CN104263796A - Preparation method of R-1-aminotetralin - Google Patents

Preparation method of R-1-aminotetralin Download PDF

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CN104263796A
CN104263796A CN201410463547.5A CN201410463547A CN104263796A CN 104263796 A CN104263796 A CN 104263796A CN 201410463547 A CN201410463547 A CN 201410463547A CN 104263796 A CN104263796 A CN 104263796A
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preparation
tetrahydro naphthylamine
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optical purity
naphthylamine
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CN104263796B (en
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王际宽
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Jiangxi Kai Di biotechnology Co Ltd
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王际宽
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Abstract

The invention relates to a preparation method of R-1-aminotetralin. The preparation method comprises the following steps: taking 1-tetralone (I) as a raw material and KT-02 (nickel type) as a catalyst to carry out reductive amination under the condition of high pressure to obtain 1-aminotetralin (II); after obtaining II, introducing hydrogen to an autoclave to resolve II by using Novozym435 as resolvase, D-(-)-O-acetylmandelic acid as an acyl donor and KT-02 as a racemisation catalyst and completely transforming II to obtain a compound III (with ee value of 99%); after purifying III, carrying out acidolysis on III to obtain a compound IV and alkalifying, extracting, drying and concentrating IV to obtain R-1-aminotetralin (V), wherein the product yield is over 90% and the ee value is more than 99% in each step. The preparation method has the characteristics of cheap and accessible catalyst, full utilization of the raw material, good product yield, high optical purity, and the like and has great guidance and application values in production and preparation of R-1-aminotetralin.

