CN106431933A - Prochiral ketone amination and biological separation method - Google Patents
Prochiral ketone amination and biological separation method Download PDFInfo
- Publication number
- CN106431933A CN106431933A CN201610813896.4A CN201610813896A CN106431933A CN 106431933 A CN106431933 A CN 106431933A CN 201610813896 A CN201610813896 A CN 201610813896A CN 106431933 A CN106431933 A CN 106431933A
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- CN
- China
- Prior art keywords
- tert
- verdone
- butyl
- butyl cyclohexylamine
- cyclohexylamine
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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
- C07C209/24—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
-
- 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
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
-
- 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
-
- 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
- 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
Abstract
The invention discloses a reductive amination and separation method taking ortho tert butyl cyclohexanone as a raw material. The method particularly includes the steps: performing reductive amination for the ortho tert butyl cyclohexanone under the action of catalyst to generate racemic ortho tert butyl cyclohexanamine; combining the ortho tert butyl cyclohexanamine and racemic catalyst by lipase, and performing dynamic kinetic separation to obtain R-ortho tert butyl cyclohexanamine. The reductive amination and separation method has the advantages of simplicity in operation, wide raw material source, good product yield, high optical purity of separated products and the like.
Description
Technical field
The present invention relates to a kind of synthesis of Chiral Amine and method for splitting, more particularly, to one kind are by the adjacent tertiary fourth of chemical method synthesis
The synthesis of basic ring hexylamine and then the method that split by enzymatic Dynamic Kinetic.
Background technology
O-tert-butyl cyclohexylamine is a kind of chiral intermediate, and the preparation method with regard to o-tert-butyl cyclohexylamine is only at present
Being reported as verdone is raw material, carries out reductive amination process with ammonium formate and obtain o-tert-butyl in the presence of catalyst
Cyclohexylamine（Branched amide (1S) of L-a (1S) partyl-D-amino acid dipeptide (1S), U.
(1S)., 4411925, 25 Oct 1983）.And the resolution reaction with regard to its chiral amino center then has no report.
Content of the invention
The present invention is intended to provide a kind of amination of verdone and method for splitting, and Kinetic Resolution is carried out to it
Obtain o-tert-butyl cyclohexylamine.In order to realize this target, concrete operations are as follows：1）In autoclave, with methyl alcohol or ethanol as solvent,
Verdone is raw material, adds catalyst in the ratio of verdone mass fraction 5%-20%；Sealing 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, rises
Temperature, to 70-100 DEG C of reaction, is observed and is stopped reaction after no longer inhaling hydrogen；After terminating reaction, through filtering, concentration operation obtains o-tert-butyl
Cyclohexylamine crude product；Crude product can purify, after acid, alkali process, the o-tert-butyl cyclohexylamine obtaining that purity is 99%；2）Step 1）Gained
O-tert-butyl cyclohexylamine is dissolved in toluene solvant, adds acry radical donor in the ratio of o-tert-butyl cyclohexylamine 1.0-2.0 equivalent, presses
The ratio of o-tert-butyl cyclohexylamine mass fraction 5%-10% adds lipase, by o-tert-butyl cyclohexylamine mass fraction 5%-20%'s
Ratio adds racemization catalyst, is warming up to 40-60 DEG C of reaction 6-14 hour, you can o-tert-butyl cyclohexylamine is fully converted to R-
The amide compound of o-tert-butyl cyclohexylamine；Stop reaction, filter, concentration steams toluene and must split crude product；3）By step 2）
Gained crude product is recrystallized with dimethylbenzene, can obtain R- o-tert-butyl cyclohexylamine acyl compounds sterling, purity>99%；Acyl group chemical combination
Thing operates through acidolysis, alkali process etc. again, can obtain R- o-tert-butyl cyclohexylamine；And product ee value is up to more than 99%.Walk in the present invention
Rapid 1）In reducing catalyst be nickel/alumina load catalyst SN-6000P；Step 2）In acyl compounds can for (-)-
Neomenthol acetic acid esters；Step 2）In lipase used be Pseudomonas fluorecens lipase Lipase AK；Step 2）In used
Racemization catalyst be nickel/alumina load catalyst SN-6000P, this catalyst is to urge from the fast triumphant catalysis industry bought of work
Agent.
The method that the present invention is announced is successfully prepared o-tert-butyl cyclohexylamine, and fractionation prepares R- neighbour uncle further
Butylcyclohexyl amine.The present invention is also equipped with the features such as simple to operate, product yield is good, purity is high simultaneously.In o-tert-butyl cyclohexylamine
Production and split in research, there is great guidance and using value.
