CN105859519B - A kind of synthetic method of chiral vicinal diol and products thereof - Google Patents
A kind of synthetic method of chiral vicinal diol and products thereof Download PDFInfo
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- CN105859519B CN105859519B CN201610244323.4A CN201610244323A CN105859519B CN 105859519 B CN105859519 B CN 105859519B CN 201610244323 A CN201610244323 A CN 201610244323A CN 105859519 B CN105859519 B CN 105859519B
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- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
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Abstract
The present invention provides a kind of synthetic methods of chiral vicinal diol, include the following steps：(1) it will be added in reaction unit as the alkene of the precursor of the chiral vicinal diol and dichloromethane, and alkali be added；Then at a temperature of 50 DEG C to 15 DEG C, phase transfer catalyst is added, then potassium permanganate is added portionwise or sodium permanganate is reacted, obtains intermediate a；(2) intermediate a is added in reaction unit, is added with stirring ether and petroleum ether, boric acid is then added portionwise；The aqueous solution that potassium hydroxide is added dropwise is reacted, and intermediate b is obtained；(3) the intermediate b is added in reaction unit, adds ether and water, then under ice bath cooling condition, hydrofluoric acid is added dropwise, low temperature is stirred overnight, and the chiral vicinal diol is made.Present invention uses cheap, toxicity, as reaction reagent, the industrialization for realizing chiral vicinal diol class compound is synthetically produced for low and small environmental pollution potassium permanganate or sodium permanganate.
Description
Technical field
The present invention relates to a kind of methodology of organic synthesis more particularly to a kind of synthetic methods of chiral vicinal diol.
Background technology
Chiral (Chirality) is one of essential attribute of nature.Big point of biology as vital movement important foundation
Son, such as protein, polysaccharide, nucleic acid and enzyme are almost chiral entirely, these small molecules often have important physiology work(in vivo
Energy.Presently used drug is mostly less than 50 molecular organic molecules of original, wherein greatly also there is chirality, he
Pharmacological action realized by stringent chirality is matched with molecular recognition between internal macromolecular.Containing chiral centre
There are significant differences for pharmacological activity, metabolic process and toxicity of the enantiomer of chemicals in human body.Current chiral drug
Research have become one of the Main way of international new drug research.
Chiral pharmacy is the Disciplinary Frontiers of pharmaceuticals industry, and Nobel chemistry Prize in 2001 just authorizes the master of molecular chiral catalysis
Want contributor.There are many chipal compounds in nature, there are two enantiomters for these chipal compounds tool.Enantiomter
Like the right-hand man of people, they seem closely similar, but not exactly the same.When a chipal compounds enter life entity
When, its two enantiomters would generally show different bioactivity.For chiral drug, an isomers may be
Effectively, and another isomers may be invalid even harmful.Chiral pharmacy is exactly this principle using compound,
Develop that drug effect is high, drugs of Small side effects.In terms of clinical treatment, taking the chiral drug of enantiomer-pure can not only exclude
Toxic side effect caused by invalid (bad) enantiomer, moreover it is possible to it is negative to the metabolism of invalid enantiomer to reduce pharmaceutical quantities and human body
Load, has better control to pharmacokinetics and dosage, improves the specificity of drug.Thus with very vast market prospect
With huge economic value.The total number of drugs used in the world at present is about that 1900 kinds of chiral drugs account for 50% or more, in clinic
In common 200 kinds of drugs, up to 114 kinds of chiral drug.
In the synthesis of chiral drug, wherein common method is to be introduced directly into chiral source, pass through compound and chiral source
In conjunction with generating required chiral drug.And chiral diol class pharmaceutical intermediate is a kind of important chiral drug source.It is chiral adjacent
Glycol can be widely used for the synthesis of medical bulk pharmaceutical chemicals, pesticide and food additives etc. as important intermediate.Chiral vicinal diol
It is drug development and the important key intermediate of material science with light, heat and chemical stability.
Chiral vicinal diol class compound is to prepare the important intermediate of bulk pharmaceutical chemicals, such as (+) pinane diol be prepare it is antitumor
The key intermediate of drug bortezomib；(S)-(+) -1- vinylbenzenes -1,2- glycol and (S)-(+)-phenyl -1,2- ethylene glycol are
Indispensable important source material and chiral additives in liquid crystal, and become and prepare medicine, pesticide and work(with optical activation
The important intermediate of energy material.
