CN106397218A - S-alpha-cyclohexyl benzene methanamine - Google Patents
S-alpha-cyclohexyl benzene methanamine Download PDFInfo
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- CN106397218A CN106397218A CN201610800768.6A CN201610800768A CN106397218A CN 106397218 A CN106397218 A CN 106397218A CN 201610800768 A CN201610800768 A CN 201610800768A CN 106397218 A CN106397218 A CN 106397218A
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- cyclohexyl benzene
- cyclohexyl
- benzene methylamine
- methylamine
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 10
- BMFYCFSWWDXEPB-UHFFFAOYSA-N cyclohexyl(phenyl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1CCCCC1 BMFYCFSWWDXEPB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000006340 racemization Effects 0.000 claims abstract description 5
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- GVDONFUHZNOGQH-UHFFFAOYSA-N n-[cyclohexyl(phenyl)methylidene]hydroxylamine Chemical compound C=1C=CC=CC=1C(=NO)C1CCCCC1 GVDONFUHZNOGQH-UHFFFAOYSA-N 0.000 claims description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000003855 acyl compounds Chemical class 0.000 claims description 5
- -1 cyclohexyl phenyl Chemical group 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 4
- 102000019280 Pancreatic lipases Human genes 0.000 claims description 4
- 108050006759 Pancreatic lipases Proteins 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 102000038379 digestive enzymes Human genes 0.000 claims description 4
- 108091007734 digestive enzymes Proteins 0.000 claims description 4
- 235000019439 ethyl acetate Nutrition 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 229940116369 pancreatic lipase Drugs 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 3
- 150000002923 oximes Chemical class 0.000 abstract description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract description 2
- 102000004882 Lipase Human genes 0.000 abstract 1
- 108090001060 Lipase Proteins 0.000 abstract 1
- 239000004367 Lipase Substances 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 235000019421 lipase Nutrition 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005576 amination reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- CSDFHCDNAZPVKH-UHFFFAOYSA-N 2,3,3a,7a-tetrahydro-1h-indazole Chemical compound C1=CC=CC2CNNC21 CSDFHCDNAZPVKH-UHFFFAOYSA-N 0.000 description 1
- ZHDHTEOEZSHAMZ-UHFFFAOYSA-N 3-(1h-indazol-3-yl)benzenesulfonamide Chemical class NS(=O)(=O)C1=CC=CC(C=2C3=CC=CC=C3NN=2)=C1 ZHDHTEOEZSHAMZ-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 150000004768 bromobenzenes Chemical class 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HHNHBFLGXIUXCM-GFCCVEGCSA-N cyclohexylbenzene Chemical compound [CH]1CCCC[C@@H]1C1=CC=CC=C1 HHNHBFLGXIUXCM-GFCCVEGCSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- WJMWEDMHIXNQSH-UHFFFAOYSA-N n-[3-(3-sulfamoylphenyl)-1h-indazol-5-yl]acetamide Chemical class C12=CC(NC(=O)C)=CC=C2NN=C1C1=CC=CC(S(N)(=O)=O)=C1 WJMWEDMHIXNQSH-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/40—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of hydroxylamino or oxyimino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
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- General Engineering & Computer Science (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses a resolution preparation method of S-alpha-cyclohexyl benzene methanamine by combining a chemical synthesis method with bio-enzyme catalytic resolution. The method particularly comprises the steps of reacting cyclohexyl phenyl ketone serving as a raw material with hydroxylamine to obtain oxime, performing hydrogenation reduction on the oxime to obtain recemic amine, performing on-pot dynamic kinetic resolution reaction on the product amine obtained by the reaction, lipase, a racemization catalyst and an acyl donor, and hydrolyzing the resolution reaction product to obtain the S-alpha-cyclohexyl benzene methanamine. The method has the characteristics of simplicity in operation, high product yield, high optical purity of the resolution product and the like.
Description
Technical field
The present invention relates to a kind of preparation method of optical homochiral amine compound, more particularly, to one kind pass through chemosynthesis
Method is combined with the Dynamic Kinetic Resolution of biological enzyme the method preparing S- α-cyclohexyl benzene methylamine.
