CN103553931A - Method for synthesizing chiral diketone compound - Google Patents

Method for synthesizing chiral diketone compound Download PDF

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CN103553931A
CN103553931A CN201310508404.7A CN201310508404A CN103553931A CN 103553931 A CN103553931 A CN 103553931A CN 201310508404 A CN201310508404 A CN 201310508404A CN 103553931 A CN103553931 A CN 103553931A
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罗三中
徐长明
张龙
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Institute of Chemistry CAS
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Abstract

The invention discloses a method for synthesizing a chiral diketone compound. The method comprises the following steps: taking a compound as shown in a formula I as a catalyst, mixing the compound with a strong acid in an organic solvent, removing the solvent through evaporation and then evenly mixing the obtained mixture with a weak acid, 1,3-diketone as shown in a formula IV and alpha,beta-unsaturated ketone as shown in a formula V for Robinson reaction, and obtaining a compound as shown in a formula III after the reaction is terminated. The catalyst adopted by the method is simple in structure; the synthetic route is short; and the synthetic method is simple and easy to operate. The chiral diketone compound synthesized by using the catalyst has high yield and high enantioselectivity; the synthetic method comprises only one step and is free of solvent, so that the synthetic cost is greatly reduced and the synthetic cycle is shortened; besides, the synthetic method is friendly to environment and easy for large-scale production; and after magnification, the yield and the enantioselectivity both can be remained.

Description

The method of synthesis of chiral cyclohexadione compounds
Technical field
The invention belongs to technical field of organic synthesis, relate to a kind of method of synthesis of chiral cyclohexadione compounds.
Background technology
Last century the seventies early stage, the people such as the people such as Hajos and Eder have been developed the triketone 2a of L-PROLINE (L-proline) catalysis and the asymmetric cyclization of 2b (2a and 2b are made with methyl ethylene reactive ketone respectively by 1a and 1b) independently of one another, Stereoselective generates dicyclo ketenes 3a and 3b, Hajos-Parrish-Eder-Sauer-Wiechert reaction (as shown in Figure 3) that people know that Here it is.Conventionally, people are referred to as Hajos-Parrish ketone (3a is called for short H-P ketone) by the dicyclo ketenes of reaction product five-ring six-ring, and the dicyclo ketenes of six-ring six-ring is referred to as Wieland-Miechert ketone (3b is called for short W-M ketone).
Chirality dicyclo ketenes is very useful building block, at many natural products, especially in terpene and steroid compound complete synthesis, has important application.For example, Danishefsky is synthetic to taxol skeleton, Yamamoto H., in synthetic dull and stereotyped mycin carbon skeleton process, and has used W-M ketone and analogue thereof when synthetic (-)-Anominine of the people such as Bonjoch J. and Bradshaw B. as building block recently.
Synthetic H-P ketone, can reach comparatively desirable result with Proline-Catalyzed, but synthetic W-M ketone can only provide medium productive rate and enantioselectivity (70-75%ee) with Proline-Catalyzed.In order to obtain the W-M ketone of enantiomer-pure, generally need follow-up multiple recrystallization, complex operation, very uneconomical.In addition, traditional method because needs are used high boiling polar aprotic solvent as DMF, DMSO etc., post-reaction treatment also comparatively bothers, and because Proline-Catalyzed activity is lower, reaction needed heating, and the reaction times is longer, combined coefficient is very low, and all these does not meet the requirement of Modern Green Chemistry.
Last decade, has reported a lot of novel chiral organic micromolecule catalysts in order to synthetic H-P ketone and W-M ketone successively, and they are having large increase than proline(Pro) aspect stereoselectivity and catalytic activity.But also there is following defect in these method great majority: first, the complex structure of chiral catalyst, synthetic route is longer; Secondly, chiral catalyst consumption excessive (great majority are all more than 10mol%), cost is higher; Again, synthetic H-P ketone and W-M ketone need polystep reaction and purification operations repeatedly, and a large amount of organic solvents of building-up process needs.These defects are all the key factors of its suitability for industrialized production of restriction.Therefore the synthetic method of, finding a kind of simple in structure, catalytic efficiency is high, enantioselectivity is good chiral catalyst and exploring a kind of single stage method (directly catalyzing and synthesizing 3a, 3b by 1a, 1b), the synthetic H-P ketone of solvent-free green, W-M ketone is significant.
