CN106008411A - Method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone - Google Patents
Method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone Download PDFInfo
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- BNWCETAHAJSBFG-UHFFFAOYSA-N CC(C)(C)OC(CBr)=O Chemical compound CC(C)(C)OC(CBr)=O BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- CAXLCRGKHDWKRY-JTQLQIEISA-N CN([C@@H](Cc1ccccc1)CO1)C1=O Chemical compound CN([C@@H](Cc1ccccc1)CO1)C1=O CAXLCRGKHDWKRY-JTQLQIEISA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
The invention provides a method for preparing chiral 4-substituted dihydrofuran-2(3H)-ketone. The method comprises the following steps: (a) dropwise adding acyl chloride (3) into an organic solvent solution of a compound (1), enabling reaction to obtain an acyl chloride intermediate solution, then dropwise adding an organic solvent solution of a compound (2) and enabling reaction to obtain a compound (4); (b) dropwise adding a bis(trimethylsilyl)amide alkali metal salt solution into an organic solvent solution of the compound (4), enabling reaction, dropwise adding a compound (5) into the obtained reaction liquid and enabling reaction to obtain a compound (6); (c) enabling reaction between the compound (6) and alkali to obtain a compound (7); (d) enabling reaction between the compound (7) and a reducing agent to obtain a compound (8), wherein R is selected from aryl, arylmethyl or alkyl, R1, R2 and R3 are independently selected from alkyl, and X is selected from Cl, Br or I. The method is simple in process, strong in operability and easy for industrial production. The reaction route is shown in the description.
Description
Technical field
The present invention relates to chemicals synthesis technical field, particularly to a kind of chirality 4-substituent group dihydrofuran-2
(3H) preparation method of-one.
Background technology
The method that there is several preparation chirality 4-substituent group dihydrofuran-2 (3H)-one in prior art, but these sides
Method the most all there are disadvantages that, is unsuitable for industrial applications.Existing preparation chirality 4-substituent group dihydrofuran-2
(3H) method of-one mainly includes following several:
Method 1: paper (Journal of Organic Chemistry, 65 (18), 5623-5631,2000) discloses
One prepares the method for chirality 4-substituent group dihydrofuran-2 (3H)-one.The method is primarily present following shortcoming: rising of the first step
Beginning raw material need to use (1R, 2S, 5R)-(-)-menthol (S)-to toluenesulfinic acid ester, it does not commercially have supplier, and
Preparation cost is high, difficulty in process；Noble Metal Rhodium catalyst RhCl (PPh) used3Expensive；Final step needs to use three
Butyl stannane, it is that a kind of toxicity greatly and has the liquid making us the most joyful abnormal smells from the patient.Thus, consider the one-tenth of raw material
Basis, process operability and human body environment's safety of used raw material, the method is dfficult to apply to industrialized production.
Method 2: paper (Journal of the Chemical Society, Perkin Transactions 1:
Organic and Bio-Organic Chemistry (1972-1999), (5), 935-43,1989) disclosing one prepares hands
The method of property 4-substituent group dihydrofuran-2 (3H)-one.The method have the disadvantage in that initiation material that the first step reacts (1R,
2R)-(-)-N, N'-dimethyl-1,2-cyclohexanediamine is expensive, and dichloride pi-allyl phosphine does not has supplier on market；3rd
Step needs to use ozone, and ozone has strong oxidizing property and high risk, and the highest to the equipment requirements produced, cost is the most high
Expensive.Therefore, consider human body environment's safety of the cost of raw material, process operability and used raw material, though the method
So finally can arrive (R)-4-propyl group dihydrofuran-2 (3H)-one of high-optical-purity, but its application still rests on academic research
Aspect, is difficult to apply to industrialized production.
Method 3: paper [1.Journal of Organic Chemistry, 52 (5), 719-28,1987；2.e-EROS
Encyclopedia of Reagents for Organic Synthesis, No pp.given, 2001；3.Journal of
The American Chemical Society, 107 (13), 4088-90；1985] a kind of 4-preparing enantiomer-pure is disclosed
The method of substituent group dihydrofuran-2 (3H)-one.The method has the disadvantage in that the initiation material of the first step reaction of the method
2 (5H)-furanones are expensive；Initiation material pi-allyl is to unavailability business on toluenesulfinic acid ester market, if oneself is prepared,
Its preparation cost is high, complex process, and character is unstable, needs now-making-now-using, brings uncertainty to production.Thus, comprehensively examine
Consider the cost of raw material, process operability, although the method finally can arrive (R)-4-propyl group dihydrofuran-2 of high-optical-purity
(3H)-one, but its application still rests on academic research aspect, is difficult to apply to industrialized production.
