CN105087742B - Dynamic Kinetic Resolution prepares R-6- hydroxyl -1- aminoidans - Google Patents
Dynamic Kinetic Resolution prepares R-6- hydroxyl -1- aminoidans Download PDFInfo
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Abstract
The present invention relates to a kind of methods that Dynamic Kinetic Resolution prepares 6 hydroxyls of R, 1 aminoidan.The present invention is in autoclave, in the presence of hydrogen; using fold Candida lipase as biological resolution catalyst; D () O acetyl group mandelic acid is acry radical donor; armorphous Raney nickel KT 02 is racemization catalyst; carry out the Dynamic Kinetic Resolution reaction of one pot of change; convert 6 hydroxyl, 1 aminoidan to 6 hydroxyls of R, 1 aminoidan acyl compounds, acyl compounds operate 6 hydroxyls of R, 1 aminoidan to obtain ee values and be more than 99% through sour water solution, alkali are free etc..The present invention has the features such as easy to operate, racemization catalyst is cheap and easy to get, raw material utilization is complete, optical purity of products is high, in prepared by the production of 6 hydroxyls of R, 1 aminoidan, has great instruction and application value.
Description
Technical field
The present invention relates to a kind of fractionation preparation methods of optical homochiral compound more particularly to a kind of Dynamic Kinetic to tear open
Divide the method for preparing R-6- hydroxyl -1- aminoidans.
Background technology
Indene compound can be used as the intermediate of medicine and pesticide, and recent years, domestic outgoing has been opened much using indenes as parent
Series compound drug and veterinary drug.R-6- hydroxyl -1- aminoidans chiral medicinal the intermediate important as one of which,
In existing correlative study, it is rarely reported on how to which optical voidness R-6- hydroxyl -1- aminoidans are prepared.By studying text
It offers it can be found that yet there are no on how to prepare R-6- hydroxyl -1- amino indenes using dynamics and Dynamic Kinetic Resolution
It is full.The present invention is to split catalyst with fold Candida lipase, and KT-02 is racemization catalyst, by selecting D- (-)-O- second
Acyl group mandelic acid is that acry radical donor is successfully realized Dynamic Kinetic Resolution preparation R-6- hydroxyl -1- aminoidans, and final production
Product yield is good, and purity is high.
Invention content
To solve the above-mentioned problems, the present invention is on the basis of Kinetic Resolution, it is proposed that prepared by Dynamic Kinetic Resolution
R-6- hydroxyl -1- aminoidans.Concrete operations are as follows：It is catalyzed by biological resolution of fold Candida lipase in autoclave
Agent, D- (-)-O- acetyl group mandelic acids are acry radical donor, and KT-02 is racemization catalyst, exist in hydrogen, under certain temperature to
6- hydroxyl -1- aminoidans carry out Dynamic Kinetic Resolution, convert 6- hydroxyl -1- aminoidans to R-6- hydroxyl -1- amino
Indane acyl compounds, acyl compounds using under nitrogen protection sour water solution and alkali is free can be obtained R-6- hydroxyls -1-
Aminoidan, and the optical purity of final products is more than 99%.Biological resolution catalyst used is fold candida albicans fat in the present invention
Fat enzyme, addition is the 1%-10% of 6- hydroxyl -1- aminoidan quality in reaction system；Solvent is toluene, and volume number is 6-
5-20 times of hydroxyl -1- amino indenes mass numbers；Acry radical donor is D- (-)-O- acetyl group mandelic acids, with 6- hydroxyl -1- amino
The rate of charge of indenes is molar ratio 1:1~2.0；Racemization catalyst is KT-02, and addition is 6- hydroxyl -1- amino indenes in reaction system
The 5%-20% of quality；The pressure for being passed through hydrogen is 1.0-2.0MPa；The temperature of reaction is 45-70 DEG C.
The present invention is successfully prepared R-6- hydroxyl -1- aminoidans using the method for Dynamic Kinetic Resolution.The present invention's
Technique can ensure that raw material 6- hydroxyl -1- aminoidans are fully utilized, while resulting product optical purity is high, and ee values are reachable
99% or more；The racemization catalyst utilized in invention is KT-02, it is a kind of industrialized armorphous ni-loaded catalyst, is had
The racemization ability of Raney nickel, while property is stablized, and is contacted with air reactionless, ensure that the safety of operation, while price
Also more cheap, it is very suitable for industrial applications.It is urged using complete, easy to operate, racemization in conclusion the present invention has raw material
The features such as agent is cheap and easy to get, optical purity of products is high has very big in prepared by the production of R-6- hydroxyl -1- aminoidans
Guidance and application value.
Specific implementation method：
Embodiment 1
1, the fractionation of 6- hydroxyls -1- aminoidans
In 1000ML autoclaves, 500ML toluene, 74.5G6- hydroxyl -1- aminoidans, 115.9g D- (-)-O- is added
Acetyl group mandelic acid, 6g folds Candida lipase and 10g KT-02, sealing autoclave are set air in kettle with nitrogen
Hydrogen is passed through after changing in autoclave to pressure 1.0MP, opens stirring, and be warming up to 50 DEG C and reacted；After 19 hours, sampling
Detection, 6- hydroxyl -1- aminoidans are fully converted to the acetyl compounds of R-6- hydroxyl -1- aminoidans；After reaction,
The solution is concentrated, column chromatography, obtains the acetyl compounds 90.8g of pure R-6- hydroxyls -1- aminoidans, yield 95.1%.
