CN106397383A

CN106397383A - Reductive amination and resolution of isochroman-4-one

Info

Publication number: CN106397383A
Application number: CN201610800757.8A
Authority: CN
Inventors: 王际菊
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-09-04
Filing date: 2016-09-04
Publication date: 2017-02-15

Abstract

The invention discloses a method for preparation of isochroman-4-amine from isochroman-4-one through reductive amination and further dynamic resolution of isochroman-4-amine for preparation of R-isochroman-4-amine. The method provided by the invention has the advantages of simple operation, usage of easily available raw materials, good product yield, high optical purity of the products, etc.

Description

The reduction amination of different chroman-4-on and fractionation

Technical field

The present invention relates to a kind of synthesis of Chiral Amine and method for splitting, the reduction amine of more particularly, to a kind of different chroman-4-on Change and prepare the method that heterochromatic full -4- amine is further carried out Dynamic Kinetic Resolution.

Background technology

Different chroman-4-on is as a kind of latent chiral intermediate.In existing correlational study, with regard to how using its preparation The method of heterochromatic full -4- amine be mainly first with sodium borohydride by heterochromatic full -4- alcohol, then in toluene solvant with nitrine di(2-ethylhexyl)phosphate Phenyl ester and DBU react and obtain（Preparation of bicyclic compounds as aspartyl protease and β secretase inhibitors for treating conditions associated with Amyloidosis such as Alzheimer's disease, PCT Int. Appl., 2005087714,22 Sep 2005）；And with regard to how splitting the report preparing the heterochromatic full -4- amine of its optical purity R- then fail to see.

Content of the invention

The present invention is intended to provide a kind of synthesis is simple to operation prepares heterochromatic full -4- amine by different chroman-4-on Method, and then it is split carry out, thus providing a kind of method preparing the heterochromatic full -4- amine of R-.In order to realize this target, specifically Operation is as follows：1）In autoclave, with methanol or ethanol as solution, add the different chroman-4-on of raw material, by necessarily heterochromatic The ratio of full -4- ketone mass fraction 5-15% adds catalyst；Sealing autoclave, after nitrogen displacement, rubs by with different chroman-4-on You compare 1:The ratio of 3-10 is passed through liquefied ammonia or ammonia, is finally passed through hydrogen to pressure 3-5MPa, is warmed up to 70-90 DEG C of reaction 8-12 Hour, observe and no longer inhale stopped reaction after hydrogen；After terminating reaction, through filtering, concentration operation obtains heterochromatic full -4- amine crude product；Crude product Can purify, after acid, alkali process, the heterochromatic full -4- amine obtaining that purity is 99%；2）Step 1）Heterochromatic full -4- the ketoamine of gained is dissolved in first In benzene solvent, by with heterochromatic full -4- amine mol ratio 1:The ratio of 1.0-2.0 adds acry radical donor, by the heterochromatic full -4- amine matter of raw material The ratio of amount fraction 5%-10% adds Digestive Enzyme, adds racemization to urge in the ratio of the heterochromatic full -4- amine mass fraction 5%-10% of raw material Agent, is warming up to 40-60 DEG C of reaction 9-14 hour, you can heterochromatic full -4- amine is fully converted to the amide of the heterochromatic full -4- amine of R- Compound；Stopped reaction, filters, concentration steams toluene and must split crude product；3）By step 2）Gained crude product dimethylbenzene weight Crystallization, can obtain the heterochromatic full -4- amine acyl compounds sterling of R-, purity>99%, yield is up to 90% about；Acyl compounds warp again Acidolysis, alkali process etc. operate, and can obtain the heterochromatic full -4- amine of R-；And product ee value is up to more than 99%；Wherein step 1）Described in Reducing catalyst is：Nickel/alumina load catalyst SN-6000P；Step 2）Described in acyl compounds can for (-)-new Herba Menthae alcohol acetic ester；Step 2）In Digestive Enzyme used be porcine pancreatic lipase（PPL）；Step 2）In racemization catalyst used be Nickel/alumina load catalyst SN-6000P, this catalyst is the industrial catalyst bought from fast triumphant catalysis work.

The method that the present invention is announced is successfully prepared heterochromatic full -4- amine, and further split prepare R- heterochromatic full - 4- amine.The present invention is also equipped with the features such as simple to operate, product yield is good, purity is high simultaneously.In the production of heterochromatic full -4- amine with tear open Divide in research, there is great guidance and using value.

