CN106467454A - Germacrone reduction and fractionation - Google Patents

Germacrone reduction and fractionation Download PDF

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CN106467454A
CN106467454A CN201610800767.1A CN201610800767A CN106467454A CN 106467454 A CN106467454 A CN 106467454A CN 201610800767 A CN201610800767 A CN 201610800767A CN 106467454 A CN106467454 A CN 106467454A
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alcohol
germacrone
dimethyl
cyclodecadiene
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王际菊
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
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    • 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
    • C12P7/62—Carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

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

Description

Germacrone reduction and fractionation
Technical field
The present invention relates to a kind of preparation method of optical homochiral hydroxy compound, especially spread out with germacrone for raw material Life is prepared (3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol and is gone forward side by side Mobile state kinetics The method splitting.
Background technology
Synthesis (3E, 7E) -3,7- dimethyl -10- (1- methyl the ethylidene) -3,7- cyclodecadiene -1- alcohol of report Method is to be obtained using lithium aluminium hydride reduction germacrone（Preparation of germacrone derivatives For treating liver cancer, Faming Zhuanli Shenqing, 105439913,30 Mar 2016； Efficient synthesis of the anticancer β-elemene and other bioactive elemanes From sustainable germacrone, Organic ＆ Biomolecular Chemistry, 9 (4), 1118- 1125; 2011）.
Synthesis side with regard to S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol The existing report of method, then be with germacrone as raw material, with (S) -2- methyl-CBS- oxazaborolidine for catalyst through asymmetric Reduction reaction obtains（Efficient synthesis of the anticancer β-elemene and other Bioactive elemanes from sustainable germacrone, Organic ＆ Biomolecular Chemistry, 9(4), 1118-1125; 2011）；The method products obtained therefrom haves the shortcomings that optical purity is not high.
Content of the invention
In order to study to germacrone further, the present invention with germacrone as raw material, by its prochiral ketone Group is further reacted obtains chiral hydroxyl group neutrality, further splits, obtains the compound of optically pure hydroxyl.Tool It is as follows that body realizes process：
1）Under condition of ice bath, with alcohol as solvent, add raw material germacrone, sodium borohydride by a certain percentage, then keep low Reacted under the conditions of temperature, obtained compound ii, that is,-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- ring Decadinene -1- alcohol；
2）In organic solvent toluene, with step 1) gained compound ii as raw material, by a certain percentage add acry radical donor, fat Enzyme, carries out kinetic resolution reaction at a certain temperature, obtains compound III, i.e. R-(3E, 7E) -3,7- dimethyl -10- The acyl compounds of (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol；And compounds Ⅳ, i.e. S-(3E, 7E) -3,7- bis- Methyl isophthalic acid 0- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol；After reaction terminates, filter, concentrate, column purification excessively arrives respectively To pure compound III and compounds Ⅳ；
3）In organic solvent toluene, with step 1) gained compound ii, add acry radical donor, Digestive Enzyme 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 i.e. acyl compounds of R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol；
4）By step 2）Or step 3）Gained R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- ring last of the ten Heavenly stems two The acyl compounds of alkene -1- alcohol are added in the oxolane prepared by a certain percentage and the mixed solution of Lithium hydrate, room temperature It is stirred overnight reaction, detection detection extent of reaction, after reaction terminates, cross column purification and can obtain sterling R-(3E, 7E) -3,7- diformazan Base -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, the optical purity of final products can reach more than 99%；
Step 2）And step 3）Described in acry radical donor be parachlorophenol acetass, its addition rubs for starting compound II 1.0 ~ 1.5 times of that amount；Step 2）And step 3）Described in Digestive Enzyme be porcine pancreatic lipase, its addition be raw material chemical combination The 1% ~ 10% of thing II mass number；Step 3）Described in racemization catalyst be acidic resins D006, its addition be raw material chemical combination The 5% ~ 20% of thing II mass；
