CN106381324A - Preparation method of R-7-chloro-1-tetralinylamine - Google Patents
Preparation method of R-7-chloro-1-tetralinylamine Download PDFInfo
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- CN106381324A CN106381324A CN201610802068.0A CN201610802068A CN106381324A CN 106381324 A CN106381324 A CN 106381324A CN 201610802068 A CN201610802068 A CN 201610802068A CN 106381324 A CN106381324 A CN 106381324A
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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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- 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
- C07C209/28—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 other reducing agents
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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
- 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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Abstract
The invention discloses a preparation method of R-7-chloro-1-tetralinylamine. The method comprises the following steps: carrying out reduction ammonification reaction on the raw material 7-chloro-1-tetralone to obtain 7-chloro-1,2,3,4-tetrahydronaphthyl-1-amine, and carrying out dynamic kinetic resolution on the 7-chloro-1,2,3,4-tetrahydronaphthyl-1-amine by using the combination of lipase and a racemization catalyst to obtain the R-7-chloro-1,2,3,4-tetrahydronaphthyl-1-amine. The method is simple to operate, and has the characteristics of wide raw material sources, favorable product yield, high optical purity of the resolution product 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 a kind of chloro- by chemical method synthesis 7-
1,2,3,4- naphthane -1- amine and then the method that split by enzymatic Dynamic Kinetic.
Background technology
7- chloro- 1,2,3,4- naphthane -1- amine is as a kind of chiral intermediate.In existing correlational study, with regard to such as
What preparation 7- chloro- 1,2,3,4- naphthane -1- amine and fractionation are rarely reported.By Research Literature it is found that yet there are no
With regard to how to prepare R-7- chloro- 1,2,3,4- naphthane -1- amine using kinetics and Dynamic Kinetic Resolution.
Content of the invention
The present invention is intended to provide a kind of method of synthesis chloro- 1,2,3, the 4- naphthane -1- amine of 7-, and kinetics are carried out to it
Split to obtain 7- chloro- 1,2,3,4- naphthane -1- amine.In order to realize this target, concrete operations are as follows：1）In autoclave,
With methanol or ethanol as solution, add raw material 7- chloro- 1- tetralone, then add reduction in the ratio of raw materials quality fraction 5%-20%
Catalyst；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 2-4MPa, it is warmed up to 70-90 DEG C of reaction, observe and no longer inhale stopped reaction after hydrogen；After terminating reaction, through filtering, concentrating
Operate to obtain 7- chloro- 1,2,3,4- naphthane -1- amine crude product；Crude product can purify, after acid, alkali process, the 7- obtaining that purity is 99%
Chloro- 1,2,3,4- naphthane -1- amine；2）Step 1）Chloro- 1,2,3, the 4- naphthane -1- amine of gained 7- are dissolved in toluene solvant, press
The ratio of chloro- 1,2,3, the 4- naphthane -1- amine 1.0-2.0 equivalents of 7- adds acry radical donor, by chloro- 1,2,3, the 4- tetrahydrochysenes of raw material 7-
The ratio of naphthalene -1- amine mass fraction 5%-10% adds Digestive Enzyme, by chloro- 1,2,3, the 4- naphthane -1- amine mass fractions of raw material 7-
The ratio of 5%-15% adds racemization catalyst, is warming up to 40-60 DEG C of reaction 6-8 hour, you can by chloro- for 7- 1,2,3,4- tetrahydrochysenes
Naphthalene -1- amine is fully converted to the amide compound of R-7- chloro- 1,2,3,4- naphthane -1- amine；Stopped reaction, filters, concentrates and steam
Go out toluene and must split crude product；3）By step 2）Gained crude product dimethylbenzene recrystallization, can obtain chloro- 1,2,3, the 4- tetrahydrochysenes of R-7-
Naphthalene -1- amine acyl compounds sterling, purity>99.5%；Acyl compounds operate through acidolysis, alkali process etc. again, can obtain R-7- chloro-
1,2,3,4- naphthane -1- amine；And product ee value is up to more than 99%.In the present invention, reducing catalyst used is SN-600P；
Acyl compounds are：(-)-neomenthol acetass, (-)-neomenthol propionic ester, (-)-neomenthol n-butyric acie ester；Fat
Enzyme is porcine pancreatic lipase（PPL）, racemization catalyst is nickel/alumina load catalyst, and this catalyst is from fast triumphant catalysis work purchase
The industrial catalyst entering.
