CN102584538A - Synthesis method of chiral 2,3-pinanediol - Google Patents
Synthesis method of chiral 2,3-pinanediol Download PDFInfo
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- CN102584538A CN102584538A CN2012100142554A CN201210014255A CN102584538A CN 102584538 A CN102584538 A CN 102584538A CN 2012100142554 A CN2012100142554 A CN 2012100142554A CN 201210014255 A CN201210014255 A CN 201210014255A CN 102584538 A CN102584538 A CN 102584538A
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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 compound method that a kind of olefin oxidation is the cis glycol, particularly a kind of chirality 2, the compound method of 3-pinine glycol.
(2) background technology:
At present; Malignant tumour remains one of principal disease that threatens people's life, and American Cancer Society reports in " the global cancer fact and the data " on December 17th, 2007, newly-increased cancer sufferer 1,200 ten thousand examples in the whole world in 2007; 7,600,000 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.Show according to Ministry of Health's statistical information; The annual newly-increased patient of China's malignant tumour has 148.5 ten thousand people approximately; Innocent tumour whole nation morbidity reaches 0.93 ‰ in addition; According to country's total population 1,300,000,000 is radix, and China innocent tumour patient is newly-increased about 1,200,000 at the beginning of 08, and both add up to annual newly-increased 268.5 ten thousand the tumour patient that has approximately.See from the tumor mortality rate, China annual tumour patient mortality ratio whole nation add up to per approximately 100,000 people have 119.54 people die from oncosis because of, that is to say that national tumor mortality number has 1,540,000 people every year approximately.Though treatment for cancer has been made significant headway at present, also fail fundamentally thoroughly to be cured the cancer patients.Though the cancer therapy drug of listing has certain curative effect at present, they are cell toxicity medicament mostly, have severe side effect, and therefore how going out to send the new type anticancer medicine of studying target property from effective tumour target spot becomes the task of top priority.
Ubiquitin-Proteasome Pathway (Ubiquitin-Proteasome Pathway; Abbreviation UPP) the proteinic level that can regulate and control to participate in cell cycle control, the morbidity of this approach and cancer, cardiovascular and cerebrovascular diseases and nervous system degenerative disease all has important relationship.Use some effective inhibitors to suppress this approach excessive degradation key protein and will new thinking be provided for above-mentioned treatment of diseases.
Chirality 2,3-pinine glycol be the important intermediate of synthetic this proteinase inhibitor just.Along with people's is to the pay attention to day by day of the research and development and the production of cancer therapy drug, and chirality 2, the market demand of 3-pinine glycol are also increasing year by year, and price also raises gradually.
Present stage, preparation chirality 2, the method for 3-pinine glycol mainly contains following several kinds:
1, α-Pai Xi generates 2, the 3-pinine glycol under the effect of perosmic anhydride.This method need be used the highly toxic substance perosmic anhydride, because of perosmic anhydride volatile, bigger during use to human body and environmental hazard.
2, be raw material with proline(Pro) boron ester, it be decomposed into 2 with resolving agent, 3-pinine glycol, or alpha-alcohol ketone is the raw material Synthetic 2, the 3-pinine glycol, the used cost of material of these two kinds of methods is all very expensive, and synthetic cost is high.
3, with the α-Pai Xi be raw material, generate 2 with potassium permanganate oxidation, the 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.
Problems such as above method is expensive because of cost of material, and toxicity is big, 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, for solving a difficult problem that exists in the prior art, product purity that suddenly wait to find a compound method simple possible, pollute less, cost is low, obtains and enantiomeric excess value height, the practicable compound 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 chirality 2; The compound method of 3-pinine glycol; Chirality 2, business-like α-Pai Xi is a starting raw material to the structural formula of 3-pinine glycol on market for
or
selects for use, adds oxidation retarder and the alkali lye that contains oxygenant; React; Obtain final product chirality 2, the 3-pinine glycol, this method raw material is easy to get; Low price; Product purity and enantiomeric purity are higher, and stable process conditions is simple to operate; Being applicable to large-scale production, is a kind of method of simple environmental protection.