Summary of the invention
A kind of method that the object of this invention is to provide synthesis of chiral cyclohexadione compounds.
Catalyzer used when first the present invention provides a kind of synthesis of chiral cyclohexadione compounds, is also compound shown in formula I,
Figure BDA0000401384180000021
In described formula I, R 3, R 4and R 5all be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl;
N 2for the integer of 1-9, concrete, n 2be 1;
Concrete, shown in described formula I, compound is
Figure BDA0000401384180000022
The method of compound shown in the described formula I of preparation provided by the invention, comprises the steps: compound shown in formula II and reductive agent to reflux and carry out reduction reaction in organic solvent, reacts the complete compound shown in formula I that obtains;
Figure BDA0000401384180000023
In described formula II, R 3, R 4, R 5definition with respectively with formula I in R 3, R 4, R 5definition identical;
N 3integer for 0-9.
Concrete, shown in described formula II, compound is
Figure BDA0000401384180000024
In described formula II, n 3be specially 0;
In aforesaid method, described reductive agent is selected from lithium aluminium hydride, red aluminum solutions, B 2h 6, NaBH (CH 3cOO) 3, at least one in sodium aluminum hydride and aluminum hydride potassium;
Shown in described formula II, the molar ratio of compound, reductive agent and organic solvent is 1:2-4:5-10, is specially 1:3:10;
In described reduction reaction step, the time is 1-4 hour;
Described organic solvent is selected from least one in tetrahydrofuran (THF), methylene dichloride, ether, acetonitrile, toluene and benzene.
A kind of method of preparing the cyclohexadione compounds of chirality shown in formula III provided by the invention, comprise the steps: take that shown in aforementioned formula I provided by the invention, compound is catalyzer, mix in organic solvent with strong acid, after steaming desolventizes by shown in gained mixture and weak acid, formula IV 1, α shown in 3-diketone and formula V, alpha, beta-unsaturated ketone mixes and carries out Robinson reaction, reacts the complete compound shown in described formula III that obtains;
Figure BDA0000401384180000031
In described formula III, R 1and R 2all be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, allyl group, propargyl, butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl;
N 1integer for 0-5;
Figure BDA0000401384180000032
In described formula IV, R 6be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, allyl group, propargyl, butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl; n 1integer for 0-5;
Figure BDA0000401384180000033
In described formula V, R 7, R 8and R 9all be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl, indyl.
In aforesaid method, in described formula III and formula IV, n 1be specially 1,2 or 1-2;
Described strong acid is selected from trifluoroacetic acid, trichoroacetic acid(TCA), acetic acid, trifluoromethanesulfonic acid, methylsulfonic acid, Phenylsulfonic acid, contains at least one in substituent Phenylsulfonic acid, Tetrafluoroboric acid, four aryl boric acids, phosphofluoric acid, hydrochloric acid, sulfuric acid, nitric acid, perchloric acid and hypochlorous acid;
Wherein, described in contain in substituent Phenylsulfonic acid, substituting group is selected from least one in methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, nitro, hydroxyl, amido, fluorine atom, chlorine atom, bromine atoms, iodine atom;
Described weak acid is selected from phenylformic acid, naphthoic acid, contains substituent phenylformic acid and contain at least one in substituent naphthoic acid, is specially M-NITROBENZOIC ACID;
Described containing in substituent phenylformic acid and naphthoic acid, substituting group is selected from least one in methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, nitro, hydroxyl, amido, fluorine atom, chlorine atom, bromine atoms and iodine atom.