The main method of synthesis of chiral vicinal diamines class pharmaceutical intermediate used by people was urged by osmium tetroxide in the past
Change olefine reaction to realize cis- glycol；However, osmium tetroxide has price very high, toxicity is very big, reaction condition
Very harsh disadvantage；If preparing a small amount of c/s-diol class medicine intermediate in laboratory, osmium tetroxide can be used on a small quantity,
If, can be because of the high toxicity of osmium tetroxide, expensive price and harshness but by this synthetic method for industrialized production
Working condition, and it is unfavorable for industrialized production；What this was advocated with China establish resource-conserving and environment-friendly society sound of laughing not
Enter.
In the prior art, usually first brominated olefins, then hydrolyze, then the method being combined with chemical resolution and biological resolution
Target product is made.However, the shortcomings that this method is that biological resolution is of high cost, and is not easy to mass produce, in addition using
Bromine, environmental pollution pressure are larger.
Therefore, inventor is quasi- is used as reaction examination by cheap, toxicity is low, environmental pollution is small potassium permanganate or sodium permanganate
Agent largely prepares chiral vicinal diol class medicine intermediate.
Invention content
For the above-mentioned technical problems in the prior art, the first aspect of the present invention provides a kind of chiral adjacent two
The synthetic method of alcohol, includes the following steps：
(1) it will be added in reaction unit, and be added strong as the alkene of the precursor of the chiral vicinal diol and dichloromethane
Alkali；Then at a temperature of -50 DEG C to -15 DEG C, phase transfer catalyst is added, then potassium permanganate or sodium permanganate is added portionwise
Aqueous solution is reacted, and until the reaction is complete, post-processing obtains intermediate a；
(2) the intermediate a is added in reaction unit, is added with stirring ether and petroleum ether, is then added portionwise
Boric acid；Then the aqueous solution for potassium hydroxide being added dropwise is reacted, and until the reaction is complete, post-processing obtains intermediate b；
(3) the intermediate b is added in reaction unit, adds ether and water, then under ice bath cooling condition,
Hydrofluoric acid is added dropwise, after being added dropwise, low temperature is stirred overnight；Ether is added into reaction solution, post-processes, the chiral neighbour two is made
Alcohol.
Preferably, the alkene is selected from following any：Left-handed firpene, dextrorotation firpene, 1- butylene, styrene, cyclohexene.
Preferably, the alkali is sodium hydroxide or potassium hydroxide.
Preferably, the hydrofluoric acid is the hydrofluoric acid that mass fraction is 40%.
Preferably, the phase transfer catalyst is selected from following any：Benzyltriethylammoinium chloride, tetrabutylammonium bromide,
Tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, myristyl three
Ammonio methacrylate.
Preferably, the post-processing described in the step (1) is：It is filtered to remove solid residue, then reaction solution is concentrated.
Preferably, the post-processing described in the step (2) is：Filtering removes solvent.
Preferably, the post-processing described in the step (3) is：Organic phase is extracted, multiple, merging is then extracted with ether
Organic phase；It is dried with anhydrous sodium sulfate, ether is evaporated off, recycling ether is applied mechanically.
The second aspect of the present invention provides a kind of chiral vicinal diol, which is characterized in that it is by above-mentioned synthetic method system
.
The synthetic method of chiral vicinal diol provided by the present invention, has used that cheap, toxicity is low and environmental pollution is small
Potassium permanganate or sodium permanganate as reaction reagent, the industrialization for realizing chiral vicinal diol class compound is synthetically produced.It should
Synthetic method is easy to operate, and raw material and each step reagent are cheap and easy to get, is a kind of environmental type synthetic method.
Specific implementation mode
The present invention is further elaborated With reference to embodiment, but the present invention is not limited to following embodiment party
Formula.
The first aspect of the present invention provides a kind of synthetic method of chiral vicinal diol, includes the following steps：
(1) it will be added in reaction unit, and be added strong as the alkene of the precursor of the chiral vicinal diol and dichloromethane
Alkali；Then at a temperature of -50 DEG C to -15 DEG C, phase transfer catalyst is added, then potassium permanganate or sodium permanganate is added portionwise
Aqueous solution is reacted, and until the reaction is complete, post-processing obtains intermediate a；
(2) the intermediate a is added in reaction unit, is added with stirring ether and petroleum ether, is then added portionwise
Boric acid；Then the aqueous solution for potassium hydroxide being added dropwise is reacted, and until the reaction is complete, post-processing obtains intermediate b；
(3) the intermediate b is added in reaction unit, adds ether and water, then under ice bath cooling condition,
Hydrofluoric acid is added dropwise, after being added dropwise, low temperature is stirred overnight；Ether is added into reaction solution, post-processes, the chiral neighbour two is made
Alcohol.
