CN106397116A - 1-acenaphthenol synthesis and enantiomer separation method - Google Patents
1-acenaphthenol synthesis and enantiomer separation method Download PDFInfo
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- CN106397116A CN106397116A CN201610800685.7A CN201610800685A CN106397116A CN 106397116 A CN106397116 A CN 106397116A CN 201610800685 A CN201610800685 A CN 201610800685A CN 106397116 A CN106397116 A CN 106397116A
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- acenaphthene
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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
- C07C29/145—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 with hydrogen or hydrogen-containing gases
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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
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
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- 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
Abstract
The invention discloses a 1-acenaphthenol synthesis and enantiomer separation method. The method particularly comprises the following steps that 1-acenaphthenone serves as a raw material, catalytic reduction hydrogenation can be conducted through a catalyst to obtain racemic 1-acenaphthenol, the racemic 1-acenaphthenol is subjected to dynamic kinetic splitting and then separated to obtain an R-1-acenaphthenol acyl compound and S-1-acenaphthenol, the 1-acenaphthenol is subjected to dynamic kinetic splitting, only an R-1-acenaphthenol acyl compound is obtained, the R-1-acenaphthenol acyl compound obtained through kinetic splitting or dynamic kinetic splitting is hydrolyzed, and then R-1-acenaphthenol can be obtained. The method has the advantages of being easy to implement, high in product yield, good in optical purity and the like, and great guidance and application value is achieved in 1-acenaphthenol synthesis and splitting research.
Description
Technical field
The present invention relates to a kind of preparation method of optical homochiral hydroxy compound.More particularly, to a kind of 1- acenaphthene ketone reduction alcoholization
Prepare the method that 1- hydroxyl acenaphthene and Dynamic Kinetic Resolution separate its enantiomer.
Background technology
At present existing research in, be related to 1- acenaphthene ketone as raw material, refine further 1- hydroxyl acenaphthene method, it lead
If with 1- acenaphthene ketone as raw material, obtaining through sodium borohydride reduction（ansa-Ruthenium(II) Complexes of
R2NSO2DPEN-(CH2)n(η6-Aryl) Conjugate Ligands for Asymmetric Transfer
Hydrogenation of Aryl Ketones, Advanced Synthesis & Catalysis, 357(11), 2540-
2546; 2015）；Or with 1- naphthalene acetic acid as raw material, be cyclized into 1- acenaphthene ketone through thionyl chloride, aluminum chloride effect, then through boron
Hydrogenation sodium reduction obtains 1- hydroxyl acenaphthene（Preparation of piperidinylindoline derivatives for use
As nervous system agents, PCT Int. Appl., 2014106238,03 Jul 2014）；In these methods
Due to using sodium borohydride to be reacted, there is post processing and during boron sodium chloride meeting moment releasing a large amount of hydrogen are quenched, exist
Larger potential safety hazard, and the waste water producing in last handling process is more.
The synthetic method with regard to R-1- hydroxyl acenaphthene and S-1- hydroxyl acenaphthene having report again is then 1- hydroxyl acenaphthene elder generation and second
Anhydride reaction generate 1- hydroxyl acenaphthene acetass, then 1- hydroxyl acenaphthene acetass carry out in the presence of Digestive Enzyme CAL-B asymmetric
Hydrolysis, gained ee R=96%, ee S=10%（Enantiocomplementary preparation of (S)-
and (R)-arylalkylcarbinols by lipase-catalyzed resolution and Mitsunobu
inversion:Impact of lipase amount, Catalysts, 4 (3), 215-225,11 pp.; 2014）.This
The method of kind haves the characteristics that products therefrom optical purity is not high.
Content of the invention
In order to solve the above problems, the offer of the present invention is simple to operation, product yield, purity and all high 1- of ee value
The synthesis of hydroxyl acenaphthene and method for splitting.