Description

A kind of preparation method of R-1-tetrahydro naphthylamine
Technical field
The present invention relates to a kind of preparation method of optical homochiral amine, particularly relate to the preparation method of optical purity R-1-tetrahydro naphthylamine.
Background technology
R-1-tetrahydro naphthylamine, as important medicinal intermediates, has a wide range of applications in new drug synthesis field.In recent years, the great interest of medicament research and development personnel is caused.It is the important intermediate that protein inhibitor of dying is adjusted in synthesis.Adjusting dies is one of mechanism of necrocytosis, utilizes this effect can Therapeutic cancer, senile dementia and autoimmune conditions etc. effectively.
At present, prepare R-1-tetrahydro naphthylamine and generally adopt first preparation 1-tetrahydro naphthylamine racemic modification (USP2001003136.2001-07-07; Bio.Med.Chem.2004.12 (15):
Method 4189-4196) split again, also has (the J.Org.Chem.2006.71.6859-6862 adopting asymmetric catalysis to obtain optical purity 1-tetrahydro naphthylamine; Tetrahedron Asym.1998.9,4369-4379).But all there is the problems such as the low and the finished product optical purity of product yield is bad in these methods reported.
Summary of the invention
The technical problem to be solved in the present invention is that R-1-tetrahydro naphthylamine was preparing the high yield in planting and high-optical-purity.
In order to solve the problem, the invention provides a kind of preparation method of optical purity R-1-tetrahydro naphthylamine: 1) in autoclave, add ALPHA-tetralone (I) and anhydrous methanol in the ratio of mass volume ratio 1:5-10, then add KT-02(ni-type catalyzer in the ratio of ALPHA-tetralone massfraction 1%-10%); Air passes into liquefied ammonia in the ratio of 50%-80%, passes into hydrogen to pressure 2-5MPa in last autoclave after getting rid of, and heats up and reacts; After TLC detection ALPHA-tetralone transforms completely, terminate reaction, concentrated, obtain 1-tetrahydro naphthylamine (II); 2) in autoclave, take toluene as solvent, the ratio of 1:1.0-2.0 adds raw material 1-tetrahydro naphthylamine and acry radical donor D-(-)-O-ethanoyl amygdalic acid in molar ratio, then lipase Novozym 435 and KT-02 is added in the ratio of raw material 1-tetrahydro naphthylamine massfraction 1%-10%, after nitrogen replacement is carried out in autoclave sealing, pass into hydrogen to pressure 0.1-1.0MPa and be warming up to 40-70 DEG C reaction 24 hours, 1-tetrahydro naphthylamine can be converted into compound completely, and product ee value reaches 99%; After reaction terminates, solution is concentrated, column chromatography, obtain compound III sterling; 3) be dissolved in the alcohol of 10 times of volume ratios and the mixing solutions of acid solution (v/v=1:1) by compound III sterling obtained in step 2, then heating reflux reaction 15 hours, compound III complete hydrolysis obtains compounds Ⅳ; 4) step 3 gained compounds Ⅳ is carried out alkalinisation treatment, then by organic solvent extraction, drying, concentrated can obtain optically pure R-1-tetrahydro naphthylamine, final whole step product yield can reach more than 90%, and optical purity of products is 99%.
The present invention is in preparation R-1-tetrahydro naphthylamine process, and use KT-02 as reduction amination catalyzer and racemization catalyst, have catalyzer cheap and easy to get, use safety, catalytic efficiency is good, transformation efficiency advantages of higher.1-tetrahydro naphthylamine is that acry radical donor can ensure under the condition of high transformation efficiency with D-(-)-O-ethanoyl amygdalic acid in split process, and optical purity of products might as well.
Specific implementation method:
1) preparation of 1-tetrahydro naphthylamine
In the autoclave of 2000ML, add 146G Tetralone an intermediate of Sertraline (I), 1000ML anhydrous methanol, 15GKT-02; After nitrogen replacement excluding air, pass into 102G liquefied ammonia, pass into hydrogen in last autoclave to pressure 5MPa, be warmed up to 80 DEG C and react; After TLC detection ALPHA-tetralone transforms completely, terminate reaction, filter, concentrate, obtain 1-tetrahydro naphthylamine (II) 145G;
2) preparation of compound III
1000mL toluene is added as solvent in the autoclave of 2000mL, add 117.6g1-tetrahydro naphthylamine, 172g D-(-)-O-ethanoyl amygdalic acid successively, 10g lipase Novozym 435 and 12gKT-02, after adding, with nitrogen, air in still is replaced after sealing autoclave, then in autoclave, pass into hydrogen to pressure 1.0MP, open and stir, and be warming up to 70 DEG C and react; After 24 hours, sampling detects, and 1-tetrahydro naphthylamine disappears and is converted into compound III completely, and product ee value reaches 99%; After reaction terminates, concentrated by solution, be then that the normal hexane of 10:1 and alcohol mixed solvent carry out column chromatography by volume ratio, obtain pure compound III 144.2G, yield is 95.4%.
3) compound III acidolysis obtains compounds Ⅳ
Joined by compound III 94.6g obtained in upper step in the solution that the ethanol of 1000ml and concentrated hydrochloric acid mix with volume ratio 1:1, then reflux, reacted after 12 hours, put plate detection compound III complete hydrolysis and obtained compounds Ⅳ.
4) alkalization obtains R-1-tetrahydro naphthylamine (V)
The solution that past step 3 gained reacts completely adds the methylene dichloride of 500mL, then slowly sodium hydroxide solution is dripped, and stir, detect solution pH value to 13, stop adding sodium hydroxide solution, separatory, upper water liquid uses the dichloromethane extraction 3 times of 200mL again, carry out drying by extracting the dichloromethane solution anhydrous sodium sulphate obtained several times, concentrated to obtain R-1-tetrahydro naphthylamine (V) 67.7g, yield is the ee value that 92.1%, HPLC detects the finished product is 99.5%.

Claims (5)

