CN105017035A - Method for preparing (S)-6-hydroxy-1-aminoindane through dynamic kinetic resolution - Google Patents
Method for preparing (S)-6-hydroxy-1-aminoindane through dynamic kinetic resolution Download PDFInfo
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- CN105017035A CN105017035A CN201510495063.3A CN201510495063A CN105017035A CN 105017035 A CN105017035 A CN 105017035A CN 201510495063 A CN201510495063 A CN 201510495063A CN 105017035 A CN105017035 A CN 105017035A
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- Prior art keywords
- aminoidan
- hydroxyl
- kinetic resolution
- dynamic kinetic
- aminoindane
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- 238000000034 method Methods 0.000 title abstract description 7
- MOUPGBDOLGDVNW-VIFPVBQESA-N (3s)-3-amino-2,3-dihydro-1h-inden-5-ol Chemical compound C1=C(O)C=C2[C@@H](N)CCC2=C1 MOUPGBDOLGDVNW-VIFPVBQESA-N 0.000 title abstract 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims abstract description 7
- 239000004367 Lipase Substances 0.000 claims abstract description 7
- 102000004882 Lipase Human genes 0.000 claims abstract description 7
- 108090001060 Lipase Proteins 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 235000019421 lipase Nutrition 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 230000006340 racemization Effects 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 claims abstract description 3
- 239000003513 alkali Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 229960002510 mandelic acid Drugs 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 4
- -1 acetyl compound Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- MOUPGBDOLGDVNW-UHFFFAOYSA-N 3-amino-2,3-dihydro-1h-inden-5-ol Chemical compound C1=C(O)C=C2C(N)CCC2=C1 MOUPGBDOLGDVNW-UHFFFAOYSA-N 0.000 abstract 2
- DQVWXLRNCXQVKH-VIFPVBQESA-N acetyl (2s)-2-hydroxy-2-phenylacetate Chemical compound CC(=O)OC(=O)[C@@H](O)C1=CC=CC=C1 DQVWXLRNCXQVKH-VIFPVBQESA-N 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002469 indenes Chemical class 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention relates to a method for preparing (S)-6-hydroxy-1-aminoindane through dynamic kinetic resolution. According to the method, 6-hydroxy-1-aminoindane serves as the raw materials, fold candida lipase serves as a resolution catalyst, L-(+)-O-acetyl-Alpha-hydroxyphenylacetic acid serves as an acyl donor, KT-02 serves as a racemization catalyst, reaction is performed in a hydrogen environment, and the 6-hydroxy-1-aminoindane can be converted into an acetyl compound of the (S)-6-hydroxy-1-aminoindane. After the compound is purified, acid hydrolysis and alkali free operation are performed on the compound under the protection of nitrogen, then the (S)-6-hydroxy-1-aminoindane is obtained, and an ee value of the final product is above 99 percent. According to the method, the advantages that operation is easy, the racemization catalyst is low in price and easy to obtain, the raw materials can be completely utilized and the optical purity of the product is high are achieved, and great instruction and application value is achieved in the production preparation of the (S)-6-hydroxy-1-aminoindane.
Description
Technical field
The present invention relates to a kind of fractionation preparation method of optical homochiral compound, particularly relate to the method for a kind of Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan.
Background technology
Indene compound can be used as the intermediate of medicine and agricultural chemicals, recent years, and domestic outgoing has opened the series compound medicine and the veterinary drug that with indenes are much parent.S-6-hydroxyl-1-aminoidan, as wherein a kind of important chiral medicinal intermediate, in existing 6-hydroxyl-1-aminoidan relevant report, then rarely has report about how preparing optical purity S-6-hydroxyl-1-aminoidan.Can be found by Research Literature, utilize kinetics and Dynamic Kinetic Resolution to prepare S type compound, be all a technical barrier for any product.How to prepare optically pure S-6-hydroxyl-1-aminoidan simply and easily and become problem to be solved by this invention.