In a preferred embodiment, the alkene is selected from following any：Left-handed firpene, dextrorotation firpene, 1- butylene, benzene
Ethylene, cyclohexene.
In a preferred embodiment, the alkali is sodium hydroxide or potassium hydroxide.
In a preferred embodiment, the hydrofluoric acid is the hydrofluoric acid that mass fraction is 40%.
In a preferred embodiment, the phase transfer catalyst is selected from following any：Benzyltriethylammoinium chloride, four
Butylammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride,
Tetradecyl trimethyl ammonium chloride.
In a preferred embodiment, the post-processing described in the step (1) is：It is filtered to remove solid residue, then will
Reaction solution concentrates.
In a preferred embodiment, the post-processing described in the step (2) is：Filtering removes solvent.
In a preferred embodiment, the post-processing described in the step (3) is：Organic phase is extracted, ether is then used
Extraction is multiple, merges organic phase；It is dried with anhydrous sodium sulfate, ether is evaporated off, recycling ether is applied mechanically.
The second aspect of the present invention provides a kind of chiral vicinal diol, which is characterized in that it is by above-mentioned synthetic method system
.
Embodiment 1 synthesizes (1R, 2R, 3S, 5R)-(-) -2,3- pinane diols
(1) dextrorotation firpene 272kg is added in 5000L reaction kettles, dichloromethane 800L is added under stiring, adds hydrogen
At a temperature of -50 DEG C to -30 DEG C 3kg dodecyl trimethyl ammonium chloride is added, then permanganic acid is added portionwise in sodium oxide molybdena 10kg
The aqueous solution of potassium (320kg).After reacting 10h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and remaining few
Dextrorotation firpene is measured, (1R, 2R, 3S, 5R)-(-) -2,3- pinane diol crude products are obtained.
(2) by (1R, 2R, 3S, 5R)-(-) -2,3- pinane diol crude products are added into 1000L reaction kettles, under stirring condition
200L ether is added, then 62kg boric acid is added portionwise in 200L petroleum ethers；Then aqueous solution (the 65kg hydrogen of potassium hydroxide is added dropwise
Potassium oxide is dissolved in 150kg water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate pinane diol boric acid
Potassium.
(3) the intermediate pinane diol potassium borate is added into 2000L reaction kettles, adds 200L ether and 100L
The hydrofluoric acid of 200kg 40% is slowly added dropwise under ice cooling, 4 in water thereto, and after being added dropwise, low temperature is stirred overnight.To this
It walks and 200L ether is added in the reaction solution of reaction, extract organic phase, then use the ether of 100L × 3 to extract, merge organic phase.It will
Combined organic phase is dried with anhydrous sodium sulfate 50kg, and ether then is evaporated off with distillation still, and recycling ether is applied mechanically.Finally it is made
(1R, 2R, 3S, 5R)-(-) -2,3- pinane diol sterlings, quality 236kg, yield 69% measure content 99.6%, and chirality contains
Amount 99.9%.
Embodiment 2 synthesizes (1S, 2S, 3R, 5S)-(+) -2,3- pinane diols
(1) left-handed firpene 272kg is added in 5000L reaction kettles, dichloromethane 800L is added under stiring, adds hydrogen
At a temperature of -40 DEG C to -15 DEG C 4kg tetrabutylammonium chlorides are added, then potassium permanganate (320kg) is added portionwise in potassium oxide 16kg
Aqueous solution.After reacting 10h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and the left-handed pinane of remaining minute quantity
Alkene obtains (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol crude products.
(2) by (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol crude products are added into 1000L reaction kettles, under stirring condition
200L ether is added, then 62kg boric acid is added portionwise in 200L petroleum ethers；Then aqueous solution (the 65kg hydrogen of potassium hydroxide is added dropwise
Potassium oxide is dissolved in 150kg water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate pinane diol boric acid
Potassium.
