CN106397217A - Method for synthesizing dextral alpha-cyclohexylbenzylamine - Google Patents
Method for synthesizing dextral alpha-cyclohexylbenzylamine Download PDFInfo
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- CN106397217A CN106397217A CN201610800706.5A CN201610800706A CN106397217A CN 106397217 A CN106397217 A CN 106397217A CN 201610800706 A CN201610800706 A CN 201610800706A CN 106397217 A CN106397217 A CN 106397217A
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- cyclohexyl benzene
- benzene methylamine
- methylamine
- cyclohexyl
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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
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
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- 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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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a method for synthesizing dextral alpha-cyclohexylbenzylamine. The method comprises synthesizing racemic alpha-cyclohexylbenzylamine through catalytic reduction of cyclohexyl phenyl ketone in the presence of a reduction catalyst, and carrying out dynamic kinetic resolution on alpha-cyclohexylbenzylamine under combined action of lipase and a racemization catalyst to obtain alpha-cyclohexylbenzylamine. The method has the characteristics of simple operation, wide raw material source, good product yield and high optical purity of the resolution product.
Description
Technical field
The present invention relates to a kind of synthesis of Chiral Amine and method for splitting, more particularly, to one kind synthesize α-hexamethylene by chemical method
The synthesis of base benzene methanamine and then the method that split by enzymatic Dynamic Kinetic.
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.
With regard to S- α-cyclohexyl benzene methylamine preparation method relatively conventional be then with cyclohexyl phenyl ketone as raw material, enter
Row asymmetric reduction amination obtains（A Versatile Ru Catalyst for the Asymmetric Transfer
Hydrogenation of Both Aromatic and Aliphatic Sulfinylimines, Chemistry-A
European Journal, 18(7), 1969-1983, S1969/1-S1969/156; 2012）；This preparation R- α-hexamethylene
There are severe reaction conditions in the method for base benzene methanamine, 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 method of synthesis α-cyclohexyl benzene methylamine, and kinetic resolution is carried out to it obtain α-ring
Hexyl benzene methanamine.In order to realize this target, concrete operations are as follows：1）In autoclave, with methanol or ethanol as solution, plus
Enter raw material cyclohexyl phenyl ketone, then add reducing catalyst in the ratio of raw materials quality fraction 5%-20%；Sealing autoclave, nitrogen
After gas displacement, with mol ratio 1:The ratio of 5-10 is passed through liquefied ammonia or ammonia, is finally passed through hydrogen to pressure 2-4MPa, is warmed up to
70-100 DEG C of reaction, observes and no longer inhales stopped reaction after hydrogen；After terminating reaction, through filtering, concentration operation obtains α-cyclohexyl benzene first
Amine crude product；Crude product can purify, after acid, alkali process, the α-cyclohexyl benzene methylamine obtaining that purity is 99%；2）Step 1）Gained α-ring
Hexyl benzene methanamine is dissolved in toluene solvant, adds acry radical donor in the ratio of α-cyclohexyl benzene methylamine 1.0-2.0 equivalent, by raw material
The ratio of α-cyclohexyl benzene methylamine mass fraction 5%-10% adds Digestive Enzyme, by raw material α-cyclohexyl benzene methylamine mass fraction 5%-
20% ratio adds racemization catalyst, is warming up to 40-60 DEG C of reaction 6-12 hour, you can turn α-cyclohexyl benzene methylamine completely
Turn to the amide compound of R- α-cyclohexyl benzene methylamine；Stopped reaction, filters, concentration steams toluene and must split crude product；3）Will
Step 2）Gained crude product dimethylbenzene recrystallization, can obtain R- α-cyclohexyl benzene methylamine acyl compounds sterling, purity>99.5%；
Acyl compounds operate through acidolysis, alkali process etc. again, can obtain R- α-cyclohexyl benzene methylamine；And product ee value is up to more than 99%.This
In invention, reducing catalyst used is nickel/kieselguhr supported catalyst KT-02；Acyl compounds are：(-)-neomenthol second
Acid esters；Digestive Enzyme is porcine pancreatic lipase（PPL）, racemization catalyst is nickel/alumina load catalyst SN-6000P, this catalyst
It is the industrial catalyst bought from fast triumphant catalysis work.
The method that the present invention is announced is successfully prepared α-cyclohexyl benzene methylamine, and fractionation prepares R- α-ring further
Hexyl benzene methanamine.The present invention is also equipped with the features such as simple to operate, product yield is good, purity is high simultaneously.In α-cyclohexyl benzene methylamine
Production and split in research, there is great guidance and using value.
