CN106282293A - The reduction of tonalid and fractionation - Google Patents

The reduction of tonalid and fractionation Download PDF

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Publication number
CN106282293A
CN106282293A CN201610800776.0A CN201610800776A CN106282293A CN 106282293 A CN106282293 A CN 106282293A CN 201610800776 A CN201610800776 A CN 201610800776A CN 106282293 A CN106282293 A CN 106282293A
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tetrahydrochysene
hexamethyl
compound
ethanol
tonalid
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CN201610800776.0A
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陈永军
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic

Abstract

The invention discloses a kind of tonalid reduction and method for splitting.The present invention is with tonalid as raw material, compound ii is obtained through sodium borohydride reduction, compound ii reacts to obtain compound III and compounds Ⅳ by enzymatic kinetic resolution again, or obtains the compound III of yield more than 90% through Dynamic Kinetic Resolution, and compound III can obtain compound V through hydrolysis.Prochiral ketone base in tonalid is become chiral hydroxyl group center by the present invention further, and splits further；The features such as the present invention possesses simple to operate, and product yield is high, optical purity is good.

Description

The reduction of tonalid and fractionation
Technical field
The present invention relates to the preparation method of a kind of optical homochiral hydroxy compound, particularly relating to a kind of is former with tonalid 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol the method carrying out splitting are prepared in material reduction.
Background technology
The method of tonalid reduction alcoholization is then to prepare 1-(5,6,7,8-tetra-by lithium aluminium hydride reduction tonalid Hydrogen-3,5,5,6,8,8 ,-hexamethyl-2-naphthyl) ethanol (Preparation and uses of microcapsules Containing fragrances for cosmetic use, PCT Int. Appl., 2013079435,06 Jun 2013)；And how to split about 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8 ,-hexamethyl-2-naphthyl) two kinds of isomers of ethanol Preparation, then have no relevant report.
Summary of the invention
In order to study tonalid further, the present invention is with tonalid as raw material, by its prochiral ketone group Further react and obtain chiral hydroxyl group neutrality, further split, obtain the compound of optically pure hydroxyl.Concrete real Existing process is as follows:
1) under condition of ice bath, with alcohol as solvent, add raw material tonalid, sodium borohydride by a certain percentage, then keep low temperature Under the conditions of react, obtain compound ii, i.e.-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) second Alcohol；
2) in organic solvent toluene, with step 1) gained compound ii as raw material, add acry radical donor, fat by a certain percentage Enzyme, carries out kinetic resolution reaction at a certain temperature, obtains compound III, i.e. R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6, 8,8-hexamethyl-2-naphthyl) acyl compounds of ethanol；And compounds Ⅳ, i.e. S-1-(5,6,7,8-tetrahydrochysene-3,5,5,6, 8,8-hexamethyl-2-naphthyl) ethanol；After reaction terminates, filter, concentrate, cross column purification respectively to pure compound III and Compounds Ⅳ；
3) in organic solvent toluene, with step 1) gained compound ii, add acry radical donor, lipase by a certain percentage, disappear Rotation catalyst carries out Dynamic Kinetic Resolution reaction at a certain temperature, compound ii can be fully converted to compound III, The acyl compounds of i.e. R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol；
4) by step 2) or step 3) gained R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol Acyl compounds joins in the mixed solution of oxolane and the Lithium hydrate prepared by a certain percentage, and stirred overnight at room temperature is anti- Should, detection detection extent of reaction, reaction terminate after, cross column purification can obtain sterling R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8, 8-hexamethyl-2-naphthyl) ethanol, the optical purity of final products can reach more than 99%；More than step 2 in operation) and step 3) acry radical donor described in is parachlorophenol acetas, and its addition is 1.0 ~ 1.5 times of starting compound II mole；Step Rapid 2) and the lipase described in step 3) is Pseudomonas fluorecens lipase Lipase AK, its addition is raw material chemical combination The 1% ~ 10% of thing II mass number；Racemization catalyst described in step 3) is solid super-strong acid SO42-_Fe2O3, its addition For starting compound II mass 5% ~ 20%.
The present invention reduces to obtain-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-pregnancy with tonalid for raw material is hydrogenated Base-2-naphthyl) ethanol；Alcohol obtains R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-through Dynamic Kinetic Resolution again Naphthyl) glycolyl compound, then be hydrolyzed final R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2- Naphthyl) ethanol；Or respectively obtain R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthalene through kinetic resolution Base) glycolyl compound and S-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol, separate R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) the glycolyl compound arrived again through hydrolysis operation, R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol.This method possesses simple to operate, produces The features such as product yield is high, optical purity is good, have in the preparation research of tonalid derivant and instruct greatly and application valency Value.
Detailed description of the invention
Embodiment 1
1), under the conditions of 0 DEG C, in single port flask, add 350ml absolute methanol, 25.8g tonalid, after stirring 15min, add 13g sodium borohydride, after having fed intake, uses balloon sealed flask, keeps 0 DEG C of conditioned response 4h, TLC detection tonalid to react Entirely, stopped reaction；With the dilute hydrochloric acid solution sodium borohydride that goes out to no longer there being bubble to emerge, after methanol is evaporated off, use 100ml dichloromethane Alkane extract three times, combined dichloromethane, be dried, concentrate after can obtain 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2- Naphthyl) ethanol 25.79g, yield is 99.2%.