(3) the intermediate pinane diol potassium borate is added into 2000L reaction kettles, adds 200L ether and 100L
The hydrofluoric acid of 200kg 40% is slowly added dropwise under ice cooling, 4 in water thereto, and after being added dropwise, low temperature is stirred overnight.To this
It walks and 200L ether is added in the reaction solution of reaction, extract organic phase, then use the ether of 100L × 3 to extract, merge organic phase.It will
Combined organic phase is dried with anhydrous sodium sulfate 50kg, and ether then is evaporated off with distillation still, and recycling ether is applied mechanically.Finally it is made
(1S, 2S, 3R, 5S)-(+) -2,3- pinane diol sterlings, quality 230kg, yield 67.6% measure content 99.7%, chiral
Content 99.9%.
Embodiment 3 synthesizes (R) -1,2- butanediols
(1) in 2000L reaction kettles, 1- butylene 56.11kg is dissolved in 200L dichloromethane, potassium hydroxide is added
At a temperature of -30 DEG C to -25 DEG C 0.8kg tetrabutylammonium chlorides are added, then the water of potassium permanganate (160kg) is added portionwise in 12kg
Solution.After reacting 10h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and remaining minute quantity 1- butylene.It obtains
(R) -1,2- butanediols crude product.
(2) by (R) -1,2- butanediol crude products are added into 1000L reaction kettles, and 200L ether is added under stirring condition,
Then 35kg boric acid is added portionwise in 200L petroleum ethers, then (38kg potassium hydroxide is dissolved in 80kg to the aqueous solution of dropwise addition potassium hydroxide
Water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate butanediol potassium borate.
(3) the intermediate butanediol potassium borate is added into the reaction kettle of 2000L, adds 200L ether and 100L
The hydrofluoric acid of 120kg40% is slowly added dropwise under ice cooling, 4 in water thereto, and after being added dropwise, low temperature is stirred overnight.To this
It walks and 200L ether is added in the reaction solution of reaction, extract organic phase, then use the ether of 100L × 3 to extract, merge organic phase.It will
Combined organic phase is dried with anhydrous sodium sulfate 50kg, and ether then is evaporated off with distillation still, and recycling ether is applied mechanically.Finally it is made
(R) -1,2- butanediol sterlings, quality 68.8kg, yield 76.3% measure content 99.2%, chiral content 99.3%.
Embodiment 4 synthesizes (R) -1- phenyl -1,2- ethylene glycol
(1) styrene 208.3kg is added in 5000L reaction kettles, dichloromethane 700L is added under stiring, and hydrogen is added
At a temperature of -40 DEG C to -25 DEG C 2.5kg benzyltriethylammoinium chlorides are added, then potassium permanganate is added portionwise in potassium oxide 18kg
The aqueous solution of (328kg).After reacting 15h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and remaining minute quantity
Styrene obtains (R) -1- phenyl -1,2- ethylene glycol crude products.
(2) (R) -1- phenyl -1,2- ethylene glycol crude products are added into 1000L reaction kettles, 180L is added under stirring condition
Then 32kg boric acid is added portionwise in ether, 200L petroleum ethers, then (36kg potassium hydroxide is molten for the aqueous solution of dropwise addition potassium hydroxide
In 166kg water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate (R) -1- phenyl -1,2- ethylene glycol
Potassium borate.
(3) intermediate (R) -1- phenyl -1,2- ethylene glycol potassium borates are added into 2000L reaction kettles, are added
The hydrofluoric acid of 110kg 40%, after being added dropwise, low temperature is slowly added dropwise under ice cooling, 4 in 120L ether and 60L water thereto
It is stirred overnight.110L ether is added into the reaction solution of this step reaction, extracts organic phase, the ether of 100L × 3 is then used to extract,
Merge organic phase.It by combined organic phase, is dried with anhydrous sodium sulfate 50kg, ether then is evaporated off with distillation still, recycle ether
It applies mechanically.(R) -1- phenyl -1,2- ethylene glycol sterlings, quality 77.3kg is finally made, yield 55.9% measures content
98.7%, chiral content 98.1%.
5 synthesizing cis -1,2- cyclohexanediols of embodiment
(1) cyclohexene 164.3kg is added into the reaction kettle of 5000L, dichloromethane 900L is added under stiring, and add
Enter potassium hydroxide 18kg, at a temperature of -50 DEG C to -40 DEG C, 1.9kg tetrabutylammonium bromide is added, then potassium permanganate is added portionwise
The aqueous solution of (328kg).After reacting 15h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and remaining minute quantity
Cyclohexene obtains cis- -1,2- cyclohexanediol crude products.
