CN109535107A - One kind (R) -4- propyl-dihydrofuran -2- ketone preparation method - Google Patents
One kind (R) -4- propyl-dihydrofuran -2- ketone preparation method Download PDFInfo
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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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
(R) -4- propyl-dihydrofuran -2- ketone method, key intermediate formula B compound, formula C compound and preparation method thereof are prepared the invention discloses a kind of；(R) -4- propyl-dihydrofuran -2- ketone preparation method process operability is strong, is suitble to industrialized production.
Description
Technical field
The invention belongs to chemicals synthesis technical fields, are related to the preparation of one kind (R) -4- propyl-dihydrofuran -2- ketone
Method
Background technique
(R) -4- propyl-dihydrofuran -2- ketone is in synthesizing new anti-epileptic stype Wa Xitan (Brivaracetam)
Key intermediate.Currently, having there is the synthetic method of the more document report compound.Synthetic method is seen earliest,
Journal of American Chemical Society, 1985,107,4088-4090.Using the allyl of no market supply
Base is starting material, with high costs, no industrial value to toluenesulfinic acid ester；After this, there is document report synthesis successively
Method (such as: Journal of American Chemical Society, 2003,125,11253-11258), cost is high
It is high, no industrial value.
Patent CN106008411A, it was recently reported that the method for relative inexpensiveness.Synthetic route is as follows:
Patent description after obtaining intermediate 6, obtains intermediate 7 through hydrolysis, then through borane dimethylsulf iotade or boron hydrogen
Change sodium reduction, obtains target product (R) -4- propyl-dihydrofuran -2- ketone.Our company is when reappearing the method for the patent, discovery
Reduction step generates bulk gas, limits further industry amplification.And two step yield of reductive hydrolysis is relatively low, cost is relatively
It is high.
Therefore, a kind of low in cost, strong operability and industrialized production is suitble to prepare (R) -4- propyl-dihydrofuran -
The preparation method of 2- ketone is at current problem in the urgent need to address.
Summary of the invention
The present invention overcomes the defects of the prior art, provide the preparation method of Bu Waxitan intermediate formula D compound, at
This cheap, strong operability, it is few to generate exhaust gas in production process, is suitble to industrialized production, and formula D compound light purity
It is high.
The present invention provides one kind (R) -4- propyl-dihydrofuran -2- ketone preparation method, comprises the following steps:
Formula C compound is added sour water and is quenched, obtain formula D compound after reduction reaction,
Preferably, the reduction reaction are as follows: formula C compound is dissolved in organic solvent 1, under stirring, reducing agent, drop is added
Alcohols solvent is added, carries out reduction reaction.
It is highly preferred that
The organic solvent 1 is selected from tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane, acetonitrile and N, N- diformazan
One of base formamide is several；
And/or the reducing agent is selected from one of sodium borohydride, potassium borohydride and lithium borohydride or several；
And/or the alcohols solvent is selected from one of methanol, ethyl alcohol, isopropanol, n-butanol and tert-butyl alcohol or several
Kind；
And/or the adding manner is to be added dropwise；
And/or temperature is -70~-10 DEG C, preferably -25~-10 DEG C when the addition alcohols solvent；
And/or after the addition alcohols solvent, the temperature of reaction is 10~40 DEG C, preferably 20~30 DEG C；
And/or the sour water is quenched, acid used is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, perchloric acid
Or it is several；
And/or specific steps are as follows: formula C compound is dissolved in organic solvent 1, is stirred, addition reducing agent, -25~-10
Alcohols solvent is added dropwise at DEG C, is added dropwise, reacts 1h~5h；Then it is warming up to 10~40 DEG C again, reacts 5~15h, sour water is added
It is quenched, obtains formula D compound；
It and/or further include purification step；
And/or, further includes: resulting formula D compound is beaten with solvent, is filtered, filtrate is concentrated to dryness, for mashing
Solvent is preferably one of normal heptane, n-hexane, methyl tertiary butyl ether(MTBE) and ether or several.
Preferably, the reduction reaction are as follows: formula C compound is dissolved in alcohols solvent, reduction is added portionwise under stirring
Agent, carry out reduction reaction.
It is highly preferred that
And/or reducing agent adding manner is to be added portionwise；
And/or temperature is -70~-10 DEG C, preferably -25~-10 DEG C when reducing agent addition；
And/or the alcohols solvent is selected from one of methanol, ethyl alcohol, isopropanol, n-butanol and tert-butyl alcohol or several
Kind；
And/or after the addition alcohols solvent, the temperature of reaction is 10~40 DEG C, preferably 20~30 DEG C；
And/or the sour water is quenched, acid used is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, perchloric acid
Or it is several；
And/or specific steps are as follows: formula C compound is dissolved in alcohols solvent, is added portionwise also under -25~-10 DEG C of stirrings
1h~5h is reacted in former agent；Then it is warming up to 10~40 DEG C again, reacts 5~15h, sour water is added and is quenched, obtains formula D compound；
It and/or further include purification step；
And/or, further includes: resulting formula D compound is beaten with solvent, is filtered, filtrate is concentrated to dryness, for mashing
Solvent is preferably one of normal heptane, n-hexane, methyl tertiary butyl ether(MTBE) and ether or several.
