CN106397225A - Preparation method of chiral compound - Google Patents
Preparation method of chiral compound Download PDFInfo
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- CN106397225A CN106397225A CN201610800684.2A CN201610800684A CN106397225A CN 106397225 A CN106397225 A CN 106397225A CN 201610800684 A CN201610800684 A CN 201610800684A CN 106397225 A CN106397225 A CN 106397225A
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- methoxyl group
- amine
- tetralin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- 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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- 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
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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
Abstract
The invention discloses a preparation method of a chiral compound S-5-methoxy-1-tetrahydronaphthalene amine. A particular method of the preparation method of the chiral compound S-5-methoxy-1-tetrahydronaphthalene amine comprises the following steps of using 5-methoxy-1-tetralone as a raw material, making the 5-methoxy-1-tetralone react with hydroxylamine to generate oxime, then carrying out catalytic hydrogenation reduction on the oxime through a catalyst to obtain 5-methoxy-1-tetrahydronaphthalene amine, and then carrying out a dynamic kinetic resolution reaction catalyzed by a biological enzyme on the amine, so that the S-5-methoxy-1-tetrahydronaphthalene amine can be obtained. The preparation method of the chiral compound S-5-methoxy-1-tetrahydronaphthalene amine has the characteristics that the operation is simple, a product is high in yield, a resolved product is high in optical purity, and the like, and has extremely high guide value and application value in the preparation process of the S-5-methoxy-1-tetrahydronaphthalene amine.
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 5- methoxy by chemical method
The synthesis of base -1- tetralin amine simultaneously and then carries out splitting the method preparing S-5- methoxyl group -1- tetralin amine by kinetics.
Background technology
5- methoxyl group -1- tetralin amine is a kind of chiral aminated compoundss possessing Chiral Amine active center, in existing report
With regard to the synthetic method of 5- methoxyl group -1- tetralin amine in road, it is with 5- methoxyl group -1- tetralone as raw material mostly, through mazidox
Diphenyl phthalate, the synergism of DBU, Pd, reaction generates 5- methoxyl group -1- tetralin amine（Carbonic anhydrase
inhibitory properties of novel sulfonamide derivatives of aminoindanes and
Aminotetralins, Journal of Enzyme Inhibition and Medicinal Chemistry, 29 (1),
35-42; 2014；）, this method haves the shortcomings that severe reaction conditions, expensive starting materials；In addition the method also having been reported that is then
Oxime is become with azanol reaction with 5- methoxyl group -1- tetralone, then obtains 5- methoxyl group -1- through dimethylamino monoborane catalysis reduction amination
Tetralin amine（Dioxopyrimidinecarboxamides as inhibitors of endothelial lipase and
Their preparation, PCT Int. Appl., 2013151877,10 Oct 2013）There is post processing in this method
Shortcoming more than sewage.
And the method for the synthetic method with regard to S-5- methoxyl group -1- tetralin amine, report is then by 5- methoxyl group -1- naphthalene
Full ketone obtains the imidoyl compound of the chirality of S configuration with S-1- phenethylamine by additive reaction, then again through the de- S-1- of Pd reduction
Phenethylamine base obtains S-5- methoxyl group -1- tetralin amine（Analogues of σ Receptor Ligand 1-Cyclohexyl-4-
[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with
Added Polar Functionality and Reduced Lipophilicity for Potential Use as
Positron Emission Tomography Radiotracers, Journal of Medicinal Chemistry, 54
(4), 1022-1032; 2011）, there are severe reaction conditions in this method, the shortcomings of optical purity of products is high.