Specific embodiment
Embodiment 1
1）The preparation of α-cyclohexyl benzene methylamine
In 1000ml autoclave, add 94g cyclohexyl phenyl ketone, 600ml dehydrated alcohol 12g catalyst KT-02, sealing reaction
Kettle, extracts the air in kettle with vacuum pumping pump, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；Under condition of negative pressure
It is filled with 80g ammonia, ammoniated gas finishes, and is filled with hydrogen to 4MPa in autoclave, and is warming up to 100 DEG C and reacted.Reaction 9 is little
Shi Hou, finds not re-absorption hydrogen, then stopped reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give α-hexamethylene
Base benzene methanamine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate α-cyclohexyl benzene first
Amine salt, and be dissolved in aqueous solution, and remove organic impuritiess with ethyl acetate essence aqueous, after point liquid, retain aqueous phase, aqueous phase
After being taken twice with ethyl acetate essence again, adjust pH value to alkalescence with sodium hydroxide, then taken 3 times with ethyl acetate essence, now receive
Collection adjusts the ethyl acetate phase of extraction after pH value, concentrates, obtain α-cyclohexyl benzene methylamine sterling 85.0g, yield is after being dried
90.0%, and HPLC detects that its purity is 99.3%.
2）The Dynamic Kinetic Resolution of α-cyclohexyl benzene methylamine
In autoclave, add step 1) gained 37.6g α-cyclohexyl benzene methylamine sterling, 40g (-)-neomenthol acetass are dissolved in
In 500ml toluene, add 7g racemization catalyst SN-6000P, 3g porcine pancreatic lipase（PPL）, sealed reactor, use evacuation
Pumping removes the air in kettle, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with autoclave
Hydrogen is to 1.0MPa, and is warming up to 45 DEG C and is reacted；After 12 hours of reaction, stopped reaction, detects α-cyclohexyl benzene methylamine
It is wholly absent, be converted into R- α-cyclohexyl benzene methylamine acetyl compounds.After stopped reaction, filter, be concentrated to give R- α-cyclohexyl
Benzene methanamine acetyl compounds with (-)-neomenthol, (-) crude product of-neomenthol acetate mixture.
3）The preparation of R- α-cyclohexyl benzene methylamine
By step 2）Gained crude product dimethylbenzene recrystallization obtains R- 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 R- α-
After cyclohexyl benzene methylamine acetyl compounds complete hydrolysis become R- α-cyclohexyl benzene methylamine, cooling, methanol is evaporated off, adjust pH value to
Alkalescence, is taken 3 times with ethyl acetate essence, merges organic faciess, obtains R- α-cyclohexyl benzene methylamine 35.4g, yield is after drying, concentration
94.1%, and HPLC detects that its ee value is 99.4%.
Embodiment 2
1）The preparation of α-cyclohexyl benzene methylamine
In autoclave, addition 188g cyclohexyl phenyl ketone, 1000ml dehydrated alcohol, 18g catalyst KT-02, sealed reactor,
Extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen to 0.5MPa, then use vacuum pumping pump evacuation；It is filled with condition of negative pressure
85g ammonia, ammoniated gas finishes, and is filled with hydrogen to 4MPa in autoclave, and is warming up to 100 DEG C and is reacted.Discovery system is no longer
When absorbing hydrogen, then stopped reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give α-cyclohexyl benzene methylamine thick
Product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate α-cyclohexyl benzene methylamine salt, and molten
Solution is in aqueous solution, and removes organic impuritiess with ethyl acetate essence aqueous, after point liquid, retains aqueous phase, aqueous phase uses acetic acid again
After ethyl ester essence takes twice, adjust pH value to alkalescence with sodium hydroxide, then taken 3 times with ethyl acetate essence, now collect and adjust PH
The ethyl acetate phase of extraction after value, concentrates after being dried, obtains α-cyclohexyl benzene methylamine sterling 169.5g, and yield is 89.7%, and HPLC
Detect that its purity is 99.6%.
2）The Dynamic Kinetic Resolution of α-cyclohexyl benzene methylamine
In autoclave, add step 1) gained 18.9g α-cyclohexyl benzene methylamine sterling, 20g (-)-neomenthol acetass are dissolved in
In 200ml toluene, add 2.0g catalyst SN-6000P, 1.2g porcine pancreatic lipase（PPL）, sealed reactor, use evacuation
Pumping removes the air in kettle, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with autoclave
Hydrogen is to 1.0MPa, and is warming up to 45 DEG C and is reacted；After 12 hours of reaction, stopped reaction, detects α-cyclohexyl benzene methylamine
It is wholly absent, be converted into R- α-cyclohexyl benzene methylamine acetyl compounds.After stopped reaction, filter, be concentrated to give R- α-cyclohexyl
Benzene methanamine acetyl compounds with (-)-neomenthol, (-) crude product of-neomenthol acetate mixture.
3）The preparation of R- α-cyclohexyl benzene methylamine
By step 2）Gained crude product dimethylbenzene recrystallization obtains R- 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 R- α-
After cyclohexyl benzene methylamine acetyl compounds complete hydrolysis become R- α-cyclohexyl benzene methylamine, cooling, methanol is evaporated off, adjust pH value to
Alkalescence, is taken 3 times with ethyl acetate essence, merges organic faciess, obtains R- α-cyclohexyl benzene methylamine 17.1g, yield is after drying, concentration
90.7%, and HPLC detects that its ee value is 99.5%.