The present invention provides formula C compound
The present invention also provides a kind of preparation methods of formula C compound, comprise the following steps:
Under inert gas shielding, the tetrahydrofuran solution that will contain two (trimethyl silicon substrate) alkali amide salt is added containing centre
In 2 solution of organic solvent of body B, stirring adds bromo-acetic acid tert-butyl, and reaction obtains formula C compound.
Preferably, the organic solvent 2 is selected from methyl tertiary butyl ether(MTBE), toluene, methylene chloride, tetrahydrofuran, 2- methyl
One or more of tetrahydrofuran and ether；The more preferably one or two of tetrahydrofuran, 2- methyltetrahydrofuran.
Preferably, two (trimethyl silicon substrate) the alkali amide salt is two (trimethyl silicon substrate) amino bases sodium, two (front threes
Base silicon substrate) one of alkali amide potassium or several；
Preferably, the reaction temperature is -70~-30 DEG C, preferably -40~-30 DEG C；
Preferably, the mixing time is 0.5~5h, preferably 1.5~3h；
Preferably, the adding manner is to be added dropwise；It is highly preferred that be added dropwise two (trimethyl silicon substrate) amino bases sodium salts or
When the solution of sylvite, reaction temperature is -70 DEG C~-30 DEG C, is added dropwise, and stir 0.5h-5.0h within this temperature range.
Preferably, further comprise post-processing step.
Preferably, further comprise re-crystallization step, the solvent that the recrystallization uses is selected from methyl tertiary butyl ether(MTBE), second
One of ether, normal heptane, n-hexane and ethyl acetate or several solvents；More preferably methyl tertiary butyl ether(MTBE) and normal heptane
Mixed solvent is preferably in a proportion of 1:1~1:10.
The present invention also provides formula B compounds
The present invention also provides the preparation methods of formula B compound, comprise the following steps:
(1) positive valeric acid, organic base are dissolved in organic solvent 3, pivaloyl chloride is added, is stirred to react；
(2) formula A compound is dissolved in organic solvent 3, is added into reaction solution obtained by step (1), in the work of lithium salts
Formula B compound is obtained with lower reaction.
Preferably, the organic solvent 3 is selected from methyl tertiary butyl ether(MTBE), toluene, methylene chloride, tetrahydrofuran, 2- methyl
One or more of tetrahydrofuran and ether；
Preferably, the organic base is selected from one of triethylamine, pyridine, diisopropylethylamine or several；
Preferably, step (1) reaction temperature is -70~20 DEG C, preferably -20~-5 DEG C；
Preferably, step (2) reaction temperature is -70~20 DEG C, preferably -20~-5 DEG C；
Preferably, the step (1) and/or (2) adding manner are to be added dropwise；It is highly preferred that the step (1) and step
It (2) is to be added dropwise, and temperature is -20~-5 DEG C when step (1) dropwise addition, it is 2~5h that the rear reaction time, which is added dropwise,.
Preferably, in step (2), lithium salts can be one of lithium bromide and lithium chloride or several.
The present invention also provides one kind (R) -4- propyl-dihydrofuran -2- ketone preparation methods, using following reactional equation
Formula:
Preferably, as described above by formula B preparation of compounds of formula C compound reaction condition.
Preferably, as described above by formula C preparation of compounds of formula D compound reaction condition.
The present invention also provides one kind (R) -4- propyl-dihydrofuran -2- ketone preparation methods, using following reactional equation
Formula:
Preferably, as described above by formula A preparation of compounds of formula B compound reaction condition.
Preferably, as described above by formula B preparation of compounds of formula C compound reaction condition.
Preferably, as described above by formula C preparation of compounds of formula D compound reaction condition.
The present invention also provides formula A compound, formula B compound, formula C compounds to prepare the purposes in Bu Waxitan.
Advantageous effects of the invention:
1, the present invention provides the novel intermediate formula B compound of Bu Waxitan and formula C compounds.
2, the preparation method of Bu Waxitan intermediate formula C compound provided by the invention, formula C compound is through further tying again
After crystalline substance, optical purity height (usual > 99.0%).
3, the preparation method of Bu Waxitan intermediate formula D compound provided by the invention is restored by mono- step of compound C and is made
It is standby, the bulk gas generated during reduction reaction under prior art reaction condition is overcome, and improve the receipts of formula D compound
Rate.