Thus, low cost, workable and be suitable to the preparation chirality 4-substituent group dihydrofuran-2 of industrialized production
(3H) method of-one becomes a kind of urgent needs of this area research.
Summary of the invention
For solving above-mentioned technical problem, it is an object of the invention to provide a kind of chirality 4-substituent group dihydrofuran-2 (3H)-
The preparation method of ketone.The method synthetic route is short, raw material is easy to get, technique is simple, thus low cost and be suitable to industrialized production.
For achieving the above object, present invention employs techniques below scheme:
The preparation method of a kind of chirality 4-substituent group dihydrofuran-2 (3H)-one, comprises the following steps:
A () drips acyl chlorides (3) in the organic solvent solution of compound (1), reaction obtains acyl in the presence of a base
The solution of chloromethylated intermediate, is added drop-wise in the solution of described acid chloride intermediate react by the organic solvent solution of compound (2),
Obtain compound (4)；
B (), under inert gas shielding, drips two (trimethyl is silica-based) amino in the organic solvent solution of compound (4)
Alkali metal salt soln, obtains reactant liquor, then drips compound (5) in reactant liquor, at 20～50 DEG C after reacting 0.5～3 hour
Lower reaction obtains compound (6)；
C () in organic solvent, compound (6) and alkali reaction obtain compound (7)；
D () in organic solvent, compound (7) and reducing agent generation reduction reaction obtain compound (8)；
Reaction scheme is as follows:
Wherein: R is selected from aryl, arylmethyl or alkyl；
R1、R2、R3Independently selected from alkyl；
X is selected from Cl, Br or I.
Preferably, R is phenyl, benzyl or isopropyl.
Preferably, R1For C1-C4Alkyl, R2For the tert-butyl group, R3For the tert-butyl group.
It is highly preferred that R1For n-pro-pyl, R2For the tert-butyl group, R3For the tert-butyl group.
In one embodiment, R is phenyl, R1For n-pro-pyl, R2For the tert-butyl group, R3For the tert-butyl group, X is bromine.
In another specific embodiment, R is benzyl, R1For n-pro-pyl, R2For the tert-butyl group, R3For the tert-butyl group, X is bromine.
In still another embodiment, R is isopropyl, R1For n-pro-pyl, R2For the tert-butyl group, R3For the tert-butyl group, X is bromine.
Further, in step (a), at-40 DEG C～5 DEG C, reaction obtains the solution of acid chloride intermediate.Response time
Preferably 0.5～10 hour.
Preferably, in step (a), alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, three second
One or more in amine and diisopropylethylamine.
Preferably, in step (a), organic solvent is selected from oxolane, 2-methyltetrahydrofuran, ether, methyl-tert fourth
One or more in base ether, dichloromethane.
Preferably, in step (a), the organic solvent solution of compound (2) is added drop-wise in the solution of acid chloride intermediate
10～40 DEG C are reacted, and obtain compound (4).The preferably 4～16 hours time of reaction.
Further, in step (b), at-70 DEG C～-40 after the saline solution of dropping two (trimethyl is silica-based) alkali amide
React at DEG C.
Preferably, reaction is reacted after 0.5～3 hour and is obtained reactant liquor completely.
Preferably, two (trimethyl is silica-based) alkali amide salt is two (trimethyl is silica-based) Sodamide .s or two (trimethyl silicanes
Base) potassamide.
Further, in step (b), after dropping compound (5), at 20～50 DEG C, reaction obtains compound (6).Instead
Between Ying Shi preferably 10～30 minutes.
Preferably, in step (b), organic solvent is selected from oxolane, 2-methyltetrahydrofuran, ether, methyl-tert fourth
One or more in base ether.
Further, in step (c), reacting and carry out under conditions of stirring, the temperature of reaction is 20～50 DEG C, reaction
Time be 5～48 hours.
