CN102584538B - Synthesis method of chiral 2,3-pinanediol - Google Patents
Synthesis method of chiral 2,3-pinanediol Download PDFInfo
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- CN102584538B CN102584538B CN201210014255.4A CN201210014255A CN102584538B CN 102584538 B CN102584538 B CN 102584538B CN 201210014255 A CN201210014255 A CN 201210014255A CN 102584538 B CN102584538 B CN 102584538B
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Abstract
The invention relates to a synthesis method of chiral 2,3-pinanediol. The structural formula of chiral 2,3-pinanediol is showed in the specification. The synthesis method comprises the step of adding an oxidation inhibitor and alkali liquor containing an oxidant in alpha-pinene which is commercialized in the market and selected as a starting material for reaction so that a final product, namely chiral 2,3-pinanediol, can be obtained. According to the method, a target product with high liquid phase purity and high ee (enantiomeric excess) value of a product enantiomer can be obtained, wherein the liquid phase purity is stabilized above 98%, the ee value of the enantiomer is stabilized above 99% and the yield is 60.7-76.6%. According to the synthesis method, the materials are easy to obtain, the price is cheap, the chemical reaction condition is mild during the production process, the technical condition is stable, the operation is simple, pollution is less; the synthesis method is suitable for on-scale production, and a new idea and method can be provided for preparing chiral 2,3-pinanediol.
Description
(1) technical field:
The present invention relates to the synthetic method of synthetic method, particularly a kind of chiral 2,3-pinanediol that a kind of olefin oxidation is cis glycol.
(2) background technology:
At present, malignant tumour remains one of principal disease threatening people's life, American Cancer Society reports in the < < whole world on December 17th, the 2007 cancer fact and data > >, newly-increased cancer sufferer 1,200 ten thousand examples in the whole world in 2007,7600000 people die from cancer, are equivalent to dead 20,000 people every day.Wherein developing country increases cancer patients 5,400,000 people then newly, and 2,900,000 people are because of cancer mortality.According to Ministry of Health's statistical information, show, China's malignant tumour every year newly-increased patient approximately has 148.5 ten thousand people, innocent tumour whole nation morbidity reaches 0.93 ‰ in addition, according to country's total population 1,300,000,000, it is radix, newly-increased 1,200,000 left and right of China's innocent tumour patient at the beginning of 08, both add up to annual newly-increased 268.5 ten thousand the tumour patient that approximately has.From tumor mortality rate, the annual tumour patient mortality ratio of China whole nation adds up to approximately every 100,000 people to have 119.54 people to die from tumor etiology, that is to say that national tumor mortality number approximately has 1,540,000 people every year.Although the treatment of cancer has been made significant headway at present, also fail fundamentally to obtain thoroughly curing cancer patients.Although at present the cancer therapy drug of listing has certain curative effect, they are cell toxicity medicament mostly, have severe side effect, and the new type anticancer medicine that therefore how goes out to send research targeting from effective tumour target spot becomes the task of top priority.
Ubiquitin-Proteasome Pathway (Ubiquitin-Proteasome Pathway, abbreviation UPP) can regulate and control to participate in the level of the protein of cell cycle control, the morbidity of this approach and cancer, cardiovascular and cerebrovascular diseases and nervous system degenerative disease has important relationship.With some effective inhibitor, suppress this approach excessive degradation key protein new thinking will be provided for the treatment of above-mentioned disease.
Chiral 2,3-pinanediol is the important intermediate of synthetic this proteinase inhibitor just.Along with the pay attention to day by day of people to the research and development of cancer therapy drug and production, the market demand of chiral 2,3-pinanediol is also increasing year by year, and price also raises gradually.
Present stage, the method for preparing chiral 2,3-pinanediol mainly contains following several:
1, α-pinene, under the effect of perosmic anhydride, generates 2,3-pinine glycol.This method need to be used highly toxic substance perosmic anhydride, because of perosmic anhydride volatile, larger to human body and environmental hazard during use.
2, take proline(Pro) boron ester is raw material, with resolving agent, is decomposed into 2,3-pinine glycol, or alpha-alcohol ketone is synthetic 2, the 3-pinine glycol of raw material, and these two kinds of methods cost of material used is all very expensive, and synthetic cost is high.