4, the preparation method of Bu Waxitan intermediate formula D compound provided by the invention, with current open preparation method phase
3 step only than, reaction step, formula A compound elder generation preparation formula B compound preparation formula D compound again, the process costs are cheap, operation
Property it is strong, can steadily obtain the high formula D compound of optical purity.
Further, after to the mashing of formula D crude compound, filtering, filter cake purity is 97%-99%, can be recycled in high yield anti-
Answer object A；The formula A compound of recycling, which can directly be used to change again in technique, carrys out preparation formula D compound as raw material.
Specific embodiment
Sub combined with specific embodiments below, the present invention is further elaborated.Operating parameter in embodiment is only to make
It is not whole limitation ranges of the invention to illustrate；Raw material employed in following embodiment is market without specified otherwise
On the raw material that can arbitrarily purchase.
The preparation of Examples 1 to 5 formula B compound
Embodiment 1
Into the reaction kettle of 30L, the positive valeric acid of 428.31g and 6.0L tetrahydrofuran is added, under stirring, 951.23g tri- is added
Ethamine under nitrogen protection, is cooled to -15 DEG C, 510.77g pivaloyl chloride is added dropwise, is added dropwise, in -20 DEG C of reaction 1.0h, addition
After keeping the temperature 10min, the tetrahydrofuran solution (2.4L tetrahydrofuran) of the reactant A containing 600.0g, control is added dropwise in 187.21g lithium chloride
- 20 DEG C of temperature；It is added dropwise, after reacting 4.0h, is warming up to 20 DEG C, stirs 12.0h, after reaction, 10% carbonic acid of 6.0L is added
The aqueous solution of potassium after stirring 10.0min, is concentrated under reduced pressure and removes tetrahydrofuran, adds the extraction of 6L methyl tertiary butyl ether(MTBE)；Water phase is again
It is primary with the extraction of 4.8L methyl tertiary butyl ether(MTBE), finally merge organic layer, organic layer uses the hydrochloric acid and 3.0L carbon of 3.0L 1M respectively again
Sour hydrogen sodium water solution washed once, and finally concentration removes solvent and obtains 849.46g, yield 96.0%, purity 96.77%；Nuclear-magnetism
Data are as follows: 1.23-1.26 (t, 3H), 1.38-1.42 (m, 6H), 2.74-2.80 (m, 1H), 3.19-3.23 (m, 1H),
4.12-4.21 (m, 2H), 4.66-4.72 (m, 1H), 7.20-7.34 (m, 5H) ESI+, [M+H]+: 262.3, [M+Na]+: 284.1
Embodiment 2
Into the reaction kettle of 30L, the positive valeric acid of 428.31g and 6.0L 2- methyltetrahydrofuran is added, under stirring, is added
743.54g pyridine under nitrogen protection, is cooled to -15 DEG C, 510.77g pivaloyl chloride is added dropwise, is added dropwise, reacts in -5 DEG C
187.21g lithium chloride is added in 1.0h, and after keeping the temperature 10min, the 2- methyltetrahydrofuran solution of the reactant A containing 600.0g is added dropwise
(2.4L2- methyltetrahydrofuran), -5 DEG C of temperature control；It is added dropwise, after reacting 2.0h, is warming up to 20 DEG C, stir 12.0h, reaction knot
The aqueous solution of 10% potassium carbonate of 6.0L is added in Shu Hou, after stirring 10.0min, is concentrated under reduced pressure and removes 2- methyltetrahydrofuran, then
The extraction of 6L methyl tertiary butyl ether(MTBE) is added；Water phase uses the extraction of 4.8L methyl tertiary butyl ether(MTBE) primary again, finally merges organic layer, organic layer
It washed once respectively with the hydrochloric acid of 3.0L 1M and 3.0L sodium bicarbonate aqueous solution again, finally concentration removes solvent and obtains
852.09g, yield 96.30%, purity 97.20%；Nuclear magnetic data is the same as embodiment 1.
Embodiment 3
Into the reaction kettle of 30L, the positive valeric acid of 428.31g and 6.0L ether is added, under stirring, 1214.85g diisopropyl is added
Base ethamine under nitrogen protection, is cooled to -20 DEG C, 510.77g pivaloyl chloride is added dropwise, is added dropwise, in 10 DEG C of reaction 1.0h, adds
Enter 187.21g lithium bromide, after keeping the temperature 10min, the diethyl ether solution (2.4L ether) of the reactant A containing 600.0g, temperature control -20 is added dropwise
℃；It is added dropwise, after reacting 3.0h, is warming up to 20 DEG C, stirs 12.0h, after reaction, 10% potassium carbonate of 6.0L is added
Aqueous solution after stirring 10.0min, is concentrated under reduced pressure and removes ether, adds the extraction of 6L methyl tertiary butyl ether(MTBE)；Water phase uses 4.8L first again
The extraction of base tertbutyl ether is primary, finally merges organic layer, and organic layer uses the hydrochloric acid and 3.0L sodium bicarbonate water of 3.0L 1M respectively again
Solution washed once, and finally concentration removes solvent and obtains 862.08g, yield 97.43%, purity 97.85%.Nuclear magnetic data is the same as real
Apply example 1.
