CN1233608C - Method for synthesizing high antimer pure pine needle bee sex pharomone (2S, 3S, 7S)-3,7-dimethyl-2-pentadeca alcohol ester - Google Patents
Method for synthesizing high antimer pure pine needle bee sex pharomone (2S, 3S, 7S)-3,7-dimethyl-2-pentadeca alcohol ester Download PDFInfo
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Abstract
The present invention relates to a method for synthesizing high-enantiomer pure pine needle bee sex pheromones of (2S, 3S, 7S)-3, 7-dimethyl-2-pentadecyl alcohol ester. Natural (S)-malic acid with high-enantiomer purity, which is cheap and easy for acquirement is used as a raw material for the high-stereoselectivity synthesis of a series of significant intermediate compounds, such as (S)-1, 3-butanediol 4, (2S, 3S)-2-methyl-1, 3-butanediol 12, (S)-3-methyl-undecanol 8 and (2S, 3S, 7S)-3, 7-dimethyl-2-pentadecyl alcohol 15, of pine needle bee sex pheromones, wherein the (2S, 3S, 7S)-3, 7-dimethyl-2-pentadecyl alcohol 15 is acylated to obtain a pine needle bee sex pheromone of (2S, 3S, 7S)-3, 7-dimethyl-2-pentadecyl alcohol carboxylic acid ester 16 and a pine needle bee sex pheromone of (2S, 3S, 7S)-3, 7-dimethyl-2-pentadecyl alcohol carboxylic acid ester 17. The synthesized pine needle bee sex pheromones with optical activity have the advantages of high-enantiomer purity, short procedures, higher yield of most of the procedures and adoption of usual reagents.
Description
(1) technical field
The present invention relates to a kind of have optical activity generated in high enantiomeric purity pine sawfoy sex pheromone (2S, 3S, 7S)-3, the synthetic method of 7-dimethyl-2-pentadecanol acetic ester and propionic ester and important intermediate chiral diol thereof.
(2) background technology
Insect pheromone is the main mode of carrying out information interchange, population identification, sex attraction or attack defence between the insect.Utilizing the insect sex pheromone pest control to have economical and effective, free from environmental pollution, protection natural enemy, easy to use and advantages such as safety, non-resistant, is a kind of new technology and novel method of carrying out the insect integrated controls of worm group prediction, a large amount of trappings.But the quantity of insect secretion infochemicals is very low, obtain the insect sex pheromone of milligram number of stages, needs with thousands of heads even 1,000,000 insects.The sex pheromone that therefore will obtain q.s carries out necessary biological study, and the prerequisite of successfully carrying out pest control just must the practical chemical synthesis process of development.
Pine sawfoy (Hymenoptera:Diprionidae) is the primary pest of harm softwood tree (pine tree, dragon spruce, fir and fir etc.), is distributed widely in North America, Asia and Europe.Jewett in 1976 etc. identify that the sex pheromone of Neodiprion lecontei and Neodiprion sertifer is 3 in the diprionidae, 7-dimethyl-2-pentadecanol acetic ester, the sex pheromone of Dirprion similis is 3,7-dimethyl-2-pentadecanol propionic ester (D.M.Jewett, F.Matsumura, and H.C.Coppel, Science, 192,51 (1976)).In living things system, stereoisomerism identification is extremely tangible, and the optical stereo isomer of isomorphism type does not have different biological activitys.European patent EP 130951 A2 disclose in 1985 to be utilized by H.G.Magnusson and J.W.Loefqvist research group has different diastereomers 3,7-dimethyl-2-pentadecanol acetic ester and propionic ester as diprionidae sex attractant and inhibitor sex pheromone research and carry out the effective ways of diprionidae population prediction.Result of study shows that (7S)-3,7-dimethyl-2-pentadecanol acetic ester and propionic ester have very strong attracting action to pine sawfoy for 2S, 3S.And 3, the acetic ester and the propionic ester of 7-dimethyl-2-pentadecanol, there are three chiral centres to have 8 possible steric isomers, can only obtain the mixture of 8 possibility steric isomers with general method, so synthetic generated in high enantiomeric purity pine sawfoy sex pheromone (2S of development, 3S, 7S)-3, the asymmetric method of 7-dimethyl-2-pentadecanol acetic ester and propionic ester has important practical significance.
Japanese Patent JP 54/106405 A2 has announced in 1979 by K.Mori research group with (R)-(+)-geraniol and tartrate as starting raw material, the method for synthetic pine sawfoy sex pheromone.They are from (R)-(+)-geraniol, and earlier synthetic (S)-4-methyl isophthalic acid-bromo-dodecane is made organic copper lithium reagent, with (2S, 3S)-butylene oxide ring reaction synthetic (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol and carboxylicesters (Tetrahedron Lett.10,901-904,1978; Tetrahedron.35,1279-1284,1979).The product that this method obtains is the product of high-optical-purity, but route is oversize, and overall yield is not high.
1984, Akira etc. are raw material with 2-methyl-3-ketobutyric acid methyl esters, with (S, S)-nickel catalyzator of tartrate modification carries out asymmetric hydrogenation to it, obtain 2-methyl-3-beta-hydroxymethyl butyrate, then through separate, split obtain at last optically pure (2S, 3S)-2-methyl-3-tetrahydro-pyran oxy-1-butanols tolysulfonyl ester.Another segment with (R)-(+)-lemongrass acid esters as starting raw material, reaction obtains (S)-3-methyl isophthalic acid-bromo-undecane through 5 steps, make organic copper reagent and optically pure (2S, 3S)-reaction of 2-methyl-3-tetrahydro-pyran oxy-1-butanols tolysulfonyl ester just obtain (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol and carboxylicesters (Bull.Chem.Soc.Jpn. thereof, 57,1954-1960,1984).This route is longer, also relates to the fractionation of complex operation.
Toshiyuki in 1986 etc. obtain optically active (3S)-hydroxyl thioesters with β-ketone thioesters that α-sulfane base replaces with Baker yeast Stereoselective reduction, method with Nozaki changes into (3S)-butyric ester, obtain (S)-1-benzyloxy-3-tolysulfonyl oxygen base butane through 7 steps again, after linked reaction increases carbochain.Last and chiral reagent (2S, 3S)-2-methyl-3-THP trtrahydropyranyl-methyl thiobutyrate reacts, obtain optically pure (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol and carboxylicesters thereof (Tetrahedron Lett., 27,5405-5408,1986).This route reaction step is long, and raw material is difficult to obtain, and the sulfocompound environmental pollution is very big.