In aforesaid method, shown in described formula I, the molar ratio of compound, strong acid and weak acid is 1:0.5-2:0.1-2, is specially 1:1:0.5;
Shown in formula IV 1, shown in 3-diketone and formula V, the molar ratio of alpha, beta-unsaturated ketone is 1:1-5, is specially 1:1.2 or 1:1.5 or 1:1.2-1.5;
Compound shown in formula I is shown in formula IV 1, and the 0.5-10% of the mole dosage that feeds intake of 3-diketone, is specially 2%;
In described Robinson reaction, temperature is 20 ℃～100 ℃, is specially 60 ℃; Time is 1-6 days, is specially 2 days, 3 days, 5 days or 2-5 days.
Concrete, shown in formula IV 1,3-diketone is
Figure BDA0000401384180000041
Alpha, beta-unsaturated ketone shown in described formula V is methyl vinyl ketone
Figure BDA0000401384180000042
Compound shown in formula III is any one in following compound:
Figure BDA0000401384180000043
The present invention compared with prior art has the following advantages:
1, catalyst structure used in the present invention is simple, and synthetic route is shorter, and synthetic method is simple, easy handling, and gained chirality dicyclo ketene compounds has higher productive rate and enantioselectivity;
2, the method for synthesis of chiral dicyclo ketenes involved in the present invention adopts single stage method synthetic, greatly reduces synthetic cost and synthesis cycle;
3, these are easy to the Methods For Purification of suitability for industrialized production in the synthetic method of catalyzer involved in the present invention and the finished product, to adopt underpressure distillation, recrystallization and extraction, simple to operate efficient;
4, the amount of synthetic method used catalyst involved in the present invention can be reduced to 2mol%, and catalytic efficiency is high, enantioselectivity good, effectively reduces production cost;
5, the present invention adopts solvent-free synthetic method, environmental protection;
6, method involved in the present invention is easy to scale operation, and after amplifying, productive rate and enantioselectivity can both keep.
Accompanying drawing explanation
Fig. 1 is compound 8 1h NMR.
Fig. 2 is compound 8 13c NMR.
Fig. 3 is Hajos-Parrish-Eder-Sauer-Wiechert reaction equation.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Described method is ordinary method if no special instructions.Described starting material all can obtain from open commercial sources if no special instructions.
Following embodiment 1 reactant compound 7 used is prepare in accordance with the following steps and obtain:
Figure BDA0000401384180000051
1) sodium hydroxide, S-Leucine, water are added in reactor by the mol ratio of 1:1:5～1:1:10, then by (Boc) with S-Leucine equimolar amount 2o is dissolved in the Isosorbide-5-Nitrae-dioxane of 5～10 times, slowly splashes in reactor, drips off rear stirring at room 2～12 hours.Concentrated solvent to add after half and concentrate after the isopyknic ethyl acetate of reaction solution, then add half the hydrochloric acid of 4mol/L of ethyl acetate volume, separatory, organic phase with isopyknic washing once, is steamed and is desolventized and obtain compound 5 after anhydrous sodium sulfate drying.
2) compound 5 and dry methylene dichloride are added in reactor by the mol ratio of 1:5～1:10, then under ice-water bath, slowly drip and the DCC(N of compound 5 equimolar amounts, N '-dicyclohexylcarbodiimide) dichloromethane solution, after dripping off, add again the diethylamine with compound 5 equimolar amounts, drip off rear stirring at room 2～12 hours.Remove by filter white precipitate, organic phase is used respectively and isopyknic 2% hydrochloric acid of reaction solution, 4% sodium bicarbonate, saturated common salt water washing, after anhydrous sodium sulfate drying, steams and desolventizes and obtain compound 6.