(2) cis- -1,2- cyclohexanediol crude products are added into 1000L reaction kettles, 180L ether are added under stirring condition,
Then 66kg boric acid is added portionwise in 200L petroleum ethers, then (66kg potassium hydroxide is dissolved in the aqueous solution of dropwise addition potassium hydroxide
280kg water), it will produce solid after being added dropwise.Filtering, remove solvent, obtain intermediate it is cis- -1,2- cyclohexanediol boric acid
Potassium.
(3) by the intermediate it is cis- -1,2- cyclohexanediol potassium borates are added into 2000L reaction kettles, add 180L
The hydrofluoric acid of 220kg40% is slowly added dropwise under ice cooling, 4 in ether and 100L water thereto, after being added dropwise, low temperature stirring
Overnight.200L ether is added into the reaction solution of this step reaction, extracts organic phase, then uses the ether of 100L × 3 to extract, merges
Organic phase.It by combined organic phase, is dried with anhydrous sodium sulfate 50kg, ether then is evaporated off with distillation still, recycling ether is applied mechanically.
Cis- -1,2- cyclohexanediol sterlings, quality 148.8kg, yield is finally made：64.1%.Content 98.9% is measured, chirality contains
Amount 98.8%.
Embodiment 6 synthesizes (1R, 2R, 3S, 5R)-(-) -2,3- pinane diols
(1) dextrorotation firpene 272kg is added in 5000L reaction kettles, dichloromethane 800L is added under stiring, adds hydrogen
At a temperature of -50 DEG C to -30 DEG C 3kg dodecyl trimethyl ammonium chloride is added, then permanganic acid is added portionwise in sodium oxide molybdena 10kg
The aqueous solution of sodium (trihydrate) (397kg).After reacting 15h, it is filtered to remove solid residue.Concentration of reaction solution, remove solvent and
Remaining minute quantity dextrorotation firpene obtains (1R, 2R, 3S, 5R)-(-) -2,3- pinane diol crude products.
(2) by (1R, 2R, 3S, 5R)-(-) -2,3- pinane diol crude products are added into 1000L reaction kettles, under stirring condition
200L ether is added, then 62kg boric acid is added portionwise in 200L petroleum ethers；Then aqueous solution (the 65kg hydrogen of potassium hydroxide is added dropwise
Potassium oxide is dissolved in 150kg water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate pinane diol boric acid
Potassium.
(3) the intermediate pinane diol potassium borate is added into 2000L reaction kettles, adds 200L ether and 100L
The hydrofluoric acid of 200kg 40% is slowly added dropwise under ice cooling, 4 in water thereto, and after being added dropwise, low temperature is stirred overnight.To this
It walks and 200L ether is added in the reaction solution of reaction, extract organic phase, then use the ether of 100L × 3 to extract, merge organic phase.It will
Combined organic phase is dried with anhydrous sodium sulfate 50kg, and ether then is evaporated off with distillation still, and recycling ether is applied mechanically.Finally it is made
(1R, 2R, 3S, 5R)-(-) -2,3- pinane diol sterlings, quality 228.5kg, yield 66.8% measure content 99.5%, hand
Property content 99.9%.
Embodiment 7 synthesizes (1S, 2S, 3R, 5S)-(+) -2,3- pinane diols
(1) left-handed firpene 272kg is added in 5000L reaction kettles, dichloromethane 800L is added under stiring, adds hydrogen
4kg tetrabutylammonium chlorides are added at a temperature of -40 DEG C to -15 DEG C in potassium oxide 16kg, then sodium permanganate (three hydrations are added portionwise
Object) (397kg) aqueous solution.After reacting 15h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and remaining few
Left-handed firpene is measured, (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol crude products are obtained.
(2) by (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol crude products are added into 1000L reaction kettles, under stirring condition
200L ether is added, then 62kg boric acid is added portionwise in 200L petroleum ethers；Then aqueous solution (the 65kg hydrogen of potassium hydroxide is added dropwise
Potassium oxide is dissolved in 150kg water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate pinane diol boric acid
Potassium.