Elder generations such as Larcheveque were raw material with the D-Threonine in 1988, synthetic (2S, 3S)-2-methyl-3-benzyloxy butanols, behind the bromo with another several steps of fragment coupling obtain the finished product optically pure (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol and carboxylicesters (Tetrahedron thereof, 44,6407-6418,1988).This route is the same with above-reported equally, and step is oversize, and complex operation does not have practicality.
Nineteen ninety Hogberg etc. are raw material with 2-ethyl-4-methoxyl group Malignant azoles quinoline chiral reagent, synthesize optically pure (S)-2-methyl capric acid, obtain bromo-derivative through reduction, esterification, bromo and make organolithium reagent.Another segment from tartrate synthetic (2S, 3S)-butylene oxide ring, again through 4 steps synthetic (3S, 4S)-3,4-dimethyl-gamma-butyrolactone.Organolithium reagent with (3S, 4S)-3, that the reaction of 4-dimethyl-gamma-butyrolactone just obtains is optically pure (2S, 3S, 7S)-3,7-dimethyl-its carboxylicesters of 2-pentadecanol (Tetrahedron, 46,3007-3018,1990).This route is synthetic induces alkylating stereoselectivity not ideal by chiral auxiliary group, and reduction back derivatize records has only 60%～75%ee.Need to improve the ee value through further splitting.
In addition, also have many other research groups to report 3, synthesizing of 7-dimethyl-its carboxylicesters of 2-pentadecanol much all is racemic modification still, perhaps the not high isomer of other activity.
(3) summary of the invention
It is raw material with natural compounds (S)-oxysuccinic acid cheap, that be easy to get that purpose of the present invention aims to provide a kind of, synthesize a kind of optical activity generated in high enantiomeric purity pine sawfoy sex pheromone (2S that has, 3S, 7S)-3, the novel method of 7-dimethyl-2-pentadecanol acetic ester and propionic ester and important intermediate chiral diol thereof.
Concrete synthetic route of the present invention is as follows:
Among narration below and the embodiment subsequently, specific that synthetic product is to represent with Arabic numerals according to the numbering in the structural formula.R
1The expression alkyl, Me represents methyl here, and Et represents ethyl, and Ts represents p-toluenesulfonyl, and TBS represents that tertiary butyl dimethyl is silica-based, THP represents THP trtrahydropyranyl, R
2The expression acyl group, Ac represents ethanoyl here, COEt represents propionyl.
The present invention said synthetic a kind of have optical activity generated in high enantiomeric purity pine sawfoy sex pheromone (2S, 3S, 7S)-3, the method for 7-dimethyl-2-pentadecanol important intermediate chiral diol, its concrete synthesis step is as follows:
Under step 1 normal temperature, natural (S)-oxysuccinic acid 1 obtains compound 2 with thionyl chloride reaction 4～20h in a kind of alcohol, and said alcohol mainly is meant C
1-C
4Monohydroxy-alcohol, particularly methyl alcohol, ethanol.
Step 2 is a solvent with the methylene dichloride under-10～30 ℃, and compound 2 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 3.Said that alkali is tertiary amine, mainly refer to pyridine, triethylamine, carboxylic acid halides mainly refers to Tosyl chloride, methylsulfonyl chloride and naphthalic sulfonic chloride.
Step 3 compound 3 under-20～80 ℃, with a kind of reductive agent reaction 4～24h, obtains compound 4 behind column chromatography in a kind of ether.Said ether is C
2-C
4Aliphatic ether, be meant ether and tetrahydrofuran (THF) especially, said reductive agent refers to lithium aluminium hydride.
Step 4 compound 4 under-20～30 ℃, with a kind of chlorosilane reaction 20～30h, obtains compound 5 through separation in a kind of alkali in DMF or dichloromethane solvent.Said alkali refers to imidazoles, pyridine and triethylamine, and chlorosilane refers to TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane and trimethylchlorosilane.
Step 5 is a solvent with the methylene dichloride under-10～30 ℃, and compound 5 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 6.Said alkali is tertiary amine, mainly refers to pyridine, triethylamine, and carboxylic acid halides mainly refers to Tosyl chloride, methylsulfonyl chloride and naphthalic sulfonic chloride.
Step 6 compound 6 is made catalyzer at-78～30 ℃ of following reaction 20～30h with a kind of Grignard reagent with cuprous iodide in a kind of ether, extracted with diethyl ether, concentrate and silica gel column chromatography after obtain compound 7.Said ether is C
2-C
4Aliphatic ether, be meant ether and tetrahydrofuran (THF) especially, said Grignard reagent refers to C
1-C
12Iodo, bromo or the hydrochloric ether Grignard reagent made of bromooctane and MAGNESIUM METAL particularly.
Step 7 compound 7 is made solvent with alcohol under acidic conditions, react 20～30h at normal temperatures, and concentrating and separating obtains compound 8; Or compound 7 under-20～80 ℃, with a kind of reductive agent reaction 4～24h, obtains compound 8 behind column chromatography in a kind of ether; Said acidic conditions refers to direct adding hydrochloric acid or by Acetyl Chloride 98Min. and the hydrogenchloride that produces as the alcohol of solvent, said alcohol mainly is meant C
1-C
4Monohydroxy-alcohol particularly methyl alcohol, ethanol; Said ether is C
2-C
4Aliphatic ether, be meant ether and tetrahydrofuran (THF) especially, said reductive agent refers to lithium aluminium hydride.
Step 8 is a solvent with the methylene dichloride under-10～30 ℃, and compound 8 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain a thick liquid, under 30～80 ℃, makes solvent and lithiumbromide reaction 3～10h with acetone, and filtering and concentrating obtains compound 9.Said alkali is tertiary amine, mainly refers to pyridine, triethylamine, and carboxylic acid halides mainly refers to Tosyl chloride, methylsulfonyl and naphthalic sulfonic chloride.