3) compound 6 and anhydrous methanol are added in reactor by the mol ratio of 1:5～1:10, then slowly drip the Acetyl Chloride 98Min. of 1～5 times of compound 6 molar weight, reflux was steamed and is desolventized after 1～5 hour, add again and the isopyknic methylene dichloride of methyl alcohol and water, with salt of wormwood, regulate aqueous pH values to separate organic phase to weakly alkaline.In organic phase, add isopyknic water, with dilute hydrochloric acid, regulate aqueous pH values to separate water to slightly acidic.In water, add isopyknic methylene dichloride, then regulate aqueous pH values to weakly alkaline with salt of wormwood, separate organic phase, after anhydrous sodium sulfate drying, steam and desolventize and obtain compound 7.
Compound shown in embodiment 1, preparation formula I (being also compound 8)
Reaction process is as follows:
Figure BDA0000401384180000061
By the compound 7(n of compound shown in ownership formula II 3=0, R 3for the tertiary butyl, R 4and R 5be ethyl) and dry tetrahydrofuran (THF) by the mol ratio of 1:10, add in reactor, the slow reductive agent lithium aluminium hydride of 3 times of compound 7 molar weights under ice-water bath then, reflux is carried out reduction reaction and is cooled to room temperature after 4 hours.Under ice-water bath, drip half saturated aqueous sodium sulfate of tetrahydrofuran (THF) volume, after adding, remove by filter precipitation, filtrate extracts by isopyknic ethyl acetate, steams and desolventizes, more obtain compound 8 shown in formula I with oil pump underpressure distillation after anhydrous sodium sulfate drying;
Its nuclear magnetic data following (spectrogram is as illustrated in fig. 1 and 2): 1h NMR (300MHz, CDCl 3): 2.67-2.53 (m, 3H), 2.45-2.34 (m, 3H), 2.15-2.07 (m, 1H), 1.49 (br, 2H), 0.99 (t, J=6.90Hz, 6H), 0.89 (s, 9H); 13c NMR (75MHz, CDCl 3): 57.4,55.6,47.5,33.2,26.4,12.2.
Specific rotatory power [α] d 20=+124.1 (c=0.50, MeOH).
As from the foregoing, this product structure is correct, for belonging to the compound of formula I, wherein, n 2be 1, R 3for the tertiary butyl, R 4and R 5be ethyl.
Embodiment 2
Figure BDA0000401384180000062
1) hydroresorcinol (150mmol) is dissolved in aqueous sodium hydroxide solution (5M, 30mL), adds methyl iodide (200mmol), be heated to 65 ℃ of reaction 24h.Cooled and filtered gained white solid obtains the 2-methyl isophthalic acid of ownership formula IV, hydroresorcinol (n 1be 2, R 6for methyl), productive rate 65%.
2) by 2-methyl isophthalic acid, the methyl vinyl ketone (R of hydroresorcinol (50mmol) and ownership formula V 7and R 9be methyl, R 8for hydrogen atom) (60mmol) add in reactor, again prepared by embodiment 1 to gained catalyst compound 8(1mmol) by 1ml organic solvent dichloromethane, dissolve, splash into strong acid trifluoromethanesulfonic acid (1mmol), steam except after methylene dichloride this catalyzer is added in reactor, finally add weak acid M-NITROBENZOIC ACID (0.5mmol), be heated to 60 ℃, mechanical stirring was carried out Robinson reaction after 3 days, and reaction completes, and with oil pump underpressure distillation, obtains W-M ketone, productive rate 83%, ee value 90%.
W-M ketone nuclear magnetic data is as follows: 1h NMR (300MHz, CDCl 3): δ (ppm)=5.83 (s, 1H), 2.65-2.76 (m, 2H), 2.41-2.52 (m, 4H), 2.08-2.17 (m, 3H), 1.69 (m, 1H), 1.43 (s, 3H); 13c NMR (100MHz, CDCl 3): 211.0,198.3,165.8,125.8,50.6,37.6,33.6,31.7,29.6,23.3,22.9.
Its specific rotatory power [α] d 20=-13 (c=0.5, CHCl 3). its ee value is by high-performance liquid chromatogram determination [Daicel Chiralpak OD-H column, λ=254nm, 2-propanol:n-Hexane=3:97, flow rate=0.8mL/min]: t r=35.47min (minor), t r=38.24min (major).