(3) the intermediate pinane diol potassium borate is added into 2000L reaction kettles, adds 200L ether and 100L
The hydrofluoric acid of 200kg 40% is slowly added dropwise under ice cooling, 4 in water thereto, and after being added dropwise, low temperature is stirred overnight.To this
It walks and 200L ether is added in the reaction solution of reaction, extract organic phase, then use the ether of 100L × 3 to extract, merge organic phase.It will
Combined organic phase is dried with anhydrous sodium sulfate 50kg, and ether then is evaporated off with distillation still, and recycling ether is applied mechanically.Finally it is made
(1S, 2S, 3R, 5S)-(+) -2,3- pinane diol sterlings, quality 228kg, yield 67% measure content 99.4%, and chirality contains
Amount 99.9%.
Embodiment 8 synthesizes (R) -1,2- butanediols
(1) in 2000L reaction kettles, 1- butylene 56.11kg is dissolved in 200L dichloromethane, potassium hydroxide is added
At a temperature of -30 DEG C to -25 DEG C 0.8kg tetrabutylammonium chlorides are added, then sodium permanganate (trihydrate) is added portionwise in 12kg
The aqueous solution of (198kg).After reacting 15h, it is filtered to remove solid residue.Concentration of reaction solution removes solvent and remaining minute quantity
1- butylene.Obtain (R) -1,2- butanediol crude products.
(2) by (R) -1,2- butanediol crude products are added into 1000L reaction kettles, and 200L ether is added under stirring condition,
Then 35kg boric acid is added portionwise in 200L petroleum ethers, then (38kg potassium hydroxide is dissolved in 80kg to the aqueous solution of dropwise addition potassium hydroxide
Water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate butanediol potassium borate.
(3) the intermediate butanediol potassium borate is added into the reaction kettle of 2000L, adds 200L ether and 100L
The hydrofluoric acid of 120kg40% is slowly added dropwise under ice cooling, 4 in water thereto, and after being added dropwise, low temperature is stirred overnight.To this
It walks and 200L ether is added in the reaction solution of reaction, extract organic phase, then use the ether of 100L × 3 to extract, merge organic phase.It will
Combined organic phase is dried with anhydrous sodium sulfate 50kg, and ether then is evaporated off with distillation still, and recycling ether is applied mechanically.Finally it is made
(R) -1,2- butanediol sterlings, quality 68kg, yield 75.4% measure content 99.1%, chiral content 99.4%.
Embodiment 9 synthesizes (R) -1- phenyl -1,2- ethylene glycol
(1) styrene 208.3kg is added in 5000L reaction kettles, dichloromethane 700L is added under stiring, and hydrogen is added
At a temperature of -40 DEG C to -25 DEG C 2.5kg benzyltriethylammoinium chlorides are added, then sodium permanganate is added portionwise in potassium oxide 18kg
The aqueous solution of (trihydrate) (406.7kg).After reacting 18h, it is filtered to remove solid residue.Concentration of reaction solution, remove solvent and
Remaining few weight phenylethylene obtains (R) -1- phenyl -1,2- ethylene glycol crude products.
(2) (R) -1- phenyl -1,2- ethylene glycol crude products are added into 1000L reaction kettles, 180L is added under stirring condition
Then 32kg boric acid is added portionwise in ether, 200L petroleum ethers, then (36kg potassium hydroxide is molten for the aqueous solution of dropwise addition potassium hydroxide
In 166kg water), it will produce solid after being added dropwise.Filtering removes solvent, obtains intermediate (R) -1- phenyl -1,2- ethylene glycol
Potassium borate.
(3) intermediate (R) -1- phenyl -1,2- ethylene glycol potassium borates are added into 2000L reaction kettles, are added
The hydrofluoric acid of 110kg 40%, after being added dropwise, low temperature is slowly added dropwise under ice cooling, 4 in 120L ether and 60L water thereto
It is stirred overnight.110L ether is added into the reaction solution of this step reaction, extracts organic phase, the ether of 100L × 3 is then used to extract,
Merge organic phase.It by combined organic phase, is dried with anhydrous sodium sulfate 50kg, ether then is evaporated off with distillation still, recycle ether
It applies mechanically.(R) -1- phenyl -1,2- ethylene glycol sterlings, quality 75.3kg is finally made, yield 54.5% measures content
98.5%, chiral content 98.2%.
