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 PDF

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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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aminoidan
hydroxyl
kinetic resolution
dynamic kinetic
aminoindane
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CN105017035B (en
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陈永军
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Shandong Provincial Hospital
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陈永军
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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

Dynamic Kinetic Resolution preparation (S)-6-hydroxyl-1-aminoidan
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.
CN201510495063.3A 2015-08-13 2015-08-13 Method for preparing (S)-6-hydroxy-1-aminoindane through dynamic kinetic resolution Expired - Fee Related CN105017035B (en)

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Cited By (1)

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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

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WO2010054278A2 (en) * 2008-11-10 2010-05-14 Schering Corporation Compounds for the treatment of inflammatory disorders
CN102533922A (en) * 2011-12-14 2012-07-04 浙江大学 Method for catalyzing dynamic kinetic resolution of arylamine via racemization catalyst
CN104630170A (en) * 2013-11-08 2015-05-20 中国科学院天津工业生物技术研究所 New (R)-transaminase from Trichoderma reesei and application thereof
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Cited By (2)

* Cited by examiner, † Cited by third party
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

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