Summary of the invention
In order to solve the problem; the invention provides the method for a kind of Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan: with 6-hydroxyl-1-aminoidan be raw material, fold Candida lipase for splitting catalyzer, L-(+)-O-ethanoyl amygdalic acid is that acry radical donor, KT-02 are for racemization catalyst; react under atmosphere of hydrogen, 6-hydroxyl-1-aminoidan is converted into the acetyl compounds of (S)-6-hydroxyl-1-aminoidan.After product purification, under nitrogen protection, dissociate through acid hydrolysis and alkali and operate (S)-6-hydroxyl-1-aminoidan, and the finished product ee value >99%.In aforesaid operations, solvent used is toluene, and its volume number is 10-20 times of 6-hydroxyl-1-aminoidan total mass number; Acry radical donor is L-(+)-O-ethanoyl amygdalic acid, and the feed ratio of itself and 6-hydroxyl-1-aminoidan is mol ratio 1:1 ~ 2.0; Enzyme is fold Candida lipase, and in reaction system, add-on is the 1%-10% of 6-hydroxyl-1-aminoidan quality; Racemization catalyst is KT-02, and in reaction system, add-on is the 5%-20% of 6-hydroxyl-1-aminoidan quality; The pressure of hydrogen is 1.0-2.0MPa, and temperature of reaction is 45-70 DEG C.
The present invention utilizes common raw material successfully to achieve with Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan, also possess simultaneously simple to operate, racemization catalyst is cheap and easy to get, prepared using is complete, optical purity of products high.In the manufacture of (S)-6-hydroxyl-1-aminoidan, have and instruct greatly and using value.
Specific implementation method:
Embodiment 1
1, the fractionation of 6-hydroxyl-1-aminoidan
In 1000ML autoclave, add 500ML toluene successively, 74.5G6-hydroxyl-1-aminoidan, 115.9g L-(+)-O-ethanoyl amygdalic acid, 6g fold Candida lipase and 10g KT-02, sealing autoclave, with nitrogen, air in still is replaced, then in autoclave, pass into hydrogen to pressure 1.0MP, open and stir, and be warming up to 55 DEG C and react; After 20 hours, sampling detects, and 6-hydroxyl-1-aminoidan is converted into the acetyl compounds of (S)-6-hydroxyl-1-aminoidan completely; After reaction terminates, concentrated by solution, column chromatography, obtain the acetyl compounds 90.3g of pure (S)-6-hydroxyl-1-aminoidan, yield is 94.6%.
2, acidolysis obtains (S)-6-hydroxyl-1-aminoidan salt
Getting the acetyl compounds 95.5g repeating obtained (the S)-6-hydroxyl-1-aminoidan of previous step several times joins in the solution that the ethanol of 1000ml and concentrated hydrochloric acid mix with volume ratio 1:1; under nitrogen protection; reflux is after 8 hours, and the acetyl compounds complete hydrolysis that some plate detects (S)-6-hydroxyl-1-aminoidan obtains (S)-6-hydroxyl-1-aminoidan hydrochloride.
3, alkalization obtains (S)-6-hydroxyl-1-aminoidan
The solution that up step gained reacts completely slowly drips sodium hydroxide solution, and stir, detect solution pH value to 12, stop adding sodium hydroxide solution, then add 300ML methylene dichloride, separatory, upper water liquid uses the dichloromethane extraction 3 times of 100mL again, carry out drying by extracting the dichloromethane solution anhydrous sodium sulphate obtained several times, concentrated to obtain (S)-6-hydroxyl-1-aminoidan 67.9g, yield is the ee value that 91.2%, HPLC detects the finished product is 99.6%.
Embodiment 2
1, the fractionation of 6-hydroxyl-1-aminoidan
In 1000ML autoclave, add 500ML toluene successively, 74.5G6-hydroxyl-1-aminoidan, 144.9g L-(+)-O-ethanoyl amygdalic acid, 7g fold Candida lipase and 12g KT-02, sealing autoclave, with nitrogen, air in still is replaced, then in autoclave, pass into hydrogen to pressure 1.5MP, open and stir, and be warming up to 65 DEG C and react; After 15 hours, sampling detects, and 6-hydroxyl-1-aminoidan is converted into the acetyl compounds of (S)-6-hydroxyl-1-aminoidan completely; After reaction terminates, concentrated by solution, column chromatography, obtain the acetyl compounds 88.9g of pure (S)-6-hydroxyl-1-aminoidan, yield is 93.1%.
2, acidolysis obtains (S)-6-hydroxyl-1-aminoidan salt
Getting the acetyl compounds 95.5g repeating obtained (the S)-6-hydroxyl-1-aminoidan of previous step several times joins in the solution that the ethanol of 1000ml and the vitriol oil mix with volume ratio 2:1; reflux under nitrogen protection; react after 10 hours, the acetyl compounds complete hydrolysis that some plate detects (S)-6-hydroxyl-1-aminoidan obtains (S)-6-hydroxyl-1-aminoidan vitriol.