Specific embodiment
Embodiment 1
1）The preparation of o-tert-butyl cyclohexylamine
In autoclave, add 77g verdone, 500ml absolute ethyl alcohol, 13g catalyst SN-6000P, sealing reaction
Kettle, extracts the air in kettle with vacuum pumping pump, is re-filled with nitrogen and vacuumizes to 0.5MPa, then with vacuum pumping pump；Under condition of negative pressure
It is filled with 40g ammonia, fills ammonia and finish, be filled with hydrogen in autoclave to 4MPa, and be warming up to 95 DEG C and reacted.Reaction 10 is little
Shi Hou, finds not re-absorption hydrogen, then stop reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give adjacent tertiary fourth
Basic ring hexylamine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate o-tert-butyl hexamethylene
Amine salt, and be dissolved in the aqueous solution, and remove organic impurities 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 NaOH, then taken 3 times with ethyl acetate essence, now receive
Collection adjusts the ethyl acetate phase of extraction after pH value, concentrates, obtain o-tert-butyl cyclohexylamine sterling 70.53g, yield is after being dried
91.0%, and HPLC detects that its purity is 99.4%.
2）The Dynamic Kinetic Resolution of o-tert-butyl cyclohexylamine
In autoclave, add step 1) gained 38.5g o-tert-butyl cyclohexylamine sterling, 40g (-)-neomenthol acetic acid esters is dissolved in
In 500ml toluene, add 7g racemization catalyst SN-6000P, 3.5g Pseudomonas fluorecens lipase Lipase AK, sealing is anti-
Answer kettle, extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen and vacuumize to 0.5MPa, then with vacuum pumping pump；It is replaced,
It is filled with hydrogen in autoclave to 1.0MPa, and is warming up to 45 DEG C and reacted；After 14 hours of reaction, stop reaction, detection is adjacent
T-butylcyclohexyl amine is wholly absent, and is converted into R- o-tert-butyl cyclohexylamine acetyl compounds.After stopping reaction, filter, concentrate
R- o-tert-butyl cyclohexylamine acetyl compounds with (-)-neomenthol, (-) crude product of-neomenthol acetate mixture.
3）The preparation of R- o-tert-butyl cyclohexylamine
By step 2）Gained crude product dimethylbenzene recrystallizes to obtain R- o-tert-butyl cyclohexylamine acetyl compounds sterling；To recrystallize
Sterling is dissolved in hydrochloric acid and the mixed solution of methyl alcohol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, waits R- adjacent
After t-butylcyclohexyl amine acetyl compounds complete hydrolysis become R- o-tert-butyl cyclohexylamine, cooling, methyl alcohol is evaporated off, adjust pH value to
Alkalescence, is taken 3 times with ethyl acetate essence, merges organic phase, obtains R- o-tert-butyl cyclohexylamine 36.07g, yield is after drying, concentration
93.7%, and HPLC detects that its ee value is 99.4%.
Embodiment 2
1）The preparation of o-tert-butyl cyclohexylamine
In autoclave, add 154g verdone, 1200ml absolute ethyl alcohol, 30g catalyst SN-6000P, sealing reaction
Kettle, extracts the air in kettle with vacuum pumping pump, is re-filled with nitrogen and vacuumizes to 0.5MPa, then with vacuum pumping pump；Under condition of negative pressure
It is filled with 85g ammonia, fills ammonia and finish, be filled with hydrogen in autoclave to 4MPa, and be warming up to 100 DEG C and reacted.Discovery system
Not during re-absorption hydrogen, then stop reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give o-tert-butyl hexamethylene
Amine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate o-tert-butyl cyclohexylamine salt,
And be dissolved in the aqueous solution, and remove organic impurities with ethyl acetate essence aqueous, after point liquid, retain aqueous phase, aqueous phase is used again
After ethyl acetate essence takes twice, adjust pH value to alkalescence with NaOH, then taken 3 times with ethyl acetate essence, now collect and adjust
After section pH value, the ethyl acetate phase of extraction, concentrates after being dried, obtains o-tert-butyl cyclohexylamine sterling 142.91g, and yield is 92.2%,
And HPLC detects that its purity is 99.4%.
