CN104263796B - A kind of preparation method of the tetrahydro naphthylamines of R 1 - Google Patents
A kind of preparation method of the tetrahydro naphthylamines of R 1 Download PDFInfo
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- CN104263796B CN104263796B CN201410463547.5A CN201410463547A CN104263796B CN 104263796 B CN104263796 B CN 104263796B CN 201410463547 A CN201410463547 A CN 201410463547A CN 104263796 B CN104263796 B CN 104263796B
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- tetrahydro
- naphthylamines
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- JRZGPXSSNPTNMA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-amine Chemical class C1=CC=C2C(N)CCCC2=C1 JRZGPXSSNPTNMA-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims abstract description 15
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 13
- 230000003287 optical effect Effects 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 108010084311 Novozyme 435 Proteins 0.000 claims abstract description 4
- 238000005576 amination reaction Methods 0.000 claims abstract description 3
- 230000006340 racemization Effects 0.000 claims abstract description 3
- 230000009467 reduction Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 14
- JRZGPXSSNPTNMA-SNVBAGLBSA-N (1r)-1,2,3,4-tetrahydronaphthalen-1-amine Chemical class C1=CC=C2[C@H](N)CCCC2=C1 JRZGPXSSNPTNMA-SNVBAGLBSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 abstract description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- 229960002510 mandelic acid Drugs 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract 1
- 102000004190 Enzymes Human genes 0.000 abstract 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 150000005002 naphthylamines Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The present invention relates to a kind of preparation method of the tetrahydro naphthylamines of R 1.With 1 tetralone (I) for raw material, KT 02（Ni-type）For catalyst, under elevated pressure conditions, reduction amination obtains 1 tetrahydro naphthylamine (II)；After obtaining II, with Novozym 435 to split enzyme, D () O acetyl group mandelic acid is acry radical donor, and KT 02 is racemization catalyst, and be passed through hydrogen in autoclave splits to II, and II converts to obtain compound III completely（Ee values 99%）；III carries out acidolysis after purification obtains compounds Ⅳ, and IV operates to obtain the tetrahydro naphthylamines of R 1 (V) by alkalization, extraction, dry, concentration etc., and each product yield that walks is more than 99% up to more than 90%, ee values.The present invention has the characteristics that catalyst is cheap and easy to get, raw material utilization is complete, product yield is good, optical purity is high.In prepared by the production of the tetrahydro naphthylamines of R 1, 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 preparation of optical voidness R-1- tetrahydro naphthylamines
Method.
Background technology
R-1- tetrahydro naphthylamines, as important drug synthesis intermediate, had a wide range of applications in new drug synthesis field.Closely
Nian Lai, cause the great interest of medicament research and development personnel.It is that the important intermediate for dying protein inhibitor is adjusted in synthesis.It is thin that tune, which is died,
One of dead mechanism of born of the same parents, cancer, senile dementia and autoimmune conditions etc. can be effectively treated using this effect.
At present, prepare general use of R-1- tetrahydro naphthylamines and first prepare 1- tetrahydro naphthylamine racemic modifications
(USP2001003136.2001-07-07; Bio.Med.Chem.2004.12(15)：
Method 4189-4196) split again, also have and optical voidness 1- tetrahydro naphthylamines are obtained using asymmetric catalysis
(J.Org.Chem.2006.71.6859-6862; Tetrahedron Asym.1998.9,4369-4379).But these are
The problems such as product yield is low and final products optical purity is bad in the method for report all be present.
The content of the invention
The technical problem to be solved in the present invention is R-1- tetrahydro naphthylamines in kind was prepared in high yield and high optical voidness
Degree.