As from the foregoing, this product structure is correct, is target compound shown in formula III, wherein, and R 1for methyl, R 2for hydrogen, n 1be 2.
Embodiment 3
1) 1,3-cyclopentanedione (20mmol) is dissolved in aqueous sodium hydroxide solution (5M, 4mL), adds Tetrabutyl amonium bromide (2mmol) and methyl iodide (40mmol), be heated to 65 ℃ of reaction 24h.After cooling, add dilute hydrochloric acid (15mL), by ethyl acetate (15mL * 3), extract three times, anhydrous sodium sulfate drying, steams and desolventizes the 2-methyl isophthalic acid that rear column chromatography obtains ownership formula IV, 3-cyclopentanedione (n 1be 1, R 6for methyl), productive rate 45%.
2) by step 1) gained 2-methyl isophthalic acid, the methyl vinyl ketone (R of 3-cyclopentanedione (10mmol) and ownership formula V 7and R 9be methyl, R 8for hydrogen atom) (15mmol) add in reactor, again prepared by embodiment 1 to gained catalyst compound 8(0.2mmol) with 0.5ml methylene dichloride, dissolve, splash into trifluoromethanesulfonic acid (0.2mmol), steam except after methylene dichloride this catalyzer is added in reactor, finally add M-NITROBENZOIC ACID (0.1mmol), be heated to 60 ℃, magnetic agitation was carried out Robinson reaction after 5 days, and reaction completes, with sherwood oil: ethyl acetate=2:1 column chromatography obtains H-P ketone, productive rate 80%, ee value 76%.
H-P ketone nuclear magnetic data is as follows: 1h NMR (300MHz, CDCl 3): δ (ppm)=5.96 (s, 1H), 3.05-2.92 (m, 1H), 2.86-2.75 (m, 2H), 2.60-2.38 (m, 3H), 2.20-2.09 (m, 1H), 1.91-1.80 (m, 1H), 1.34 (s, 3H); 13c NMR (100MHz, CDCl 3): 216.4,198.0,169.7,123.8,48.6,35.8,32.9,29.2,26.8,20.5.
Its specific rotatory power [α] d 20=-150 (c=0.5, CHCl 3). its ee value is by high-performance liquid chromatogram determination [Daicel Chiralpak AD-H column, λ=254nm, 2-propanol:n-Hexane=1:9, flow rate=1.0mL/min]: t r=10.09min (minor), t r=10.53min (major).
As from the foregoing, this product structure is correct, is target compound shown in formula III, wherein, and R 1for methyl, R 2for hydrogen, n 1be 1.
Embodiment 4
Figure BDA0000401384180000081
1) by 1, hydroresorcinol (20mmol) is dissolved in aqueous sodium hydroxide solution (5M, 4mL), add copper powder (0.1g) and bromopropylene (24mmol), after stirring at room 8h, filter, gained precipitation is removed to copper powder with refiltering after dissolve with methanol, steam except column chromatography after methyl alcohol, obtain 2-allyl group-hydroresorcinol (n that white solid obtains ownership formula IV 1be 2, R 6for allyl group), productive rate 54%.
2) by the methyl vinyl ketone (R of 2-allyl group-hydroresorcinol (10mmol) and ownership formula V 7and R 9be methyl, R 8for hydrogen atom) (12mmol) add in reactor, again prepared by embodiment 1 to gained catalyst compound 8(0.2mmol) with 0.5ml methylene dichloride, dissolve, splash into trifluoromethanesulfonic acid (0.2mmol), steam except after methylene dichloride this catalyzer is added in reactor, finally add M-NITROBENZOIC ACID (0.1mmol), be heated to 60 ℃, mechanical stirring was carried out Robinson reaction after 3 days, and reaction completes, with sherwood oil: ethyl acetate=2:1 column chromatography obtains target product, productive rate 84%, ee value 88%.