Background technology
In existing correlational study, existing report is mainly raw material ring with regard to the method preparing α-cyclohexyl benzene methylamine
Hexyl phenyl ketone is obtained with sodium cyanoborohydride concerted reaction with ammonium acetate in methanol solvate（Discovery of
inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-
Indazol-5-yl) acetamides and carboxamides, Bioorganic ＆ Medicinal Chemistry, 22
(17), 4968-4997; 2014；Indazole compounds as kinase inhibitors and their
Preparation and method for the treatment of cancer, PCT Int. Appl., 2013053051,18 Apr
2013, Preparation of 3-indazolylbenzenesulfonamides as kinase inhibitors
useful in treating cancer；PCT Int. Appl., 2011123937, 13 Oct 2011）, or hexamethylene
Base phenyl ketone becomes oxime with azanol reaction, then by lithium aluminium hydride reduction amination（Preparation of
Tetrahydroindazole cannabinoid modulators, PCT Int. Appl., 2005095353,13 Oct
2005；）, directly and ammonia enters to go back reduction amination also metal complex catalysts catalysis cyclohexyl phenyl ketone
（Chemoselective reductive alkylation of ammonia with carbonyl compounds:
Synthesis of primary and symmetrical secondary amines, Tetrahedron, 60 (7),
1463-1471; 2004）.In above method, the first employs sodium cyanoborohydride as reduction respectively with second method
, due to the presence of which so that post-processing operation is cumbersome, and there is certain danger in agent；As for using metal combination
The method of thing catalyst, then have the shortcomings that the difficult acquisition of catalyst, product yield are low.
Preparation method with regard to S- α-cyclohexyl benzene methylamine mostly then is with cyclohexyl formaldehyde and bromobenzene（Isoquinolinone
derivatives as NK3 antagonists and their preparation, pharmaceutical
Compositions and use in the treatment of psychosis and schizophrenia, PCT Int.
Appl., 2008131779, 06 Nov 2008）Or the grignard reagent of benzonitrile and cyclohexyl（Absolute
configuration determinations of chiral α-substituted benzylamines using
Liquid crystal-induced circular dichroism, Journal of Organic Chemistry, 47
(20), 3987-91; 1982）Carry out what asymmetric reduction reaction obtained.Both preparation S- α-cyclohexyl benzene methylamines all exist
Severe reaction conditions, product yield is low, the not high shortcoming of optical purity.
Content of the invention
The present invention is intended to provide a kind of be simply easily achieved with cyclohexyl phenyl ketone prepare S- α-cyclohexyl benzene methylamine
Method.In order to realize this target, concrete operations are as follows：
1）With methanol as solvent, cyclohexyl phenyl ketone is that raw material reacts to obtain cyclohexyl benzene with oxammonium hydrochloride., sodium hydroxide solution
Base ketoxime；2）Step 1）Gained cyclohexyl phenyl ketone oxime is raw material, through reduction catalystses in the methanol solution be connected with ammonia
Agent catalytic hydrogenation obtains α-cyclohexyl benzene methylamine, and amine can carry out purification with the method that acid, alkali are processed successively；3）In autoclave
Interior, by step 2）Gained α-cyclohexyl benzene methylamine is dissolved in toluene, then by α-cyclohexyl benzene methylamine acry radical donor mol ratio is
1：The ratio of 1.0-2.0 adds acry radical donor, adds Digestive Enzyme in the ratio of α-cyclohexyl benzene methylamine mass fraction 2%-10%, presses
The ratio of raw material α-cyclohexyl benzene methylamine mass fraction 5%-20% adds racemization catalyst, is warming up to 35-60 DEG C of reaction 12-14 little
When, you can α-cyclohexyl benzene methylamine is fully converted to the acyl compounds of S- α-cyclohexyl benzene methylamine；Stopped reaction, filter,
Concentration steams toluene and must split crude product；4）By step 3）Gained crude product dimethylbenzene recrystallization, can obtain S- α-cyclohexyl benzene
Methylamine acyl compounds sterling；Acyl compounds are operated through hydrolysis, alkali process etc., S- α-cyclohexyl benzene methylamine can be obtained；Finally
Product purity>99.5%, product ee value is up to more than 99%；The step 2 of aforesaid operations method）In reducing catalyst used be nickel/
Kieselguhr supported catalyst KT-02；Step 3）In acry radical donor used be (+)-D- Herba Menthae alcohol acetic ester；Step 3）Described in
Digestive Enzyme be porcine pancreatic lipase（PPL）；Step 3）Described in racemization catalyst be nickel/alumina load catalyst SN-
6000P.
The method that the present invention is announced is successfully prepared S- α-cyclohexyl benzene methylamine.The present invention possesses simple to operate, raw material
Be easy to get, the features such as final products yield is good, purity is high.In the production and fractionation research of S- α-cyclohexyl benzene methylamine, there is pole
Big guidance and using value.