10 synthesizing cis -1,2- cyclohexanediols of embodiment
(1) cyclohexene 164.3kg is added into the reaction kettle of 5000L, dichloromethane 900L is added under stiring, and add
Enter potassium hydroxide 18kg, at a temperature of -50 DEG C to -40 DEG C, 1.9kg tetrabutylammonium bromide is added, then sodium permanganate is added portionwise
The aqueous solution of (trihydrate) (406.7kg).After reacting 18h, it is filtered to remove solid residue.Concentration of reaction solution, remove solvent and
Remaining minute quantity cyclohexene obtains cis- -1,2- cyclohexanediol crude products.
(2) cis- -1,2- cyclohexanediol crude products are added into 1000L reaction kettles, 180L ether are added under stirring condition,
Then 66kg boric acid is added portionwise in 200L petroleum ethers, then (66kg potassium hydroxide is dissolved in the aqueous solution of dropwise addition potassium hydroxide
280kg water), it will produce solid after being added dropwise.Filtering, remove solvent, obtain intermediate it is cis- -1,2- cyclohexanediol boric acid
Potassium.
(3) by the intermediate it is cis- -1,2- cyclohexanediol potassium borates are added into 2000L reaction kettles, add 180L
The hydrofluoric acid of 220kg40% is slowly added dropwise under ice cooling, 4 in ether and 100L water thereto, after being added dropwise, low temperature stirring
Overnight.200L ether is added into the reaction solution of this step reaction, extracts organic phase, then uses the ether of 100L × 3 to extract, merges
Organic phase.It by combined organic phase, is dried with anhydrous sodium sulfate 50kg, ether then is evaporated off with distillation still, recycling ether is applied mechanically.
Cis- -1,2- cyclohexanediol sterlings, quality 147.4kg, yield is finally made：63.5%.Content 98.7% is measured, chirality contains
Amount 98.5%.
Specific embodiments of the present invention are described in detail above, but it is intended only as example, the present invention is simultaneously unlimited
It is formed on particular embodiments described above.To those skilled in the art, it is any to the equivalent modifications that carry out of the present invention and
It substitutes also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by impartial conversion and
Modification, all should be contained within the scope of the invention.
Claims (6)
1. a kind of synthetic method of chiral vicinal diol, which is characterized in that include the following steps：
(1) it will be added in reaction unit as the alkene of the precursor of the chiral vicinal diol and dichloromethane, and highly basic be added；So
Afterwards at a temperature of -50 DEG C to -15 DEG C, phase transfer catalyst is added, then the water-soluble of potassium permanganate or sodium permanganate is added portionwise
Liquid is reacted, and until the reaction is complete, post-processing obtains intermediate a；
(2) the intermediate a is added in reaction unit, is added with stirring ether and petroleum ether, boric acid is then added portionwise；
Then the aqueous solution for potassium hydroxide being added dropwise is reacted, and until the reaction is complete, post-processing obtains intermediate b；
(3) the intermediate b is added in reaction unit, adds ether and water, then under ice bath cooling condition, be added dropwise
Hydrofluoric acid, after being added dropwise, low temperature is stirred overnight；Ether is added into reaction solution, post-processes, the chiral vicinal diol is made；
Wherein, the alkene is selected from following any：Left-handed firpene, dextrorotation firpene, 1- butylene, styrene, cyclohexene；
Wherein, the phase transfer catalyst is selected from following any：Tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutyl sulfuric acid
Hydrogen ammonium, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride.
2. the synthetic method of chiral vicinal diol according to claim 1, which is characterized in that the highly basic be sodium hydroxide or
Potassium hydroxide.
3. the synthetic method of chiral vicinal diol according to claim 1, which is characterized in that the hydrofluoric acid is mass fraction
For 40% hydrofluoric acid.
4. the synthetic method of chiral vicinal diol according to claim 1, which is characterized in that described in the step (1)
Post-processing is：It is filtered to remove solid residue, then reaction solution is concentrated.
5. the synthetic method of chiral vicinal diol according to claim 1, which is characterized in that described in the step (2)
Post-processing is：Filtering removes solvent.
6. the synthetic method of chiral vicinal diol according to claim 1, which is characterized in that described in the step (3)
Post-processing is：Organic phase is extracted, multiple, merging organic phase is then extracted with ether；It is dried with anhydrous sodium sulfate, ether is evaporated off,
Recycling ether is applied mechanically.
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