The method that the present invention is announced is successfully prepared chloro- 1,2,3, the 4- naphthane -1- amine of 7-, and splits preparation further
Obtain R-7- chloro- 1,2,3,4- naphthane -1- amine.The present invention is also equipped with the spies such as simple to operate, product yield is good, purity is high simultaneously
Point.In the production and fractionation research of chloro- 1,2,3, the 4- naphthane -1- amine of 7-, there is great guidance and using value.
Specific embodiment
Embodiment 1
1）The preparation of 7- chloro- 1,2,3,4- naphthane -1- amine
In 1000ml autoclave, add 90g7- chloro- 1- tetralone, 600ml dehydrated alcohol 12g catalyst SN-600P, sealing is anti-
Answer kettle, extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen to 0.5MPa, then use vacuum pumping pump evacuation；Condition of negative pressure
Under be filled with 80g ammonia, ammoniated gas finishes, and is filled with hydrogen to 4MPa in autoclave, and is warming up to 90 DEG C and is reacted.Reaction 9
After hour, find that Hydrogen Vapor Pressure no longer declines, then stopped reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give
7- chloro- 1,2,3,4- naphthane -1- amine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow it to react
Generate chloro- 1,2,3, the 4- naphthane -1- amine salt of 7-, and be dissolved in aqueous solution, and had with ethyl acetate essence aqueous removing
Machine impurity, after point liquid, retains aqueous phase, after aqueous phase is taken twice with ethyl acetate essence again, adjusts pH value to alkalescence with sodium hydroxide,
Taken 3 times with ethyl acetate essence again, now collect the ethyl acetate phase extracting after adjusting pH value, concentrate after being dried, obtain 7- chloro- 1,2,
3,4- naphthane -1- amine sterlings 81.6g, yield is 90.2%, and HPLC detects that its purity is 99.2%.
2）The Dynamic Kinetic Resolution of 7- chloro- 1,2,3,4- naphthane -1- amine
In autoclave, add step 1) chloro- 1,2,3, the 4- naphthane -1- amine sterlings of gained 36.2g7-, 40g (-)-neomenthol
Acetass are dissolved in 400ml toluene, add 4.5g catalyst SN-6000P, 1.5g porcine pancreatic lipase（PPL）, 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；It is replaced, high
It is filled with hydrogen to 1.0MPa in pressure kettle, and is warming up to 40 DEG C and reacted；After 14 hours of reaction, stopped reaction, 7- is chloro- for detection
1,2,3,4- naphthane -1- amine is wholly absent, and is converted into chloro- 1,2,3, the 4- naphthane -1- amine acetyl compounds of R-7-.Stop
After reaction, filter, be concentrated to give chloro- 1,2,3, the 4- naphthane -1- amine acetyl compounds of R-7- with (-)-neomenthol, (-)-new
The crude product of menthol acetate mixture.
3）The preparation of R-7- chloro- 1,2,3,4- naphthane -1- amine
By step 2）It is pure that gained crude product dimethylbenzene recrystallization obtains R-7- chloro- 1,2,3,4- naphthane -1- amine acetyl compounds
Product；Recrystallization sterling is dissolved in the mixed solution that hydrochloric acid is with methanol, is heated to reflux being hydrolyzed, TLC tracing detection hydrolyzes
Progress, wait chloro- 1,2,3, the 4- naphthane -1- amine acetyl compounds complete hydrolysis of R-7- become chloro- 1,2,3, the 4- naphthanes of R-7- -
After 1- amine, cooling, methanol is evaporated off, adjusts pH value to alkalescence, taken 3 times with ethyl acetate essence, merge organic faciess, be dried, after concentration
Obtain chloro- 1,2,3, the 4- naphthane -1- amine 33.2g of R-7-, yield is 92.1%, and HPLC detects that its ee value is 99.5%.