Step 9, with a kind of halohydrocarbons reaction 30～50h, with Glacial acetic acid cancellation reaction, dichloromethane extraction, concentrates, obtains compound 10 behind drying and the silica gel column chromatography in a kind of ether solvents under a kind of alkali at-78～-20 ℃ of following compounds 2.Said alkali mainly is meant lithium diisopropyl amido, hexamethyl two silica-based amido lithiums, and said ether is C
2-C
4Aliphatic ether, be meant ether and tetrahydrofuran (THF) especially, said halohydrocarbon is meant C
1-C
8Iodo, hydrobromic ether, particularly methyl iodide.
Step 10 is a solvent with the methylene dichloride under～10～30 ℃, and compound 10 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 11.Said alkali is tertiary amine, mainly refers to pyridine, triethylamine, and carboxylic acid halides mainly refers to Tosyl chloride, methylsulfonyl and naphthalic sulfonic chloride.
Step 11 compound 11 under-20～80 ℃, with a kind of reductive agent reaction 4～24h, obtains compound 12 behind column chromatography in a kind of ether.Said ether is C
2-C
4Aliphatic ether, be meant ether and tetrahydrofuran (THF) especially, said reductive agent refers to lithium aluminium hydride.
Step 12 is a solvent with the methylene dichloride under-30～30 ℃, and compound 12 reacts 20～40h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 13.Said alkali is tertiary amine, mainly refers to pyridine, triethylamine, and carboxylic acid halides mainly refers to Tosyl chloride, methylsulfonyl and naphthalic sulfonic chloride.
Step 13 compound 13 is solvent and dihydropyrane reaction 4～20h with the methylene dichloride at normal temperatures, and the evaporating column chromatography obtains compound 14.
Step 14 is reacted in a kind of ether solvents by compound 9 and magnesium and is made grignard reagent, make catalyzer at-78～30 ℃ of following and compound 14 reactions 20～30h with cuprous iodide, solvent is made with alcohol in extracted with diethyl ether, concentrated back under acidic conditions, react 2～20h down at 25～60 ℃, concentrating and separating obtains the optically pure (2S of compound, 3S, 7S)-3,7-dimethyl-2-pentadecanol 15.Promptly obtain said generated in high enantiomeric purity pine sawfoy sex pheromone (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol important intermediate chiral diol, said here ether is C
2-C
4Aliphatic ether, be meant ether and tetrahydrofuran (THF) especially.Here said acidic conditions refers to direct adding hydrochloric acid or by Acetyl Chloride 98Min. and the hydrogenchloride or the tosic acid that produce as the alcohol of solvent.
In order to synthesize a kind of optical activity generated in high enantiomeric purity pine sawfoy sex pheromone (2S that has, 3S, 7S)-3,7-dimethyl-2-pentadecanol acetic ester or propionic ester, can be with generated in high enantiomeric purity pine sawfoy sex pheromone (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol important intermediate chiral diol (being above-mentioned steps 14 resulting compounds 15) is catalyzer and a kind of acid anhydrides or acyl chloride reaction with DMAP in a kind of alkali, dichloromethane extraction, concentrates, obtains compound 16 and 17 (seeing above-mentioned concrete synthetic route) behind drying and the silica gel column chromatography.Said alkali is tertiary amine, mainly refers to pyridine, triethylamine; Said acid anhydrides mainly is meant fatty acid anhydride, particularly diacetyl oxide and propionic anhydride; Said acyl chlorides mainly is meant Acetyl Chloride 98Min. and propionyl chloride.
The present invention is to be raw material with natural (the S)-oxysuccinic acid with high antimer purity cheap, that be easy to get, highly-solid selectively has synthesized the novel method of generated in high enantiomeric purity pine sawfoy pheromone, synthesized a series of important intermediate compounds (S)-1,3 butylene glycol 4, (2S, 3S)-the 2-methyl isophthalic acid, 3-butyleneglycol 12, (S)-3-methyl-undecyl alcohol 8 and (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol 15.(2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol 15 through acidylate promptly obtain the pine sawfoy sex pheromone (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol acetic ester 16 and propionic ester 17.This synthetic route synthetic optical activity pine sawfoy sex pheromone has high antimer purity, and its step is the shortest in the chirality synthetic route of having reported, and most of step productive rate is higher, and agents useful for same is common agents, has good application prospects.
(4) embodiment
Following examples elaborate to the present invention.
Embodiment 1
Step 1 is synthesized (S)-oxysuccinic acid dimethyl ester 2a
(12.0g adds methyl alcohol 200mL in single neck bottle 89.6mmo1) toward filling (S)-oxysuccinic acid 1.Dripping thionyl chloride under ice bath (14mL, 197mmol), after be raised under the room temperature and react 15h, concentrate and drain solvent, in ice bath, add methylene dichloride 50mL, with the neutralization of 11mL saturated sodium bicarbonate solution, tell organic phase, (anhydrous sodium sulfate drying is used in 3 * 10mL) extractions, the organic phase of merging 5mL saturated common salt water washing to water with methylene dichloride, rapid column chromatography (ethyl acetate: sherwood oil=1: 1) obtain compound 2a behind filtration, the concentrating under reduced pressure, 13.4g, colourless liquid, productive rate 93%.
Step 2 is synthesized (S)-2-tolysulfonyl oxygen base oxysuccinic acid dimethyl ester 3a
Under nitrogen atmosphere, in the ice bath, compound 2a (9.6g, 59.3mmol) be dissolved in the 80mL exsiccant methylene dichloride, add pyridine (14mL, 174mmol) and the DMAP of catalytic amount, drip Tosyl chloride (13.5g, methylene dichloride 71mmol) (10mL) solution again.After rising to stirring at room 12h, dilute with the 50mL ether, ice bath drips 2N hydrochloric acid (20mL) cancellation reaction down, tells organic phase, and (3 * 10mL) extract water with ether, the organic phase that merges 5mL saturated common salt water washing, use anhydrous sodium sulfate drying, rapid column chromatography (ethyl acetate: sherwood oil=1: 2) obtain compound 3a, 17.1g behind filtration, the concentrating under reduced pressure, colourless thickness oily matter, productive rate 91%.