In order to solve the above problems, the invention provides a kind of preparation method of optical voidness R-1- tetrahydro naphthylamines：1）In height
Press in reactor, by mass volume ratio 1：5-10 ratio adds ALPHA-tetralone (I) and absolute methanol, then by ALPHA-tetralone
Mass fraction 1%-10% ratio adds KT-02（Ni-type catalyst）；After air excludes, liquefied ammonia is passed through in 50%-80% ratio,
Hydrogen to pressure 2-5MPa, heating is passed through in last autoclave to be reacted；After the conversion completely of TLC detections ALPHA-tetralone, knot
Shu Fanying, concentration, obtains 1- tetrahydro naphthylamines (II)；2）In autoclave, using toluene as solvent, in molar ratio 1:1.0-2.0
Ratio add raw material 1- tetrahydro naphthylamines and acry radical donor D- (-)-O- acetyl group mandelic acids, then by raw material 1- tetrahydro naphthylamine matter
The ratio for measuring fraction 1%-10% adds lipase Novozym 435 and KT-02, after autoclave sealing carries out nitrogen displacement, is passed through
Hydrogen to pressure 0.1-1.0MPa and be warming up to 40-70 DEG C react 24 hours, you can 1- tetrahydro naphthylamines are fully converted to chemical combination
Thing, and product ee values are up to 99%；After reaction terminates, solution is concentrated, column chromatography, obtain compound III sterling；3）By step 2
In obtained compound III sterling be dissolved in the alcohol and acid solution of 10 times of volume ratios（v/v=1:1）Mixed solution in, then heat
Back flow reaction 15 hours, compound III complete hydrolysis obtains compounds Ⅳ；4）Step 3 gained compounds Ⅳ is subjected to basification,
Then extracted, dried by organic solvent, concentrated and can obtain optically pure R-1- tetrahydro naphthylamines, final whole step product is received
Rate is up to more than 90%, and optical purity of products is 99%.
The present invention is catalyzed during R-1- tetrahydro naphthylamines are prepared using KT-02 as reduction amination catalyst and racemization
Agent, there is the advantages that catalyst is cheap and easy to get, and safe to use, catalytic efficiency is good, high conversion rate.1- tetrahydro naphthylamines are in split process
In can ensure under conditions of high conversion ratio by acry radical donor of D- (-)-O- acetyl group mandelic acid, optical purity of products
It is good.
Specific implementation method：
1）The preparation of 1- tetrahydro naphthylamines
In 2000ML autoclave, 146G tetralones (I), 1000ML absolute methanols, 15GKT-02 are added；Nitrogen
After gas displacement excludes air, 102G liquefied ammonia is passed through, hydrogen is passed through in last autoclave to pressure 5MPa, 80 DEG C is warming up to and carries out instead
Should；After the conversion completely of TLC detections ALPHA-tetralone, terminate reaction, filtering, concentration, obtain 1- tetrahydro naphthylamines (II) 145G；
2）The preparation of compound III
1000mL toluene is added in 2000mL autoclave as solvent, sequentially adds 117.6g1- tetrahydro naphthylamines, 172g
D- (-)-O- acetyl group mandelic acids, 10g lipase Novozym 435 and 12gKT-02, after addition, are used after sealing autoclave
Air in kettle is entered line replacement by nitrogen, then toward hydrogen is passed through in autoclave to pressure 1.0MP, opens stirring, and be warming up to 70
DEG C reacted；After 24 hours, sampling detection, 1- tetrahydro naphthylamines, which disappear, is fully converted to compound III, and product ee values reach
99%；After reaction terminates, solution is concentrated, is then 10 with volume ratio:1 normal hexane carries out post with alcohol mixed solvent
Chromatography, obtains the 144.2G of pure compound III, yield 95.4%.
3）Compound III acidolysis obtains compounds Ⅳ
Obtained compound III 94.6g in upper step is added to 1000ml ethanol and concentrated hydrochloric acid with volume ratio 1:1 mixing
Solution in, be then heated to reflux, after reaction 12 hours, the complete hydrolysis of point plate detection compound III obtains compounds Ⅳ.