Embodiment 4
Into the reaction kettle of 30L, the positive valeric acid of 428.31g and 6.0L toluene is added, under stirring, 475.61g triethylamine is added
With 371.77g pyridine, under nitrogen protection, -10 DEG C are cooled to, 510.77g pivaloyl chloride is added dropwise, is added dropwise, is reacted in -30 DEG C
187.21g lithium bromide is added in 1.0h, and after keeping the temperature 10min, the toluene solution (2.4L toluene) of the reactant A containing 600.0g, control is added dropwise
- 70 DEG C of temperature；It is added dropwise, after reacting 5.0h, is warming up to 20 DEG C, stirs 12.0h, after reaction, 10% carbonic acid of 6.0L is added
The aqueous solution of potassium after stirring 10.0min, is concentrated under reduced pressure and removes toluene, adds the extraction of 6L methyl tertiary butyl ether(MTBE)；Water phase is used again
The extraction of 4.8L methyl tertiary butyl ether(MTBE) is primary, finally merges organic layer, and organic layer uses the hydrochloric acid and 3.0L carbonic acid of 3.0L 1M respectively again
Hydrogen sodium water solution washed once, and finally concentration removes solvent and obtains 865.81g, yield 97.85%, purity 98.13%.Nuclear-magnetism number
According to same embodiment 1.
Embodiment 5
Into the reaction kettle of 30L, the positive valeric acid of 428.31g and 6.0L tetrahydrofuran is added, under stirring, 951.23g tri- is added
Ethamine under nitrogen protection, is cooled to -15 DEG C, 510.77g pivaloyl chloride is added dropwise, is added dropwise, in -20 DEG C of reaction 1.0h, addition
After keeping the temperature 10min, the tetrahydrofuran solution (2.4L tetrahydrofuran) of the reactant A containing 600.0g, control is added dropwise in 187.21g lithium chloride
- 20 DEG C of temperature；It is added dropwise, after reacting 4.0h, is warming up to 20 DEG C, stirs 12.0h, after reaction, post-processing obtains
868.19g, yield 98.12%, purity 98.74%.Nuclear magnetic data is the same as embodiment 1.
Implement the preparation of 6~10 formula C compounds
Embodiment 6
It weighs 1 gained 222.2.0g B of embodiment to be added in the reaction flask of 5L, and 1.60L tetrahydrofuran, nitrogen is added
It is cooled to -40 DEG C under protection, the tetrahydrofuran solution of two (trimethyl silicon substrate) amino bases sodium salts that 920ml concentration is 1M is added dropwise,
It -40 DEG C of temperature control, is added dropwise, after keeping the temperature 1.0h.- 50 DEG C are cooled to, 196.51g 2- bromo-acetic acid tert-butyl, temperature control -40 is added dropwise
℃；Drop finishes, and after stirring 1.5h, is warming up to 15 DEG C, reacts sample detection after 2h, end of reaction.The ammonium chloride of 1.0L 15% is added dropwise
Aqueous solution quenching reaction stands after stirring 30.0min, separates organic layer；Organic layer washs one with 20% sodium chloride solution again
It is secondary.Concentration of organic layers obtains 383.00g yellow solid to doing.With the mixing of 250ml methyl tertiary butyl ether(MTBE) and 2500ml normal heptane
Solvent recrystallization, drying obtain 259.15g white solid formula C compound, yield 81.25%, purity 99.46%, chiral purity
100%；；Nuclear magnetic data is as follows: CDCl3, 400MHz, 0.89-0.93 (t, 3H), 1.33-1.48 (m, 12H), 1.61-1.67
(m, 1H), 2.45-2.50 (dd, 1H), 2.71-2.84 (m, 2H), 3.33-3.37 (dd, 1H), 4.14-4.21 (m, 4H),
4.64-4.68 (m, 1H), 7.25-7.36 (m, 5H)；ESI+, [M+Na]+: 398.2.
Embodiment 7
It weighs 4 gained 222.2.0g B of embodiment to be added in the reaction flask of 5L, and 1.60L tetrahydrofuran, nitrogen is added
It is cooled to -30 DEG C under protection, the tetrahydrofuran solution of two (trimethyl silicon substrate) amino bases sodium salts that 920ml concentration is 1M is added dropwise,
It -30 DEG C of temperature control, is added dropwise, after keeping the temperature 1.0h.- 20 DEG C are cooled to, 196.51g 2- bromo-acetic acid tert-butyl, temperature control -30 is added dropwise
℃；Drop finishes, and after stirring 3h, is warming up to 10 DEG C, reacts sample detection after 2h, end of reaction.The ammonium chloride water of 1.0L 15% is added dropwise
Solution quenching reaction stands after stirring 30.0min, separates organic layer；Organic layer washed once with 20% sodium chloride solution again.
