CN105503629B - A kind of separation method of 16 amino iso steviol ethyl ester non-enantiomer mixture - Google Patents
A kind of separation method of 16 amino iso steviol ethyl ester non-enantiomer mixture Download PDFInfo
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- CN105503629B CN105503629B CN201510889032.6A CN201510889032A CN105503629B CN 105503629 B CN105503629 B CN 105503629B CN 201510889032 A CN201510889032 A CN 201510889032A CN 105503629 B CN105503629 B CN 105503629B
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- ethyl ester
- amino iso
- iso steviol
- steviol
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the separation technology field of pharmaceutical-chemical intermediate diastereoisomer, a kind of separation method of 16 amino iso steviol ethyl ester non-enantiomer mixture is specifically disclosed.16 amino iso steviol ethyl ester non-enantiomer mixture ethanol are dissolved, the ethanol solution of the o-nitrobenzoic acid of 0.5 molar equivalent is added dropwise into system under condition of ice bath, after completion of dropping, concentrate reaction system, crystallized with ethyl acetate, filtering, filter cake is the salt of 16 amino iso steviol ethyl ester isomers of one of which configuration, the salt adds alkali lye neutralisation treatment to deacidify again, obtain 16 amino iso steviol ethyl ester isomers of one of which configuration, and filtrate is then again through column chromatography for separation, obtain 16 amino iso steviol ethyl ester isomers of another configuration.Separation method of the present invention is easy to operate, and separation is thorough.
Description
Technical field
The invention belongs to the separation technology field of pharmaceutical-chemical intermediate diastereoisomer, and in particular to a kind of 16- ammonia
The separation method of base iso steviol ethyl ester non-enantiomer mixture.
Background technology
Iso steviol (Isosteviol) is by the obtained chiral skeleton containing tetracyclic diterpene of natural products stevioside hydrolysis
Bioactive molecule, by introducing the bio-active groups such as amino, hydroxyl and hydrazone on iso steviol skeleton, it is derivative not
Congener compound shows special bioactivity mostly.During 16- carbonyl structure transformations, the reduction of carbonyl
It is critically important class reaction with ammonification.The introducing of amino is usually that the process by oximate, hydrogenation is obtained, but hydrogenation process
What is obtained is the mixture of a pair of 16- amino iso steviol ethyl ester diastereoisomers, and the separation method of such a mixture
Have no document report.
The content of the invention
To overcome the shortcomings of the prior art, it is an object of the invention to provide a kind of this different spy of 16- amino
Tie up the separation method of alcohol ethyl ester non-enantiomer mixture.
To achieve the above object, the technical scheme that the present invention takes is as follows：
A kind of separation method of 16- amino iso steviol ethyl ester non-enantiomer mixture：By this different spy of 16- amino
Dimension alcohol ethyl ester non-enantiomer mixture ethanol dissolves, and the neighbour of 0.5 molar equivalent is added dropwise into system under condition of ice bath
After the ethanol solution of nitrobenzoic acid, completion of dropping, reaction system is concentrated, is crystallized with ethyl acetate, filtered, filter cake is wherein one
The salt of the 16- amino iso steviol ethyl ester isomers of configuration is planted, the salt adds alkali lye neutralisation treatment to deacidify, that is, obtained wherein again
A kind of 16- amino iso steviol ethyl ester isomers of configuration, and filtrate obtains another configuration then again through column chromatography for separation
16- amino iso steviol ethyl ester isomers.
16- amino iso steviol ethyl ester non-enantiomer mixtures can be passed through by prior art by natural products stevioside
Hydrolysis, oximate, hydrogenation are prepared, and for the reduction of oxime, palladium carbon catalytic hydrogenation, sodium borohydride reduction are usually taken at present
Method, is reduced by both approaches, and reaction system is complicated, and without principal product generation.The present invention preferably takes Raney Ni to reduce, and has
Body is：By prior art prepare compound 1, then compound 1 is dissolved in tetrahydrofuran, addition accounts for the mass 25- of compound 1
35% Raney Ni, is passed through at hydrogen, 40-80 DEG C in 2-6atm catalytic hydrogenation 3-7h, filtering, concentration produce 16- amino it is different this
Spy's dimension alcohol ethyl ester non-enantiomer mixture；The structural formula of the compound 1 is：
Using the Raney Ni reducing process of the present invention, making reaction 3-7h at solvent, 40-80 DEG C with tetrahydrofuran can react
Entirely.
During column chromatography for separation, the eluant, eluent used is VEthyl acetate:VPetroleum ether=1:3-1:1.
The beneficial effects of the invention are as follows：The present invention can obtain the 16- amino iso steviol ethyl esters of two kinds of configurations simultaneously
Isomers, separation method is easy to operate, and separation is thorough.
Embodiment
Below by embodiment, the present invention will be further elaborated, but protection scope of the present invention is not limited to
This.