The present invention reduces-(3E, 7E) -3,7- dimethyl -10- (1- methyl Asia second with germacrone for raw material is hydrogenated Base) -3,7- cyclodecadiene -1- alcohol；Alcohol obtains R-(3E, 7E) -3,7- dimethyl -10- (1- methyl through Dynamic Kinetic Resolution again Ethylidene) -3,7- cyclodecadiene -1- alcohol acyl compounds, more final R-(3E, 7E) -3,7- dimethyl -10- that is hydrolyzed (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol；Or respectively obtain R-(3E, 7E) -3,7- diformazan through kinetic resolution Base -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol acyl compounds and S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, (1- methyl is sub- to separate R-(3E, 7E) -3,7- dimethyl -10- obtaining Ethyl) -3,7- cyclodecadiene -1- alcohol acyl compounds are again through hydrolysis operation, you can R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol.This method possesses simple to operate, the spy such as product yield is high, optical purity is good Point, has great guidance and using value in the preparation research of Bulgarian geranium ketone derivatives.
Specific embodiment
Embodiment 1
1）Under the conditions of 0 DEG C, addition 250ml absolute methanol in single-necked flask, 21.8g germacrone, after stirring 15min, plus Enter 13g sodium borohydride, after the completion of feeding intake, use balloon sealed flask, keep 0 DEG C of conditioned response 3.5h, TLC detects germacrone Reaction is complete, stopped reaction；Go out sodium borohydride to no longer there being bubble to emerge with dilute hydrochloric acid solution, after methanol is evaporated off, uses 100ml Dichloromethane extracts three times, combined dichloromethane, drying, can obtain-(3E, 7E) -3,7- dimethyl -10- (1- methyl after concentration Ethylidene) -3,7- cyclodecadiene -1- alcohol 21.3g, yield is 96.8%.
2）In constant-temperature table, with 200ml indigo plant lid bottle as reaction vessel, add 60ml toluene ,-(3E, the 7E)-of 11g 3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, 11g parachlorophenol acetass, 0.6g Pancreas Sus domestica fat Enzyme PPL, 2.0g acidic resins D006, feeds intake and finishes, and is warming up to 40 DEG C and is reacted, after 12 hours, detection-(3E, 7E) -3, 7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol disappears, be converted into R-(3E, 7E) -3,7- dimethyl - 10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol acetyl compound；Reacted solution is cooled down, filter, concentrate, obtain Crude product.
3）By step 2）Middle gained crude product is added in 150ml oxolane, and adds Lithium hydrate 7g, is stirred at room temperature Carry out reacting 24 hours, point plate detection R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene - Stopped reaction when 1- alcohol acetyl compound point disappears；After adding 150ml water, reactant liquor is concentrated, is boiled off oxolane, then With dichloromethane, surplus solution is carried out extracting, divide liquid, drying, be concentrated to give containing R-(3E, 7E) -3,7- dimethyl -10- (1- Methyl ethylidene) -3,7- cyclodecadiene -1- alcohol crude product.
4）By step 3）Gained contains R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- ring last of the ten Heavenly stems two The crude product volume ratio of alkene -1- alcohol is 10:1 petroleum ether and the mixed solution of ethyl acetate carry out silica gel column chromatography.Finally may be used Obtain R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol 10.1g, yield 91.5%, warp Detection, the ee value of final products R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol For 99.4%.
5）In constant-temperature table, with 200ml indigo plant lid bottle as reaction vessel, add 60ml toluene ,-(3E, the 7E)-of 11g 3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, 11g parachlorophenol acetass, 0.6g Pancreas Sus domestica fat Enzyme PPL, feeds intake and finishes, and is warming up to 40 DEG C and is reacted, after 6 hours, detection-(3E, 7E) -3,7- dimethyl -10- (1- first Base ethylidene) -3,7- cyclodecadiene -1- alcohol conversion reaches 50%；Stopped reaction, reacted solution cooled down, filters, concentrating, Cross post, respectively obtain S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol 5.4g, receive Rate is 98.2%, product ee value 99.9%；Obtain S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- ring last of the ten Heavenly stems two Alkene -1- alcohol second elder generation based compound 6.4g, yield is 97.6%.