Concentration of organic layers obtains 391.03g yellow solid to doing.Mixing with 250ml methyl tertiary butyl ether(MTBE) and 2500ml normal heptane is molten
Agent recrystallization, drying obtain 262.03g white solid formula C compound, yield 82.15%, purity 99.59%, chiral purity
100%；Nuclear magnetic data is the same as embodiment 6.
Embodiment 8
It weighs 2 gained 222.2.0g B of embodiment to be added in the reaction flask of 5L, and 1.60L tetrahydrofuran, nitrogen is added
It is cooled to -30 DEG C under protection, the tetrahydrofuran solution of two (trimethyl silicon substrate) amino bases sodium salts that 920ml concentration is 1M is added dropwise,
It -70 DEG C of temperature control, is added dropwise, after keeping the temperature 1.0h.- 40 DEG C are cooled to, 196.51g 2- bromo-acetic acid tert-butyl, temperature control -20 is added dropwise
℃；Drop finishes, and after stirring 5h, is warming up to 5 DEG C, reacts sample detection after 2h, end of reaction.The ammonium chloride water of 1.0L 15% is added dropwise
Solution quenching reaction stands after stirring 30.0min, separates organic layer；Organic layer washed once with 20% sodium chloride solution again.
Concentration of organic layers obtains 380.05g yellow solid to doing.With the mixed solvent weight of 250ml ethyl acetate and 2500ml normal heptane
Crystallization, drying obtain 255.58g white solid formula C compound, yield 80.13%, purity 99.37%, chiral purity
99.98%；Nuclear magnetic data is the same as embodiment 6.
Embodiment 9
It weighs 3 gained 222.2.0g B of embodiment to be added in the reaction flask of 5L, and 1.60L tetrahydrofuran, nitrogen is added
It is cooled to -45 DEG C under protection, the tetrahydrofuran solution of two (trimethyl silicon substrate) amino bases sodium salts that 920ml concentration is 1M is added dropwise,
It -35 DEG C of temperature control, is added dropwise, after keeping the temperature 1.0h.- 30 DEG C are cooled to, 196.51g 2- bromo-acetic acid tert-butyl is added dropwise, controls -50 DEG C；
Drop finishes, and after stirring 0.5h, is warming up to 15 DEG C, reacts sample detection after 2h, end of reaction.The ammonium chloride water of 1.0L 15% is added dropwise
Solution quenching reaction stands after stirring 30.0min, separates organic layer；Organic layer washed once with 20% sodium chloride solution again.
Concentration of organic layers obtains 378.95.g yellow solid to doing.Mixing with 250ml methyl tertiary butyl ether(MTBE) and 2500ml normal heptane is molten
Agent recrystallization, drying obtain 254.69g white solid formula C compound, yield 79.85%, purity 99.57%, chiral purity
99.99%；Nuclear magnetic data is the same as embodiment 6.
Embodiment 10
It weighs 5 gained 222.2.0g B of embodiment to be added in the reaction flask of 5L, and 1.60L tetrahydrofuran, nitrogen is added
It is cooled to -40 DEG C under protection, the tetrahydrofuran solution of two (trimethyl silicon substrate) amino bases sodium salts that 920ml concentration is 1M is added dropwise,
It -40 DEG C of temperature control, is added dropwise, after keeping the temperature 1.0h.- 50 DEG C are cooled to, 196.51g 2- bromo-acetic acid tert-butyl, temperature control -40 is added dropwise
℃；Drop finishes, and after stirring 1.5h, is warming up to 15 DEG C, reacts sample detection after 2h, and the ammonium chloride of 1.0L 15% is added dropwise in end of reaction
Aqueous solution quenching reaction post-processes and is refining to obtain 252.29g white solid formula C compound, yield 79.10%, purity
99.89%, chiral purity 100%；Nuclear magnetic data is the same as embodiment 6.