Step 3 is synthesized (S)-1,3 butylene glycol 4
Under nitrogen atmosphere, toward lithium aluminium hydride (2063mg is housed, 54.2mmol) three-necked bottle in add the 100mL tetrahydrofuran (THF), drip compound 3a (2853mg, 9.0mmol) tetrahydrofuran (THF) (8mL) solution, drop to-20 ℃ behind the backflow 4h, add entry (2.8mL) successively, 15% sodium hydroxide solution (2.8mL), water (8.4mL) cancellation.Filter, extract the merging filtrate, (elutriant: ethyl acetate) obtain compound 4,442mg, colourless thickness oily matter, productive rate 54% of rapid column chromatography behind the concentrating under reduced pressure with tetrahydrofuran (THF) (50mL).[α]
D 20+30.0(c?1.0，EtOH)IR(film)v
max：3337，2963，2926，2854，1730，1653，1458，1376，1288，1261，1132，1075，1053，1008，964，906，851，798cm
-1；
1HNMR(500MHz，CDCl
3)δ：1.24(d，3H，J＝6.29Hz，H-4)，1.70(m，2H，H-2)，3.05(br，2H，-OH)，3.81(ddd，J＝5.72，5.72，11.10Hz，1H，H-1)，3.88(ddd，J＝5.18，5.18，10.55Hz，1H，H-1)，4.07(m，1H，H-3)ppm.
13CNMRδ：23.76，40.03，61.55，68.18ppm.MS(ESI)：91(M
++1，100).
Step 4 is synthesized (S)-1-tertiary butyl dimethyl Si base-3-hydroxyl butane 5
Toward compound 4 (420mg, 4.6mmol), imidazoles (625mg, 9.2mmol) and dry DMF (10mL) solution of the DMAP of catalytic amount in, under ice bath, drip TERT-BUTYL DIMETHYL CHLORO SILANE (768mg, 5.1mmol) methylene dichloride (5mL) solution reaction 24h after, add 50mL water, (anhydrous sodium sulfate drying is used in 5 * 10mL) extractions, the organic phase of merging 2mL saturated common salt water washing with ether, rapid column chromatography (ethyl acetate: sherwood oil=1: 10) obtain compound 5 behind filtration, the concentrating under reduced pressure, 835mg, colourless liquid, productive rate 89%.
Step 5 is synthesized (S)-1-tertiary butyl dimethyl Si base-3-tolysulfonyl oxygen base butane 6
Toward compound 5 (820mg, 4.0mmol), pyridine (0.7mL, 9.0mmol) and methylene dichloride (8mL) solution of the DMAP of catalytic amount in, under ice bath, drip Tosyl chloride (1282mg, 6.7mmol) methylene dichloride (2mL) solution, after spending the night, stirring pours in the 5mL2N hydrochloric acid, (3 * 5mL) extract, and the organic phase of merging is used 1mL saturated sodium bicarbonate solution and the water washing of 1mL saturated common salt successively, uses anhydrous sodium sulfate drying with ether, filter, (the ethyl acetate: sherwood oil=1: 10) obtain compound 6 of rapid column chromatography behind the concentrating under reduced pressure, 1223mg, colourless viscous liquid, productive rate 85%.
Step 6 is synthesized (S)-3-methyl isophthalic acid-tertiary butyl dimethyl Si base-undecane 7
With magnesium chips (260mg, 10.8mmol) and positive bromo spicy silane (1.87mL, 10.8mmol) in tetrahydrofuran (THF) (4mL), make Grignard reagent, at-78 ℃ of cuprous iodides that add catalytic amount down, drip compound 6 (1015mg again, 2.8mmol) tetrahydrofuran (THF) (2mL) solution, allow its be warmed up to naturally 5 ℃ and keep 3h after be raised to stirred overnight at room temperature.Ice bath adds saturated ammonium chloride solution (2mL) cancellation down, with ether (3 * 2mL) extractions, the organic phase that merges is used 0.5mL saturated sodium bicarbonate solution and the water washing of 0.5mL saturated common salt successively, use anhydrous sodium sulfate drying, rapid column chromatography (elutriant: sherwood oil) obtain compound 7 behind filtration, the concentrating under reduced pressure, 665mg, colourless liquid, productive rate 79%.
Step 7 is synthesized (S)-3-methyl hendecanol 8
(0.2mL 2.7mmol), adds compound 7 (665mg behind the stirring 10min to add Acetyl Chloride 98Min. in methyl alcohol (9mL), 2.2mmol) stir and to spend the night, drain rapid column chromatography (ethyl acetate: sherwood oil=1: 10) obtain compound 8,268mg behind the solvent, colourless viscous liquid, productive rate 65%.
Step 8 is synthesized (S)-3-methyl isophthalic acid-bromo undecane 9
Toward compound 8 (260mg, 1.3mmol), pyridine (0.21mL, 2.6mmol) and methylene dichloride (4mL) solution of the DMAP of catalytic amount in, under ice bath, drip Tosyl chloride (381mg, 2.0mmol) methylene dichloride (2mL) solution, pour into after stirring is spent the night in the 5mL2N hydrochloric acid, (3 * 5mL) extract, and the organic phase of merging is used 1mL saturated sodium bicarbonate solution and the water washing of 1mL saturated common salt successively with ether, use anhydrous sodium sulfate drying, filter, behind the concentrating under reduced pressure in acetone (5mL) solution, add lithiumbromide (573mg, 6.6mmol), react 3h down at 50～60 ℃, filter and wash filter residue with ether, filtrate decompression concentrates back rapid column chromatography (elutriant: sherwood oil) obtain compound 9,268mg, weak yellow liquid, productive rate 83%.
Step 9 synthetic (2S, 3R)-3-methyl malic acid dimethyl ester 10a
Ice bath is down toward filling Diisopropylamine (5.5mL, 39.3mmol) tetrahydrofuran (THF) (17mL) solution in drip the n-Butyl Lithium (22.6mL of 1.6M, 36.1mmol) hexane solution, drop to-78 ℃, drip compound 2a (2.99g behind the 15min, 18.5mmol) tetrahydrofuran (THF) (4mL) solution, behind-78 ℃ of stirring 1.5h, drip methyl iodide (2.7mL, 43.0mmol), react 44h down at-78 ℃, with 3.7g Glacial acetic acid cancellation reaction, add the dilution of 200mL methylene dichloride, use the neutralization of cold saturated sodium bicarbonate (20mL) solution again, (3 * 10mL) extract, and the organic phase of merging is used 10mL water successively with methylene dichloride, 10mL saturated sodium bicarbonate solution and the water washing of 10mL saturated common salt, use anhydrous sodium sulfate drying, filter, (the ethyl acetate: sherwood oil=1: 2) obtain compound 10a, 2.35g of rapid column chromatography behind the concentrating under reduced pressure, colourless liquid, productive rate 72%.The stereoselectivity of this reaction is 9/1.
