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester.
2. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (1), 1,9-bis-bromononanes prepare gained by following methods: in reaction vessel, add 1,9-nonanediol and part Hydrogen bromide, stir fully and dissolve, and is warming up to 40 ℃, drip the vitriol oil to finishing, add the residual hydrogen bromic acid, slowly be warming up to back flow reaction, gas-chromatography is followed the tracks of the detection reaction process to finishing, use n-hexane extraction, organic phase is used respectively saturated NaHCO
3Solution, saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, filter also rotary evaporation and obtain light yellow liquid 1,9-bis-bromononanes after concentrating.
3. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (1), grignard reagent sec-butyl bromination magnesium prepares gained by following methods: in reaction vessel, add magnesium chips and the part anhydrous tetrahydro furan crossed through 5% dilute hydrochloric acid and Ethanol Treatment, stir and also first add part 2-n-butyl bromide, add thermal booster reaction, slowly splashing into remaining 2-n-butyl bromide and tetrahydrofuran (THF) mixed solution, finish, back flow reaction, to reacting completely, obtains the tetrahydrofuran solution of sec-butyl bromination magnesium.
4. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (1), under nitrogen protection, add the tetrachloro ketone acid lithium of 0.1mol/L-tetrahydrofuran solution 5.3mL and 6.8mL N-Methyl pyrrolidone in reactor, drip 17.5mmol1 under room temperature, the anhydrous THF solution of 9-bis-bromononanes, dropwise, continue stirring reaction 1h under room temperature; Then slowly add grignard reagent sec-butyl bromination magnesium 45mL, finish, continue reaction 3h under room temperature, with gas-chromatography, follow the tracks of the detection reaction process; Reaction is used solvent extraction after finishing, and extraction liquid uses respectively saturated NH4Cl solution, saturated common salt water washing to neutral, and after anhydrous Na 2SO4 drying, rotary evaporation reclaims solvent, and crude product is further purified through column chromatography, obtains the bromo-dodecane of 3-methyl isophthalic acid 2-.
5. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (2), in reactor, add anhydrous THF, triphenylphosphine and the bromo-dodecane of 3-methyl isophthalic acid 2-, reflux 12h, steam THF, with anhydrous diethyl ether, wash again, until residual without triphenylphosphine, obtain light yellow paste 10-methyl-dodecyl triphenyl bromide phosphine.
6. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (3), prepared by following methods by 4-benzyloxy-2-butanone:
In reactor, add 4-hydroxy-2-butanone, ethylene glycol, citric acid and toluene, heating reflux reaction is to finishing; After reaction finishes, rotary evaporation reclaims band aqua and unreacted ethylene glycol, and underpressure distillation, collect 106-108 ℃ of cut and obtain 4-hydroxy-2-butanone condensed ethandiol;
Under nitrogen protection, use petroleum ether NaH, decompressing and extracting, add anhydrous tetrahydro furan, drips 4-hydroxy-2-butanone condensed ethandiol, dropwises stirring reaction 1h; Drip the tetrahydrofuran solution of cylite, heating reflux reaction, follow the tracks of the detection reaction process with gas-chromatography; Reaction is used n-hexane extraction after finishing, and organic phase is used respectively saturated NH
4Cl solution, saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, rotary evaporation reclaims solvent, obtains 4-benzyloxy-2-butanone ethylene ketal;
In reaction vessel, add methyl alcohol, Glacial acetic acid and distilled water, drip 4-benzyloxy-2-butanone ethylene ketal, slowly heating systems starts back flow reaction, and reaction adds water after finishing, and with the hexanaphthene extraction, extraction liquid is used respectively saturated NaHCO
3Solution and saturated common salt water washing, to neutral, are used anhydrous Na
2SO
4Drying, after filtering, rotary evaporation reclaims solvent, obtains light yellow oily liquid, through column chromatography, is further purified and obtains 4-benzyloxy-2-butanone.
7. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (3), in reaction vessel, add anhydrous THF and n-Butyl Lithium, after being cooled to-70 ℃, add 10-methyl-dodecyl triphenyl bromide phosphine, stirring reaction 2h, make Wittig reagent; 4-benzyloxy-2-butanone is dissolved in THF, and splashes in Wittig reagent, at room temperature react 3h, then react 2h under 50 ℃; Reaction solution is poured in frozen water, regulated pH to 1-2, use n-hexane extraction 3 times, merge organic phase, extremely neutral with the saturated common salt water washing, anhydrous Na
2SO
4Drying, concentrated, through silica gel column chromatography, obtain 3,13-dimethyl-3-, ten pentaene base benzylic ethers.
8. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (4), by 3,13-dimethyl-3-ten pentaene base benzylic ethers are dissolved in methyl alcohol, add the Pd-C catalyzer, pass into H
2, under 30 ℃, react 12h; Reaction solution boils off solvent after removing catalyzer after filtration, through column chromatography, obtains 3,13-dimethyl-1-pentadecylic alcohol; By acetone and 3,13-dimethyl-1-pentadecylic alcohol adds reaction vessel, and ice-water bath is cooling, after making system temperature be down to 0 ℃, add Jones reagent, slowly rise to room temperature and react 5h, then adding the Virahol termination reaction, after reaction solution is concentrated, add distilled water, use n-hexane extraction, extremely neutral with distilled water and saturated brine washing organic phase successively, anhydrous Na
2SO
4Drying, after concentrated rear concentrating, resistates separates through silicagel column, take n-hexane/ethyl acetate (50:1, v/v) as eluent, obtains 3,13-dimethyl pentadecylic acid.
9. according to claim 13,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-synthetic method of amylalcohol ester, it is characterized in that: in step (5), in reaction vessel, add toluene, 3,13-dimethyl pentadecylic acid and SOCl
2, the oil bath heating is reacted 3h under 80 ℃, and air distillation obtains the acyl chlorides intermediate; Add normal hexane, (S)-2-methyl-3-amylalcohol in reaction vessel, and, after dripping pyridine, ice bath is cooled to 0-5 ℃, drips the acyl chlorides intermediate, reaction 1h; Reaction solution is with after the normal hexane dilution, extremely neutral with the saturated brine washing, the organic phase anhydrous Na
2SO
4Drying, then through silicagel column separate obtain 3,13-dimethyl pentadecylic acid (S)-2 '-methyl-3 '-the amylalcohol ester.
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