CN106380460A - L-isochroman-4-amine - Google Patents
L-isochroman-4-amine Download PDFInfo
- Publication number
- CN106380460A CN106380460A CN201610807204.5A CN201610807204A CN106380460A CN 106380460 A CN106380460 A CN 106380460A CN 201610807204 A CN201610807204 A CN 201610807204A CN 106380460 A CN106380460 A CN 106380460A
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- Prior art keywords
- amine
- heterochromatic full
- heterochromatic
- full
- handed
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- KFOXDILMEHCWMS-MRVPVSSYSA-N C[C@H]1c2ccccc2COC1 Chemical compound C[C@H]1c2ccccc2COC1 KFOXDILMEHCWMS-MRVPVSSYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- 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 method for preparing l-isochroman-4-amine through DKR (Dynamic Kinetic Resolution). The method specifically comprises the following steps: carrying out the DKR by taking racemic isochroman-4-amine as a raw material, PPL (Porcine Pancreatic Lipase) as a biological resolution catalyst, a nickel/aluminum oxide-supported catalyst SN-6000P as a racemic catalyst and (+)-D-menthol organic fatty acid ester as an acyl donor, thus obtaining an acyl compound of S-isochroman-4-amine; then hydrolyzing, thus obtaining the left-handed isochroman-4-amine. The method disclosed by the invention has the characteristics of simpleness in operation, good product yield, high optical purity of resolution products and the like.
Description
Technical field
Invention is related to a kind of fractionation preparation method of optical homochiral amine compound, and more particularly, to one kind is by dynamically moving
The method that the heterochromatic full -4- amine of S- is prepared in mechanics fractionation.
Background technology
In existing correlational study, it is mainly first with boron with regard to how to prepare the method for heterochromatic full -4- amine using it
Sodium hydride is by heterochromatic full -4- alcohol, then reacts and obtain with diphenyl phosphate azide and DBU in toluene solvant
（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 to split system
The standby report obtaining the heterochromatic full -4- amine of its optical purity S- then fails to see.
Content of the invention
The present invention is intended to provide a kind of method that the heterochromatic full -4- amine of S- is prepared by Dynamic Kinetic Resolution.In order to realize
This target, concrete operations are as follows： 1）In autoclave, by heterochromatic full -4- amine solvent in toluene, then press heterochromatic full -4-
Amine：Acry radical donor mol ratio is 1：The ratio of 1.0-2.0 adds acry radical donor, by the heterochromatic full -4- amine mass fraction 2%- of raw material
10% ratio adds Digestive Enzyme, adds racemization catalyst in the ratio of the heterochromatic full -4- amine mass fraction 5%-20% of raw material, heats up
To 35-60 DEG C of reaction 10-12 hour, you can heterochromatic full -4- amine to be fully converted to the acyl compounds of the heterochromatic full -4- amine of S-；
Stopped reaction, filters, concentration steams toluene and must split crude product；2）By step 1）Gained crude product dimethylbenzene recrystallization, can
Obtain the heterochromatic full -4- amine acyl compounds sterling of S-；Acyl compounds are operated through acidolysis, alkali process etc., the heterochromatic full -4- of S- can be obtained
Amine；Final products purity>99.5%, yield more than 90%, product ee value is up to more than 99%.Step 1) described in acry radical donor
For (+)-D- Herba Menthae alcohol acetic ester；Step 1）In Digestive Enzyme used be porcine pancreatic lipase（PPL）；Step 1）In used disappearing
Rotation catalyst is nickel/alumina load catalyst SN-6000P.
The method that the present invention is announced is successfully prepared the heterochromatic full -4- amine of S-.The present invention possesses simple to operate, product yield
Well, the features such as purity is high.In the production and fractionation research of the heterochromatic full -4- amine of S-, there is great guidance and using value.