Embodiment 1
By prior art, (Ma Zhiwei and asymmetric is urged at the design synthesis of the new organic catalyst based on Isosteviol
Change performance study doctor thesis) prepare compound 1 (structural formula is shown in formula 1), compound 1 is then dissolved in 200mL tetrahydrochysene furans
In muttering, the Raney Ni for accounting for the mass 20% of compound 1 is added, is passed through at hydrogen, 50 DEG C in 3atm catalytic hydrogenation 5h, filters, concentration
Produce 16- amino iso steviol ethyl ester non-enantiomer mixtures (structural formula is shown in formula 2).Specifically route is：
The separation method of above-mentioned 16- amino iso steviol ethyl ester non-enantiomer mixture：By this different spy of 16- amino
Alcohol ethyl ester non-enantiomer mixture anhydrous alcohol solution is tieed up, 0.5 molar equivalent is added dropwise into system under condition of ice bath
The ethanol solution of the o-nitrobenzoic acid of (i.e. isomer mixture 2mol, o-nitrobenzoic acid 1mol), in ortho-nitrophenyl
After formic acid completion of dropping, detected through TLC, it is found that one of isomers disappears, and one polarity of generation is larger and has
Fluorescent absorption spot concentration reaction system, crystallized with ethyl acetate, filter, obtain one of which configuration 16- amino it is different this
The salt 2b ' of spy's dimension alcohol ethyl ester isomers, salt 2b ' again plus the deacidification of NaOH aqueous solution neutralisation treatment, produce compound 2b, and filtrate
Then again through column chromatography for separation, eluant, eluent is：Ethyl acetate:Petroleum ether=1:1, obtain compound 2a.Disjunctive path is：
Compound 2a, 2b ' respectively by IR,1H NMR and HR-MS, are confirmed, data are as follows to its structure：
Compound 2a：
IR(KBr,cm-1):3355,2939,2845,1722,1661,1451,1374,1231,1177,1151,1094,
1048；[α]D 20：- 47.4 ° (c 0.54, EtOH)；1H NMR(400MHz,CDCl3)δ0.73(s,3H,-CH3),0.84(s,
3H,-CH3), 0.97~1.05 (m, 4H), 1.16 (s, 3H ,-CH3), 1.25 (t, J=7.2Hz, 3H ,-CH3), 1.31~1.36
(m, 6H), 1.56~1.81 (m, 9H), 2.14~2.17 (m, 1H), 2.87~2.91 (m, 1H ,-NHCH-), 4.06~4.11
(m,2H,-OCH2CH3)；13C NMR(CDCl3)δ:13.3,14.0,18.9,20.5,21.7,24.9,28.9,33.3,38.0,
40.0,41.5,41.7,41.8,42.9,43.6,55.7,56.5,57.1,59.8,61.1,177.5,178.0；HR-MS m/z:
calcd.For C22H38NO2(M+H)+348.2903,found 348.2904.
Compound 2b '：
mp:186~188 DEG C；IR(KBr,cm-1):3062,3025,2939,2849,1720,1660,1600,1569,
1532,1468,1375,1235,1152,1095,1041,828,780,739,697；[α]D 20：- 23.1 ° (c 0.56, EtOH)
；1H NMR(400MHz,CDCl3)δ0.53(s,3H,-CH3), 0.77~0.82 (m, 3H), 0.970.77~0.82 (m, 3H),
0.93~0.99 (m, 2H), 1.13 (s, 3H ,-CH3), 0.99~1.13 (m, 3H), 1.22~1.25 (t, J=7.2Hz, 3H ,-
CH3), 1.26~1.48 (m, 6H), 1.63~1.77 (m, 4H), 2.11 (m, 2H), 3.04~3.05 (m, 1H ,-NHCH-),
4.02~4.15 (m, 2H ,-OCH2CH3), 7.40~7.44 (t, J=8.0Hz, 1H, ArH), 7.55~7.59 (t, J=8.0Hz,
1H, ArH), 7.72~7.74 (d, J=4.0Hz, 1H, ArH), 7.77~7.79 (d, J=4.0Hz, 1H, ArH), 8.24~
8.25(br,2H,-NH2)；HR-MS m/z:calcd.For C29H43N2O6(M+H)+515.3121,found 515.3.
Compound 2a 16 carbon atom absolute configuration bibliography (Ma Zhiwei, it is new organic based on Isosteviol
The design synthesis of catalyst and asymmetry catalysis performance study doctor thesis) it is defined as R types, compound 2b 16 carbon originals
Sub- absolute configuration is then S types.
Claims (3)
1. a kind of separation method of 16- amino iso steviol ethyl ester non-enantiomer mixture, it is characterised in that：By 16-
Amino iso steviol ethyl ester non-enantiomer mixture ethanol dissolves, and being added dropwise 0.5 into system under condition of ice bath rubs
After the ethanol solution of the o-nitrobenzoic acid of your equivalent, completion of dropping, reaction system is concentrated, is crystallized with ethyl acetate, filtered, filter
Cake is the salt of the 16- amino iso steviol ethyl ester isomers of one of which configuration, and the salt adds alkali lye neutralisation treatment to deacidify again,
The 16- amino iso steviol ethyl ester isomers of one of which configuration is obtained, and filtrate obtains another then again through column chromatography for separation
A kind of 16- amino iso steviol ethyl ester isomers of outer configuration；
The structural formula of the 16- amino iso steviol ethyl ester non-enantiomer mixture is：
2. the separation method of 16- amino iso steviol ethyl ester non-enantiomer mixture as claimed in claim 1, it is special
Levy is that 16- amino iso steviol ethyl ester non-enantiomer mixtures are prepared as follows：By prior art system
Compound 1, is then dissolved in tetrahydrofuran by standby compound 1, adds the Raney Ni for accounting for the mass 25-35% of compound 1, is passed through hydrogen
Gas, in 2-6atm catalytic hydrogenation 3-7h at 40-80 DEG C, filtering, concentration produces 16- amino iso steviol ethyl ester diastereo-isomerisms
Body mixture；The structural formula of the compound 1 is：
3. the separation method of 16- amino iso steviol ethyl ester non-enantiomer mixture as claimed in claim 1 or 2,
It is characterized in that during column chromatography for separation, the eluant, eluent used is VEthyl acetate:VPetroleum ether=1:3-1:1.
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