2）The Dynamic Kinetic Resolution of o-tert-butyl cyclohexylamine
In autoclave, add step 1) gained 77.5g o-tert-butyl cyclohexylamine sterling, 80g (-)-neomenthol acetic acid esters is dissolved in
In 800ml toluene, add 12g catalyst SN-6000P, 7g Pseudomonas fluorecens lipase Lipase AK, sealed reactor,
Extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen and vacuumize to 0.5MPa, then with vacuum pumping pump；It is replaced, high pressure
It is filled with hydrogen in kettle to 1.0MPa, and is warming up to 45 DEG C and reacted；After 12 hours of reaction, stop reaction, the adjacent tertiary fourth of detection
Basic ring hexylamine is wholly absent, and is converted into R- o-tert-butyl cyclohexylamine acetyl compounds.After stopping reaction, filter, be concentrated to give R-
O-tert-butyl cyclohexylamine acetyl compounds with (-)-neomenthol, (-) crude product of-neomenthol acetate mixture.
3）The preparation of R- o-tert-butyl cyclohexylamine
By step 2）Gained crude product dimethylbenzene recrystallizes to obtain R- o-tert-butyl cyclohexylamine acetyl compounds sterling；To recrystallize
Sterling is dissolved in hydrochloric acid and the mixed solution of methyl alcohol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, waits R- adjacent
After t-butylcyclohexyl amine acetyl compounds complete hydrolysis become R- o-tert-butyl cyclohexylamine, cooling, methyl alcohol is evaporated off, adjust pH value to
Alkalescence, is taken 3 times with ethyl acetate essence, merges organic phase, obtains R- o-tert-butyl cyclohexylamine 70.60g, yield is after drying, concentration
91.1%, and HPLC detects that its ee value is 99.3%.
Claims (5)
1. a kind of amination of verdone and method for splitting it is characterised in that：1) in autoclave, with methyl alcohol or ethanol
For solvent, verdone is raw material, adds catalyst in the ratio of verdone mass fraction 5%-20%；
Sealing autoclave, 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, is warmed up to 70-100 DEG C of reaction, observes and stops reaction after no longer inhaling hydrogen；After terminating reaction, obtain adjacent through filtration, concentration operation
T-butylcyclohexyl amine crude product；Crude product can purify, after acid, alkali process, the o-tert-butyl cyclohexylamine obtaining that purity is 99%；2) step
1) gained o-tert-butyl cyclohexylamine is dissolved in toluene solvant, adds acyl group in the ratio of o-tert-butyl cyclohexylamine 1.0-2.0 equivalent
Donor, adds lipase in the ratio of o-tert-butyl cyclohexylamine mass fraction 5%-10%, divides by o-tert-butyl cyclohexylamine quality
The ratio of number 5%-20% adds racemization catalyst, is warming up to 40-60 DEG C of reaction 6-14 hour, you can by o-tert-butyl cyclohexylamine
It is fully converted to the amide compound of R- o-tert-butyl cyclohexylamine；Stop reaction, filter, concentration steams toluene and must split thick product
Product；3) by step 2) gained crude product dimethylbenzene recrystallization, R- o-tert-butyl cyclohexylamine acyl compounds sterling, purity can be obtained
>99%；Acyl compounds operate through acidolysis, alkali process etc. again, can obtain R- o-tert-butyl cyclohexylamine；And product ee value is up to 99%
More than；In sum, the synthesis of the present invention and resolution reaction equation are as follows：
2. according to claim 1 a kind of amination of verdone and method for splitting it is characterised in that：Claim
Step 1 described in 1) in reducing catalyst be nickel/alumina load catalyst SN-6000P.
3. according to claim 1 a kind of amination of verdone and method for splitting it is characterised in that：Claim
Step 2 described in 1) in acyl compounds can for (-)-neomenthol acetic acid esters.
4. according to claim 1 a kind of amination of verdone and method for splitting it is characterised in that：Claim
Step 2 described in 1) in lipase used be Pseudomonas fluorecens lipase Lipase AK.
5. according to claim 1 a kind of amination of verdone and method for splitting it is characterised in that claim 1
Described in step 2) in racemization catalyst used be nickel/alumina load catalyst SN-6000P.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610813896.4A CN106431933A (en) | 2016-09-09 | 2016-09-09 | Prochiral ketone amination and biological separation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610813896.4A CN106431933A (en) | 2016-09-09 | 2016-09-09 | Prochiral ketone amination and biological separation method |
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| Publication Number | Publication Date |
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| CN106431933A true CN106431933A (en) | 2017-02-22 |
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| CN201610813896.4A Pending CN106431933A (en) | 2016-09-09 | 2016-09-09 | Prochiral ketone amination and biological separation method |
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| CN (1) | CN106431933A (en) |
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2016
- 2016-09-09 CN CN201610813896.4A patent/CN106431933A/en active Pending
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Application publication date: 20170222 |