Technical scheme of the present invention: a kind of chirality 2, the compound method of 3-pinine glycol is characterized in that concrete steps are following:
In the presence of water and alcoholic solvent; Add main raw material α-Pai Xi and peroxo-suppressor factor, temperature of reaction is 10～40 ℃, drips the strong base solution of PH=11～14 that contain oxygenant; Dropwise; In 10～40 ℃ of insulations down, soaking time is 2～10h, reacts completely; Add the reductive agent termination reaction; Separatory, extraction concentrates and obtains product chirality 2; 3-pinine glycol, its structural formula are
or
Wherein the amount ratio of main raw material α-Pai Xi and water is 1g/0.5～5.0mL; Main raw material α-Pai Xi and alcoholic solvent amount ratio are 1g/3.0～20.0mL; The mol ratio of main raw material α-Pai Xi and peroxo-suppressor factor 1: 0.5～3.0; The mol ratio of main raw material α-Pai Xi and oxygenant is 1: 1.0～10.0; Main raw material α-Pai Xi and alkaline mol ratio are 1: 0.1～2.0; The mol ratio of main raw material α-Pai Xi and reductive agent is 1: 5.0～20.0.
The amount ratio of above-mentioned said main raw material α-Pai Xi and water is 1g/1.0～4.0mL; Main raw material α-Pai Xi and alcoholic solvent amount ratio are 1g/8.0～16.0mL; The mol ratio of main raw material α-Pai Xi and peroxo-suppressor factor is 1: 1.1～2.8; The mol ratio of main raw material α-Pai Xi and oxygenant is 1: 3.0～8.0; Main raw material α-Pai Xi and alkaline mol ratio are 1: 0.8～1.8; Temperature of reaction is 15～35 ℃; Soaking time is 3～8h; Main raw material α-Pai Xi and reductive agent mol ratio be 1: 10.0～16.0.
The amount ratio of above-mentioned said main raw material α-Pai Xi and water is 1g/2.0～3.0mL; Main raw material α-Pai Xi and alcoholic solvent amount ratio are 1g/10.0～15.0mL; The mol ratio of main raw material α-Pai Xi and peroxo-suppressor factor is 1: 1.2～2.5; The mol ratio of main raw material α-Pai Xi and oxygenant is 1: 5.0～7.0; Main raw material α-Pai Xi and alkaline mol ratio are 1: 1.0～1.5; Temperature of reaction is 20～30 ℃; Soaking time is 4～6h; Main raw material α-Pai Xi and reductive agent mol ratio be 1: 12.0～14.0.
Above-mentioned said α-Pai Xi is left-handed α-Pai Xi or dextrorotation α-Pai Xi.
Above-mentioned said alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol, Virahol or propyl carbinol.
Above-mentioned said peroxo-suppressor factor is terepthaloyl moietie or USP Kosher.
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 sulfite anhy 96, S-WAT or Sodium Pyrosulfite.
Above-mentioned said α-Pai Xi is left-handed α-Pai Xi or dextrorotation α-Pai Xi; Said alcoholic solvent is methyl alcohol, ethanol or the trimethyl carbinol; Said peroxo-suppressor factor is a terepthaloyl moietie; Said oxygenant is a potassium permanganate; The strong base solution of said PH=11～14 is sodium hydroxide solution or potassium hydroxide solution; Said reductive agent is a sulfurous gas.
Meliority of the present invention: 1, the raw material of the present invention's employing is business-like raw material, is easy to get and low price, can satisfy needs of scale production; 2, the sulfur dioxide gas of the present invention's employing is made reductive agent, has reduced the generation of solid slag, helps protecting environment; 3, the chemical reaction condition that the present invention adopted is gentle, in the whole technological process, and stable process conditions; Simple to operate, pollute and lack, can obtain the product of high chemical purity, high antimer ee value after the reaction; 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 on this Technology, possess the ability of large-scale production.
(4) description of drawings:
Fig. 1 is the related a kind of chirality 2 of the present invention, the chemical reaction step schema of the compound method of 3-pinine glycol.
Fig. 2 is the related a kind of chirality 2 of the present invention, the chemical reaction process schema of the compound method of 3-pinine glycol.