Specific embodiment

Embodiment 1

1）The preparation of heterochromatic full -4- amine

In 1000ml autoclave, add the different chroman-4-on of 74g, 700ml dehydrated alcohol 11g catalyst SN-600P, 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 44g ammonia, ammoniated gas finishes, and is filled with hydrogen to 4.0MPa in autoclave, and is warming up to 95 DEG C and 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 Heterochromatic full -4- amine crude product.By crude product in the case of stirring, it is added in dilute hydrochloric acid solution, allow its reaction generate heterochromatic full -4- Amine hydrochlorate, and be dissolved in aqueous solution, and remove organic impuritiess with ethyl acetate essence aqueous, after point liquid, retain aqueous phase, After aqueous phase is taken twice with ethyl acetate essence again, adjust pH value to alkalescence with sodium hydroxide, then taken 3 times with ethyl acetate essence, this When collect ethyl acetate phase, concentrate after being dried, obtain heterochromatic full -4- amine sterling 66.7g, yield is 89.5%, and HPLC detects that it is pure Spend for 99.2%.

2）The Dynamic Kinetic Resolution of heterochromatic full -4- amine

In autoclave, add step 1) the heterochromatic full -4- amine sterling of gained 14.9,20g (-)-neomenthol acetass are dissolved in 200ml In toluene, add 1.5g catalyst SN-6000P, 1.1g porcine pancreatic lipase（PPL）, sealed reactor, extracted with vacuum pumping pump Air in kettle, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with hydrogen in autoclave extremely 0.5 MPa, and be warming up to 45 DEG C and reacted；After 12 hours of reaction, stopped reaction, detect that heterochromatic full -4- amine is wholly absent, It is converted into the heterochromatic full -4- amine acetyl compounds of R-.After stopped reaction, filter, be concentrated to give the heterochromatic full -4- amine acetyl group chemical combination of R- Thing with (-)-neomenthol, (-) crude product of-neomenthol acetate mixture.

3）The preparation of the heterochromatic full -4- amine of R-

By step 2）Gained crude product dimethylbenzene recrystallization obtains the heterochromatic full -4- amine acetyl compounds sterling of R-；Recrystallization is pure Product are dissolved in hydrochloric acid and the mixed solution of methanol, are heated to reflux being hydrolyzed, and TLC tracing detection hydrolyzes progress, waits R- heterochromatic After full -4- amine acetyl compounds complete hydrolysis become the heterochromatic full -4- amine of R-, cooling, adjust pH value to alkalescence, methanol is evaporated off, use Ethyl acetate essence takes 3 times, merges organic faciess, be dried, concentrate after the heterochromatic full -4- amine 13.6g of R-, yield is 91.4%, and HPLC Detect that its ee value is 99.2%.

Claims

1. the reduction amination of different chroman-4-on and method for splitting it is characterised in that：1) in autoclave, with methanol or second Alcohol is solution, adds the different chroman-4-on of raw material, adds catalyst in the ratio of necessarily different chroman-4-on mass fraction 5-15%； Sealing autoclave, after nitrogen displacement, by with different chroman-4-on mol ratio 1:The ratio of 3-10 is passed through liquefied ammonia or ammonia, finally leads to Enter hydrogen to pressure 3-5MPa, be warmed up to 70-90 DEG C of reaction 8-12 hour, observe and no longer inhale stopped reaction after hydrogen；Terminate reaction Afterwards, through filtering, concentration operation obtains heterochromatic full -4- amine crude product；Crude product through acid, can purify after alkali process obtain purity be 99% different Chromane -4- amine；2) step 1) the heterochromatic full -4- ketoamine of gained is dissolved in toluene solvant, by with heterochromatic full -4- amine mol ratio 1:1.0- 2.0 ratio adds acry radical donor, adds Digestive Enzyme in the ratio of the heterochromatic full -4- amine mass fraction 5%-10% of raw material, by former Expect that the ratio of heterochromatic full -4- amine mass fraction 5%-10% adds racemization catalyst, be warming up to 40-60 DEG C of reaction 9-14 hour, Heterochromatic full -4- amine can be fully converted to the amide compound of the heterochromatic full -4- amine of R-；Stopped reaction, filters, concentration steams first Benzene must split crude product；3) by step 2) gained crude product dimethylbenzene recrystallization, the heterochromatic full -4- amine acyl compounds of R- can be obtained Sterling, purity>99%, yield is up to 90% about；Acyl compounds again through acidolysis, alkali process etc. operate, can obtain R- heterochromatic full- 4- amine；And product ee value is 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 the reduction amination of different chroman-4-on and method for splitting it is characterised in that：In claim 1 Described step 1) in reducing catalyst be：Nickel/alumina load catalyst SN-6000P.

3. according to claim 1 the reduction amination of different chroman-4-on and method for splitting it is characterised in that：In claim 1 Described step 2) in acry radical donor can for (-)-neomenthol acetass.

4. according to claim 1 the reduction amination of different chroman-4-on and method for splitting it is characterised in that：In claim 1 Described step 2) in Digestive Enzyme used be porcine pancreatic lipase (PPL).

5. according to claim 1 the reduction amination of different chroman-4-on and method for splitting it is characterised in that：In claim 1 Described step 2) in racemization catalyst used be nickel/alumina load catalyst SN-6000P.