Preferably, in step (c), one or more in Lithium hydrate, sodium hydroxide, potassium hydroxide of alkali.
Preferably, in step (c), organic solvent is selected from oxolane, 2-methyltetrahydrofuran, ether, methyl-tert fourth
One or more in base ether, dichloromethane, methanol, ethanol.
Further, in step (d), reducing agent is borane dimethylsulf iotade or sodium borohydride.
Preferably, in step (d), borane dimethylsulf iotade is 10～65 DEG C as the temperature of the reduction reaction of reducing agent,
Sodium borohydride is-30～5 DEG C as the temperature of the reduction reaction of reducing agent.
Preferably, in step (d), described organic solvent is selected from oxolane, dimethyl-tetrahydrofuran, ether and methyl
One or more in tertbutyl ether.
In the present invention, the reagent used can be buied by commercial sources, such as, and two (trimethyl is silica-based) amino bases gold
Belong to saline solution can directly buy and obtain.
By such scheme, compared with prior art, the invention have the advantages that and the invention provides a kind of chirality 4-
The preparation method of substituent group dihydrofuran-2 (3H)-one, the method uses the raw material that low cost and commercial sources are easy to get, and preparation
Technique is simple, workable, it is easy to industrialized production.
Described above is only the general introduction of technical solution of the present invention, in order to better understand the technological means of the present invention,
And can be practiced according to the content of description, after describing in detail such as with presently preferred embodiments of the present invention below.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail it should be understood that these embodiments are only used
The explanation purpose of the present invention for example rather than limitation of the scope of the invention.
Embodiment 1
Synthesis (S)-4-benzyl-3-valeryl oxazolidine-2-ketone (compound 4a)
Adding 1L oxolane, 70.47 grams of valeric acids (compound 1a), 155.83 grams of triethylamines in reaction bulb, nitrogen is protected
Protect and be cooled to-10 DEG C.It is slowly added dropwise 83.49 cut valeric chlorides (compound 3a).Keep-10 DEG C to stir 0.5 hour, add
31.37 gram anhydrous Lithium chloride.The oxolane being slowly added dropwise 100.89 grams of (S)-4-benzyl oxazolidine-2-ketone (compound 2a) is molten
Liquid.Warm naturally to room temperature (20～25) DEG C, continue stirring 16 hours.Filter, filtrate adds 10% potassium carbonate 1.2L, stirring
10 minutes, decompression was distilled off oxolane, and the tertiary ether of first extracts.The tertiary ether layer of first is satisfied with 500mL 5% dilute hydrochloric acid, 500mL successively
Wash with sodium bicarbonate.Be dried, filter, be concentrated to dryness, obtain 140 grams of colorless oil (S)-4-benzyl-3-valeryl oxazolidines-
2-ketone (compound 4a, purity 90%, yield 94%).
Embodiment 2
Synthesis (R)-3 ((S)--4-benzyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6a)
140 grams of (S)-4-benzyl-3-valeryl oxazolidine-2-ketone (compound 4a) are dissolved in 1L oxolane, nitrogen
Protection, is cooled to-70 DEG C～-65 DEG C.Two (trimethyl is silica-based) Sodamide. (NaHMDS) of dropping 290mL 2mol/L, controls temperature
Spend less than-65 DEG C.Drip complete insulation 0.5 hour.Drip 134.4 grams of bromo-acetic acid tert-butyls (compound 5a).Drip complete from
So it is warming up to room temperature (20～25 DEG C), continues stirring 10 minutes.Add 500mL saturated ammonium chloride cancellation.With first tertiary ether (800mL
× 3) extractive reaction liquid, is dried, and filters, is evaporated to do.Then recrystallization (the tertiary ether of first: petroleum ether=1:5) obtains 143 grams
(R)-3 ((S)--4-benzyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6a, yield 72%,
D.e.98.5%).