1H?NMR(300MHz,CDCl 3):δ(ppm)=5.90(s,1H),,5.89-5.54(m,1H),5.16(d,J=16.0Hz,1H),5.12(d,J=8.5Hz,1H,),2.81-2.38(m,8H),2.25-1.99(m,3H),1.76-1.66(m,1H); 13C?NMR(75MHz,CDCl 3):δ(ppm)=209.1,198.2,164.9,131.6,126.5,119.5,54.7,39.9,38.4,33.3,31.9,26.2,23.3.
Its specific rotatory power [α] d 20=-43 (c=0.5, CHCl3). its ee value is by high-performance liquid chromatogram determination [Daicel Chiralpak OD-H column, λ=254nm, 2-propanol:n-Hexane=1:19, flow rate=1.0mL/min]: t r=14.89min (major), t r=16.29min (minor).
As from the foregoing, this product structure is correct, is target compound shown in formula III, wherein, and R 1for-CH 2cH=CH 2, R 2for hydrogen, n 1be 2.
Embodiment 5
Figure BDA0000401384180000091
1) hydroresorcinol (20mmol) is dissolved in methyl alcohol (20mL), adds sodium methylate (20mmol) and propargyl bromide (24mmol), be heated to 60 ℃ of reaction 24h.Cooling rear steaming, except methyl alcohol, adds water (15mL), with methylene dichloride (15mL * 3), extracts three times, and anhydrous sodium sulfate drying, steams and desolventize 2-propargyl-hydroresorcinol (n that rear column chromatography obtains ownership formula IV 1be 2, R 6for propargyl), productive rate 42%.
2) by the methyl vinyl ketone (R of 2-propargyl-hydroresorcinol (10mmol) and ownership formula V 7and R 9be methyl, R 8for hydrogen atom) (12mmol) add in reactor, again prepared by embodiment 1 to gained catalyst compound 8(0.2mmol) with 0.5ml methylene dichloride, dissolve, splash into trifluoromethanesulfonic acid (0.2mmol), steam except after methylene dichloride this catalyzer is added in reactor, finally add M-NITROBENZOIC ACID (0.1mmol), be heated to 60 ℃, magnetic agitation was carried out Robinson reaction after 3 days, reaction completes, with sherwood oil: ethyl acetate=2:1 column chromatography obtains target product, productive rate 81%, ee value 92%.
1H?NMR(300MHz,CDCl 3):δ=5.92(d,J=1.6Hz,1H),2.82-2.66(m,4H),2.58-2.45(m,4H),2.35(dt,J=14.4,4.6Hz,1H),2.20-2.10(m,3H),1.72(qt,J=13.4,4.4Hz,1H); 13C?NMR(100MHz,CDCl 3):δ=208.0,197.8,163.0,127.3,78.0,73.3,53.5,38.1,33.5,31.9,27.3,26.1,23.2.
Its specific rotatory power [α] d 20=-18 (c=0.5, CHCl 3). its ee value is by high-performance liquid chromatogram determination [Daicel Chiralpak AD-H column, λ=254nm, 2-propanol:n-Hexane=1:9, flow rate=1.0mL/min]: t r=13.05min (major), t r=13.95min (minor).
As from the foregoing, this product structure is correct, is target compound shown in formula III, wherein, and R 1for-CH 2c ≡ CH, R 2for hydrogen, n 1be 2.
Embodiment 6
Figure BDA0000401384180000101
By 2-methyl isophthalic acid, the methyl vinyl ketone (R of hydroresorcinol (50mmol) and ownership formula V 7and R 9be methyl, R 8for hydrogen atom) (60mmol) add in reactor, again prepared by embodiment 1 to gained catalyst compound 8(2.5mmol) with 1ml methylene dichloride, dissolve, splash into trifluoromethanesulfonic acid (2.5mmol), steam except after methylene dichloride this catalyzer is added in reactor, finally add M-NITROBENZOIC ACID (2.5mmol), stirring at room carries out having reacted after Robinson reaction 10h, with oil pump underpressure distillation, obtains W-M ketone, productive rate 85%, ee value 92%.
