CN104263798B - The preparation of S-1- tetrahydronaphthalene amines - Google Patents
The preparation of S-1- tetrahydronaphthalene amines Download PDFInfo
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- CN104263798B CN104263798B CN201410463618.1A CN201410463618A CN104263798B CN 104263798 B CN104263798 B CN 104263798B CN 201410463618 A CN201410463618 A CN 201410463618A CN 104263798 B CN104263798 B CN 104263798B
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Abstract
The present invention relates to a kind of Dynamic Kinetic Resolution preparation methods of 1 tetrahydronaphthalene amines of S.It is to split catalyst with Novozym 435,1 benzyl carbinol acetic acid esters of S is acry radical donor, and Raney's nickel is racemization catalyst, and hydrogen pair I is passed through in autoclave and is split, and I converts to obtain compound ii completely with 1 tetrahydronaphthalene amine (I) for raw material（Ee values 99%）；II carries out acidolysis after purification obtains compound III, and III operates to obtain 1 tetrahydronaphthalene amines of final products S (IV) by alkalization, extraction, drying, concentration etc. again, and each step product yield is all higher than 99% up to 90% or more, ee values.The present invention has the features such as catalyst cheap and easy to get, complete utilization of raw materials, good product yield, high optical purity.In prepared by the production of 1 tetrahydronaphthalene amines of S, there is great instruction and application value.
Description
Technical field
The present invention relates to a kind of preparation method of optical homochiral amine more particularly to the dynamics of optical voidness S-1- tetrahydronaphthalene amines
Kinetic Resolution preparation method.
Background technology
S-1- tetrahydronaphthalene amines have a wide range of applications as important drug synthesis intermediate in new drug synthesis field.Closely
Nian Lai causes the great interest of medicament research and development personnel.
1- tetrahydronaphthalene amine racemic modifications are first prepared currently, preparing S-1- tetrahydronaphthalene amines and generally using
(USP2001003136.2001-07-07; Bio.Med.Chem.2004.12(15)：Method 4189-4196) split again,
But this method for splitting has that raw material availability is low.Also have and optical voidness 1- tetrahydrochysenes are obtained using asymmetric catalysis
(the J.Org. Chem.2006.71.6859-6862 of naphthylamines;Tetrahedron Asym. 1998.9,4369-4379), but
It is that this method prepares S-1- tetrahydronaphthalene amines not there is only the low problem of product yield, asks there is also optical purity of products is not high
Topic.It is then rarely reported as to how preparing S-1- tetrahydronaphthalene amines using Enzymatic Resolution, S-1- is prepared using Enzymatic Resolution even if having
Tetrahydronaphthalene amine, it is also desirable to which generating enzyme-specific by bacterial screening could realize.
Invention content
The technical problem to be solved by the present invention is to utilize common lipase, and the racemization catalyst being easy to get successfully is realized and is moved
State Kinetic Resolution prepares S-1- tetrahydronaphthalene amines.
To solve the above-mentioned problems, the present invention provides a kind of preparation methods of optical voidness S-1- tetrahydronaphthalene amines：1）In height
It presses in reaction kettle, using toluene as solvent, in molar ratio 1:Raw material 1- tetrahydronaphthalene amines and acry radical donor S- is added in the ratio of 1.0-2.0
Then lipase Novozym 435 and thunder is added in the ratio of 1- tetrahydronaphthalene amine mass fractions 1%-10% in 1- benzyl carbinol acetic acid esters
Buddhist nun's nickel after autoclave sealing carries out nitrogen displacement, is passed through hydrogen to pressure 0.1-1.0MPa and to be warming up to 40-90 DEG C of reaction 24 small
When, you can 1- tetrahydronaphthalene amines are fully converted to compound ii, and product ee values are up to 99%；After reaction, solution is carried out dense
Contracting, column chromatography obtain compound ii sterling；2）By compound ii sterling obtained in step 1 be dissolved in the alcohol of 10 times of volume ratios with
Acid solution（v/v=1:1）Mixed solution in, then heating reflux reaction 15 hours, compound ii complete hydrolysis obtain compound III；
3）Step 2 gained compound III is subjected to basification, optics then can be obtained by organic solvent extraction, dry, concentration
Pure S-1- tetrahydronaphthalene amines（Ⅳ）, final entire step product yield is up to 90% or more, and optical purity of products is 99%.
The present invention is simple and easy to get using Novozym 435 as catalyst is split during preparing S-1- tetrahydronaphthalene amines,
Cheap and easy to get using Raney's nickel as racemization catalyst, catalytic efficiency is good, and in entire split process, product yield is high, light
It is good to learn purity.It is with the above advantages, the present invention in the production and preparation process of S-1- tetrahydronaphthalene amines, have greatly guidance and
Application value.