Specific embodiment
Embodiment 1
1）The Dynamic Kinetic Resolution of heterochromatic full -4- amine
In autoclave, add the heterochromatic full -4- amine sterling of 14.9g, 20g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 200ml toluene, then
Add 2.5g catalyst SN-6000P, 1.2g porcine pancreatic lipase（PPL）, sealed reactor, the sky in kettle is extracted with vacuum pumping pump
Gas, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with hydrogen in autoclave to 1.0MPa, and
It is warming up to 40 DEG C to be reacted；After 11 hours of reaction, stopped reaction, detects that heterochromatic full -4- amine is wholly absent, is converted into S- different
Chromane -4- amine acetyl compounds.After stopped reaction, filter, be concentrated to give thick containing the heterochromatic full -4- amine acetyl compounds of S-
Product.
2）The preparation of the heterochromatic full -4- amine of S-
By step 1）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 S- heterochromatic
After full -4- amine acetyl compounds complete hydrolysis become the heterochromatic full -4- amine of S-, cooling, adjust pH value to alkalescence, methanol is evaporated off, use
Dichloromethane essence takes 3 times, merges organic faciess, be dried, concentrate after the heterochromatic full -4- amine 13.4g of R-, yield is 90.0%, and HPLC
Detect that its ee value is 99.3%.
Embodiment 2
In autoclave, add the heterochromatic full -4- amine sterling of 44.7g, 65g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 700ml toluene, then
Add 6.0g catalyst SN-6000P, 3.0g porcine pancreatic lipase（PPL）, sealed reactor, the sky in kettle is extracted with vacuum pumping pump
Gas, is re-filled with nitrogen to .05MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with hydrogen in autoclave to 1.0MPa, and
It is warming up to 45 DEG C to be reacted；After 12 hours of reaction, stopped reaction, detects that heterochromatic full -4- amine is wholly absent, is converted into S- different
Chromane -4- amine acetyl compounds.After stopped reaction, filter, be concentrated to give containing the heterochromatic full -4- amine acetyl compounds of S- with (+) -
D- menthol, (+) crude product of-D- menthol acetate mixture.
2）The preparation of the heterochromatic full -4- amine of S-
By step 1）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 S- heterochromatic
After full -4- amine acetyl compounds complete hydrolysis become the heterochromatic full -4- amine of S-, cooling, adjust pH value to alkalescence, methanol is evaporated off, use
Dichloromethane essence takes 3 times, merges organic faciess, be dried, concentrate after the heterochromatic full -4- amine 16.1g of S-, yield is 90.0%, and HPLC
Detect that its ee value is 99.5%.
Embodiment 2
1）The Dynamic Kinetic Resolution of heterochromatic full -4- amine
In autoclave, add the heterochromatic full -4- amine sterling of 88.5g, 105g (+)-D- Herba Menthae alcohol acetic ester is dissolved in 700ml toluene,
Add 12g catalyst SN-6000P, 6g porcine pancreatic lipase（PPL）, sealed reactor, the sky in kettle is extracted with vacuum pumping pump
Gas, is re-filled with nitrogen to 0.5MPa, then uses vacuum pumping pump evacuation；It is replaced, be filled with hydrogen in autoclave to 1.5MPa, and
It is warming up to 45 DEG C to be reacted；After 14 hours of reaction, stopped reaction, detects that heterochromatic full -4- amine is wholly absent, is converted into S- different
Chromane -4- amine acetyl compounds.After stopped reaction, filter, be concentrated to give the heterochromatic full -4- amine acetyl compounds of S- with (+)-D-
Menthol, (+) crude product of-D- menthol acetate mixture.
2）The preparation of the heterochromatic full -4- amine of S-
By step 1）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 S- heterochromatic
After full -4- amine acetyl compounds complete hydrolysis become the heterochromatic full -4- amine of S-, cooling, adjust pH value to alkalescence, methanol is evaporated off, use
Dichloromethane essence takes 3 times, merges organic faciess, be dried, concentrate after the heterochromatic full -4- amine 41.7g of S-, yield is 93.2%, and HPLC
Detect that its ee value is 99.5%.