The structural confirmation result of this product is identical with embodiment 2, repeats no more.
As from the foregoing, this product structure is correct, is target compound shown in formula III, wherein, and R 1for methyl, R 2for hydrogen, n 1be 2.
Embodiment 7
Figure BDA0000401384180000111
By 2-methyl isophthalic acid, the methyl vinyl ketone (R of hydroresorcinol (1.0mol) and ownership formula V 7and R 9be methyl, R 8for hydrogen atom) (1.2mol) add in reactor, again prepared by embodiment 1 to gained catalyst compound 8(20mmol) with 10ml methylene dichloride, dissolve, splash into trifluoromethanesulfonic acid (20mmol), steam except after methylene dichloride this catalyzer is added in reactor, finally add M-NITROBENZOIC ACID (10mmol), be heated to 60 ℃, mechanical stirring was carried out Robinson reaction after 2 days, and reaction completes, and with oil pump underpressure distillation, obtains W-M ketone, productive rate 90%, ee value 90%.Again with obtaining the product that ee value is greater than 99% after the mixed solvent recrystallization of ethyl acetate and normal hexane.
The structural confirmation result of this product is identical with embodiment 2, repeats no more.
As from the foregoing, this product structure is correct, is target compound shown in formula III, wherein, and R 1for methyl, R 2for hydrogen, n 1be 2.

Claims (10)

1. compound shown in formula I,
Figure FDA0000401384170000011
In described formula I, R 3, R 4and R 5all be selected from any one in hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl;
N 2integer for 1-9.
2. compound according to claim 1, is characterized in that: shown in described formula I, compound is
Figure FDA0000401384170000012
3. prepare a method for compound shown in formula I described in claim 1 or 2, comprise the steps: compound shown in formula II and reductive agent to reflux and carry out reduction reaction in organic solvent, react the complete compound shown in formula I that obtains;
Figure FDA0000401384170000013
In described formula II, R 3, R 4, R 5definition with respectively with formula I in R 3, R 4, R 5definition identical;
N 3integer for 0-9.
4. method according to claim 3, is characterized in that: shown in described formula II, compound is
Figure FDA0000401384170000014
5. according to the method described in claim 3 or 4, it is characterized in that: described reductive agent is selected from lithium aluminium hydride, red aluminum solutions, B 2h 6, NaBH (CH 3cOO) 3, at least one in sodium aluminum hydride and aluminum hydride potassium;
Shown in described formula II, the molar ratio of compound, reductive agent and organic solvent is 1:2-4:5-10, is specially 1:3:10;
In described reduction reaction step, the time is 1-4 hour;
Described organic solvent is selected from least one in tetrahydrofuran (THF), methylene dichloride, ether, acetonitrile, toluene and benzene.
6. a method of preparing compound shown in formula III, comprise the steps: to using shown in the arbitrary described formula I of claim 1 or 2 that compound is as catalyzer, mix in organic solvent with strong acid, after steaming desolventizes by shown in gained mixture and weak acid, formula IV 1, α shown in 3-diketone and formula V, alpha, beta-unsaturated ketone mixes and carries out Robinson reaction, reacts the complete compound shown in described formula III that obtains;
Figure FDA0000401384170000021
In described formula III, R 1and R 2all be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, allyl group, propargyl, butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl;
N 1integer for 0-5;
In described formula IV, R 6be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, allyl group, propargyl, butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl; n 1integer for 0-5;
Figure FDA0000401384170000023
In described formula V, R 7, R 8and R 9all be selected from any one in following group: hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indyl.