Embodiment 3
Synthesis (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a)
318 grams (R)-3 ((S)--4-benzyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6a) is dissolved in
In the mixed solvent of 2.25L oxolane and 0.75L water, ice bath stirs.Keep 428 grams of hydrogen peroxide of less than 5 DEG C droppings.Add
70.4 gram lithium hydroxide monohydrate.Room temperature (20～25 DEG C) stirs 15 hours.Add water dilution, drip sodium sulfite under ice bath molten
Liquid (476 grams of sodium sulfite are dissolved in 2L water), controls temperature less than 10 DEG C.Adding 1.5L ethyl acetate, stir separatory, water layer is again
Wash once by 800mL ethyl acetate.Add 400 grams of citric acid water transfer layers to pH=3, with ethyl acetate extraction (600 milliliters ×
3).Be dried, filter, be concentrated to give 165 grams of grease (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acids (compound 7a,
Yield 91%).
Embodiment 4
Synthesis (R)-4-propyl group dihydrofuran-2 (3H)-one (compound 8a)
165 grams of (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a) are dissolved in 1L oxolane, ice
The lower borane dimethylsulf iotade dripping 84mL 10mol/L of bath, keeps temperature less than 10 DEG C.Drip complete room temperature (20～25 DEG C) to stir
Mix 16 hours.Reactant liquor is cooled to 0 DEG C, the hydrochloric acid of dropping 300mL18%.Drip complete continuation room temperature (20～25 DEG C) stirring 24
Hour.Reactant liquor adds 500mL saturated sodium-chloride, extracts (500mL × 3) with methyl tertiary butyl ether(MTBE).It is dried, filters, concentrate, residual
Excess decompression distillation obtains 76 grams of colourless liquid (R)-4-propyl group dihydrofuran-2 (3H)-one, (compound 8a, 110 DEG C/
18mmHg, 78% yield).
Embodiment 5
Synthesis (S)-4-phenyl-3-valeryl oxazolidine-2-ketone (compound 4b)
1L methyl tertiary butyl ether(MTBE), 69.78 grams of valeric acids (compound 1a, 1.2 equivalents), sodium bicarbonate is added in reaction bulb
(19.1 grams, 2.7 equivalents), nitrogen protection is cooled to-40 DEG C.(compound 3a, 1.2 work as to be slowly added dropwise 82.38 cut valeric chlorides
Amount).Stir 10 hours at keeping-40 DEG C, add 31.38 grams of anhydrous Lithium chlorides (1.3 equivalent).(S)-4-oxazolyl phenyl alkane-2-
Ketone (compound 2b, 92.91 grams) is configured to the solution of methyl tertiary butyl ether(MTBE), is slowly added dropwise to reactant liquor.It is warming up to 35～40 DEG C,
Continue stirring 4 hours.Filtering, the solution adding sodium hydroxide in filtrate neutralizes, and is sufficiently stirred for, and decompression is distilled off solvent, uses
Solvent extraction.Organic layer with dilute hydrochloric acid, saturated aqueous common salt washing, is dried, filters, desolventizing, obtain 125 grams of colorless oil successively
Thing (S)-4-phenyl-3-valeryl oxazolidine-2-ketone (compound 4b, purity 90%, yield 89%).
Embodiment 6
Synthesis (R)-3-((S)-4-phenyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6b)
100 grams of (S)-4-phenyl-3-valeryl oxazolidine-2-ketone (compound 4b) are dissolved in 1L methyl tertiary butyl ether(MTBE),
Under inert gas shielding, it is cooled to-45 DEG C to-40 DEG C.Two (trimethyl is silica-based) potassamide of dropping 290mL 2mol/L, controls
Temperature-40 DEG C～less than-65 DEG C.Drip complete insulation 3 hours.Drip 102.54 grams of bromo-acetic acid tert-butyls (compound 5a).
Drip complete, be warming up to 45～50 DEG C of reactions, continue reaction 10 minutes, add 500mL saturated ammonium chloride cancellation.Reactant liquor first
Tertiary ether extracts, and is dried, and filters, is evaporated to do.Be then passed through recrystallizing and refining, obtain 110 grams (R)-3 ((S)-4-phenyl-
2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6b, 75% yield, d.e 97.1%).