Content of the invention
The present invention is intended to provide a kind of synthesize the synthesis of 5- methoxyl group -1- tetralin amine by chemical method and and then pass through
Kinetics carry out splitting the method preparing S-5- methoxyl group -1- tetralin amine, and this method is simply it is easy to operate, and raw material sources
Extensively.In order to realize this target, concrete operations are as follows：）With methanol as solvent, 5- methoxyl group -1- tetralone is raw material and hydrochloric acid
Azanol, sodium hydroxide solution react to obtain 5- methoxyl group -1- tetralin ketoxime；2）Step 1）Gained 5- methoxyl group -1- tetralin ketoxime is
Raw material, obtains 5- methoxyl group -1- tetralin amine through reducing catalyst catalytic hydrogenation in the methanol solution be connected with ammonia, and amine can be used
The method that acid, alkali are processed successively carries out purification；3）In autoclave, by 5- methoxyl group -1- tetralin amine solvent in toluene,
Pressing 5- methoxyl group -1- tetralin amine acry radical donor mol ratio again is 1：The ratio of 1.0-2.0 adds acry radical donor, by raw material 5- methoxy
The ratio of base -1- tetralin amine mass fraction 2%-10% adds Digestive Enzyme, by raw material 5- methoxyl group -1- tetralin amine mass fraction 5%-
20% ratio adds racemization catalyst, is warming up to 40-70 DEG C of reaction 10-14 hour, you can will be complete for 5- methoxyl group -1- tetralin amine
Entirely it is converted into the acyl compounds of S-5- methoxyl group -1- tetralin amine；Stopped reaction, filters, concentration steams toluene and must split thick product
Product；4）By step 3）Gained crude product dimethylbenzene recrystallization, can obtain S-5- methoxyl group -1- tetralin amine acyl compounds sterling；
Acyl compounds are operated through acidolysis, alkali process etc., S-5- methoxyl group -1- tetralin amine can be obtained；Final products purity>99.5%, receive
Rate more than 90%, product ee value is up to more than 99%.Step 2）Described reducing catalyst is nickel/alumina load catalyst SN-
6000P, this catalyst buys industrial catalyst for the triumphant Chemical Co., Ltd. of upper Hisoon；Step 3）Described acry radical donor is
(+)-D- Herba Menthae alcohol acetic ester；Step 3）In Digestive Enzyme used be Pseudomonas fluorecens lipase LipaseAK；Step 3）In
Racemization catalyst used is nickel/alumina load catalyst SN-6000P, and this catalyst is the triumphant Chemical Co., Ltd. of upper Hisoon
Buy industrial catalyst.
The method that the present invention is announced is successfully prepared S-5- methoxyl group -1- tetralin amine.The present invention possesses simple to operate, product
The features such as product yield is good, purity is high.In the production and fractionation research of S-5- methoxyl group -1- tetralin amine, there is great guidance
And using value.
Specific embodiment
Embodiment 1
1）The synthesis of 5- methoxyl group -1- tetralin ketoxime
In there-necked flask, add 500ml methanol as solvent, add 88g raw material 5- methoxyl group -1- tetralone, 40g hydrochloric acid hydroxyl
Amine, under conditions of stirring at normal temperature in batches Deca concentration be 40% sodium hydroxide solution to system pH value be alkalescence, add follow-up
Continuous stirring reaction 3 hours, when point plate detection raw material 5- methoxyl group -1- tetralone point disappears, stopped reaction；Under stirring condition, past
Add the water of 2000ml in system, have a large amount of white solids to separate out；Sucking filtration, gained filter cake is cleaned to neutrality with water again, dries
Standby, this walks to obtain 5- methoxyl group -1- tetralin ketoxime 93.7g, and yield is 98.1%.
2）The reduction amination of 5- methoxyl group -1- tetralin ketoxime
In autoclave, 700ml absolute methanol is added to be to make solvent, as raw material, 15g urges 5- methoxyl group -1- tetralin ketoxime 93.7g
Agent SN-6000P, sealing autoclave, displaces the air of kettle, then is passed through ammonia 9g, then is passed through and keeps Hydrogen Vapor Pressure extremely
3.0MPa is reacted, etc. system not re-absorption hydrogen when, stopped reaction；Filter, to be concentrated to give 5- methoxyl group -1- tetralin amine thick
Product；Crude product is first become salt with hydrochloric acid reaction, and washes away impurity, then the 5- methoxy being dissociated after purification with sodium hydroxide with ethyl acetate
Base -1- tetralin amine hydrochlorate, ethyl acetate extracts, is dried, is concentrated to give 5- methoxyl group -1- tetralin amine sterling 83.1g, and this walks yield
95.7%.