Specific embodiment
Embodiment 1
1）The synthesis of cyclohexyl phenyl ketone oxime
In there-necked flask, add 500ml methanol as solvent, add 94g raw material cyclohexyl phenyl ketone, 39g oxammonium hydrochloride., often
Temperature stirring under conditions of in batches Deca concentration be 40% sodium hydroxide solution to system pH value be alkalescence, continue after adding to stir
Mix reaction 2.5 hours, when point plate detection raw material cyclohexyl phenyl ketone point disappears, stopped reaction；Under stirring condition, toward in system
Add the water of 2000ml, have a large amount of white solids to separate out；Sucking filtration, gained filter cake is cleaned to neutrality with water again, dry for standby, this
Walk to obtain cyclohexyl phenyl ketone oxime 99.6g, yield is 98.1%.
2）The reduction amination of cyclohexyl phenyl ketone oxime
In autoclave, 600ml absolute methanol is added to be to make solvent, cyclohexyl phenyl ketone oxime 99.6g is catalyzed as raw material, 10g
Agent KT-02, sealing autoclave, displaces the air of kettle, is passed through ammonia 12g, then is passed through and keeps Hydrogen Vapor Pressure to enter to 3.5MPa
Row reaction, etc. system not re-absorption hydrogen when, stopped reaction；Filter, be concentrated to give α-cyclohexyl benzene methylamine crude product；By crude product first with
Hydrochloric acid reaction becomes salt, and washes away impurity, then the α-cyclohexyl benzene methylamine hydrochloric acid being dissociated after purification with sodium hydroxide with ethyl acetate
Salt, ethyl acetate extracts, is dried, is concentrated to give α-cyclohexyl benzene methylamine sterling 85.8g, and this walks yield 92.5%.
3）The Dynamic Kinetic Resolution of α-cyclohexyl benzene methylamine
In autoclave, add 18.9g α-cyclohexyl benzene methylamine sterling, 20g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 200ml toluene
In, add 2.6g catalyst SN-6000P, 1.5g porcine pancreatic lipase（PPL）, sealed reactor, extracted in kettle with vacuum pumping pump
Air, be re-filled with nitrogen to 0.5MPa, then use vacuum pumping pump evacuation；It is replaced, be filled with hydrogen in autoclave extremely
1.5MPa, and be warming up to 45 DEG C and reacted；After 14 hours of reaction, stopped reaction, detection α-cyclohexyl benzene methylamine disappears completely
Lose, be converted into S- α-cyclohexyl benzene methylamine acetyl compounds.After stopped reaction, filter, be concentrated to give α containing S--cyclohexyl benzene first
The crude product of amine acetyl compounds.
4）The preparation of S- α-cyclohexyl benzene methylamine
By step 3）Gained crude product dimethylbenzene recrystallization obtains S- α-cyclohexyl benzene methylamine acetyl compounds sterling；By recrystallization
Sterling is dissolved in the mixed solution of hydrochloric acid and methanol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, wait S- α-
After cyclohexyl benzene methylamine acetyl compounds complete hydrolysis become S- α-cyclohexyl benzene methylamine, cooling, adjust pH value to alkalescence, be evaporated off
Methanol, is taken 3 times with dichloromethane essence, merges organic faciess, obtains R- α-cyclohexyl benzene methylamine 17.6g, yield is after drying, concentration
93.2%, and HPLC detects that its ee value is 99.4%.
Embodiment 2
1）The synthesis of cyclohexyl phenyl ketone oxime
In there-necked flask, add 1000ml methanol as solvent, add 188g raw material cyclohexyl phenyl ketone, 80g oxammonium hydrochloride.,
Under conditions of stirring at normal temperature in batches Deca concentration be 40% sodium hydroxide solution to system pH value be alkalescence, after adding continue
Stirring reaction 3 hours, when point plate detection raw material cyclohexyl phenyl ketone point disappears, stopped reaction；Under stirring condition, toward in system
Add the water of 4000ml, have a large amount of white solids to separate out；Sucking filtration, gained filter cake is cleaned to neutrality with water again, dry for standby, this
Walk to obtain cyclohexyl phenyl ketone oxime 201.4g, yield is 99.2%.
2）The reduction amination of cyclohexyl phenyl ketone oxime
In autoclave, 1000ml absolute methanol is added to be to make solvent, as raw material, 25g urges cyclohexyl phenyl ketone oxime 201.4g
Agent KT-02, sealing autoclave, displaces the air of kettle, then is passed through ammonia 25g, then is passed through and keeps Hydrogen Vapor Pressure extremely
3.5MPa is reacted, etc. system not re-absorption hydrogen when, stopped reaction；Filter, be concentrated to give α-cyclohexyl benzene methylamine crude product；Will
Crude product first becomes salt with hydrochloric acid reaction, and washes away impurity, then the α-cyclohexyl benzene being dissociated after purification with sodium hydroxide with ethyl acetate
Methylamine hydrochloride, ethyl acetate extracts, is dried, is concentrated to give α-cyclohexyl benzene methylamine sterling 177.7g, and this walks yield 94.8%.