Embodiment 2
1）The preparation of 7- chloro- 1,2,3,4- naphthane -1- amine
In 1000ml autoclave, add 90g7- chloro- 1- tetralone, 600ml dehydrated alcohol 10g catalyst SN-600P, sealing is anti-
Answer kettle, extract the air in kettle with vacuum pumping pump, be re-filled with nitrogen to 0.5MPa, then use vacuum pumping pump evacuation；Condition of negative pressure
Under be filled with 51g ammonia, ammoniated gas finishes, and is filled with hydrogen to 4MPa in autoclave, and is warming up to 80 DEG C and is reacted.Reaction 10
After hour, find that Hydrogen Vapor Pressure no longer declines, then stopped reaction.It is down to after room temperature after system temperature, reacting liquid filtering, it is concentrated to give
7- chloro- 1,2,3,4- naphthane -1- amine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow it to react
Generate chloro- 1,2,3, the 4- naphthane -1- amine salt of 7-, and be dissolved in aqueous solution, and had with ethyl acetate essence aqueous removing
Machine impurity, after point liquid, retains aqueous phase, after aqueous phase is taken twice with ethyl acetate essence again, adjusts pH value to alkalescence with sodium hydroxide,
Taken 3 times with ethyl acetate essence again, now collect the ethyl acetate phase extracting after adjusting pH value, concentrate after being dried, obtain 7- chloro- 1,2,
3,4- naphthane -1- amine sterlings 79.5g, yield is 87.8%, and HPLC detects that its purity is 99.4%.
2）The Dynamic Kinetic Resolution of 7- chloro- 1,2,3,4- naphthane -1- amine
In autoclave, add step 1) chloro- 1,2,3, the 4- naphthane -1- amine sterlings of gained 18.1g7-, 20g (-)-neomenthol
Acetass are dissolved in 200ml toluene, add 2.0g catalyst SN-6000P, 0.9g porcine pancreatic lipase（PPL）, 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；It is replaced, high
It is filled with hydrogen to 1.0MPa in pressure kettle, and is warming up to 45 DEG C and reacted；After 12 hours of reaction, stopped reaction, 7- is chloro- for detection
1,2,3,4- naphthane -1- amine is wholly absent, and is converted into chloro- 1,2,3, the 4- naphthane -1- amine acetyl compounds of R-7-.Stop
After reaction, filter, be concentrated to give chloro- 1,2,3, the 4- naphthane -1- amine acetyl compounds of R-7- with (-)-neomenthol, (-)-new
The crude product of menthol acetate mixture.
3）The preparation of R-7- chloro- 1,2,3,4- naphthane -1- amine
By step 2）It is pure that gained crude product dimethylbenzene recrystallization obtains R-7- chloro- 1,2,3,4- naphthane -1- amine acetyl compounds
Product；Recrystallization sterling is dissolved in the mixed solution that hydrochloric acid is with methanol, is heated to reflux being hydrolyzed, TLC tracing detection hydrolyzes
Progress, wait chloro- 1,2,3, the 4- naphthane -1- amine acetyl compounds complete hydrolysis of R-7- become chloro- 1,2,3, the 4- naphthanes of R-7- -
After 1- amine, cooling, methanol is evaporated off, adjusts pH value to alkalescence, taken 3 times with ethyl acetate essence, merge organic faciess, be dried, after concentration
Obtain chloro- 1,2,3, the 4- naphthane -1- amine 16.7g of R-7-, yield is 92.4%, and HPLC detects that its ee value is 99.5%.