Can understand the technical scheme of foregoing invention more intuitively in conjunction with Fig. 1 and/or Fig. 2.
(5) embodiment:
For the interval range that occurs in the embodiment, be owing to certain the floating of carrying out meeting appearance of temperature in single test with reaction process; The statement of pH value test result also is 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 following:
In the 8000L reaction kettle, add the 250kg water (1g/2.5mL) and the 975kg trimethyl carbinol (1g/12.5mL), add 100kg dextrorotation α-Pai Xi (1eq), 82.0kg terepthaloyl moietie (1: 1.8eq); Temperature control is 25 ± 5 ℃, drips 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)), dropwise that 4290.2kg contains PH=13.0 ± 0.5 of potassium permanganate; Insulation 5h reacts completely under 25 ± 5 ℃, feeds 610.7kg sulfurous gas (1: 13.0eq) termination reaction; Separatory, extraction concentrates and obtains product (1S; 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 following:
In the 5000L reaction kettle, add 40.0kg water (1g/0.5mL) and 189.6kg ethanol (1g/3.0mL), add the left-handed α-Pai Xi of 80.0kg (1eq), the 27.0kg USP Kosher (1: 0.5～3.0eq); Temperature control is 12 ± 2 ℃, drips potassium hydroxide solution (the 92.9kg potassium permanganate (1: 1.0eq)+3.3kg Pottasium Hydroxide (1: 0.1eq)+313.5kg water (consumption is determined by pH)), dropwise that 409.7kg contains PH=11.5 ± 0.5 of potassium permanganate; Insulation 2h reacts completely under 12 ± 2 ℃ ℃, feeds 188.1kg sulfurous gas (1: 5.0eq) termination reaction; Separatory, extraction concentrates and obtains product (1S; 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 following:
In the 8000L reaction kettle, add the ethanol (1g/20.0mL) of 325.0kg water (1g/5.0mL) and 1027.0kg, add the left-handed α-Pai Xi of 65.0kg (1eq), 88.8kg terepthaloyl moietie (1: 3.0eq); Temperature control is 37 ± 3 ℃, drips 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)), dropwise that 4573.6kg contains PH=13.5 ± 0.5 of sodium permanganate; Insulation 10h reacts completely under 37 ± 3 ℃ ℃, adds 611.3kg sulfurous gas (1: 20.0eq) termination reaction; Separatory, extraction concentrates and obtains product (1R; 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 following:
The Virahol (1g/10.1mL) that in the 5000L reaction kettle, adds 220kg water (1g/2.5mL) and 695.2kg, the left-handed α-Pai Xi (1eq) of adding 88kg, 103.9kg USP Kosher (1: 1.2eq); Temperature control is 20 ± 5 ℃, drips 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)), dropwise that 2899.0kg contains PH=12.5 ± 0.5 of potassium permanganate; Insulation 4h reacts completely under 20 ± 5 ℃, feeds 432kg sulfurous gas (1: 10.4eq) termination reaction; Separatory, extraction concentrates and obtains product (1R; 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 following:
The trimethyl carbinol (1g/9.1mL) that in the 3000L reaction kettle, adds 100kg water (1g/2.0mL) and 355.5kg, the dextrorotation α-Pai Xi (1eq) of adding 50kg, 40.9kg terepthaloyl moietie (1: 1.8eq); Temperature control is 30 ± 5 ℃, drips 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)), dropwise that 1847.7kg contains PH=13.0 ± 0.5 of sodium permanganate; Insulation h reacts completely under 30 ± 5 ℃, adds 330.0kg sulfurous gas (1: 14.0eq) termination reaction; Separatory, extraction concentrates and obtains product (1S; 2S, 3R, 5S)-(+)-2; 3-pinine glycol 47.9kg. yield 75.0%, liquid chromatography purity (HPLC): 98.2%, enantiomorph ee value: 99.2%.
This shows, disclosed chirality 2 among the present invention, the improvement of 3-pinine glycol compound method can obtain liquid phase purity, the higher title 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%, and said compound method raw material is easy to get; And low price, in the production process, chemical reaction condition is gentle; Stable process conditions, simple to operate, pollute few; Be applicable to large-scale production, be preparation chirality 2, the 3-pinine glycol provides a kind of new thinking and method.