3）The Dynamic Kinetic Resolution of 5- methoxyl group -1- tetralin amine
In autoclave, add 17.7g5- methoxyl group -1- tetralin amine sterling, 22g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 180ml first
In benzene, add 2.5g catalyst SN-6000P, 1.5g Pseudomonas fluorecens lipase LipaseAK, sealed reactor, with taking out
Vacuum pump extracts the air in kettle, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, in autoclave
It is filled with hydrogen to 1.0MPa, and is warming up to 40 DEG C and reacted；After 12 hours of reaction, stopped reaction, detects 5- methoxyl group -1-
Tetralin amine is wholly absent, and is converted into S-5- methoxyl group -1- tetralin amine acetyl compounds.After stopped reaction, filter, be concentrated to give S-
5- methoxyl group -1- tetralin amine acetyl compounds with (+)-D- menthol, (+) crude product of-D- menthol acetate mixture.
4）The preparation of S-5- methoxyl group -1- tetralin amine
By step 3）Gained crude product dimethylbenzene recrystallization obtains R-5- methoxyl group -1- tetralin amine acetyl compounds sterling；To weigh
Crystallization sterling is dissolved in hydrochloric acid and the mixed solution of methanol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, etc.
After S-5- methoxyl group -1- tetralin amine acetyl compounds complete hydrolysis become S-5- methoxyl group -1- tetralin amine, cooling, methanol is evaporated off,
Adjust pH value to alkalescence, taken 3 times with dichloromethane essence, merge organic faciess, be dried, concentrate after obtain R-5- methoxyl group -1- tetralin amine
16.1g, yield is 91.1%, and HPLC detects that its ee value is 99.4%.
Embodiment 2
1）The synthesis of the chloro- 1 tetralin ketoxime of 7-
In there-necked flask, add 1000ml methanol as solvent, add chloro- 1 tetralone of 176g raw material 7-, 80g 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 3.5 hours, when the chloro- 1 tetralone point of point plate detection raw material 7- disappears, stopped reaction；Under stirring condition, add toward in system
Enter 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 step
Obtain the chloro- 1 tetralin ketoxime 189.1g of 7-, yield is 99.0%.
2）The reduction amination of the chloro- 1 tetralin ketoxime of 7-
In autoclave, 1000ml absolute methanol is added to be to make solvent, the chloro- 1 tetralin ketoxime 189.1g of 7- is catalyzed as raw material, 30g
Agent SN-6000P, sealing autoclave, displaces the air of kettle, then is passed through ammonia 20g, then is passed through and keeps Hydrogen Vapor Pressure extremely
3.5MPa is reacted, etc. system not re-absorption hydrogen when, stopped reaction；Filter, to be concentrated to give 5- methoxyl group -1- tetralin amine thick
Product；Crude product is first become salt with hydrochloric acid reaction, and washes away impurity, then the 5- methoxy being dissociated after purification with sodium hydroxide with ethyl acetate
Base -1- tetralin amine hydrochlorate, ethyl acetate extracts, is dried, is concentrated to give 5- methoxyl group -1- tetralin amine sterling 167.2g, and this step is received
Rate 95.4%.
3）The Dynamic Kinetic Resolution of 5- methoxyl group -1- tetralin amine
In autoclave, add 88g5- methoxyl group -1- tetralin amine sterling, 110g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 800ml toluene
In, add 15g catalyst SN-6000P, 8g Pseudomonas fluorecens lipase LipaseAK, sealed reactor, use vacuum pumping pump
Extract the air in kettle, be re-filled with nitrogen to 0.5MPa, then use vacuum pumping pump evacuation；It is replaced, in autoclave, be filled with hydrogen
Gas is to 1.5MPa, and is warming up to 40 DEG C and is reacted；After 14 hours of reaction, stopped reaction, detects 5- methoxyl group -1- tetralin amine
It is wholly absent, be converted into S-5- methoxyl group -1- tetralin amine acetyl compounds.After stopped reaction, filter, be concentrated to give S-5- methoxy
Base -1- tetralin amine acetyl compounds with (+)-D- menthol, (+) crude product of-D- menthol acetate mixture.