Claims (5)
1. a kind of synthetic method of dextrorotation α-cyclohexyl benzene methylamine it is characterised in that：1) in autoclave, with methanol or ethanol it is
Solution, cyclohexyl phenyl ketone is raw material, then puts into reducing catalyst in the ratio of raw materials quality fraction 5%-20%；Sealing is high
Pressure kettle, after nitrogen displacement, with mol ratio 1:The ratio of 5-10 is passed through liquefied ammonia or ammonia, is finally passed through hydrogen to pressure 3-5MPa,
It is warmed up to 70-100 DEG C of reaction, observe and no longer inhale stopped reaction after hydrogen；After terminating reaction, through filtering, concentration operation obtains α-hexamethylene
Base benzene methanamine crude product；Crude product can purify, after acid, alkali process, the α-cyclohexyl benzene methylamine obtaining that purity is 99%；2) step 1) institute
Obtain α-cyclohexyl benzene methylamine to be dissolved in toluene solvant, add acry radical donor in the ratio of α-cyclohexyl benzene methylamine 1.0-2.0 equivalent,
Add Digestive Enzyme in the ratio of raw material α-cyclohexyl benzene methylamine mass fraction 5%-10%, by raw material α-cyclohexyl benzene methylamine quality
The ratio of fraction 5%-20% adds racemization catalyst, is warming up to 40-60 DEG C of reaction 6-12 hour, you can by α-cyclohexyl benzene first
Amine is fully converted to the amide compound of R- α-cyclohexyl benzene methylamine；Stopped reaction, filters, concentration steams toluene and must split thick product
Product；3) by step 2) gained crude product dimethylbenzene recrystallization, R- α-cyclohexyl benzene methylamine acyl compounds sterling, purity can be obtained
>99.5%；Acyl compounds operate through acidolysis, alkali process etc. again, can obtain R- α-cyclohexyl benzene methylamine；And product ee value up to
More than 99%；In sum, the synthesis of the present invention and resolution reaction equation are as follows：
2. according to claim 1 a kind of synthetic method of dextrorotation α-cyclohexyl benzene methylamine it is characterised in that：Claim 1
Described in step 1) in reducing catalyst be：Nickel/kieselguhr supported catalyst KT-02.
3. according to claim 1 a kind of synthetic method of dextrorotation α-cyclohexyl benzene methylamine it is characterised in that：Claim 1
Described in step 2) in acyl compounds can for (-)-neomenthol acetass.
4. according to claim 1 a kind of synthetic method of dextrorotation α-cyclohexyl benzene methylamine it is characterised in that：Claim 1
Described in step 2) in Digestive Enzyme used be porcine pancreatic lipase (PPL).
5. according to claim 1 a kind of synthetic method of dextrorotation α-cyclohexyl benzene methylamine it is characterised in that in claim 1
Described step 2) in racemization catalyst used be nickel/alumina load catalyst SN-6000P.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1249375A (en) * | 1969-04-21 | 1971-10-13 | Pfizer | Aminobenzocycloalkane compounds |
| US4791103A (en) * | 1985-02-08 | 1988-12-13 | Warner-Lambert Company | 2,N6 -disubstituted adenosines, derivatives and methods of use |
| US20140051679A1 (en) * | 2011-10-12 | 2014-02-20 | Univeristy Health Networks | Kinase inhibitors and method of treating cancer with same |
| CN104263797A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
| CN104263796A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
| CN104276956A (en) * | 2014-09-12 | 2015-01-14 | 王际宽 | Method for preparing S-1-tetralin amine |
| WO2015178846A1 (en) * | 2014-05-20 | 2015-11-26 | Sp Process Development Ab | Process for the preparation of chiral amines from prochiral ketones |
-
2016
- 2016-09-04 CN CN201610800706.5A patent/CN106397217A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1249375A (en) * | 1969-04-21 | 1971-10-13 | Pfizer | Aminobenzocycloalkane compounds |
| US4791103A (en) * | 1985-02-08 | 1988-12-13 | Warner-Lambert Company | 2,N6 -disubstituted adenosines, derivatives and methods of use |
| US20140051679A1 (en) * | 2011-10-12 | 2014-02-20 | Univeristy Health Networks | Kinase inhibitors and method of treating cancer with same |
| WO2015178846A1 (en) * | 2014-05-20 | 2015-11-26 | Sp Process Development Ab | Process for the preparation of chiral amines from prochiral ketones |
| CN104263797A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
| CN104263796A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
| CN104276956A (en) * | 2014-09-12 | 2015-01-14 | 王际宽 | Method for preparing S-1-tetralin amine |
Non-Patent Citations (2)
| Title |
|---|
| GHISLANDI, V.等: "Optical resolution and configuration of α-cyclohexylbenzylamine, 1,2,3,4-tetrahydro-1-naphthylamine, and 1,2,3,4-tetrahydro-2-naphthylamine", 《FARMACO, EDIZIONE SCIENTIFICA》 * |
| 徐刚等: "新型酰基供体用于酶法动力学拆分制备(R)-1-(2-萘基)乙胺的研究", 《有机化学》 * |
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