1. the preparation method of optical purity R-1-tetrahydro naphthylamine is characterized in that: 1) in autoclave, add ALPHA-tetralone (I) and anhydrous methanol in the ratio of mass volume ratio 1:5-10, then add KT-02 in the ratio of ALPHA-tetralone massfraction 5%-20%; Air passes into liquefied ammonia in the ratio of I quality 50%-80%, passes into hydrogen to pressure 2-5MPa in last autoclave after getting rid of, and heats up and reacts; After TLC detection ALPHA-tetralone transforms completely, terminate reaction, concentrated, obtain 1-tetrahydro naphthylamine (II); 2) in autoclave, take toluene as solvent, the ratio of 1:1.0-2.0 adds raw material 1-tetrahydro naphthylamine and acry radical donor D-(-)-O-ethanoyl amygdalic acid in molar ratio, then lipase Novozym 435 and Raney's nickel is added in the ratio of raw material 1-tetrahydro naphthylamine massfraction 1%-10%, after nitrogen replacement is carried out in autoclave sealing, pass into hydrogen to pressure 0.1-1.0MPa and be warming up to 40-70 DEG C reaction 24 hours, 1-tetrahydro naphthylamine is converted into compound III completely, and product ee value reaches 99%; After reaction terminates, solution is concentrated, column chromatography, obtain compound III sterling; 3) be dissolved in the alcohol of 10 times of volume ratios and the mixing solutions of acid solution (v/v=1:1) by compound III sterling obtained in step 2, then heating reflux reaction 12 hours, compound III complete hydrolysis obtains compounds Ⅳ; 4) step 3 gained compounds Ⅳ is carried out alkalinisation treatment, then by organic solvent extraction, drying, concentrated can obtain optically pure R-1-tetrahydro naphthylamine, final each step product yield all can reach more than 90%, and optical purity of products is 99%; According to described, its reaction equation is as follows:
2. according to claim 1, the preparation method of optical purity R-1-tetrahydro naphthylamine is characterized in that step 1) in reduction amination catalyzer used be KT-02.
3. according to claim 1, the preparation method of optical purity R-1-tetrahydro naphthylamine is characterized in that step 2) in acry radical donor be D-(-)-O-ethanoyl amygdalic acid, racemization catalyst is KT-02.
4. according to claim 1, the preparation method of optical purity R-1-tetrahydro naphthylamine is characterized in that step 3) in alcohol be methyl alcohol or ethanol; Acid is hydrochloric acid or sulfuric acid.
5. according to claim 1, the preparation method of optical purity R-1-tetrahydro naphthylamine is characterized in that step 4) in alkalinisation treatment alkali used be sodium hydroxide, potassium hydroxide or ammoniacal liquor; Extracting organic solvent used is toluene, methylene dichloride, 1,2-ethylene dichloride, ether etc.
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Cited By (6)

* Cited by examiner, † Cited by third party
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CN105063161A (en) * 2015-08-18 2015-11-18 陈永军 Method for preparing R-1-aminoindan
CN105087742A (en) * 2015-08-18 2015-11-25 陈永军 Method for preparing R-6-hydroxy-1-aminoindane through dynamic kinetic resolution
CN106380408A (en) * 2016-09-04 2017-02-08 王际菊 Preparation of optical homochiral amine
CN106381324A (en) * 2016-09-04 2017-02-08 王际菊 Preparation method of R-7-chloro-1-tetralinylamine
CN106397217A (en) * 2016-09-04 2017-02-15 王际菊 Method for synthesizing dextral alpha-cyclohexylbenzylamine
CN106480117A (en) * 2016-09-04 2017-03-08 王际宽 The synthesis of 6 methoxyl group 1 tetralin amine and fractionation

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CN102766672A (en) * 2011-05-06 2012-11-07 王际宽 Kinetic resolution method of chiral amine

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105063161A (en) * 2015-08-18 2015-11-18 陈永军 Method for preparing R-1-aminoindan
CN105087742A (en) * 2015-08-18 2015-11-25 陈永军 Method for preparing R-6-hydroxy-1-aminoindane through dynamic kinetic resolution
CN105087742B (en) * 2015-08-18 2018-09-14 陈永军 Dynamic Kinetic Resolution prepares R-6- hydroxyl -1- aminoidans
CN105063161B (en) * 2015-08-18 2018-11-09 陈永军 A kind of preparation method of R-1- aminoidans
CN106380408A (en) * 2016-09-04 2017-02-08 王际菊 Preparation of optical homochiral amine
CN106381324A (en) * 2016-09-04 2017-02-08 王际菊 Preparation method of R-7-chloro-1-tetralinylamine
CN106397217A (en) * 2016-09-04 2017-02-15 王际菊 Method for synthesizing dextral alpha-cyclohexylbenzylamine
CN106480117A (en) * 2016-09-04 2017-03-08 王际宽 The synthesis of 6 methoxyl group 1 tetralin amine and fractionation

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