Claims (5)
1. a kind of chloro- 1- tetralin amine of R-7- preparation method it is characterised in that：1) in autoclave, with methanol or ethanol
For solution, add raw material 7- chloro- 1- tetralone, then add reducing catalyst in the ratio of raw materials quality fraction 5%-20%；Close
Envelope 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 2-
4MPa, is warmed up to 70-90 DEG C of reaction, observes and no longer inhales stopped reaction after hydrogen；After terminating reaction, through filtering, concentration operation obtains 7-
Chloro- 1,2,3,4- naphthane -1- amine crude product；Crude product can purify, after acid, alkali process, the 7- chloro- 1,2,3 obtaining that purity is 99%,
4- naphthane -1- amine；2) step 1) chloro- 1,2,3, the 4- naphthane -1- amine of gained 7- are dissolved in toluene solvant, by 7- chloro- 1,2,
The ratio of 3,4- naphthane -1- amine 1.0-2.0 equivalents adds acry radical donor, by chloro- 1,2,3, the 4- naphthane -1- amine matter of raw material 7-
The ratio of amount fraction 5%-10% adds Digestive Enzyme, by chloro- 1,2,3, the 4- naphthane -1- amine mass fraction 5%-10% of raw material 7-
Ratio add racemization catalyst, be warming up to 40-60 DEG C reaction 6-8 hour, you can by chloro- for 7- 1,2,3,4- naphthane -1- amine
It is fully converted to the amide compound of R-7- chloro- 1,2,3,4- naphthane -1- amine；Stopped reaction, filters, concentration steams toluene and obtains
Split crude product；3) by step 2) gained crude product dimethylbenzene recrystallization, chloro- 1,2,3, the 4- naphthane -1- amine of R-7- can be obtained
Acyl compounds sterling, purity>99.5%；Acyl compounds operate through acidolysis, alkali process etc. again, can obtain R-7- chloro- 1,2,3,
4- naphthane -1- amine；And product ee value is up to more than 99%；In sum, the synthesis of the present invention and resolution reaction equation be such as
Under：
2. according to claim 1 a kind of preparation method of the chloro- 1- tetralin amine of R-7- it is characterised in that institute in claim 1
The reducing catalyst stated is：Nickel/alumina load catalyst SN-6000P.
3. according to claim 1 a kind of preparation method of the chloro- 1- tetralin amine of R-7- it is characterised in that institute in claim 1
The acyl compounds stated can for (-)-neomenthol acetass.
4. according to claim 1 a kind of preparation method of the chloro- 1- tetralin amine of R-7- it is characterised in that institute in claim 1
State step 2) in Digestive Enzyme used be porcine pancreatic lipase PPL.
5. according to claim 1 a kind of preparation method of the chloro- 1- tetralin amine of R-7- it is characterised in that institute in claim 1
State step 2) in racemization catalyst used be nickel/alumina load catalyst SN-6000P.
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| CN201610802068.0A CN106381324A (en) | 2016-09-04 | 2016-09-04 | Preparation method of R-7-chloro-1-tetralinylamine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747939A (en) * | 2003-02-05 | 2006-03-15 | 拜尔作物科学有限公司 | Amino-1, 3, 5-triazines N-substituted with chiral bicyclic radicals, process for their preparation, compositions thereof, and their use as herbicides and plant growth regulators |
| CN104263796A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
| CN104263797A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
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2016
- 2016-09-04 CN CN201610802068.0A patent/CN106381324A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747939A (en) * | 2003-02-05 | 2006-03-15 | 拜尔作物科学有限公司 | Amino-1, 3, 5-triazines N-substituted with chiral bicyclic radicals, process for their preparation, compositions thereof, and their use as herbicides and plant growth regulators |
| CN104263796A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
| CN104263797A (en) * | 2014-09-12 | 2015-01-07 | 王际宽 | Preparation method of R-1-aminotetralin |
Non-Patent Citations (1)
| Title |
|---|
| MARIA SOLEDAD DE CASTRO等: "Lipase-Catalyzed Synthesis of Chiral Amides. A Systematic Study of the Variables that Control the Synthesis", 《TETRAHEDRON》 * |
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Application publication date: 20170208 |