Claims (10)
1. chirality 2, the compound method of 3-pinine glycol is characterized in that concrete steps are following:
In the presence of water and alcoholic solvent; Add main raw material α-Pai Xi and peroxo-suppressor factor, temperature of reaction is 10～40 ℃, drips the strong base solution of PH=11～14 that contain oxygenant; Dropwise; In 10～40 ℃ of insulations down, soaking time is 2～10h, reacts completely; Add the reductive agent termination reaction; Separatory, extraction concentrates and obtains product chirality 2; 3-pinine glycol, its structural formula are
or
Wherein the amount ratio of main raw material α-Pai Xi and water is 1g/0.5～5.0mL; Main raw material α-Pai Xi and alcoholic solvent amount ratio are 1g/3.0～20.0mL; The mol ratio of main raw material α-Pai Xi and peroxo-suppressor factor 1: 0.5～3.0; The mol ratio of main raw material α-Pai Xi and oxygenant is 1: 1.0～10.0; Main raw material α-Pai Xi and alkaline mol ratio are 1: 0.1～2.0; The mol ratio of main raw material α-Pai Xi and reductive agent is 1: 5.0～20.0.
2. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol, the amount ratio that it is characterized in that said main raw material α-Pai Xi and water is 1g/1.0～4.0mL; Main raw material α-Pai Xi and alcoholic solvent amount ratio are 1g/8.0～16.0mL; The mol ratio of main raw material α-Pai Xi and peroxo-suppressor factor is 1: 1.1～2.8; The mol ratio of main raw material α-Pai Xi and oxygenant is 1: 3.0～8.0; Main raw material α-Pai Xi and alkaline mol ratio are 1: 0.8～1.8; Temperature of reaction is 15～35 ℃; Soaking time is 3～8h; Main raw material α-Pai Xi and reductive agent mol ratio be 1: 10.0～16.0.
3. according to claim 1 or 2 said a kind of chiralitys 2, the compound method of 3-pinine glycol, the amount ratio that it is characterized in that said main raw material α-Pai Xi and water is 1g/2.0～3.0mL; Main raw material α-Pai Xi and alcoholic solvent amount ratio are 1g/10.0～15.0mL; The mol ratio of main raw material α-Pai Xi and peroxo-suppressor factor is 1: 1.2～2.5; The mol ratio of main raw material α-Pai Xi and oxygenant is 1: 5.0～7.0; Main raw material α-Pai Xi and alkaline mol ratio are 1: 1.0～1.5; Temperature of reaction is 20～30 ℃; Soaking time is 4～6h; Main raw material α-Pai Xi and reductive agent mol ratio be 1: 12.0～14.0.
4. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol is characterized in that said α-Pai Xi is left-handed α-Pai Xi or dextrorotation α-Pai Xi.
5. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol is characterized in that said alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol, Virahol or propyl carbinol.
6. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol is characterized in that said peroxo-suppressor factor is terepthaloyl moietie or USP Kosher.
7. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol is characterized in that said oxygenant is potassium permanganate or sodium permanganate.
8. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol, 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.
9. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol is characterized in that said reductive agent is sulfurous gas, sodium sulfite anhy 96, S-WAT or Sodium Pyrosulfite.
10. according to the said a kind of chirality 2 of claim 1, the compound method of 3-pinine glycol is characterized in that said α-Pai Xi is left-handed α-Pai Xi or dextrorotation α-Pai Xi; Said alcoholic solvent is methyl alcohol, ethanol or the trimethyl carbinol; Said peroxo-suppressor factor is a terepthaloyl moietie; Said oxygenant is a potassium permanganate; The strong base solution of said PH=11～14 is sodium hydroxide solution or potassium hydroxide solution; Said reductive agent is a 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 (1)
| Title |
|---|
| ROBERT G. CARLSON, ET AL.: "The Synthesis and Stereochemistry of the Four Isomeric Pinane-2,3-diols", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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