7. method according to claim 6, is characterized in that: described strong acid is selected from trifluoroacetic acid, trichoroacetic acid(TCA), acetic acid, trifluoromethanesulfonic acid, methylsulfonic acid, Phenylsulfonic acid, contains at least one in substituent Phenylsulfonic acid, Tetrafluoroboric acid, four aryl boric acids, hydrochloric acid, sulfuric acid, nitric acid, phosphofluoric acid, perchloric acid and hypochlorous acid;
Wherein, described in contain in substituent Phenylsulfonic acid, substituting group is selected from least one in methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, nitro, hydroxyl, amido, fluorine atom, chlorine atom, bromine atoms and iodine atom;
Described weak acid is selected from phenylformic acid, naphthoic acid, contains substituent phenylformic acid and contain at least one in substituent naphthoic acid, is specially M-NITROBENZOIC ACID;
Described containing in substituent phenylformic acid and naphthoic acid, substituting group is selected from least one in methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, benzyl, nitro, hydroxyl, amido, fluorine atom, chlorine atom, bromine atoms and iodine atom.
8. according to the method described in claim 6 or 7, it is characterized in that: shown in described formula I, the molar ratio of compound, strong acid and weak acid is 1:0.5-2:0.1-2, is specially 1:1:0.5;
Shown in formula IV 1, shown in 3-diketone and formula V, the molar ratio of alpha, beta-unsaturated ketone is 1:1-5, is specially 1:1.2 or 1:1.5 or 1:1.2-1.5;
Compound shown in formula I is shown in formula IV 1, and the 0.5-10% of the mole dosage that feeds intake of 3-diketone, is specially 2%;
In described Robinson reaction, temperature is 20 ℃～100 ℃, is specially 60 ℃;
Time is 5 hours-6 days, is specially 10 hours, 2 days, 3 days, 5 days or 2-5 days.
9. according to the arbitrary described method of claim 6-8, it is characterized in that: shown in described formula IV 1,3-diketone is 2-methyl isophthalic acid, 3-cyclopentanedione or 2-methyl isophthalic acid, hydroresorcinol; Or 2-allyl group-hydroresorcinol, 2-propargyl-hydroresorcinol, 2-benzyl-hydroresorcinol, 2-phenyl-hydroresorcinol;
Alpha, beta-unsaturated ketone shown in described formula V is methyl vinyl ketone or ethyl vinyl ketone.
10. according to the arbitrary described method of claim 6-9, it is characterized in that: shown in compound shown in formula III be any one in following compound:
Figure FDA0000401384170000031
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CN105541582A (en) * 2016-01-07 2016-05-04 浙江大学 MBH reaction of alpha, beta-unsaturated ketone and allyl acetate
CN107325025A (en) * 2017-07-17 2017-11-07 中国科学院化学研究所 A kind of chiral alpha amino acid derivativges and preparation method thereof
CN108101811A (en) * 2016-11-25 2018-06-01 斯福瑞（南通）制药有限公司 The method for producing N- tertbutyloxycarbonyl -2- amino -3,3- acid dimethyls
CN109776293A (en) * 2019-01-25 2019-05-21 温州大学 A method of 1,3- cyclohexadione compounds are prepared with acetylenic ketone

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105541582A (en) * 2016-01-07 2016-05-04 浙江大学 MBH reaction of alpha, beta-unsaturated ketone and allyl acetate
CN105541582B (en) * 2016-01-07 2017-07-18 浙江大学 The MBH of alpha, beta unsaturated ketone and allyl acetic acid ester reacts
CN108101811A (en) * 2016-11-25 2018-06-01 斯福瑞（南通）制药有限公司 The method for producing N- tertbutyloxycarbonyl -2- amino -3,3- acid dimethyls
CN107325025A (en) * 2017-07-17 2017-11-07 中国科学院化学研究所 A kind of chiral alpha amino acid derivativges and preparation method thereof
CN107325025B (en) * 2017-07-17 2019-04-09 中国科学院化学研究所 A kind of chiral alpha-amino acid derivatives and preparation method thereof
CN109776293A (en) * 2019-01-25 2019-05-21 温州大学 A method of 1,3- cyclohexadione compounds are prepared with acetylenic ketone
CN109776293B (en) * 2019-01-25 2022-04-05 温州大学 Method for preparing 1, 3-diketone compound from alkynone

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