Step 10 synthetic (2S, 3R)-3-methyl-2-tolysulfonyl oxygen base oxysuccinic acid dimethyl ester 11a
Under nitrogen atmosphere, in the ice bath, compound 10a (2.0g, 11.2mmol) be dissolved in the 5mL exsiccant methylene dichloride, add pyridine (1.8mL, 22.4mmol) and catalytic amount DMAP, drip Tosyl chloride (2.5g, methylene dichloride 13.4mmol) (2mL) solution again.Rise to stirring at room after 30 hours, dilute with the 25mL ether, ice bath drips 2N hydrochloric acid (5mL) cancellation reaction down, tell organic phase, (3 * 5mL) extract water with ether, the organic phase that merges 2mL saturated common salt water washing, use anhydrous sodium sulfate drying, rapid column chromatography (ethyl acetate: sherwood oil=1: 3) obtain pure compound a nti-11a, 2.0g behind filtration, the concentrating under reduced pressure, colourless thickness oily matter, the mixture mix-11a of productive rate 55% and anti-and syn-, 1.3g, productive rate 36%, overall yield are 91%.
Step 11 synthetic (2S, 3S)-the 2-methyl isophthalic acid, 3-butyleneglycol 12
Under nitrogen atmosphere, toward lithium aluminium hydride (360mg is housed, 9.5mmol) three-necked bottle in add the 15mL tetrahydrofuran (THF), drip compound a nti-11a (483mg, 1.4mmol) tetrahydrofuran (THF) (3mL) solution, drop to-20 ℃ behind the backflow 4h, add entry (0.36mL) successively, 15% sodium hydroxide solution (0.36mL), water (1.0mL) cancellation.Use diatomite filtration, filter residue extracts three times with ebullient tetrahydrofuran (THF) (10mL), the merging filtrate, (elutriant: anhydrous diethyl ether) obtain compound 12,96mg, colourless thickness oily matter, productive rate 64% of rapid column chromatography behind the concentrating under reduced pressure.[α]
D 20-7.9(c?1.0，EtOH)IR(film)v
max：337，2963，2926，2854，1730，1653，1458，1376，1288，1261，1132，1075，1053，1008，964，906，851，798cm
-1；
1HNMR(500MHz，CDCl
3)：δ0.88(d，J＝7.06Hz，3H，C2-CH
3)，1.12(d，J＝6.43Hz，3H，4-CH
3)，1.80(m，1H，H-2)，3.05(s，br，2H，-OH)，3.66(dd，J＝4.55，10.67Hz，1H，H-1)，3.70(dd，J＝7.0，10.67Hz，1H，H-1)，4.20(dq，1H，H-3)ppm；
13CNMRδ10.699，19.392，40.051，66.404，70.599ppm；MS(ESI)：127.0(M
++23，100).
Step 12 synthetic (2S, 3S)-2-methyl-3-hydroxyl-1-tolysulfonyl oxygen base butane 13
Toward compound 12 (68mg, 0.65mmol), triethylamine (0.12mL, 0.81mmol) and methylene dichloride (1.0mL) solution of the DMAP of catalytic amount in, under-20 ℃, slowly drip Tosyl chloride (1282mg, 6.7mmol) methylene dichloride (1.0mL) solution, pour in the 1.2mL water after stirring 36h, (3 * 2mL) extract, and the organic phase of merging is used 0.5mL saturated sodium bicarbonate solution and the water washing of 0.5mL saturated common salt successively, uses anhydrous sodium sulfate drying with ether, filter, (the ethyl acetate: sherwood oil=1: 4) obtain compound 13 of rapid column chromatography behind the concentrating under reduced pressure, 116mg, colourless viscous liquid, productive rate 70%.
Step 13 synthetic (2S, 3S)-2-methyl-3-THP trtrahydropyranyl-1-tolysulfonyl oxygen base butane 14
Toward compound 13 (108mg, 0.42mmol) and the solution of the methylene dichloride (9mL) of catalytic amount tosic acid in, drip dihydropyrane (0.10mL, 1.1mmol), add saturated sodium bicarbonate (2mL) after stirring 8h, methylene dichloride (3 * 2mL) extractions, anhydrous sodium sulfate drying is used in the organic phase 0.5mL saturated common salt water washing of merging, obtain compound 14 after filtering, concentrating, 129mg, colourless viscous liquid, productive rate 90%.
Step 14 synthetic (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol 15
With magnesium chips (26mg, 1.1mmol) and compound 9 (268mg, 1.1mmol) in tetrahydrofuran (THF) (5mL), make Grignard reagent, at-78 ℃ of cuprous iodides that add catalytic amount down, drip compound 14 (129mg again, 0.38mmol) tetrahydrofuran (THF) (1mL) solution, allow its be warmed up to naturally 5 ℃ and keep 3h after be raised to stirred overnight at room temperature.Ice bath adds saturated ammonium chloride solution (2mL) cancellation down, with ether (3 * 2mL) extractions, concentrate tosic acid and methyl alcohol (4mL) that the back adds catalytic amount, react 6h down at 50 ℃, (the ethyl acetate: sherwood oil=1: 10) obtain compound 15 of rapid column chromatography behind the concentrating under reduced pressure, 63mg, colourless liquid, productive rate 65%.[α]
D 20-9.9(c?4.0，hexane)IR(film)v
max：3373，2925，2855，1463，1377，1322，1089，1004，933，897，718cm
-1；
1HNMR(500MHz，CDCl
3)：δ0.85(d，J＝6.44Hz，3H，-CH
3?at?C-7)，0.88(overlapped?t?and?d，6H，-CH
3?at?C-3?and?terminal)，1.15(d，J＝6.44Hz，3H，-CH
3?at?C-2)，1.0-1.7(m，23H，-(CH
2)
10-and?2×-CH-and-OH)，3.71(m，1H，-CH(OH)-)ppm；
13CNMR：δ14.138，14.192，19.782，20.309，22.713，24.779，27.088，29.383，29.707，30.045，31.949，32.773，33.002，37.013，37.391，39.808，71.393ppm；MS(ESI)：274.3(M
++18，57)，279.1(M
++23，100).