Embodiment 7
Synthesis (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a)
226 grams (R)-3 ((S)-4-phenyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6b) is dissolved in
In the mixed solvent of 1.8L methyl tertiary butyl ether(MTBE) and 0.6L water, stirring, ice-water bath cools down.Dropping hydrogen peroxide (319 grams, 30%),
Temperature 5-10 DEG C in keeping.Add the sodium hydroxide (50 grams) of 2 equivalents.45～50 DEG C are stirred 5 hours.Add water dilution, ice bath
Lower dropping sodium sulfite solution cancellation, controls temperature 5-10 DEG C.Reactant liquor ethyl acetate processes.Add citric acid regulation water layer
To pH=3, then it is extracted with ethyl acetate.Organic layer merges, and is dried, and filters, is evaporated to do, obtains 120.4 grams of grease
(R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a, yield 89%).
Embodiment 8
Synthesis (R)-4-propyl group dihydrofuran-2 (3H)-one (compound 8a)
165 grams of (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a) are dissolved in 1L oxolane,
Drip the borane dimethylsulf iotade of 84mL 10mol/L under ice bath, keep temperature less than 10 DEG C.Drip complete, be warming up to 65 DEG C, stir
Mix 8 hours.Reactant liquor is cooled to 0 DEG C, the hydrochloric acid of dropping 300mL18%.Drip complete continuation room temperature (20～25 DEG C) stirring 24
Hour.Reactant liquor adds 500mL saturated sodium-chloride, extracts (500mL × 3) with methyl tertiary butyl ether(MTBE).It is dried, filters, concentrate, residual
Excess decompression distillation obtains 71 grams of colourless liquid (R)-4-propyl group dihydrofuran-2 (3H)-one, (compound 8a, 110 DEG C/
18mmHg, 72.8% yield).
Embodiment 9
Synthesis (S)-4-isopropyl-3-valeryl oxazolidine-2-ketone (compound 4c)
1 liter of 2-methyltetrahydrofuran, valeric acid (compound 1a, 1.2 equivalents), potassium bicarbonate (188.4 is added in reaction bulb
Gram, 2.7 equivalents), nitrogen protection is cooled to 5 DEG C.It is slowly added dropwise 100.8 cut valeric chlorides (compound 3a, 1.2 equivalents).Keep 5
Stir 5 hours at DEG C, add anhydrous Lithium chloride (38.4 grams, 1.3 equivalents).(S)-4-isopropyl-oxazolidine-2-ketone (compound
2c, 90 grams) it is configured to the solution of 2-methyltetrahydrofuran, it is slowly added dropwise to reactant liquor.Warm naturally to 10～15 DEG C), continue
Stir 10 hours.Filtering, the solution adding potassium bicarbonate in filtrate neutralizes, and is sufficiently stirred for, and decompression is distilled off solvent, uses solvent
Extraction.Organic layer with dilute hydrochloric acid, saturated aqueous common salt washing, is dried, filters, desolventizing, obtain 122 grams of colorless oil successively
(S)-4-isopropyl-3-valeryl oxazolidine-2-ketone (compound 4c, purity 92%, yield 82%).
Embodiment 10
Synthesis (R)-3-((S)-4-isopropyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6c)
100 grams of (S)-4-isopropyl-3-valeryl oxazolidine-2-ketone are dissolved in 1L dichloromethane, inert gas shielding,
It is cooled to-55 DEG C.Two (trimethyl is silica-based) potassamide of dropping 290mL 2mol/L, controls temperature less than-55 DEG C.Drip
Bi Baowen 2 hours.Drip 119 grams of bromo-acetic acid tert-butyls (compound 5a).Drip and complete warm naturally to room temperature (30 DEG C of left sides
Right), continue reaction 30 minutes, add 500mL saturated ammonium chloride cancellation.Reactant liquor dichloromethane extracts, and is dried, and filters, subtracts
Pressure is concentrated to dryness.It is then passed through recrystallizing and refining, obtains 107.5 grams of (R)-3-((S)-4-isopropyl-2-oxazolidone-3-carbonyl)
Hecanoic acid t-butyl ester (compound 6c, yield 70%, d.e 97.1%).