3, take α-pinene as raw material, with potassium permanganate oxidation, generate 2,3-pinine glycol, but potassium permanganate oxidation method in the past often yield is very low, the purity of finished product and enantiomeric purity are not high.
The problems such as above method is expensive because of cost of material, and toxicity is large, and environmental pollution is serious, and yield is low, and product purity and enantiomeric purity are low, are not suitable for large-scale production.Therefore, be to solve the difficult problem existing in prior art, the product purity that suddenly wait to find a synthetic method simple possible, pollute less, cost is low, obtains and enantiomeric excess value is high, the practicable synthetic method that can carry out large-scale production.
(3) summary of the invention:
The object of the present invention is to provide a kind of synthetic method of chiral 2,3-pinanediol, the structural formula of chiral 2,3-pinanediol is
or
selecting business-like α-pinene on market is starting raw material; the alkali lye that adds oxidation retarder and contain oxygenant, reacts, and obtains final product chirality 2; 3-pinine glycol; the method raw material is easy to get, low price, and product purity and enantiomeric purity are higher; stable process conditions; simple to operate, be applicable to large-scale production, be a kind of method of simple environmental protection.
Technical scheme of the present invention: a kind of synthetic method of chiral 2,3-pinanediol, is characterized in that concrete steps are as follows:
Under water and alcoholic solvent existence, add main raw material α-pinene and peroxidation inhibitor, temperature of reaction is 10～40 ℃, drip the strong base solution containing PH=11～14 of oxygenant, dropwise, insulation at 10～40 ℃, soaking time is 2～10h, react completely, add reductive agent termination reaction, separatory, extraction, concentrate and obtain product chiral 2,3-pinanediol, its structural formula is
or
Wherein the amount ratio of main raw material α-pinene and water is 1g/0.5～5.0mL; Main raw material α-pinene and alcoholic solvent amount ratio are 1g/3.0～20.0mL; The mol ratio 1: 0.5～3.0 of main raw material α-pinene and peroxidation inhibitor; The mol ratio of main raw material α-pinene and oxygenant is 1: 1.0～10.0; The mol ratio of main raw material α-pinene and highly basic is 1: 0.1～2.0; The mol ratio of main raw material α-pinene and reductive agent is 1: 5.0～20.0.
The amount ratio of above-mentioned said main raw material α-pinene and water is 1g/1.0～4.0mL; Main raw material α-pinene and alcoholic solvent amount ratio are 1g/8.0～16.0mL; The mol ratio of main raw material α-pinene and peroxidation inhibitor is 1: 1.1～2.8; The mol ratio of main raw material α-pinene and oxygenant is 1: 3.0～8.0; The mol ratio of main raw material α-pinene and highly basic is 1: 0.8～1.8; Temperature of reaction is 15～35 ℃; Soaking time is 3～8h; Main raw material α-pinene and reductive agent mol ratio be 1: 10.0～16.0.
The amount ratio of above-mentioned said main raw material α-pinene and water is 1g/2.0～3.0mL; Main raw material α-pinene and alcoholic solvent amount ratio are 1g/10.0～15.0mL; The mol ratio of main raw material α-pinene and peroxidation inhibitor is 1: 1.2～2.5; The mol ratio of main raw material α-pinene and oxygenant is 1: 5.0～7.0; The mol ratio of main raw material α-pinene and highly basic is 1: 1.0～1.5; Temperature of reaction is 20～30 ℃; Soaking time is 4～6h; Main raw material α-pinene and reductive agent mol ratio be 1: 12.0～14.0.
Above-mentioned said α-pinene is left-handed α-pinene or dextrorotation α-pinene.
Above-mentioned said alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol, Virahol or propyl carbinol.
Above-mentioned said peroxidation inhibitor is ethylene glycol or glycerol.
Above-mentioned said oxygenant is potassium permanganate or sodium permanganate.
The strong base solution of above-mentioned said PH=11～14 is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution or solution of potassium carbonate.