Step 15 synthetic (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol carboxylicesters 16
Toward compound 15 (23mg, 0.09mmol), add diacetyl oxide (0.35mL in the DMAP of catalytic amount and pyridine (0.12mL) solution, 0.37mmol), after spending the night, stirring dilutes with ether (2mL), add 1mL5% hydrochloric acid, with ether (3 * 1mL) extractions, the organic phase that merges is used 0.25mL saturated sodium bicarbonate solution and the water washing of 0.25mL saturated common salt successively, dry, concentrated rapid column chromatography (ethyl acetate: sherwood oil=1: 30) obtain compound 16,26mg, colourless oil liquid, productive rate 97%.[α]
D 20-5.7(c?1.3，hexane)IR(film)v
max：2957，2926，2855，1739，1463，1373，1245，1019，950，852，801，721，605cm
-1；
1HNMR(500MHz，CDCl
3)δ：0.84(d，J＝6.59Hz，3H，-CH
3?atC-7)，0.89(overlapped?t?and?d，6H，-CH
3?at?C-3?and?terminal)，1.16(d，J＝6.45?Hz，3H，-CH
3?atC-2)，1.0-1.7(m，22H，-(CH
2)
10-and?2×-CH-)，2.05(s，3H，CH
3CO)，4.83(m，1H，-CH(OH)-)ppm.
13CNMR：δ14.128，14.820，16.939，19.722，21.336，22.706，24.522，27.074，29.381，29.698，30.044，31.947，32.754，32.754，37.021，37.324，37.612，74.100，170.848?ppm；MS(ESI)：316.0(M
++18，40)，321.0(M
++23，100).
The preparation method of compound 17 is the same with 16, just replaces diacetyl oxide with propionic anhydride, obtains colourless oil liquid, productive rate 93%.
Embodiment 2
Step 1 is pressed the method for embodiment 1 by compound 1 preparation compound 2a.
Step 2 prepares compound 3a by embodiment 1 by compound 2a, makes alkali with triethylamine, and all the other operations are identical, productive rate 88%.
Step 3 prepares compound 4 according to embodiment 1 by compound 3a, makes solvent with ether, and all the other operations are identical, productive rate 41%.
Step 4 is toward compound 4 (136mg, 1.5mmol), triethylamine (0.42mL, 3.0mmol) and anhydrous methylene chloride (1.5mL) solution of the DMAP of catalytic amount in, under ice bath, drip TERT-BUTYL DIMETHYL CHLORO SILANE (271mg, 1.2mmol) methylene dichloride (1.5mL) solution reaction 24h after, add the 5mL saturated sodium bicarbonate solution, (anhydrous sodium sulfate drying is used in 3 * 5mL) extractions, the organic phase of merging 0.5mL saturated common salt water washing with ether, filter, (the ethyl acetate: sherwood oil=1: 10) obtain compound 5 of rapid column chromatography behind the concentrating under reduced pressure, 175mg, colourless liquid, productive rate 57%.
The preparation of step 5 compound 6 is with embodiment 1.
The preparation of step 6 compound 7 is with embodiment 1.
Step 7 is under nitrogen atmosphere, and (44mg adds the 1.0mL tetrahydrofuran (THF) in three-necked bottle 1.1mmol) toward lithium aluminium hydride is housed, drip compound 7 (44mg, 0.14mmol) tetrahydrofuran (THF) (0.5mL) solution, 40～50 ℃ of reactions drop to 0 ℃ behind the 12h, add several saturated aqueous common salt cancellation.Use diatomite filtration, filter residue extracts three times with ebullient tetrahydrofuran (THF) (2mL), the merging filtrate, (elutriant: ethyl acetate: sherwood oil=1: 10) obtain compound 8,12mg, colourless thickness oily matter, productive rate 46% of rapid column chromatography behind the concentrating under reduced pressure.
The preparation of step 8 compound 9 is with embodiment 1.
The preparation of step 9 compound 10a is with embodiment 1.
The preparation of step 10 compound 11a is with embodiment 1.
The preparation of step 11 compound 12 is with embodiment 1.
The preparation of step 12 compound 13 is with embodiment 1.
The preparation of step 13 compound 14 is with embodiment 1.
The preparation of step 14 compound 15 is with embodiment 1.
Step 15 compound 16 and 17 preparation are with embodiment 1.
Embodiment 3
(4.81g adds ethanol 90mL to step 1 in single neck bottle 35.8mmol) toward filling (S)-oxysuccinic acid 1.Dripping thionyl chloride (5.7mL under ice bath, 78.7mmol), after be raised under the room temperature and react 14h, concentrate and drain solvent, in ice bath, add methylene dichloride 25mL, neutralize with the 11mL saturated sodium bicarbonate solution, tell organic phase, (anhydrous sodium sulfate drying is used in 3 * 10mL) extractions, the organic phase of merging 5mL saturated common salt water washing to water with methylene dichloride, rapid column chromatography (ethyl acetate: sherwood oil=1: 1) obtain compound (S)-diethyl malate 2b behind filtration, the concentrating under reduced pressure, 6.53g, colourless liquid, productive rate 96%.
Step 2 is under nitrogen atmosphere, in the ice bath, (S)-diethyl malate 2b (5.18g, 27.2mmol) be dissolved in the 50mL exsiccant methylene dichloride, add pyridine (3.3mL, 40.8mmol) and catalytic amount DMAP, drip Tosyl chloride (5.82g, methylene dichloride 30.5mmol) (10mL) solution again.After rising to stirring at room 12h, dilute with the 50mL ether, ice bath drips 2N hydrochloric acid (10mL) cancellation reaction down, tells organic phase, and (3 * 10mL) extract water with ether, the organic phase that merges 5mL saturated common salt water washing, use anhydrous sodium sulfate drying, rapid column chromatography (ethyl acetate: sherwood oil=1: 2) obtain (S)-2-tolysulfonyl oxygen base diethyl malate 3b, 8.53g behind filtration, the concentrating under reduced pressure, colourless thickness oily matter, productive rate 91%.