6）By step 5）Middle gained S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene - 1- alcohol second elder generation based compound 6.4g is added in 150ml oxolane, and adds Lithium hydrate 7g, is stirred at room temperature and carries out reacting 24 Hour, point plate detection R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol acetylation Stopped reaction when compound point disappears；After adding 150ml water, reactant liquor is concentrated, is boiled off oxolane, then used dichloromethane Surplus solution is carried out extract, divide liquid, drying, concentration, cross column purification, obtain R-(3E, 7E) -3,7- dimethyl -10- (1- first Base ethylidene) -3,7- cyclodecadiene -1- alcohol 5.3g, this walks yield 98.1%, and product ee value is 99.6%.
Embodiment 2
1）Under the conditions of 0 DEG C, addition 1000ml absolute methanol in single-necked flask, 218g germacrone, after stirring 20min, plus Enter 150g sodium borohydride, after the completion of feeding intake, use balloon sealed flask, keep 0 DEG C of conditioned response 4h, TLC detects germacrone Reaction is complete, stopped reaction；Dilute hydrochloric acid solution goes out sodium borohydride to no longer there being bubble to emerge, and uses 300ml after methanol is evaporated off Ethyl acetate extracts three times, combined ethyl acetate, drying, can obtain-(3E, 7E) -3,7- dimethyl -10- (1- methyl after concentration Ethylidene) -3,7- cyclodecadiene -1- alcohol 216.3g, yield is 98.3%.
2）In constant-temperature table, with 1000ml indigo plant lid bottle as reaction vessel, add 700ml toluene, 110g-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, 110g parachlorophenol acetass, 10g Pancreas Sus domestica Digestive Enzyme PPL, 20g acidic resins D006, feeds intake and finishes, and is warming up to 40 DEG C and is reacted, after 12 hours, detection-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol disappears, and is converted into R-(3E, 7E) -3,7- Dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol acetyl compound；Reacted solution is cooled down, filters, Concentrate, obtain crude product.
3）By step 2）Middle gained crude product is added in 600ml oxolane, and adds Lithium hydrate 80g, and room temperature is stirred Mix and carry out reacting 24 hours, point plate detection R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3, the 7- ring last of the ten Heavenly stems two Stopped reaction when alkene -1- alcohol acetyl compound point disappears；After adding 300ml water, reactant liquor is concentrated, is boiled off tetrahydrochysene furan Mutter, then with dichloromethane, surplus solution is carried out extracting, point liquid, drying, be concentrated to give containing R-(3E, 7E) -3,7- dimethyl - The crude product of 10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol.
4）By step 3）Gained contains R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- ring last of the ten Heavenly stems two The crude product volume ratio of alkene -1- alcohol is 10:1 petroleum ether and the mixed solution of ethyl acetate carry out silica gel column chromatography.Finally may be used R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol 103.6g, yield 94.2%, After testing, the ee of final products R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol It is worth for 99.3%.
5）In constant-temperature table, with 1000ml indigo plant lid bottle as reaction vessel, add 700ml toluene, 110g-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, 110g parachlorophenol acetass, 10g Pancreas Sus domestica Digestive Enzyme PPL, feeds intake and finishes, and is warming up to 45 DEG C and is reacted, after 6 hours, detection-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol conversion reaches 50%；Stopped reaction, reacted solution is cooled down, filters, Concentrate, cross post, respectively obtain S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol 54.2g, yield is 98.5%, product ee value 99.9%；Obtain S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3, 7- cyclodecadiene -1- alcohol second elder generation based compound 64.4g, yield is 98.3%.
6）By step 5）Middle gained S-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene - 1- alcohol second elder generation based compound 64.4g is added in 600ml oxolane, and adds Lithium hydrate 70g, is stirred at room temperature and is reacted 24 hours, point plate detection R-(3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol acetyl Stopped reaction when chemical combination object point disappears；After adding 300ml water, reactant liquor is concentrated, is boiled off oxolane, then used dichloromethane Alkane carries out to surplus solution extracting, divides liquid, drying, concentration, crosses column purification, obtains R-(3E, 7E) -3,7- dimethyl -10- (1- Methyl ethylidene) -3,7- cyclodecadiene -1- alcohol 53.2g, this walks yield 98.4%, and product ee value is 99.6%.