4）The preparation of S-5- methoxyl group -1- tetralin amine
By step 3）Gained crude product dimethylbenzene recrystallization obtains R-5- methoxyl group -1- tetralin amine acetyl compounds sterling；To weigh
Crystallization sterling is dissolved in hydrochloric acid and the mixed solution of methanol, is heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, etc.
After S-5- methoxyl group -1- tetralin amine acetyl compounds complete hydrolysis become S-5- methoxyl group -1- tetralin amine, cooling, adjust pH value
To alkalescence, methanol is evaporated off, is taken 3 times with dichloromethane essence, merge organic faciess, be dried, concentrate after S-5- methoxyl group -1- tetralin amine
82.1g, yield is 93.3%, and HPLC detects that its ee value is 99.4%.
Claims (5)
1. a kind of preparation method of chipal compounds it is characterised in that：1) with methanol as solvent, 5- methoxyl group -1- tetralone is
Raw material and oxammonium hydrochloride., sodium hydroxide solution react to obtain 5- methoxyl group -1- tetralin ketoxime；2) step 1) gained 5- methoxyl group -1-
Tetralin ketoxime is raw material, obtains 5- methoxyl group -1- tetralin amine through reducing catalyst catalytic hydrogenation in the methanol solution be connected with ammonia,
Amine can carry out purification with the method that acid, alkali are processed successively；3) in autoclave, by 5- methoxyl group -1- tetralin amine solvent
To in toluene, then press 5- methoxyl group -1- tetralin amine acry radical donor mol ratio for 1：The ratio of 1.0-2.0 adds acry radical donor, presses
The ratio of raw material 5- methoxyl group -1- tetralin amine mass fraction 2%-10% adds Digestive Enzyme, by raw material 5- methoxyl group -1- tetralin amine
The ratio of mass fraction 5%-20% adds racemization catalyst, is warming up to 40-70 DEG C of reaction 10-14 hour, you can by 5- methoxy
Base -1- tetralin amine is fully converted to the acyl compounds of S-5- methoxyl group -1- tetralin amine；Stopped reaction, filters, concentration steams first
Benzene must split crude product；4) by step 3) gained crude product dimethylbenzene recrystallization, S-5- methoxyl group -1- tetralin amine acyl group can be obtained
Pure compounds；Acyl compounds are operated through acidolysis, alkali process etc., S-5- methoxyl group -1- tetralin amine can be obtained；Final products are pure
Degree>99.5%, yield more than 90%, product ee value is up to more than 99%；In sum, the synthesis of the present invention and resolution reaction side
Formula is as follows：
2. according to claim 1 a kind of preparation method of chipal compounds it is characterised in that：Step 2 in claim 1)
Described reducing catalyst is nickel/alumina load catalyst SN-6000P, and this catalyst is the triumphant Chemical Co., Ltd. of upper Hisoon
Buy industrial catalyst.
3. according to claim 1 a kind of preparation method of chipal compounds it is characterised in that：Step 3 in claim 1)
Described acry radical donor be (+)-D- Herba Menthae alcohol acetic ester.
4. according to claim 1 a kind of preparation method of chipal compounds it is characterised in that：Step 3 in claim 1)
In Digestive Enzyme used be Pseudomonas fluorecens lipase LipaseAK.
5. according to claim 1 a kind of preparation method of chipal compounds it is characterised in that：Step 3 in claim 1)
In racemization catalyst used be nickel/alumina load catalyst SN-6000P, this catalyst is the limited public affairs of the triumphant chemical industry of upper Hisoon
Department buys industrial catalyst.
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| US4791103A (en) * | 1985-02-08 | 1988-12-13 | Warner-Lambert Company | 2,N6 -disubstituted adenosines, derivatives and methods of use |
| US5300437A (en) * | 1989-06-22 | 1994-04-05 | Celgene Corporation | Enantiomeric enrichment and stereoselective synthesis of chiral amines |
| CN1191862A (en) * | 1997-01-30 | 1998-09-02 | 弗·哈夫曼-拉罗切有限公司 | 8-substituted-1,3,8-triaza-spiro [4,5] decan-4-on derivatives |
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Application publication date: 20170215 |