Step 3 is under nitrogen atmosphere, toward lithium aluminium hydride (1166mg is housed, 27.6mmol) three-necked bottle in add the 50mL tetrahydrofuran (THF), drip (S)-2-tolysulfonyl oxygen base diethyl malate 3b (1596mg, 4.6mmol) tetrahydrofuran (THF) (5mL) solution, drop to-20 ℃ behind the backflow 4h, add entry (1.2mL) successively, 15% sodium hydroxide solution (1.2mL), water (3.6mL) cancellation.Use diatomite filtration, filter residue extracts three times with ebullient tetrahydrofuran (THF) (10mL), the merging filtrate, (elutriant: ethyl acetate) obtain compound 4,231mg, colourless thickness oily matter, productive rate 56% of rapid column chromatography behind the concentrating under reduced pressure.
The preparation of step 4 compound 5 is according to embodiment 1.
The preparation of step 5 compound 6 is according to embodiment 1.
The preparation of step 6 compound 7 is according to embodiment 1.
The preparation of step 7 compound 8 is according to embodiment 1.
The preparation of step 8 compound 9 is according to embodiment 1.
Step 9 ice bath is down toward filling hexamethyl two silica-based amine (8.3mL, 39.2mmol) tetrahydrofuran (THF) (40mL) solution in drip the n-Butyl Lithium (24.5mL of 1.6M, 39.2mmol) hexane solution, drop to-78 ℃, compound 2b (3.1g behind the 15min, 16.3mmol) tetrahydrofuran (THF) (6mL) solution, behind-78 ℃ of stirring 1.5h, drip methyl iodide (2.5mL, 39.2mmol), react 44h down at-78 ℃,, add the dilution of 100mL ether with 3.7g Glacial acetic acid cancellation reaction, use cold saturated sodium bisulfite (3mL) solution neutralization again, (3 * 5mL) extract, and the organic phase of merging is used 2mL saturated sodium bicarbonate solution and the water washing of 2mL saturated common salt successively, uses anhydrous sodium sulfate drying with ether, filter, (the ethyl acetate: sherwood oil=1: 2) obtain chemical combination compound 10b of rapid column chromatography behind the concentrating under reduced pressure, 2.3g, colourless liquid, productive rate 69%.The stereoselectivity of this reaction is 12/1.
Step 10 is under nitrogen atmosphere, in the ice bath, compound 10b (2.0g, 9.8mmol) be dissolved in the 20mL exsiccant methylene dichloride, add pyridine (1.6mL, 20mmol) and catalytic amount DMAP, drip Tosyl chloride (2.4g, methylene dichloride 12.3mmol) (5mL) solution again.After rising to stirring at room 30h, dilute with the 25mL ether, ice bath drips 2N hydrochloric acid (5mL) cancellation reaction down, tell organic phase, (3 * 5mL) extract water with ether, the organic phase that merges 2mL saturated common salt water washing, use anhydrous sodium sulfate drying, rapid column chromatography (ethyl acetate: sherwood oil=1: 3) obtain compound a nti-11b, 2.1g behind filtration, the concentrating under reduced pressure, colourless thickness oily matter, the mixture mix-11b of productive rate 60% and anti-and syn-, 1.1g, productive rate 30%, overall yield are 90%.
Step 11 is under nitrogen atmosphere, toward lithium aluminium hydride (573mg is housed, 12.1mmol) three-necked bottle in add the 8mL tetrahydrofuran (THF), dropping compound a nyi-11b (723mg, tetrahydrofuran (THF) 2.0mmol) (2mL) solution spends the night 50 ℃ of stirrings, drop to 0 ℃ again, add entry (0.5mL) successively, 15% sodium hydroxide solution (0.5mL), water (1.5mL) cancellation.Filter, extract the merging filtrate, (elutriant: anhydrous diethyl ether) obtain compound 12,166mg, colourless thickness oily matter, productive rate 79% of rapid column chromatography behind the concentrating under reduced pressure with tetrahydrofuran (THF) (10mL).
The preparation of step 12 compound 13 is according to embodiment 1.
The preparation of step 13 compound 14 is according to embodiment 1.
The preparation of step 14 compound 15 is according to embodiment 1.
Step 15 compound 16 and 17 preparation are according to embodiment 1.
Claims (6)
1, a kind of synthetic generated in high enantiomeric purity pine sawfoy sex pheromone (7S)-3, the method for 7-dimethyl-2-pentadecanol acetic ester or propionic ester is characterized in that synthetic route is as follows for 2S, 3S:
Its concrete synthesis step is as follows:
Under step 1 normal temperature, (S)-oxysuccinic acid obtains compound 2 with thionyl chloride reaction 4～20h in methyl alcohol or ethanol;
Step 2 is a solvent with the methylene dichloride under-10～30 ℃, and compound 2 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 3, and said alkali is pyridine, triethylamine, and carboxylic acid halides refers to Tosyl chloride, methylsulfonyl chloride or naphthalic sulfonic chloride;
Step 3 compound 3 under-20～80 ℃, with a kind of reductive agent reaction 4～24h, obtains compound 4 behind column chromatography in a kind of ether, said ether is C
2-C
4Aliphatic ether, the reductive agent of being washed is a lithium aluminium hydride;
Step 4 compound 4 is at N, in dinethylformamide or the dichloromethane solvent, under-20～30 ℃, in a kind of alkali, react 20～30h with a kind of chlorosilane, obtain compound 5 through separation, said alkali refers to imidazoles, pyridine or triethylamine, and chlorosilane refers to TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane or trimethylchlorosilane;
Step 5 is a solvent with the methylene dichloride under-10～30 ℃, and compound 5 reacts 3-15h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 6, and said alkali is pyridine, triethylamine, and carboxylic acid halides refers to Tosyl chloride, methylsulfonyl or naphthalic sulfonic chloride;
Step 6 compound 6 is made catalyzer at-78～30 ℃ of following reaction 20～30h with a kind of Grignard reagent with cuprous iodide in a kind of ether, extracted with diethyl ether, concentrate and silica gel column chromatography after obtain compound 7, said ether is C
2-C
4Aliphatic ether, said halohydrocarbon is meant C
8Iodo, hydrobromic ether or hydrochloric ether and the Grignard reagent made of MAGNESIUM METAL;
Step 7 compound 7 is made solvent with alcohol under acidic conditions, react 20～30h at normal temperatures, and concentrating and separating obtains compound 8, and said acidic conditions refers to direct adding hydrochloric acid or by Acetyl Chloride 98Min. and the hydrogenchloride that produces as the alcohol of solvent, said alcohol refers to C
1-C
4Monohydroxy-alcohol;
Step 8 is under-10～30 ℃, with the methylene dichloride is solvent, compound 8 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain thick liquid, under 30～80 ℃, make solvent and lithiumbromide reaction 3～10h with acetone, filtering and concentrating obtains compound 9, said alkali is pyridine or triethylamine, and carboxylic acid halides is a toluene sulfonyl chloride, methylsulfonyl or naphthalic sulfonic chloride;
Step 9 at-78～-20 ℃ of following compounds 2 under a kind of alkali, in a kind of ether solvents with a kind of halohydrocarbons reaction 30～50h, react with the Glacial acetic acid cancellation, dichloromethane extraction, concentrate, obtain compound 10 behind drying and the silica gel column chromatography, said alkali is meant lithium diisopropyl amido or hexamethyl two silica-based amido lithiums, and said ether is ether or tetrahydrofuran (THF), and said halohydrocarbon is meant methyl iodide, monobromethane;
Step 10 is a solvent with the methylene dichloride under-10～30 ℃, and compound 10 reacts 3～15h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 11, and said alkali is pyridine, triethylamine, and carboxylic acid halides refers to Tosyl chloride, methylsulfonyl or naphthalic sulfonic chloride.
