CN104151171A - Method for preparing optically pure R-1-naphthylethylamine by splitting - Google Patents

Method for preparing optically pure R-1-naphthylethylamine by splitting Download PDF

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CN104151171A
CN104151171A CN201410399401.9A CN201410399401A CN104151171A CN 104151171 A CN104151171 A CN 104151171A CN 201410399401 A CN201410399401 A CN 201410399401A CN 104151171 A CN104151171 A CN 104151171A
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naphthylethylamine
naphthalene ethylamine
naphthyl
ethyl
ethanamide
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CN201410399401.9A
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CN104151171B (en
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陈永军
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Liuan Jianuo Biochemical Technology Co Ltd
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Abstract

The invention relates to a method for preparing optically-pure R-1-naphthylethylamine by splitting. The method comprises the following steps: introducing hydrogen into a high-pressure kettle filled with 1-naphthylethylamine serving as a raw material, Novozym435 serving as a splitting catalyst and D-(-)-O-acetyl mandelic acid serving as an acyl donor and KT-02 (nickel type catalyst) serving as a racemization catalyst for reacting, and fully transforming the 1-naphthylethylamine to obtain (R)-(1-(1-naphthyl)ethyl)acetamide (ee value is 99 percent); and purifying amide, performing acidolysis to obtain a R-1-naphthylethylamine salt, and performing the operation of alkalization, distillation, drying, concentration and the like on the R-1-naphthylethylamine salt to obtain the R-1-naphthylethylamine, wherein the product yield and the ee value in the whole steps can be over 90 percent. The method has the characteristics of adoption of cheap and readily-available racemization catalyst, complete utilization of the raw material, high product yield and the like. The method has extremely high guidance and application values in the production and preparation of the R-1-naphthylethylamine.

Description

The method of optical purity R-1-naphthalene ethylamine is prepared in a kind of fractionation
Technical field
The present invention relates to a kind of fractionation preparation method of optical homochiral amine, relate in particular to fractionation and the preparation method of optical purity R-1-naphthalene ethylamine.
Background technology
Optically pure Chiral Amine is a kind of very important pharmaceutical intermediate.Obtain at present optically pure Chiral Amine mainly by following several method: enzyme splits (Indian J. Chem. Sect. B 2005,44,1312-1316; J. Org. Chem. 1997,62,3488-3495); Chemistry splits: with chirality Alpha-hydroxy naphthylacetic acid (US6342636; Tetrahedron:asymmetry, 1998,9,2219-2212) or the chirality glyceryl alcohol derivative of protection split (Tetrahedron:asymmetry, 1996,7,1117-1122; Tetrahedron:asymmetry, 2002,13,2277-2282); By corresponding aldehyde, through asymmetric synthesis, obtain (WO2004/110976; J. Org. Chem. 1992,57,1237-1241).
In existing method, dissymmetric synthesis cost is high and often rare to the high product of optical purity; There is the low shortcoming of utilization ratio of raw material in chemical resolution method and enzyme process kinetic resolution, only has at most 50%; And in the enzyme process Dynamic Kinetic Resolution method of existing report, the racemization catalyst of using is the mixture of the precious metal such as some rutheniums, rhodium normally, these racemization catalyst costs are high, and while using these racemization catalyst in fractionation preparation process, although realize high conversion product, be difficult to obtain high optical purity.
Summary of the invention
The technical problem to be solved in the present invention is to find a kind of cheap racemization catalyst, realizes R-1-naphthalene ethylamine simultaneously and is splitting high yield and the high-optical-purity of preparing in planting.
In order to address the above problem, the invention provides a kind of fractionation preparation method of optical purity R-1-naphthalene ethylamine: 1) in autoclave, take toluene as solvent, the ratio of 1:1.0 ~ 2.0 adds raw material 1-naphthalene ethylamine and acry radical donor D-(-)-O-ethanoyl amygdalic acid in molar ratio, finally in the ratio of raw material 1-naphthalene ethylamine massfraction 1%-10%, add lipase novozym 435 and KT-02 again, autoclave sealing is carried out after nitrogen replacement, pass into hydrogen to pressure 0.1-1.0MPa and be warming up to 40-70 ℃ of reaction 18 hours, 1-naphthalene ethylamine can be converted into completely (R)-(N-(1-naphthyl) ethyl) ethanamide, and product ee value can reach 99%, after reaction finishes, solution is concentrated, column chromatography, obtain pure (R)-(N-(1-naphthyl) ethyl) ethanamide, 2) by step 1, make ((R)-(N-(1-naphthyl) ethyl) ethanamide is dissolved in the alcohol of 10 times of volume ratios and the mixing solutions of acid solution (v/v=1:1), then heating reflux reaction is 24 hours, and (R)-(N-(1-naphthyl) ethyl) ethanamide complete hydrolysis obtains R-1-naphthalene ethylamine salt, 3) step 2 gained R-1-naphthalene ethylamine salt is carried out to alkalinisation treatment, then by organic solvent extraction, dry, concentratedly can obtain optically pure R-1-naphthalene ethylamine, final whole step product yield can reach more than 90%, and product purity is 99%.
The racemization catalyst that the present invention uses in preparing optical purity R-1-naphthalene ethylamine process is the cheap feature being easy to get for KT-02 has, and the optical purity R-1-naphthalene ethylamine yield finally preparing is good, and optical purity is high.
specific implementation method
1) split preparation (R)-(N-(1-naphthyl) ethyl) ethanamide
In the autoclave of 1000mL, add 500mL toluene as solvent, add successively 85.5g1-naphthalene ethylamine, 106.7g D-(-)-O-ethanoyl amygdalic acid, 5g lipase novozym 435 and 7gKT-02, after adding, after sealing autoclave, with nitrogen, air in still is replaced, then in autoclave, pass into hydrogen to pressure 1.0MP, open to stir, and be warming up to 60 ℃ and react; After 20 hours, sampling detects, and 1-naphthalene ethylamine disappears and is converted into (R)-(N-(1-naphthyl) ethyl) ethanamide completely, and product ee value reaches 99%; After reaction finishes, solution is concentrated, the normal hexane that is then 10:1 by volume ratio and alcohol mixed solvent carry out column chromatography, obtain pure (R)-(N-(1-naphthyl) ethyl) ethanamide 101.6g, and yield is 95.4%.
2) acidolysis obtains R-1-naphthalene ethylamine salt
By (R) that make in upper step-(N-(1-naphthyl) ethyl) ethanamide 53g joins in the solution that the ethanol of 500ml and concentrated hydrochloric acid mix with volume ratio 1:1, then reflux, react after 24 hours, select plate and detect (R)-(N-(1-naphthyl) ethyl) ethanamide complete hydrolysis obtains R-1-naphthalene ethylamine salt.
3) alkalization obtains R-1-naphthalene ethylamine
The solution that step 2 gained is reacted completely adds the methylene dichloride of 500mL, then slowly drip sodium hydroxide solution, and stir, detect solution pH value to 13, stop dripping sodium hydroxide solution, separatory, upper water solution is used the dichloromethane extraction 3 times of 200mL again, by the dichloromethane solution that obtains of extraction several times with anhydrous sodium sulphate be dried, the concentrated R-1-naphthalene ethylamine 40.4g of obtaining, yield is that the ee value that 94.4%, HPLC detects the finished product is 99.4%.