Claims (4)

1. a kind of germacrone reduction and method for splitting are 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 germacrone, sodium borohydride by a certain percentage, then keep low Reacted under the conditions of temperature, obtained compound ii, i.e. (3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- ring last of the ten Heavenly stems two Alkene -1- alcohol；
2) in organic solvent toluene, with step 1) gained compound ii as raw material, by a certain percentage add acry radical donor, fat Enzyme, carries out kinetic resolution reaction at a certain temperature, obtains compound III, i.e. R- (3E, 7E) -3,7- dimethyl -10- (1- Methyl ethylidene) -3,7- cyclodecadiene -1- alcohol acyl compounds；And compounds Ⅳ, i.e. S- (3E, 7E) -3,7- diformazan Base -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol；Reaction terminate after, 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, Digestive Enzyme 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 i.e. acyl compounds of R- (3E, 7E) -3,7- dimethyl -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol；
4) by step 2) or step 3) gained R- (3E, 7E) -3,7- dimethyl -10- (1- methyl the ethylidene) -3,7- ring last of the ten Heavenly stems two The acyl compounds of alkene -1- alcohol are added in the oxolane prepared by a certain percentage and the mixed solution of Lithium hydrate, room temperature It is stirred overnight reaction, detection detection extent of reaction, after reaction terminates, cross column purification and can obtain sterling R- (3E, 7E) -3,7- diformazan Base -10- (1- methyl ethylidene) -3,7- cyclodecadiene -1- alcohol, the optical purity of final products can reach more than 99%, and Product yield is preferable；According to above step, equation of the present invention is as follows：
2. according to claim 1 a kind of reduction of germacrone and method for splitting it is characterised in that：Step 2) and step 3) acry radical donor described in is parachlorophenol acetass, and its addition is 1.0～1.5 times of starting compound II mole.
3. according to claim 1 a kind of reduction of germacrone and method for splitting it is characterised in that：Step 2) and step 3) Digestive Enzyme described in is porcine pancreatic lipase, and its addition is the 1%～10% of starting compound II mass number.
4. according to claim 1 a kind of reduction of germacrone and method for splitting it is characterised in that：Step 3) described in Racemization catalyst is acidic resins D006, and its addition is the 5%～20% of starting compound II mass.
CN201610800767.1A 2016-09-04 2016-09-04 Germacrone reduction and fractionation Pending CN106467454A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108752210A (en) * 2018-05-14 2018-11-06 东南大学成贤学院 A kind of preparation method of germacrone ketobutyric acid

Citations (3)

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Publication number Priority date Publication date Assignee Title
CN102605034A (en) * 2012-02-21 2012-07-25 重庆惠健生物科技有限公司 Biological enzyme resolution method for preparing optically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate
CN104262093A (en) * 2014-10-09 2015-01-07 王同俊 R-1-(3-methylphenyl)ethanol and synthesis of ester thereof
CN105439913A (en) * 2015-11-18 2016-03-30 广东药学院 Germacrone derivative as well as preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102605034A (en) * 2012-02-21 2012-07-25 重庆惠健生物科技有限公司 Biological enzyme resolution method for preparing optically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate
CN104262093A (en) * 2014-10-09 2015-01-07 王同俊 R-1-(3-methylphenyl)ethanol and synthesis of ester thereof
CN105439913A (en) * 2015-11-18 2016-03-30 广东药学院 Germacrone derivative as well as preparation method and application thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108752210A (en) * 2018-05-14 2018-11-06 东南大学成贤学院 A kind of preparation method of germacrone ketobutyric acid

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Application publication date: 20170301