Above-mentioned said reductive agent is sulfurous gas, sodium bisulfite, S-WAT or Sodium Pyrosulfite.
Above-mentioned said α-pinene is left-handed α-pinene or dextrorotation α-pinene; Said alcoholic solvent is methyl alcohol, ethanol or the trimethyl carbinol; Said peroxidation inhibitor is ethylene glycol; Said oxygenant is potassium permanganate; The strong base solution of said PH=11～14 is sodium hydroxide solution or potassium hydroxide solution; Said reductive agent is sulfurous gas.
Superiority of the present invention: the raw material that 1, the present invention adopts is business-like raw material, is easy to get and low price, can meet the needs of large-scale production; 2, the sulfur dioxide gas that the present invention adopts is made reductive agent, has reduced the generation of solid slag, is conducive to protection of the environment; 3, chemical reaction condition of the present invention is gentle; in whole technological process; stable process conditions, simple to operate, pollute few; after reaction, can obtain the product of high chemical purity, high antimer ee value; liquid phase purity is stabilized in more than 98%, and enantiomorph ee value stabilization is more than 99%, yield 60.7%～76.6%; and ripe in this Technology, possess the ability of large-scale production.
(4) accompanying drawing explanation:
Fig. 1 is the chemical reaction step schema of the synthetic method of the related a kind of chiral 2,3-pinanediol of the present invention.
Fig. 2 is the chemical reaction process schema of the synthetic method of the related a kind of chiral 2,3-pinanediol of the present invention.
In conjunction with Fig. 1 and/or Fig. 2, can understand more intuitively the technical scheme of foregoing invention.
(5) embodiment:
For the interval range occurring in embodiment, be because temperature in single test is with certain the floating of there will be of reaction process; The statement of pH value test result is also the routine statement in the synthetic field of chemical industry.
Embodiment 1: a kind of preparation (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol
method, is characterized in that concrete preparation process is as follows:
In 8000L reactor, add 250kg water (1g/2.5mL) and the 975kg trimethyl carbinol (1g/12.5mL), add 100kg dextrorotation α-pinene (1eq), 82.0kg ethylene glycol (1: 1.8eq), temperature control is 25 ± 5 ℃, drip 4290.2kg containing sodium hydroxide solution (the 696.0kg potassium permanganate (1: 6.0eq)+35.2kg sodium hydroxide (1: 1.2eq)+3559.0kg water (consumption is determined by pH)) of PH=13.0 ± 0.5 of potassium permanganate, dropwise, at 25 ± 5 ℃, be incubated 5h, react completely, pass into 610.7kg sulfurous gas (1: 13.0eq) termination reaction, separatory, extraction, concentrated product (the 1S that obtains, 2S, 3R, 5S)-(+)-2, 3-pinine glycol 95.7kg. yield 76.6%, liquid chromatography purity (HPLC): 98.8%, enantiomorph ee value: 99.5%.
Embodiment 2: a kind of preparation (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol
method, is characterized in that concrete preparation process is as follows:
In 5000L reactor, add 40.0kg water (1g/0.5mL) and 189.6kg ethanol (1g/3.0mL), add the left-handed α-pinene of 80.0kg (1eq), 27.0kg glycerol (1: 0.5～3.0eq), temperature control is 12 ± 2 ℃, drip 409.7kg containing potassium hydroxide solution (the 92.9kg potassium permanganate (1: 1.0eq)+3.3kg potassium hydroxide (1: 0.1eq)+313.5kg water (consumption is determined by pH)) of PH=11.5 ± 0.5 of potassium permanganate, dropwise, at 12 ± 2 ℃ ℃, be incubated 2h, react completely, pass into 188.1kg sulfurous gas (1: 5.0eq) termination reaction, separatory, extraction, concentrated product (the 1S that obtains, 2S, 3R, 5S)-(+)-2, 3-pinine glycol 60.7kg. yield 60.7%, liquid chromatography purity (HPLC): 98.7%, enantiomorph ee value: 99.0%.