Embodiment 11
Synthesis (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a)
180 grams (R)-3 ((S)-4-isopropyl-2-oxazolidone-3-carbonyl) hecanoic acid t-butyl ester (compound 6c) is dissolved in
In the mixed solvent of 1.8L methanol and 0.6 liter of water, stirring, ice-water bath cools down.Dropping hydrogen peroxide (280 grams, 30%), temperature in keeping
5-10℃.Add the Lithium hydrate (46 grams) of 2 equivalents.Room temperature (about 30 DEG C) stirs 48 hours.Add water dilution, under ice bath
Dropping sodium sulfite solution cancellation, controls temperature 5-10 DEG C.Reactant liquor ethyl acetate processes.Add 400 grams of citric acid water transfer
Layer is to pH=3, then is extracted with ethyl acetate.Organic layer merges, and is dried, and filters, is evaporated to do, obtains 110.6 grams of oilies
Thing (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a, yield 93%).
Embodiment 12
Synthesis (R)-4-propyl group dihydrofuran-2 (3H)-one (compound 8a)
100 grams of (R)-2-(2-(tert-butoxy)-2-oxoethyl) valeric acid (compound 7a) are dissolved in 1L oxolane, ice
Add triethylamine (56.2 grams, 1.2 equivalents) under bath, then drip isobutyl chlorocarbonate (69.5 grams, 1.1 equivalents), keep temperature
Less than 10 DEG C.Dripping complete, 20 DEG C are stirred 1 hour, filter.Filtrate is cooled to-30 DEG C, be slowly added to sodium borohydride (19 grams,
1.1 equivalents).Temperature rises to-10 DEG C and reacts 1 hour.The hydrochloric acid of dropping 300mL 18%.Drip complete continuation 50 DEG C stirring 16 little
Time.Reactant liquor adds 500mL saturated sodium-chloride, extracts (500mL × 3) with methyl tertiary butyl ether(MTBE).Being dried, concentrate, residue subtracts
Pressure distillation obtains 30.2 grams of colourless liquid (R)-4-propyl group dihydrofuran-2 (3H)-one, and (compound 8a, receives by 110 DEG C/18mmHg
Rate 51%).
The above is only the preferred embodiment of the present invention, is not limited to the present invention, it is noted that for this skill
For the those of ordinary skill in art field, on the premise of without departing from the technology of the present invention principle, it is also possible to make some improvement and
Modification, these improve and modification also should be regarded as protection scope of the present invention.
Claims (10)
1. the preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one, it is characterised in that comprise the following steps:
A () drips acyl chlorides (3) in the organic solvent solution of compound (1), obtain acyl chlorides in reaction in the presence of a base
The solution of intermediate, is added drop-wise in the solution of described acid chloride intermediate react by the organic solvent solution of compound (2),
To compound (4)；
B (), under inert gas shielding, drips two (trimethyl is silica-based) amino bases gold in the organic solvent solution of compound (4)
Belong to saline solution to react, reacted dropping compound (5) in backward gained reactant liquor and reacted, obtained compound (6)；
C () in organic solvent, compound (6) and alkali reaction obtain compound (7)；
D () in organic solvent, compound (7) and reducing agent generation reduction reaction obtain compound (8)；
Reaction scheme is as follows:
Wherein:
R is selected from aryl, arylmethyl or alkyl；
R1、R2、R3Independently selected from alkyl；
X is selected from Cl, Br or I.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
Described R is phenyl, benzyl or isopropyl.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
Described R1For C1-C4Alkyl, R2For the tert-butyl group, R3For the tert-butyl group.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (a), described alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine and diisopropyl
One or more in ethamine, described organic solvent selected from oxolane, 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether(MTBE),
One or more in dichloromethane.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (a), the organic solvent solution of compound (2) is added drop-wise in the solution of described acid chloride intermediate at 10～40 DEG C anti-
Should, obtain compound (4).
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (b), described two (trimethyl is silica-based) alkali amide salt is two (trimethyl is silica-based) Sodamide .s or two (trimethyl silicanes
Base) potassamide.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (b), described organic solvent one in oxolane, 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether(MTBE)
Or it is several.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (c), reacting and carry out under conditions of stirring, the temperature of reaction is 20～50 DEG C.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (c), one or more in Lithium hydrate, sodium hydroxide, potassium hydroxide of described alkali, described organic solvent selects
One or more in oxolane, 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether(MTBE), methanol, ethanol.
The preparation method of chirality 4-substituent group dihydrofuran-2 (3H)-one the most according to claim 1, it is characterised in that:
In step (d), described reducing agent is borane dimethylsulf iotade or sodium borohydride.
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