2) in constant-temperature table, with 200ml indigo plant lid bottle as reaction vessel, add 60ml toluene, 13g 1-(5,6,7, 8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol, 11g parachlorophenol acetas, 0.7g pseudomonas fluorescens fat Enzyme Lipase AK, 2.1g solid super-strong acid SO42-_Fe2O3, feeds intake complete, is warming up to 45 DEG C and reacts, after 12 hours, and inspection Survey-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol to disappear, be converted into R-1-(5,6,7,8- Tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl compound；Reacted solution is cooled down, filters, concentrates, Crude product.
3) by step 2) in the thick product of gained join in 150ml oxolane, and add Lithium hydrate 8g, be stirred at room temperature Carry out reacting 24 hours, some plate detection R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol acetyl Stopped reaction when chemical combination object point disappears；After adding 150ml water, reactant liquor is concentrated, boils off oxolane, then use dichloromethane Surplus solution is extracted by alkane, separatory, be dried, be concentrated to give containing R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-pregnancy Base-2-naphthyl) crude product of ethanol.
4) step 3) gained is contained R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol Crude product volume ratio is that the petroleum ether of 10:1 carries out silica gel column chromatography with the mixed solution of ethyl acetate.Finally can obtain R-1-(5, 6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol 12.16g, yield 93.5%, after testing, final products R- The ee value of 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol is 99.5%.
5) in constant-temperature table, with 200ml indigo plant lid bottle as reaction vessel, add 60ml toluene, 13g 1-(5,6,7, 8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol, 11g parachlorophenol acetas, 0.8g pseudomonas fluorescens fat Enzyme Lipase AK, feeds intake complete, is warming up to 45 DEG C and reacts, after 6 hours, detection 1-(5,6,7,8-tetrahydrochysene-3,5,5, 6,8,8-hexamethyl-2-naphthyl) ethanol conversion reaches 50%；Stopped reaction, cools down reacted solution, filters, concentrates, mistake Post, respectively obtaining S-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol 6.40g, S configuration yield is 98.5%, product ee value 99.9%；Obtain R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl group Compound 7.38g, R configuration yield is 97.7%.
6) by gained R-1-in step 5) (5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl Based compound 7.38g joins in 150ml oxolane, and adds Lithium hydrate 7g, is stirred at room temperature and carries out reacting 24 hours, point Plate detection R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl compound point stops when disappearing Reaction；After adding 150ml water, reactant liquor is concentrated, boils off oxolane, then with dichloromethane, surplus solution is extracted Take, separatory, be dried, concentrate, cross column purification, obtain R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) second Alcohol 6.23g, this walks yield 98.1%, and product ee value is 99.7%.
Embodiment 2
1), under the conditions of 0 DEG C, in single port flask, add 1000ml absolute methanol, 258g tonalid, after stirring 20min, add 150g sodium borohydride, after having fed intake, uses balloon sealed flask, keeps 0 DEG C of conditioned response 4h, TLC detection tonalid reaction Completely, stopped reaction；Dilute hydrochloric acid solution sodium borohydride that goes out, to no longer there being bubble to emerge, uses 300ml acetic acid after methanol is evaporated off Ethyl ester extract three times, combined ethyl acetate, be dried, concentrate after can obtain 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl- 2-naphthyl) ethanol 258.44g, yield is 99.4%.
2) in constant-temperature table, with 1000ml indigo plant lid bottle as reaction vessel, add 700ml toluene, 130g 1-(5,6, 7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol, 110g parachlorophenol acetas, 10g pseudomonas fluorescens fat Fat enzyme Lipase AK, 22g solid super-strong acid SO42-_Fe2O3, feeds intake complete, is warming up to 40 DEG C and reacts, after 12 hours, Detection 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol disappears, and is converted into R-1-(5,6,7,8- Tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl compound；Reacted solution is cooled down, filters, concentrates, Crude product.
3) by step 2) in the thick product of gained join in 600ml oxolane, and add Lithium hydrate 80g, room temperature is stirred Mix and carry out reacting 24 hours, some plate detection R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol second Stopped reaction when acyl compound point disappears；After adding 300ml water, reactant liquor is concentrated, boils off oxolane, then use dichloro Surplus solution is extracted by methane, separatory, be dried, be concentrated to give containing R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-six Methyl-2-naphthyl) crude product of ethanol.
4) step 3) gained is contained R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol Crude product volume ratio is that the petroleum ether of 10:1 carries out silica gel column chromatography with the mixed solution of ethyl acetate.Finally can obtain R-1-(5, 6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol 123.89g, yield 95.3%, after testing, final products R- The ee value of 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol is 99.4%.
5) in constant-temperature table, with 1000ml indigo plant lid bottle as reaction vessel, add 700ml toluene, 130g 1-(5,6, 7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol, 110g parachlorophenol acetas, 10g pig pseudomonas fluorescens Lipase Lipase AK, feeds intake complete, is warming up to 45 DEG C and reacts, after 6 hours, detection 1-(5,6,7,8-tetrahydrochysene-3, 5,5,6,8,8-hexamethyl-2-naphthyl) ethanol conversion reaches 50%；Stopped reaction, by reacted solution cool down, filter, dense Contract, cross post, respectively obtain S-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol 64.16g, S configuration Yield is 98.7%, product ee value 99.9%；Obtain R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol Acetyl compounds 74.21g, R configuration yield is 98.3%.
6) by gained R-1-in step 5) (5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl Based compound 74.21g joins in 600ml oxolane, and adds Lithium hydrate 70g, is stirred at room temperature and carries out reacting 24 hours, Point plate detection R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol acetyl compound point stops when disappearing Only reaction；After adding 300ml water, reactant liquor is concentrated, boils off oxolane, then with dichloromethane, surplus solution is carried out Extraction, separatory, it is dried, concentrates, cross column purification, obtain R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) Ethanol 62.87g, this walks yield 98.4%, and product ee value is 99.6%.