Claims (4)
1. a kind of left-handed heterochromatic full -4- amine Dynamic Kinetic Resolution preparation method it is characterised in that：1) in autoclave,
By heterochromatic full -4- amine solvent in toluene, then it is 1 by heterochromatic full -4- amine acry radical donor mol ratio：1.0-2.0 ratio add
Acry radical donor, adds Digestive Enzyme in the ratio of heterochromatic full -4- amine mass fraction 2%-10%, by the heterochromatic full -4- amine quality of raw material
The ratio of fraction 5%-20% adds racemization catalyst, is warming up to 35-60 DEG C of reaction 10-12 hour, you can by heterochromatic full -4- amine
It is fully converted to the acyl compounds of the heterochromatic full -4- amine of S-；Stopped reaction, filters, concentration steams toluene and must split crude product；2)
By step 1) gained crude product dimethylbenzene recrystallization, the heterochromatic full -4- amine acyl compounds sterling of S- can be obtained；By acyl compounds
Through the operation such as hydrolysis, alkali process, the heterochromatic full -4- amine of S- can be obtained；Final products purity>99.5%, yield more than 90%, product ee
Value is up to more than 99%；In sum, the reaction equation of the present invention is as follows：
2. according to claim 1 a kind of left-handed heterochromatic full -4- amine Dynamic Kinetic Resolution preparation method it is characterised in that：
Step 1 described in claim 1) described in acry radical donor be (+)-D- Herba Menthae alcohol acetic ester.
3. according to claim 1 a kind of left-handed heterochromatic full -4- amine Dynamic Kinetic Resolution preparation method it is characterised in that：
Step 1 described in claim 1) described in Digestive Enzyme be porcine pancreatic lipase PPL.
4. according to claim 1 a kind of left-handed heterochromatic full -4- amine Dynamic Kinetic Resolution preparation method it is characterised in that：
Step 1 described in claim 1) described in racemization catalyst be nickel/alumina load catalyst SN-6000P.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610807204.5A CN106380460A (en) | 2016-09-07 | 2016-09-07 | L-isochroman-4-amine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610807204.5A CN106380460A (en) | 2016-09-07 | 2016-09-07 | L-isochroman-4-amine |
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| Publication Number | Publication Date |
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| CN106380460A true CN106380460A (en) | 2017-02-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610807204.5A Pending CN106380460A (en) | 2016-09-07 | 2016-09-07 | L-isochroman-4-amine |
Country Status (1)
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087714A2 (en) * | 2004-03-09 | 2005-09-22 | Elan Pharmaceuticals, Inc. | Methods of treatment of amyloidosis using bi-cyclic aspartyl protease inhibitors |
| CN106397383A (en) * | 2016-09-04 | 2017-02-15 | 王际菊 | Reductive amination and resolution of isochroman-4-one |
| CN106480118A (en) * | 2016-09-04 | 2017-03-08 | 王际宽 | A kind of left-handed Chiral Amine |
-
2016
- 2016-09-07 CN CN201610807204.5A patent/CN106380460A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087714A2 (en) * | 2004-03-09 | 2005-09-22 | Elan Pharmaceuticals, Inc. | Methods of treatment of amyloidosis using bi-cyclic aspartyl protease inhibitors |
| CN106397383A (en) * | 2016-09-04 | 2017-02-15 | 王际菊 | Reductive amination and resolution of isochroman-4-one |
| CN106480118A (en) * | 2016-09-04 | 2017-03-08 | 王际宽 | A kind of left-handed Chiral Amine |
Non-Patent Citations (1)
| Title |
|---|
| 黄冠廷等: "脂肪酶手性拆分的研究进展", 《广州化工》 * |
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Application publication date: 20170208 |