The preparation of embodiment 11~18 (R) -4- propyl-dihydrofuran -2- ketone (formula D compound)
Embodiment 11
6 gained compound C and 1100ml tetrahydrofuran of 111.00g embodiment is added in the there-necked flask of 2L, is stirred, control
- 25 DEG C~-10 DEG C of temperature, is added portionwise 34.02g sodium borohydride solids, finishes, and -25 DEG C~-10 DEG C of temperature control, 220ml first is added dropwise
Alcohol.It is added dropwise, keeps the temperature 2h, then warm naturally to room temperature, react 5h, end of reaction is cooled to 0 DEG C, 500ml is slowly added dropwise
6M hydrochloric acid, is added dropwise, and stirs 6h at room temperature, and 500ml toluene is added, stands liquid separation after stirring；Water layer is separated, water layer is used again
The extraction of 500ml toluene is primary；Merge organic layer, successively with 500ml water, the sodium bicarbonate aqueous solution time and 500ml of 500ml 5%
Saturated salt solution washed once, and last anhydrous sodium sulfate dries, filters, concentrate filtrate to it is dry, be added 1000ml positive heptan
Alkane after stirring 2h at room temperature, then is cooled to 0 DEG C, filters after stirring 2h, and filter cake dries to obtain 49.30g white solid, for recycling
Obtained A, the rate of recovery 95.0%, purity 98.7%；It concentrates the filtrate to dry, obtains 33.22g weak yellow liquid, as (R)-
4- propyl-dihydrofuran -2- ketone, yield 88.47%, chemical purity 99.96%；Content of isomer 0.18%；Specific rotation :+
6.70 (1g/100ml, ethyl alcohol, 20 DEG C)；Nuclear magnetic data is as follows: CDCl3,400MHz, 0.92-0.94 (m, 3H), 1.28-1.30
(m, 2H), 1.32-1.34 (m, 2H), 2.01-2.14 (m, 1H), 2.13-2.63 (m, 2H), 3.80-3.84 (dd, 1H), 4.39-
4.44 (dd, 1H)；ESI+, [M+H]+:129.2。
Embodiment 12
7 gained compound C and 1100ml2- methyltetrahydrofuran of 111.00g embodiment is added in the there-necked flask of 2L,
Stirring, is added portionwise 48.50g potassium borohydride solid, finishes by -25 DEG C~-10 DEG C of temperature control, -25 DEG C~-10 DEG C of temperature control, is added dropwise
220ml ethyl alcohol.It is added dropwise, keeps the temperature 5h, then warm naturally to 10 DEG C, react 6h, end of reaction is cooled to 0 DEG C, is slowly added dropwise
500ml 2M sulfuric acid, is added dropwise, and stirs 6h at room temperature, and 500ml toluene is added, stands liquid separation after stirring；Water layer is separated, it is organic
Layer is primary with the extraction of 500ml toluene again；Merge organic layer, is successively washed with the sodium bicarbonate aqueous solution of 500ml water, 500ml5%
Primary and 500ml saturated salt solution washed once, and last anhydrous sodium sulfate dries, filters, and concentrate filtrate to dry, addition
1000ml n-hexane after stirring 1h at room temperature, then is cooled to 0 DEG C, filters after stirring 1.5h, and filter cake dries to obtain 49.22g white
Solid, to recycle obtained A, the rate of recovery 94.82%, purity 99.47%；It concentrates the filtrate to dry, it is faint yellow to obtain 32.22g
Liquid, as (R) -4- propyl-dihydrofuran -2- ketone, yield 85.83%, chemical purity 100.00%；Content of isomer
0.08%；Specific rotation :+7.20 (1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Embodiment 13
By 111.00g embodiment 8 gained compound C and 1100mlN, dinethylformamide is added to the there-necked flask of 2L
In, stirring, is added portionwise 19.60g lithium borohydride solid, finishes by -30 DEG C~-10 DEG C of temperature control, and -30 DEG C~-10 DEG C of temperature control, drop
Add 220ml n-butanol.It is added dropwise, keeps the temperature 3h, then warm naturally to 30 DEG C, react 8h, end of reaction is cooled to 0 DEG C, slowly
100ml trifluoroacetic acid is added dropwise, is added dropwise, stirs 6h at room temperature, 500ml toluene is added, stands liquid separation after stirring；Separate water
Layer, organic layer use the extraction of 500ml toluene primary again；Merge organic layer, successively with 500ml water, the sodium bicarbonate water of 500ml5%
Solution washed once washed once with 500ml saturated salt solution, and last anhydrous sodium sulfate dries, filters, and filtrate decompression is concentrated
To dry, addition 1000ml n-hexane, at room temperature after stirring 1h, then it is cooled to 0 DEG C, is filtered after stirring 1.5h, filter cake dries to obtain
49.23g white solid, to recycle obtained A, the rate of recovery 94.80%, purity 99.48%；It concentrates the filtrate to dry, obtains
32.23 weak yellow liquids, as (R) -4- propyl-dihydrofuran -2- ketone, yield 85.84%, chemical purity 100.00%；It is different
Structure body content 0.09%；Specific rotation :+7.10 (1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Embodiment 14
By 111.00g embodiment 9 gained compound C and 1100ml1,4- dioxane is added in the there-necked flask of 2L, stirs