Embodiment 3: a kind of preparation (1R, 2R, 3S, 5R)-(-)-2,3-pinine glycol
method, is characterized in that concrete preparation process is as follows:
To the ethanol (1g/20.0mL) that adds 325.0kg water (1g/5.0mL) and 1027.0kg in 8000L reactor, add the left-handed α-pinene of 65.0kg (1eq), 88.8kg ethylene glycol (1: 3.0eq), temperature control is 37 ± 3 ℃, drip 4573.6kg containing sodium hydroxide solution (the 677.2kg sodium permanganate (1: 10.0eq)+38.2kg sodium hydroxide (1: 2.0eq)+3858.2kg water (consumption is determined by pH)) of PH=13.5 ± 0.5 of sodium permanganate, dropwise, at 37 ± 3 ℃ ℃, be incubated 10h, react completely, add 611.3kg sulfurous gas (1: 20.0eq) termination reaction, separatory, extraction, concentrated product (the 1R that obtains, 2R, 3S, 5R)-(-)-2, 3-pinine glycol 58.6kg. yield 72.1%, liquid chromatography purity (HPLC): 98.5%, enantiomorph ee value: 99.1%.
Embodiment 4: a kind of preparation (1R, 2R, 3S, 5R)-(-)-2,3-pinine glycol
method, is characterized in that concrete preparation process is as follows:
To the Virahol (1g/10.1mL) that adds 220kg water (1g/2.5mL) and 695.2kg in 5000L reactor, the left-handed α-pinene (1eq) that adds 88kg, 103.9kg glycerol (1: 1.2eq), temperature control is 20 ± 5 ℃, drip 2899.0kg containing solution of potassium carbonate (the 229.0kg potassium permanganate (1: 2.2eq)+26.7kg salt of wormwood (1: 0.3eq)+2643.3kg water (consumption is determined by pH)) of PH=12.5 ± 0.5 of potassium permanganate, dropwise, at 20 ± 5 ℃, be incubated 4h, react completely, pass into 432kg sulfurous gas (1: 10.4eq) termination reaction, separatory, extraction, concentrated product (the 1R that obtains, 2R, 3S, 5R)-(-)-2, 3-pinine glycol 71.5kg. yield 65%, liquid chromatography purity (HPLC): 98.3%, enantiomorph ee value: 99.0%.
Embodiment 5: a kind of preparation (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol
method, is characterized in that concrete preparation process is as follows:
To the trimethyl carbinol (1g/9.1mL) that adds 100kg water (1g/2.0mL) and 355.5kg in 3000L reactor, the dextrorotation α-pinene (1eq) that adds 50kg, 40.9kg ethylene glycol (1: 1.8eq), temperature control is 30 ± 5 ℃, drip 1847.7kg containing sodium hydroxide solution (the 347.7kg sodium permanganate (1: 6.7eq)+15.0kg sodium hydroxide (1: 1.0eq)+1485.0kg water (consumption is determined by pH)) of PH=13.0 ± 0.5 of sodium permanganate, dropwise, at 30 ± 5 ℃, be incubated h, react completely, add 330.0kg sulfurous gas (1: 14.0eq) termination reaction, separatory, extraction, concentrated product (the 1S that obtains, 2S, 3R, 5S)-(+)-2, 3-pinine glycol 47.9kg. yield 75.0%, liquid chromatography purity (HPLC): 98.2%, enantiomorph ee value: 99.2%.
As can be seen here; disclosed chirality 2 in the present invention; the improvement of 3-pinine glycol synthetic method; can obtain liquid phase purity, the higher target product of product enantiomorph ee value; liquid phase purity is stabilized in more than 98%, and enantiomorph ee value stabilization is more than 99%, yield 60.7%～76.6%; described synthetic method raw material is easy to get; and low price, in production process, chemical reaction condition is gentle; stable process conditions; simple to operate, pollute less, be applicable to large-scale production; for preparing chiral 2,3-pinanediol, a kind of new thinking and method are provided.