3）The Dynamic Kinetic Resolution of α-cyclohexyl benzene methylamine
In autoclave, add 37.6g α-cyclohexyl benzene methylamine sterling, 40g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 500ml toluene
In, add 6g catalyst SN-6000P, 2.5g porcine pancreatic lipase（PPL）, sealed reactor, extracted in kettle with vacuum pumping pump
Air, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with hydrogen in autoclave to 1.0MPa,
And be warming up to 45 DEG C and reacted；After 14 hours of reaction, stopped reaction, detection α-cyclohexyl benzene methylamine is wholly absent, conversion
For S- α-cyclohexyl benzene methylamine acetyl compounds.After stopped reaction, filter, be concentrated to give α containing S--cyclohexyl benzene methylamine acetyl group
The crude product of compound.
4）The preparation of S- α-cyclohexyl benzene methylamine
By step 3）Gained crude product dimethylbenzene recrystallization obtains S- α-cyclohexyl benzene methylamine acetyl compounds sterling；By recrystallization
Sterling is dissolved in the mixed solution of hydrochloric acid and methanol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, wait S- α-
After cyclohexyl benzene methylamine acetyl compounds complete hydrolysis become S- α-cyclohexyl benzene methylamine, cooling, adjust pH value to alkalescence, be evaporated off
Methanol, is taken 3 times with dichloromethane essence, merges organic faciess, obtains R- α-cyclohexyl benzene methylamine 34.7g, yield is after drying, concentration
92.2%, and HPLC detects that its ee value is 99.5%.
Claims (5)
1. a kind of S- α-cyclohexyl benzene methylamine is it is characterised in that it is Dynamic Kinetic Resolution method preparation according to the following steps
's：1) with methanol as solvent, cyclohexyl phenyl ketone is that raw material reacts to obtain cyclohexyl phenyl with oxammonium hydrochloride., sodium hydroxide solution
Ketoxime；2) step 1) gained cyclohexyl phenyl ketone oxime be raw material, through reducing catalyst in the methanol solution be connected with ammonia
Catalytic hydrogenation obtains α-cyclohexyl benzene methylamine, and amine can carry out purification with the method that acid, alkali are processed successively；3) in autoclave
Interior, by step 2) gained α-cyclohexyl benzene methylamine is dissolved in toluene, then by α-cyclohexyl benzene methylamine acry radical donor mol ratio be
1：The ratio of 1.0-2.0 adds acry radical donor, adds Digestive Enzyme in the ratio of α-cyclohexyl benzene methylamine mass fraction 2%-10%,
Add racemization catalyst in the ratio of raw material α-cyclohexyl benzene methylamine mass fraction 5%-20%, be warming up to 35-60 DEG C of reaction 12-
14 hours, you can α-cyclohexyl benzene methylamine is fully converted to the acyl compounds of S- α-cyclohexyl benzene methylamine；Stopped reaction, mistake
Filter, concentration steam toluene and must split crude product；4) by step 3) gained crude product dimethylbenzene recrystallization, S- α-cyclohexyl can be obtained
Benzene methanamine acyl compounds sterling；Acyl compounds are operated through hydrolysis, alkali process etc., S- α-cyclohexyl benzene methylamine can be obtained；?
Finished product purity>99.5%, product ee value is up to more than 99%；In sum, the reaction equation of the present invention is as follows：
2. according to claim 1 a kind of S- α-cyclohexyl benzene methylamine it is characterised in that：Step 2 described in claim 1)
In reducing catalyst used be nickel/kieselguhr supported catalyst KT-02.
3. according to claim 1 a kind of S- α-cyclohexyl benzene methylamine it is characterised in that：Step 3 described in claim 1)
In acry radical donor used be (+)-D- Herba Menthae alcohol acetic ester.
4. according to claim 1 a kind of S- α-cyclohexyl benzene methylamine it is characterised in that：Step 3 described in claim 1)
Described in Digestive Enzyme be porcine pancreatic lipase (PPL).
5. according to claim 1 a kind of S- α-cyclohexyl benzene methylamine it is characterised in that：Step 3 described in claim 1)
Described in racemization catalyst be nickel/alumina load catalyst SN-6000P.
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