It mixes, temperature control -25~-10 DEG C, 17.01g sodium borohydride 9.80g lithium borohydride solid is added portionwise, finishes, temperature control -25 DEG C~-10
DEG C, 220ml isopropanol is added.It is added dropwise, keeps the temperature 4h, then warm naturally to 40 DEG C, react 15h, end of reaction is cooled to 0
DEG C, 100ml perchloric acid is slowly added dropwise, is added dropwise, stirs 6h at room temperature, 500ml toluene is added, stands liquid separation after stirring；Point
Water-yielding stratum, organic layer use the extraction of 500ml toluene primary again；Merge organic layer, successively with 500ml water, the bicarbonate of 500ml5%
Sodium water solution washed once washed once with 500ml saturated salt solution, and last anhydrous sodium sulfate dries, filters, by filtrate decompression
It is concentrated to dryness, 1000ml normal heptane is added, after stirring 3h at room temperature, then be cooled to 0 DEG C, filtered after stirring 1h, filter cake is dried
To 49.05g white solid, to recycle obtained A, the rate of recovery 94.50%, purity 98.93%；It concentrates the filtrate to dry, obtains
31.65g weak yellow liquid, as (R) -4- propyl-dihydrofuran -2- ketone preparation, yield 84.29%, chemical purity
98.33%；Content of isomer 0.16%；Specific rotation :+6.80 (1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Embodiment 15
6 gained compound C and 1100ml methanol of 111.00g embodiment is added in the there-necked flask of 2L, -25 DEG C of temperature control
~-10 DEG C, under stirrings, 34.10g sodium borohydride solids are added portionwise, finish, -25 DEG C~-10 DEG C of temperature control, finish, keeps the temperature 1h,
20 DEG C are warmed naturally to again, reacts 15h, and end of reaction is cooled to 0 DEG C, 100ml trifluoroacetic acid is slowly added dropwise, is added dropwise, room
6h is stirred under temperature, it is post-treated, obtain 33.51g (R) -4- propyl-dihydrofuran -2- ketone, yield 89.25%, chemical purity
98.88%；Content of isomer 0.13%；Specific rotation+7.10:(1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Embodiment 16
8 gained compound C and 1100ml ethyl alcohol of 111.00g embodiment is added in the there-necked flask of 2L, -20 DEG C of temperature control
~-10 DEG C, under stirring, 48.50g potassium borohydride solid is added portionwise, finishes, -20 DEG C~-10 DEG C of temperature control, finish, keeps the temperature 2h,
10 DEG C are warmed naturally to again, reacts 10h, and end of reaction is cooled to 0 DEG C, 100ml trifluoroacetic acid is slowly added dropwise, is added dropwise, room
6h is stirred under temperature, it is post-treated, obtain 31.20g (R) -4- propyl-dihydrofuran -2- ketone, yield 83.12%, chemical purity
99.12%；Content of isomer 0.13%；Specific rotation+6.95:(1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Embodiment 17
9 gained compound C and 1100ml isopropanol of 111.00g embodiment is added in the there-necked flask of 2L, -70 DEG C of temperature control
~-40 DEG C, under stirring, 48.50g potassium borohydride solid is added portionwise, finishes, -70 DEG C~-40 DEG C of temperature control, finish, keeps the temperature 4h,
30 DEG C are warmed naturally to again, reacts 10h, and end of reaction is cooled to 0 DEG C, 100ml trifluoroacetic acid is slowly added dropwise, is added dropwise, room
6h is stirred under temperature, it is post-treated, obtain 32.06g (R) -4- propyl-dihydrofuran -2- ketone, yield 85.39%, chemical purity
98.97%；Content of isomer 0.09%；Specific rotation+7.00:(1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Embodiment 18
10 gained compound C and the 1100ml tert-butyl alcohol of 111.00g embodiment is added in the there-necked flask of 2L, temperature control -40
DEG C~-10 DEG C, under stirring, 19.60g lithium borohydride solid is added portionwise, finishes, -40 DEG C~-10 DEG C of temperature control, finish, keeps the temperature
5h, then 40 DEG C are warmed naturally to, 5h is reacted, end of reaction is cooled to 0 DEG C, 100ml trifluoroacetic acid is slowly added dropwise, is added dropwise,
6h is stirred at room temperature, it is post-treated, obtain 31.27g (R) -4- propyl-dihydrofuran -2- ketone, yield 83.29%, chemical purity
98.57%；Content of isomer 0.10%；Specific rotation+7.05:(1g/100ml, ethyl alcohol, 20 DEG C), nuclear magnetic data is the same as embodiment 11.
Claims (10)
1. one kind (R) -4- propyl-dihydrofuran -2- ketone preparation method, comprises the following steps:
Formula C compound after carrying out reduction, is added sour water and is quenched, obtain formula D compound.
2. preparation method according to claim 1, it is characterised in that: formula C compound is dissolved in organic solvent 1, is stirred
Under, reducing agent is added, is added dropwise to alcohols solvent, carries out reduction reaction.
3. preparation method according to claim 1, it is characterised in that: formula C compound is dissolved in alcohols solvent, under stirring
Reducing agent is added portionwise, carries out reduction reaction.