3, alkalization obtains (S)-6-hydroxyl-1-aminoidan
The solution that up step gained reacts completely slowly drips ammonia soln, and stir, detect solution pH value to 13, stop adding ammonia soln, then add 300ML ethyl acetate, separatory, lower layer of water liquid uses the extraction into ethyl acetate 3 times of 100mL again, carry out drying by extracting the ethyl acetate solution anhydrous sodium sulphate obtained several times, concentrated to obtain (S)-6-hydroxyl-1-aminoidan 68.5g, yield is the ee value that 91.9%, HPLC detects the finished product is 99.5%.
Claims (7)
1. Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that: with 6-hydroxyl-1-aminoidan for raw material, fold Candida lipase is for splitting catalyzer, L-(+)-O-ethanoyl amygdalic acid is acry radical donor, KT-02 is racemization catalyst, react under atmosphere of hydrogen, 6-hydroxyl-1-aminoidan is converted into the acetyl compounds of (S)-6-hydroxyl-1-aminoidan, after product purification, under nitrogen protection, dissociate through acid hydrolysis and alkali and operate (S)-6-hydroxyl-1-aminoidan, and the finished product ee value >99%, according to described, its reaction equation is as follows:
。
2. according to claim 1, Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that the solvent described in claim 1 is toluene or normal hexane, and its volume number is 5-20 times of 6-hydroxyl-1-aminoidan total mass number.
3. according to claim 1; Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that the acry radical donor described in claim 1 is L-(+)-O-ethanoyl amygdalic acid, and the feed ratio of itself and 6-hydroxyl-1-aminoidan is mol ratio 1:1 ~ 2.0.
4. according to claim 1, Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that the enzyme described in claim 1 is fold Candida lipase, and in reaction system, add-on is the 1%-10% of 6-hydroxyl-1-aminoidan quality.
5. according to claim 1, Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that the racemization catalyst described in claim 1 is KT-02, and in reaction system, add-on is the 5%-20% of 6-hydroxyl-1-aminoidan quality.
6. according to claim 1, Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that passing into described in claim 1 pressure of hydrogen is 1.0-2.0MPa.
7. according to claim 1, Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan is characterized in that temperature of reaction described in claim 1 is 45-70 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510495063.3A CN105017035B (en) | 2015-08-13 | 2015-08-13 | Method for preparing (S)-6-hydroxy-1-aminoindane through dynamic kinetic resolution |
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| CN201510495063.3A CN105017035B (en) | 2015-08-13 | 2015-08-13 | Method for preparing (S)-6-hydroxy-1-aminoindane through dynamic kinetic resolution |
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| CN105017035B CN105017035B (en) | 2017-05-24 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3553179A1 (en) * | 2018-04-12 | 2019-10-16 | Universität Bielefeld | Enantioselective biocatalytic preparation of 4-cyano-substituted 1-aminoindane and ozanimod |
| WO2024041962A1 (en) * | 2022-08-23 | 2024-02-29 | Bayer Aktiengesellschaft | Process for the production of (1r,2s)-2,6-dimethyl-1-indanamine using dynamic kinetic stereoisomer resolution |
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2015
- 2015-08-13 CN CN201510495063.3A patent/CN105017035B/en not_active Expired - Fee Related
Patent Citations (5)
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| CA2180841A1 (en) * | 1994-01-10 | 1995-07-13 | Sasson Cohen | 1-aminoindan derivatives and compositions thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3553179A1 (en) * | 2018-04-12 | 2019-10-16 | Universität Bielefeld | Enantioselective biocatalytic preparation of 4-cyano-substituted 1-aminoindane and ozanimod |
| WO2019197571A1 (en) | 2018-04-12 | 2019-10-17 | Universität Bielefeld | Enantioselective biocatalytic preparation of 4-cyano-substituted 1-aminoindane and ozanimod |
| CN111971398A (en) * | 2018-04-12 | 2020-11-20 | 泽尔制药有限公司 | Enantioselective biocatalytic preparation of 4-cyano-substituted 1-aminoindan and azanidod |
| WO2024041962A1 (en) * | 2022-08-23 | 2024-02-29 | Bayer Aktiengesellschaft | Process for the production of (1r,2s)-2,6-dimethyl-1-indanamine using dynamic kinetic stereoisomer resolution |
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