Claims (6)
1. a synthetic method for chiral 2,3-pinanediol, is characterized in that concrete steps are as follows:
Under water and alcoholic solvent existence, add main raw material α-pinene and peroxidation inhibitor, temperature of reaction is 10～40 ℃, drip the strong base solution containing pH=11～14 of oxygenant, dropwise, insulation at 10～40 ℃, soaking time is 2～10h, react completely, add reductive agent termination reaction, separatory, extraction, concentrate and obtain product chiral 2,3-pinanediol, its structural formula is
or
Wherein the amount ratio of main raw material α-pinene and water is 1g/0.5～5.0mL; Main raw material α-pinene and alcoholic solvent amount ratio are 1g/3.0～20.0mL; Mol ratio 1:0.5～3.0 of main raw material α-pinene and peroxidation inhibitor; The mol ratio of main raw material α-pinene and oxygenant is 1:1.0～10.0; The mol ratio of main raw material α-pinene and highly basic is 1:0.1～2.0; The mol ratio of main raw material α-pinene and reductive agent is 1:5.0～20.0; Said alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol, Virahol or propyl carbinol, said peroxidation inhibitor is ethylene glycol or glycerol, said oxygenant is potassium permanganate or sodium permanganate, said reductive agent is sulfurous gas, sodium bisulfite, S-WAT or Sodium Pyrosulfite.
2. according to the synthetic method of the said a kind of chiral 2,3-pinanediol of claim 1, the amount ratio that it is characterized in that said main raw material α-pinene and water is 1g/1.0～4.0mL; Main raw material α-pinene and alcoholic solvent amount ratio are 1g/8.0～16.0mL; The mol ratio of main raw material α-pinene and peroxidation inhibitor is 1:1.1～2.8; The mol ratio of main raw material α-pinene and oxygenant is 1:3.0～8.0; The mol ratio of main raw material α-pinene and highly basic is 1:0.8～1.8; Temperature of reaction is 15～35 ℃; Soaking time is 3～8h; The mol ratio of main raw material α-pinene and reductive agent is 1:10.0～16.0.
3. according to the synthetic method of claim 1 or 2 said a kind of chiral 2,3-pinanediol, the amount ratio that it is characterized in that said main raw material α-pinene and water is 1g/2.0～3.0mL; Main raw material α-pinene and alcoholic solvent amount ratio are 1g/10.0～15.0mL; The mol ratio of main raw material α-pinene and peroxidation inhibitor is 1:1.2～2.5; The mol ratio of main raw material α-pinene and oxygenant is 1:5.0～7.0; The mol ratio of main raw material α-pinene and highly basic is 1:1.0～1.5; Temperature of reaction is 20～30 ℃; Soaking time is 4～6h; The mol ratio of main raw material α-pinene and reductive agent is 1:12.0～14.0.
4. according to the synthetic method of the said a kind of chiral 2,3-pinanediol of claim 1, it is characterized in that said α-pinene is left-handed α-pinene or dextrorotation α-pinene.
5. according to the synthetic method of the said a kind of chiral 2,3-pinanediol of claim 1, the strong base solution that it is characterized in that said pH=11～14 is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution or solution of potassium carbonate.
6. according to the synthetic method of the said a kind of chiral 2,3-pinanediol of claim 1, it is characterized in that said α-pinene is left-handed α-pinene or dextrorotation α-pinene; Said alcoholic solvent is methyl alcohol, ethanol or the trimethyl carbinol; Said peroxidation inhibitor is ethylene glycol; Said oxygenant is potassium permanganate; The strong base solution of said pH=11～14 is sodium hydroxide solution or potassium hydroxide solution; Said reductive agent is sulfurous gas.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5130136A (en) * | 1990-09-18 | 1992-07-14 | Sumitomo Chemical Company, Limited | Monoterpenediol insect repellents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5130136A (en) * | 1990-09-18 | 1992-07-14 | Sumitomo Chemical Company, Limited | Monoterpenediol insect repellents |
Non-Patent Citations (2)
| Title |
|---|
| RobertG.Carlson et al..The Synthesis and Stereochemistry of the Four Isomeric Pinane-2 |
| The Synthesis and Stereochemistry of the Four Isomeric Pinane-2,3-diols;Robert G. Carlson, et al.;《The Journal of Organic Chemistry》;19711231;第36卷(第16期);第2319-2324页 * |
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