Step 11 compound 11 under-20～80 ℃, with a kind of reductive agent reaction 4～24h, obtains compound 12 behind column chromatography in a kind of ether, said that ether is C
2-C
4Aliphatic ether, said reductive agent is a lithium aluminium hydride;
Step 12 is a solvent with the methylene dichloride under-30～30 ℃, and compound 12 reacts 20～40h with a kind of carboxylic acid halides in a kind of alkali, obtain compound 13, and said alkali is pyridine, triethylamine, and carboxylic acid halides refers to Tosyl chloride, methylsulfonyl or naphthalic sulfonic chloride;
Step 13 compound 13 is solvent and dihydropyrane reaction 4～20h with the methylene dichloride at normal temperatures, and the evaporating column chromatography obtains compound 14;
Step 14 is reacted in a kind of ether solvents by compound 9 and magnesium and is made grignard reagent, make catalyzer at-78～30 ℃ of following and compound 14 reactions 20～30h with cuprous iodide, solvent is made with alcohol in extracted with diethyl ether, concentrated back under acidic conditions, react 2～20h down at 25～60 ℃, concentrating and separating obtain compound optically pure (2S, 3S, 7S)-3,7-dimethyl-2-pentadecanol 15, said ether are C
2-C
4Aliphatic ether, said acidic conditions refers to direct adding hydrochloric acid or by Acetyl Chloride 98Min. and the hydrogenchloride or the tosic acid that produce as the alcohol of solvent;
Step 15 compound 15 is catalyzer and a kind of acid anhydrides or acyl chloride reaction with the 4-dimethylaminopyridine in a kind of alkali, dichloromethane extraction, concentrate, obtain compound 16 or 17 behind drying and the silica gel column chromatography, said alkali is pyridine, triethylamine, said acid anhydrides is meant diacetyl oxide or propionic anhydride, and said acyl chlorides refers to Acetyl Chloride 98Min. or propionyl chloride.
2, a kind of synthetic generated in high enantiomeric purity pine sawfoy sex pheromone (2S as claimed in claim 1,3S, 7S)-3, the method of 7-dimethyl-2-pentadecanol acetic ester or propionic ester, it is characterized in that step 7 is that compound 7 is in a kind of ether, under-20～80 ℃, with a kind of reductive agent reaction 4～24h, obtain compound 8 behind column chromatography, said ether is C
2-C
4Aliphatic ether, said reductive agent is a lithium aluminium hydride.
3, a kind of synthetic generated in high enantiomeric purity pine sawfoy sex pheromone (2S as claimed in claim 2,3S, 7S)-3, the method for 7-dimethyl-2-pentadecanol acetic ester or propionic ester, it is characterized in that in step 3,6,9,11,14 said ether is ether or tetrahydrofuran (THF).
4, (7S)-3, the method for 7-dimethyl-2-pentadecanol acetic ester or propionic ester is characterized in that said ether is ether or tetrahydrofuran (THF) in the step 3,6,11,14 to a kind of synthetic generated in high enantiomeric purity pine sawfoy sex pheromone as claimed in claim 1 for 2S, 3S.
5, a kind of synthetic generated in high enantiomeric purity pine sawfoy sex pheromone (2S as claimed in claim 1,3S, 7S)-3, the method for 7-dimethyl-2-pentadecanol acetic ester or propionic ester is characterized in that the Grignard reagent that said Grignard reagent refers in the step 6 bromooctane and MAGNESIUM METAL are made.
6, (7S)-3, the method for 7-dimethyl-2-pentadecanol acetic ester or propionic ester is characterized in that said monohydroxy-alcohol is methyl alcohol or ethanol in the step 7 to a kind of synthetic generated in high enantiomeric purity pine sawfoy sex pheromone as claimed in claim 1 for 2S, 3S.
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|---|---|---|---|
| CN 03145033 CN1233608C (en) | 2003-06-18 | 2003-06-18 | Method for synthesizing high antimer pure pine needle bee sex pharomone (2S, 3S, 7S)-3,7-dimethyl-2-pentadeca alcohol ester |
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|---|---|---|---|
| CN 03145033 CN1233608C (en) | 2003-06-18 | 2003-06-18 | Method for synthesizing high antimer pure pine needle bee sex pharomone (2S, 3S, 7S)-3,7-dimethyl-2-pentadeca alcohol ester |
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| CN100503550C (en) * | 2007-01-26 | 2009-06-24 | 中国科学院上海有机化学研究所 | Method for synthesizing optical purity pine sawfly sex pheromone |
| CN102167666B (en) * | 2011-03-21 | 2013-09-18 | 厦门大学 | Method for synthesizing high-enantiomer-purity diprionidae pheromone and stereo isomer |
| CN105218519A (en) * | 2014-06-04 | 2016-01-06 | 天津药物研究院 | A kind of preparation method of dabigatran etexilate intermediate |
| CN107417718B (en) * | 2017-08-18 | 2019-11-15 | 常州兰陵制药有限公司 | The preparation method of everolimus intermediate |
| CN116199607A (en) * | 2022-12-29 | 2023-06-02 | 浙江奥翔药业股份有限公司 | Preparation method of pilocarpine and intermediate compound thereof |
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