It is as follows that the synthesis of 1- hydroxyl acenaphthene and Chiral Separation method implement process：
1）In autoclave, add a certain amount of alcohol as solvent, then add raw material 1- acenaphthene ketone, hydrogenation catalyst by a certain percentage
Agent, then sealed reactor, exclude air, be warming up to suitable temperature after being passed through hydrogen and reacted, obtain 1- hydroxyl acenaphthene；
2）In organic solvent toluene, with step 1) gained 1- hydroxyl acenaphthene as raw material, by a certain percentage add acry radical donor, fat
Enzyme, carries out kinetic resolution reaction at a certain temperature, obtains acyl compounds and the S-1- hydroxyl acenaphthene of R-1- hydroxyl acenaphthene, this
Two kinds of compounds can be obtained by column chromatography for separation, and this step reaction two kinds of product yield of gained is all up to 98 about, ee value>
99%；
3）In organic solvent toluene, with step 1) gained 1- hydroxyl acenaphthene as raw material, by a certain percentage add acry radical donor, fat
Enzyme, racemization catalyst, carry out Dynamic Kinetic Resolution reaction at a certain temperature, obtain the acyl compounds of R-1- hydroxyl acenaphthene；
3）By step 2）Or step 3）The acyl compounds of gained R-1- hydroxyl acenaphthene are added to the tetrahydrochysene furan prepared by a certain percentage
Mutter with the mixed solution of Lithium hydrate in, be stirred overnight at room temperature reaction, detect extent of reaction, reaction terminate after, cross column purification can
Obtain sterling R-1- hydroxyl acenaphthene, the optical purity of final products can reach more than 99%, and product yield also has 90% about；Step 1）In
Described hydrogenation catalyst is produced ni-type catalyst AMG-1200 by upper Hisoon is triumphant；It adds quality is raw material 1- acenaphthene ketone quality
5%~20%；Step 2）And step 3）Described in acry radical donor be parachlorophenol acetass, its addition be raw material 1- hydroxyl acenaphthene
1.0 ~ 1.5 times of mole；Step 2）And step 3）Described in Digestive Enzyme be porcine pancreatic lipase, its addition be raw material 1- hydroxyl
The 1% ~ 10% of base acenaphthene quality；Step 3）Described in racemization catalyst be acidic resins D006, its addition be raw material 1- hydroxyl
The 5% ~ 20% of acenaphthene quality.
With 1- acenaphthene ketone as raw material, catalyst reduction can be crossed and be hydrogenated with to obtain raceme 1- hydroxyl acenaphthene, by raceme 1- hydroxyl
Acenaphthene enters Mobile state and moves separation after split to obtain R-1- hydroxyl acenaphthene acyl compounds and S-1- hydroxyl acenaphthene, and 1- hydroxyl acenaphthene is entered action
State is moved and is learned fractionation and get only R-1- hydroxyl acenaphthene acyl compounds, then by kinetic resolution or Dynamic Kinetic Resolution gained R-1- hydroxyl
Acenaphthene acyl compounds hydrolyze, you can obtain R-1- hydroxyl acenaphthene.This method possesses simple to operate, and product yield is high, optical purity is good etc.
Feature, has great guidance and using value in the synthesis of 1- hydroxyl acenaphthene with splitting in research.
Specific embodiment
Embodiment 1
1）In autoclave, add 150ml methanol as solvent, add 1- acenaphthene ketone, the 3g hydrogenation catalyst ni-type of 16.8g
Catalyst AMG-1200；Addition finishes, sealed reactor, first uses air in nitrogen displacement kettle twice, to be passed through H2 to pressure
4.0MPa, opens stirring, is warming up to 90 DEG C and is reacted, and reacts to system not re-absorption hydrogen, puts plate detection 1- acenaphthene ketone and disappears,
It is converted into 1- hydroxyl acenaphthene；Stopped reaction, cools down, filters, being concentrated to give 1- hydroxyl acenaphthene crude product, then obtains sterling 1- after column chromatography
Hydroxyl acenaphthene 15.2g, yield is 89.3%.
2）In constant-temperature table, with 100ml indigo plant lid bottle as reaction vessel, add 60ml toluene in bottle as solvent, then according to
Secondary addition step 1) gained 1- hydroxyl acenaphthene 8.5g, 11g parachlorophenol acetass, porcine pancreatic lipase PPL0.8g, 1.6g acidic resins
D006；Raw material addition finishes, and puts in 40 DEG C of vibration shaking tables and is reacted, and after reacting 12 hours, detection raw material 1- hydroxyl acenaphthene disappears
Lose, be converted into R-1- hydroxyl acenaphthene acetyl compound；Reacted solution is cooled down, filter, concentrate, obtain crude product and treat that lower step makes
With.
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, stopped reaction when point plate detection R -1- hydroxyl acenaphthene acetyl compound point disappears；After adding 150ml water, will
Reactant liquor is concentrated, and boils off oxolane, then with dichloromethane, surplus solution is carried out extracting, point liquid, drying, is concentrated to give and contains
There is the crude product of R -1- hydroxyl acenaphthene.