2, acidolysis obtains R-6- hydroxyl -1- aminoidans
Take repeat several times the acetyl compounds 95.5g of R-6- hydroxyl -1- aminoidans made from previous step is added
To 1000ml ethyl alcohol and concentrated hydrochloric acid with volume ratio 1:In the solution of 1 mixing, it is heated to reflux under nitrogen protection, after reacting 9 hours,
The acetyl compounds complete hydrolysis of contact plate detection R-6- hydroxyl -1- aminoidans obtains R-6- hydroxyl -1- aminoidan hydrochlorides.
3, alkalization obtains R-6- hydroxyl -1- aminoidans
Up sodium hydroxide solution is slowly added dropwise in the step gained solution that the reaction was complete, and is stirred, and detects solution pH value
To 12, stop addition sodium hydroxide solution, add 300ML dichloromethane, liquid separation, upper layer aqueous uses the dichloro of 100mL again
Methane extracts 3 times, and the dichloromethane solution being obtained by extraction several times is dried with anhydrous sodium sulfate, is concentrated to give R-6- hydroxyls-
1- aminoidan 66.0g, yield 88.6%, the ee values that HPLC detects final products are 99.7%.
Embodiment 2
1, the fractionation of 6- hydroxyls -1- aminoidans
In 1000ML autoclaves, 500ML toluene, 74.5G6- hydroxyl -1- aminoidans, 144.9g D- are sequentially added
(-)-O- acetyl group mandelic acids, 7g folds Candida lipase and 13g KT-02, sealing autoclave, with nitrogen by air in kettle
Into line replacement, it is then passed through hydrogen in autoclave to pressure 1.5MP, opens stirring, and be warming up to 70 DEG C and reacted；13 is small
Shi Hou, sample detection, 6- hydroxyl -1- aminoidans are fully converted to the acetyl compounds of R-6- hydroxyl -1- aminoidans；Instead
After answering, the solution is concentrated, column chromatography, obtains the acetyl compounds 90.4g of R-6- hydroxyl -1- aminoidans, yield
It is 94.7%.
2, acidolysis obtains R-6- hydroxyl -1- aminoidan salt
The acetyl compounds 95.5g for repeating R-6- hydroxyl -1- aminoidans made from previous step several times is taken to be added to
The ethyl alcohol and the concentrated sulfuric acid of 1000ml is with volume ratio 2:In the solution of 1 mixing, it is heated to reflux under nitrogen protection, after reacting 10 hours,
The acetyl compounds complete hydrolysis of contact plate detection R-6- hydroxyl -1- aminoidans obtains R-6- hydroxyl -1- aminoidan sulfate.
3, alkalization obtains R-6- hydroxyl -1- aminoidans
Up ammonia spirit is slowly added dropwise in the step gained solution that the reaction was complete, and is stirred, detection solution pH value to 13,
Stop addition ammonia spirit, add 300ML ethyl acetate, liquid separation, lower layer's aqueous uses the ethyl acetate extraction 3 of 100mL again
It is secondary, the ethyl acetate solution being obtained by extraction several times is dried with anhydrous sodium sulfate, is concentrated to give R-6- hydroxyl -1- aminoidans
67.6g, yield 90.7%, the ee values that HPLC detects final products are 99.6%.
Claims (7)
1. Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：In autoclave, in the presence of hydrogen,
Using fold Candida lipase as biological resolution catalyst, D- (-)-O- acetyl group mandelic acids are acry radical donor, and armorphous nickel is urged
Agent KT-02 is racemization catalyst, carries out the Dynamic Kinetic Resolution reaction of one pot of change, 6- hydroxyl -1- aminoidans are converted
For R-6- hydroxyl -1- aminoidan acyl compounds, acyl compounds through sour water solution, alkali it is free etc. operate ee values are more than 99%
R-6- hydroxyl -1- aminoidans；According to described, reaction equation is as follows：
2. according to claim 1 Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：Right is wanted
Ask the biological resolution catalyst described in 1 for fold Candida lipase, addition is 6- hydroxyl -1- amino indenes in reaction system
The 1%-10% of quality.
3. according to claim 1 Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：Right is wanted
It is toluene to seek the solvent described in 1, and volume number is 5-20 times of 6- hydroxyl -1- amino indenes mass numbers.
4. according to claim 1 Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：Right is wanted
It is D- (-)-O- acetyl group mandelic acids to seek the acry radical donor described in 1, and the rate of charge with 6- hydroxyl -1- amino indenes is molar ratio
1:1~2.0.
5. according to claim 1 Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：Right is wanted
Ask the racemization catalyst described in 1 for KT-02, addition is the 5%-20% of 6- hydroxyl -1- amino indenes quality in reaction system.
6. according to claim 1 Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：Right is wanted
It is 1.0-2.0MPa to ask and be passed through the pressure of hydrogen described in 1.
7. according to claim 1 Dynamic Kinetic Resolution prepare R-6- hydroxyl -1- aminoidans it is characterized in that：Right is wanted
It is 45-70 DEG C to seek the temperature described in 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2285769B1 (en) * | 2008-06-02 | 2014-08-13 | Generics [UK] Limited | A process for the preparation of enantiomerically pure amines |
| CN104263796A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2285769B1 (en) * | 2008-06-02 | 2014-08-13 | Generics [UK] Limited | A process for the preparation of enantiomerically pure amines |
| CN104263796A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
Non-Patent Citations (1)
| Title |
|---|
| "动态动力学拆分制备(R)-1-氨基茚满";戴晓庭等;《有机化学》;20140124;第34卷(第5期);2结论，3.4,3.5 * |
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