Claims (4)

1. a tonalid reduction and method for splitting, it is characterised in that it is realized by following operating procedure:
1) under condition of ice bath, with alcohol as solvent, add raw material tonalid, sodium borohydride by a certain percentage, then keep low temperature Under the conditions of react, obtain compound ii, i.e. 1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyls) ethanol；
2) in organic solvent toluene, with step 1) gained compound ii as raw material, add acry radical donor, fat by a certain percentage Enzyme, carries out kinetic resolution reaction at a certain temperature, obtains compound III, i.e. R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8, 8-hexamethyl-2-naphthyl) acyl compounds of ethanol；And compounds Ⅳ, i.e. S-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8, 8-hexamethyl-2-naphthyl) ethanol；After reaction terminates, filter, concentrate, cross column purification respectively to pure compound III and change Compound IV；
3) in organic solvent toluene, with step 1) gained compound ii, add acry radical donor, lipase by a certain percentage, disappear Rotation catalyst carries out Dynamic Kinetic Resolution reaction at a certain temperature, compound ii can be fully converted to compound III, The acyl compounds of i.e. R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol；
4) by step 2) or step 3) gained R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8-hexamethyl-2-naphthyl) ethanol Acyl compounds joins in the mixed solution of oxolane and the Lithium hydrate prepared by a certain percentage, and stirred overnight at room temperature is anti- Should, detection detection extent of reaction, reaction terminate after, cross column purification can obtain sterling R-1-(5,6,7,8-tetrahydrochysene-3,5,5,6,8,8- Hexamethyl-2-naphthyl) ethanol, the optical purity of final products can reach more than 99%, and product yield is preferable；More than according to Described in step, equation of the present invention is as follows:
A kind of tonalid reduction and method for splitting, it is characterised in that: step 2) and step 3) Described in acry radical donor be parachlorophenol acetas, its addition is 1.0～1.5 times of starting compound II mole.
A kind of tonalid reduction and method for splitting, it is characterised in that: step 2) and step 3) Described in lipase be Pseudomonas fluorecens lipase Lipase AK, its addition is the 1% of starting compound II mass number ～10%.
A kind of tonalid reduction and method for splitting, it is characterised in that: step 3) described in disappear Rotation catalyst is solid super-strong acid SO42-_Fe2O3, and its addition is the 5%～20% of starting compound II mass.
CN201610800776.0A 2016-09-04 2016-09-04 The reduction of tonalid and fractionation Pending CN106282293A (en)

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