4）By step 3）The crude product volume ratio that gained contains R -1- hydroxyl acenaphthene is 10:1 petroleum ether and ethyl acetate
Mixed solution carries out silica gel column chromatography.Finally can obtain R -1- hydroxyl acenaphthene 8.2g, yield 90.9%, after testing, final products R -1-
The ee value of hydroxyl acenaphthene is 99.3%.
5）In constant-temperature table, with 200ml indigo plant lid bottle as reaction vessel, add 60ml toluene, the 1- hydroxyl acenaphthene of 8.5g,
11g parachlorophenol acetass, 0.5g porcine pancreatic lipase PPL, feed intake and finish, and are warming up to 40 DEG C and are reacted, after 6 hours, detection
1- hydroxyl acenaphthene conversion ratio reaches 50%；Stopped reaction, reacted solution is cooled down, filter, concentrates, crosses post, respectively obtain S -1-
Hydroxyl acenaphthene 4.17g, yield is 98.1%, product ee value 99.8%；Obtain R-1- hydroxyl acenaphthene acetyl compounds 5.18g, yield is
97.8%, ee value is 99.8%；
6）By step 5）Middle gained S -1- hydroxyl acenaphthene second elder generation based compound 5.18g is added in 150ml oxolane, and adds
Lithium hydrate 7g, is stirred at room temperature and carries out reacting 24 hours, and point plate detection R -1- hydroxyl acenaphthene acetyl compound point stops anti-when disappearing
Should；After adding 150ml water, reactant liquor is concentrated, is boiled off oxolane, then with dichloromethane, surplus solution is extracted
Take, divide liquid, drying, concentration, cross column purification, obtain R -1- hydroxyl acenaphthene 4.076g, this walks yield 97.9%, product ee value is
99.7%.
Embodiment 2
1）In 1000ml autoclave, add 700ml methanol as solvent, add 168g1- acenaphthene ketone, 13g hydrogenation catalyst
Ni-type catalyst AMG-1200；Addition finishes, sealed reactor, first uses air in nitrogen displacement kettle twice, to be passed through H2 to pressure
4.0MPa, opens stirring, is warming up to 100 DEG C and is reacted, and reacts to no longer inhaling after hydrogen, point plate detection 1- acenaphthene ketone disappears, conversion
For 1- hydroxyl acenaphthene；Stopped reaction, cools down, filters, being concentrated to give 1- hydroxyl acenaphthene crude product；Carry out column purification again and obtain 1- hydroxyl acenaphthene sterling
160.14g, yield is 94.2%
2）In constant-temperature table, with 1000ml indigo plant lid bottle as reaction vessel, add 700ml toluene, the 1- hydroxyl acenaphthene of 85g, 110g
Parachlorophenol acetass, 9g porcine pancreatic lipase PPL, 18g acidic resins D006, feed intake and finish, be warming up to 40 DEG C and reacted, and 12
After hour, detection 1- hydroxyl acenaphthene disappears, and is converted into R -1- hydroxyl acenaphthene 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, stopped reaction when point plate detection R -1- hydroxyl acenaphthene acetyl compound point disappears；After adding 300ml 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
Crude product containing R -1- hydroxyl acenaphthene.
4）By step 3）The crude product volume ratio that gained contains R -1- hydroxyl acenaphthene is 10:1 petroleum ether and ethyl acetate
Mixed solution carries out silica gel column chromatography.Finally can obtain R -1- hydroxyl acenaphthene 80.50g, yield 94.7%, after testing, final products R -
The ee value of 1- hydroxyl acenaphthene is 99.4%
5）In constant-temperature table, with 1000ml indigo plant lid bottle as reaction vessel, add 700ml toluene, the 1- hydroxyl acenaphthene of 85g, 110g
Parachlorophenol acetass, 9g porcine pancreatic lipase PPL, feed intake and finish, and are warming up to 45 DEG C and are reacted, and after 6 hours, detect 1- hydroxyl
Base acenaphthene conversion ratio reaches 50%；Stopped reaction, reacted solution is cooled down, filter, concentrates, crosses post, respectively obtain S -1- hydroxyl
Acenaphthene 41.82g, yield is 98.4%, product ee value 99.9%；Obtain R-1- hydroxyl acenaphthene second elder generation based compound 52.21g, yield is
98.5%, product ee value 99.8%.