Specific implementation method：
1）Split prepare compound II
1000mL toluene is added in the autoclave of 2000mL as solvent, sequentially add 117.6g1- tetrahydronaphthalene amines,
144.3g S-1- benzyl carbinol acetic acid esters, 10g lipase Novozym 435 and 12g Raney's nickels, after addition, sealing autoclave
Afterwards with nitrogen by air in kettle into line replacement, hydrogen is then passed through in autoclave to pressure 1.0MP, opens stirring, and heat up
It is reacted to 75 DEG C；After 30 hours, sample detection, 1- tetrahydronaphthalene amines disappearance is fully converted to compound ii, and II ee of product
Value 99.8%；After reaction, the solution is concentrated, and it is 10 then to use volume ratio:1 mixed solvent of n-hexane and ethanol into
Row column chromatography obtains II 145.7G of pure compound, yield 96.4%.
2）Compound III acidolysis obtains compound III
Compound ii 94.6g obtained in upper step is added to ethyl alcohol and the concentrated hydrochloric acid of 1000ml with volume ratio 1:1 mixing
Solution in, be heated to reflux, reaction 8 when after, III complete hydrolysis of contact plate detection compound obtains compound III.
3）Alkalization obtains S-1- tetrahydronaphthalene amines（Ⅳ）
The dichloromethane of 500mL is added toward the solution that the reaction was complete obtained by step 2, it is molten that sodium hydroxide is then slowly added dropwise
Liquid quickly stirs, detection solution pH value to 13, stops that sodium hydroxide solution, liquid separation is added dropwise, upper layer aqueous uses 200mL's again
Dichloromethane extracts 3 times, and the dichloromethane solution being obtained by extraction several times is dried with anhydrous sodium sulfate, is concentrated to give S-1- tetra-
Hydrogen naphthylamines（Ⅴ）67.2g, yield 91.4%, the ee values that HPLC detects final products are 99.6%.
Claims (3)
1. the preparation method of optical voidness S-1- tetrahydronaphthalene amines, it is characterised in that：1) in autoclave, using toluene as solvent,
In molar ratio 1:Raw material 1- tetrahydronaphthalene amines and acry radical donor S-1- benzyl carbinol acetic acid esters is added in the ratio of 1.0-2.0, then presses 1-
Lipase Novozym 435 is added in the ratio of tetrahydronaphthalene amine mass fraction 1%-10%, by 1- tetrahydronaphthalene amine mass fractions 1%-
10% ratio is added Raney's nickel and is passed through hydrogen after autoclave sealing carries out nitrogen displacement to pressure 0.1-1.0MPa and heats up
It is reacted 24 hours to 40-90 DEG C, you can 1- tetrahydronaphthalene amines are fully converted to compound ii, and product ee values are up to 99%；Reaction
After, the solution is concentrated, column chromatography, obtains compound ii sterling；2) compound ii sterling obtained in step 1) is molten
Alcohol and acid solution by volume 1 of the solution in 10 times of volume ratios:In 1 mixed solution prepared, then heating reflux reaction 15 hours, change
It closes II complete hydrolysis of object and obtains compound III；3) compound III obtained by step 2) is subjected to basification, then passes through organic solvent
Extraction, dry, concentration can be obtained optically pure S-1- tetrahydronaphthalene amines (IV), final entire step product yield up to 90% with
On, and optical purity of products is 99%；According to described, reaction equation is as follows：
2. the preparation method of optical voidness S-1- tetrahydronaphthalene amines according to claim 1, it is characterised in that：Alcohol in step 2) is
Methanol or ethyl alcohol；Acid is hydrochloric acid.
3. the preparation method of optical voidness S-1- tetrahydronaphthalene amines according to claim 1, it is characterised in that：Alkalization in step 3)
Processing alkali used is sodium hydroxide, potassium hydroxide or ammonium hydroxide；Extraction organic solvent used is toluene, dichloromethane, 1,2-
Dichloroethanes, ether.
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| CN104263798B true CN104263798B (en) | 2018-07-17 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397218A (en) * | 2016-09-04 | 2017-02-15 | 王际菊 | S-alpha-cyclohexyl benzene methanamine |
| CN106480118A (en) * | 2016-09-04 | 2017-03-08 | 王际宽 | A kind of left-handed Chiral Amine |
| CN106467476A (en) * | 2016-09-04 | 2017-03-01 | 王际菊 | A kind of synthetic method of left-handed amine compound |
| CN106397225A (en) * | 2016-09-04 | 2017-02-15 | 王际菊 | Preparation method of chiral compound |
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| CN102675123A (en) * | 2012-06-11 | 2012-09-19 | 上海朗泽生物医药科技有限公司 | Resolving and racemization method for 1-amino-1,2,3,4-tetrahydronaphthalene |
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2014
- 2014-09-12 CN CN201410463618.1A patent/CN104263798B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| Heterogeneous Raney Nickel and Cobalt Catalysts for Racemization and Dynamic Kinetic Resolution of Amines;Andrei N. Parvulescu et al;《Adv. Synth. Catal.》;20071220;第350卷;第113页左栏第1-2段,第116页表2,第120页右栏倒数1-2段 * |
| 有机相中酶催化1-苯基乙胺的不对称酰胺化反应;徐刚等;《化工学报》;20070731;第58卷(第7期);摘要,第1742页左栏第2段,图1,右栏最后1段,第1743页表1,第2.3节,第1745页左栏第2段,结论 * |
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