4. preparation method according to claim 2, it is characterised in that:
The organic solvent 1 is selected from tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane, acetonitrile and N, N- dimethyl methyl
One of amide is several；
And/or the reducing agent is selected from one of sodium borohydride, potassium borohydride and lithium borohydride or several；
And/or the alcohols solvent is selected from one of methanol, ethyl alcohol, isopropanol, n-butanol and tert-butyl alcohol or several；
And/or the adding manner is to be added dropwise；
And/or temperature is -70~-10 DEG C, preferably -25~-10 DEG C when the addition alcohols solvent；
And/or after the addition alcohols solvent, the temperature of reaction is 10~40 DEG C, preferably 20~30 DEG C；
And/or the sour water is quenched, acid used be selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, perchloric acid or
It is several；
And/or specific steps are as follows: formula C compound is dissolved in organic solvent 1, and reducing agent is added, is stirred, -25~-10 DEG C
Lower dropwise addition alcohols solvent, is added dropwise, and reacts 1h~5h；Then it is warming up to 10~40 DEG C again, reacts 5~15h, sour water is added and quenches
It goes out, obtains formula D compound；
It and/or further include purification step；
And/or, further includes: resulting formula D compound is beaten with solvent, is filtered, filtrate is concentrated to dryness, the solvent for mashing
Preferably one of normal heptane, n-hexane, methyl tertiary butyl ether(MTBE) and ether or several.
5. preparation method according to claim 3, it is characterised in that:
And/or reducing agent adding manner is to be added portionwise；
And/or temperature is -70~-10 DEG C, preferably -25~-10 DEG C when reducing agent addition；
And/or the alcohols solvent is selected from one of methanol, ethyl alcohol, isopropanol, n-butanol and tert-butyl alcohol or several；
And/or after the addition alcohols solvent, the temperature of reaction is 10~40 DEG C, preferably 20~30 DEG C；
And/or the sour water is quenched, acid used be selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, perchloric acid or
It is several；
And/or specific steps are as follows: formula C compound is dissolved in alcohols solvent, reduction is added portionwise under -25~-10 DEG C of stirrings
1h~5h is reacted in agent；Then it is warming up to 10~40 DEG C again, reacts 5~15h, sour water is added and is quenched, obtains formula D compound；
It and/or further include purification step；
And/or, further includes: resulting formula D compound is beaten with solvent, is filtered, filtrate is concentrated to dryness, the solvent for mashing
Preferably one of normal heptane, n-hexane, methyl tertiary butyl ether(MTBE) and ether or several.
6. a kind of preparation method of formula C compound, comprises the following steps:
Under inert gas shielding, having containing intermediate B is added in the organic solvent 2 that will contain two (trimethyl silicon substrate) alkali amide salt
In solvent 2, stirring adds bromo-acetic acid tert-butyl, and reaction obtains formula C compound,
7. preparation method according to claim 6, it is characterised in that:
The organic solvent 2 is selected from methyl tertiary butyl ether(MTBE), toluene, methylene chloride, tetrahydrofuran, 2- methyltetrahydrofuran and second
One or more of ether；
And/or two (trimethyl silicon substrate) the alkali amide salt is two (trimethyl silicon substrate) amino bases sodium, two (trimethyl silicanes
Base) one of alkali amide potassium or several；
And/or the reaction temperature is -70~-30 DEG C, preferably -40~-30 DEG C；
And/or the mixing time is 0.5~5h, preferably 1.5~3h；
And/or the adding manner is to be added dropwise；
And/or further comprising re-crystallization step, the solvent that the recrystallization uses is selected from methyl tertiary butyl ether(MTBE), ether, just
One of heptane, n-hexane and ethyl acetate or several solvents.
8. the preparation method of formula B compound, comprises the following steps:
(1) positive valeric acid, organic base are dissolved in organic solvent 3, pivaloyl chloride is added, is stirred to react；
(2) formula A compound is dissolved in organic solvent 3, is added into reaction solution obtained by step (1), under the action of lithium salts
Reaction obtains formula B compound；
9. preparation method according to claim 8, it is characterised in that:
The organic solvent 3 is selected from methyl tertiary butyl ether(MTBE), toluene, methylene chloride, tetrahydrofuran, 2- methyltetrahydrofuran and second
One or more of ether；
And/or the organic base is selected from one of triethylamine, pyridine, diisopropylethylamine or several；
And/or step (1) reaction temperature is -70~20 DEG C, preferably -20~-5 DEG C；
And/or step (2) reaction temperature is -70~20 DEG C, preferably -20~-5 DEG C；
And/or step (2) adding manner is to be added dropwise；
And/or the lithium salts is halogenated lithium, preferably one of lithium bromide and lithium chloride or several.
10. following compounds:
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| CN112062740A (en) * | 2020-09-24 | 2020-12-11 | 深圳市华先医药科技有限公司 | Synthesis method of (R) -4-propyl dihydrofuran-2-ketone |
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