6）By step 5）Middle gained R -1- hydroxyl acenaphthene acetyl compounds 52.21g is added in 600ml oxolane, and
Add Lithium hydrate 70g, be stirred at room temperature and carry out reacting 24 hours, when point plate detection R -1- hydroxyl acenaphthene acetyl compound point disappears
Stopped reaction；After adding 300ml water, reactant liquor is concentrated, is boiled off oxolane, then with dichloromethane, surplus solution is entered
Row extracts, divides liquid, drying, concentration, crosses column purification, obtains R -1- hydroxyl acenaphthene 40.98g, this walks yield 97.9%, product ee value is
99.7%.
Claims (5)
1. a kind of synthesis of 1- hydroxyl acenaphthene with Chiral Separation method it is characterised in that comprising the following steps：
1) in autoclave, add a certain amount of alcohol as solvent, then add raw material 1- acenaphthene ketone, hydrogenation catalyst by a certain percentage
Agent, then sealed reactor, exclude air, be warming up to suitable temperature after being passed through hydrogen and reacted, obtain 1- hydroxyl acenaphthene；
2) in organic solvent toluene, with step 1) gained 1- hydroxyl acenaphthene as raw material, by a certain percentage add acry radical donor, fat
Enzyme, carries out kinetic resolution reaction at a certain temperature, obtains acyl compounds and the S-1- hydroxyl acenaphthene of R-1- hydroxyl acenaphthene, this
Two kinds of compounds can be obtained by column chromatography for separation, and this step reaction two kinds of product yield of gained is all up to 98 about, ee value>
99%；
3) in organic solvent toluene, with step 1) gained 1- hydroxyl acenaphthene as raw material, by a certain percentage add acry radical donor, fat
Enzyme, racemization catalyst, carry out Dynamic Kinetic Resolution reaction at a certain temperature, obtain the acyl compounds of R-1- hydroxyl acenaphthene；
4) by step 2) or step 3) acyl compounds of gained R-1- hydroxyl acenaphthene are added to the tetrahydrochysene furan prepared by a certain percentage
Mutter with the mixed solution of Lithium hydrate in, be stirred overnight at room temperature reaction, detect extent of reaction, reaction terminate after, cross column purification can
Obtain sterling R-1- hydroxyl acenaphthene, the optical purity of final products can reach more than 99%, and product yield also has 90% about；According to
Described in upper step, equation of the present invention is as follows：
2. according to claim 1 a kind of synthesis of 1- hydroxyl acenaphthene with Chiral Separation method it is characterised in that：Right will
The step 1 asking 1) described in hydrogenation catalyst produced ni-type catalyst AMG-1200 by upper Hisoon is triumphant；It adds quality is former
The 5%～20% of material 1- acenaphthene ketone quality.
3. according to claim 1 a kind of synthesis of 1- hydroxyl acenaphthene with Chiral Separation method it is characterised in that：Right will
The step 2 asking 1) and step 3) described in acry radical donor be parachlorophenol acetass, its addition rubs for raw material 1- hydroxyl acenaphthene
1.0～1.5 times of that amount.
4. according to claim 1 a kind of synthesis of 1- hydroxyl acenaphthene with Chiral Separation method it is characterised in that：Right will
The step 2 asking 1) and step 3) described in Digestive Enzyme be porcine pancreatic lipase PPL, its addition is raw material 1- hydroxyl acenaphthene quality
1%～10%.
5. according to claim 1 a kind of synthesis of 1- hydroxyl acenaphthene with Chiral Separation method it is characterised in that：Right will
The step 3 asking 1) described in racemization catalyst be acidic resins D006, its addition be raw material 1- hydroxyl acenaphthene quality 5%～
20%.
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Citations (3)
| 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 |
| WO2014106238A1 (en) * | 2012-12-31 | 2014-07-03 | Fang, Qun, Kevin | Heterocyclic compounds and methods of use thereof |
| CN104262093A (en) * | 2014-10-09 | 2015-01-07 | 王同俊 | R-1-(3-methylphenyl)ethanol and synthesis of ester thereof |
-
2016
- 2016-09-04 CN CN201610800685.7A patent/CN106397116A/en active Pending
Patent Citations (3)
| 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 |
| WO2014106238A1 (en) * | 2012-12-31 | 2014-07-03 | Fang, Qun, Kevin | Heterocyclic compounds and methods of use thereof |
| CN104262093A (en) * | 2014-10-09 | 2015-01-07 | 王同俊 | R-1-(3-methylphenyl)ethanol and synthesis of ester thereof |
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