4）Alkalization obtains R-1- tetrahydro naphthylamines（Ⅴ）
500mL dichloromethane is added toward the complete solution of reaction obtained by step 3, it is molten that sodium hydroxide is then slowly added dropwise
Liquid, and be stirred, detection solution pH value to 13, stop addition sodium hydroxide solution, liquid separation, upper strata aqueous uses 200mL again
Dichloromethane extract 3 times, the dichloromethane solution being obtained by extraction several times is dried with anhydrous sodium sulfate, is concentrated to give R-1-
Tetrahydro naphthylamine（Ⅴ）67.7g, yield 92.1%, the ee values of HPLC detection final products are 99.5%.
Claims (3)
1. the preparation method of optical voidness R-1- tetrahydro naphthylamines, it is characterised in that：1) in autoclave, by mass volume ratio
1g：5-10ml ratio adds ALPHA-tetralone (I) and absolute methanol, then the ratio by ALPHA-tetralone mass fraction 5%-20%
Example adds KT-02；After air excludes, liquefied ammonia is passed through in I mass 50%-80% ratio, hydrogen is passed through in last autoclave extremely
Pressure 2-5MPa, heating are reacted；After the conversion completely of TLC detections ALPHA-tetralone, terminate reaction, concentration, obtain 1- naphthanes
Amine (II)；2) in autoclave, using toluene as solvent, in molar ratio 1:1.0-2.0 ratio adds raw material 1- naphthanes
Amine and acry radical donor D- (-)-O- acetyl group mandelic acids, raw material 1- tetrahydro naphthylamine mass fractions 1%-10% ratio is then pressed respectively
Example adds lipase Novozym 435 and KT-02, after autoclave sealing carries out nitrogen displacement, is passed through hydrogen to pressure 0.1-
1.0MPa and be warming up to 40-70 DEG C react 24 hours, 1- tetrahydro naphthylamines are fully converted to compound III, and product ee values reach
99%；After reaction terminates, solution is concentrated, column chromatography, obtain compound III sterling；3) by obtained compound in step 2
III sterling is dissolved in the alcohol of 10 times of its volumes and acid solution by volume 1:In 1 mixed solution prepared, then it is heated to reflux anti-
Answer 12 hours, compound III complete hydrolysis obtains compounds Ⅳ；4) step 3 gained compounds Ⅳ is subjected to basification, Ran Houtong
Cross organic solvent extraction, dry, concentration can obtain optically pure R-1- tetrahydro naphthylamines, finally each step product yield it is reachable
More than 90%, and optical purity of products is 99%；According to described, its reaction equation is as follows：
2. the preparation method of optical voidness R-1- tetrahydro naphthylamines according to claim 1, it is characterised in that：Used in step 1)
KT-02 is reduction amination catalyst.
3. the preparation method of optical voidness R-1- tetrahydro naphthylamines according to claim 1, it is characterised in that：KT- in step 2)
02 is racemization catalyst.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105063161B (en) * | 2015-08-18 | 2018-11-09 | 陈永军 | A kind of preparation method of R-1- aminoidans |
| CN105087742B (en) * | 2015-08-18 | 2018-09-14 | 陈永军 | Dynamic Kinetic Resolution prepares R-6- hydroxyl -1- aminoidans |
| CN106381324A (en) * | 2016-09-04 | 2017-02-08 | 王际菊 | Preparation method of R-7-chloro-1-tetralinylamine |
| CN106380408A (en) * | 2016-09-04 | 2017-02-08 | 王际菊 | Preparation of optical homochiral amine |
| CN106480117A (en) * | 2016-09-04 | 2017-03-08 | 王际宽 | The synthesis of 6 methoxyl group 1 tetralin amine and fractionation |
| CN106397217A (en) * | 2016-09-04 | 2017-02-15 | 王际菊 | Method for synthesizing dextral alpha-cyclohexylbenzylamine |
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| JP2001149089A (en) * | 1999-11-26 | 2001-06-05 | Sumitomo Chem Co Ltd | Production of optically active amino compound |
| CN102766672A (en) * | 2011-05-06 | 2012-11-07 | 王际宽 | Kinetic resolution method of chiral amine |
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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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