Claims (4)

1. the fractionation preparation method of optical purity R-1-naphthalene ethylamine is characterized in that: 1) in autoclave, take toluene as solvent, the ratio of 1:1.0-2.0 adds raw material 1-naphthalene ethylamine and acry radical donor D-(-)-O-ethanoyl amygdalic acid in molar ratio, then in the ratio of raw material 1-naphthalene ethylamine massfraction 1%-10%, add lipase novozym 435 and KT-02(nickel type catalyzer), autoclave sealing is carried out after nitrogen replacement, pass into hydrogen to pressure 0.1-1.0MPa and be warming up to 40-70 ℃ of reaction 18 hours, 1-naphthalene ethylamine can be converted into completely (R)-(N-(1-naphthyl) ethyl) ethanamide, and product ee value reaches 99%, after reaction finishes, solution is concentrated, column chromatography, obtain pure (R)-(N-(1-naphthyl) ethyl) ethanamide, 2) (R) that make in step 1-(N-(1-naphthyl) ethyl) ethanamide is dissolved in the alcohol of 10 times of volume ratios and the mixing solutions of acid solution (v/v=1:1), then heating reflux reaction is 24 hours, and (R)-(N-(1-naphthyl) ethyl) ethanamide complete hydrolysis obtains R-1-naphthalene ethylamine salt, 3) step 2 gained R-1-naphthalene ethylamine salt is carried out to alkalinisation treatment, then by organic solvent extraction, dry, concentratedly can obtain optically pure R-1-naphthalene ethylamine, final whole step product yield can reach more than 93%, and product purity is 99%, according to described, its reaction equation is as follows:
2. according to claim 1, the preparation method of optical purity R-1-naphthalene ethylamine is characterized in that step 1) in acry radical donor be D-(-)-O-ethanoyl amygdalic acid, racemization catalyst is KT-02 nickel type catalyzer.
3. according to claim 1, the preparation method of optical purity R-1-naphthalene ethylamine is characterized in that step 2) in alcohol be methyl alcohol or ethanol; Acid is hydrochloric acid or sulfuric acid.
4. according to claim 1, the preparation method of optical purity R-1-naphthalene ethylamine is characterized in that step 3) 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.
CN201410399401.9A 2014-08-14 2014-08-14 The method of optical voidness R-1-naphthalene ethylamine is prepared in a kind of fractionation Active CN104151171B (en)

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CN105063162A (en) * 2015-08-18 2015-11-18 陈永军 Preparation of R-6-methoxy-1-aminoindane through resolution
CN105061218A (en) * 2015-08-13 2015-11-18 陈永军 Method for preparing (S)-1-aminoindane through dynamic kinetic resolution
CN105154513A (en) * 2015-08-18 2015-12-16 陈永军 Method for preparing R-5-methyl-1-aminoindan through resolution
CN111004236A (en) * 2019-12-19 2020-04-14 卓和药业集团有限公司 Dynamic kinetic resolution method of WXFL10203614 intermediate

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US4983771A (en) * 1989-09-18 1991-01-08 Hexcel Corporation Method for resolution of D,L-alpha-phenethylamine with D(-)mandelic acid
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061218A (en) * 2015-08-13 2015-11-18 陈永军 Method for preparing (S)-1-aminoindane through dynamic kinetic resolution
CN105063162A (en) * 2015-08-18 2015-11-18 陈永军 Preparation of R-6-methoxy-1-aminoindane through resolution
CN105154513A (en) * 2015-08-18 2015-12-16 陈永军 Method for preparing R-5-methyl-1-aminoindan through resolution
CN111004236A (en) * 2019-12-19 2020-04-14 卓和药业集团有限公司 Dynamic kinetic resolution method of WXFL10203614 intermediate
CN111004236B (en) * 2019-12-19 2022-04-05 卓和药业集团股份有限公司 Dynamic kinetic resolution method of WXFL10203614 intermediate

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