CN108707148A - The chiral separation method of four isomers in a kind of Racanisodamine - Google Patents
The chiral separation method of four isomers in a kind of Racanisodamine Download PDFInfo
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- CN108707148A CN108707148A CN201810596799.3A CN201810596799A CN108707148A CN 108707148 A CN108707148 A CN 108707148A CN 201810596799 A CN201810596799 A CN 201810596799A CN 108707148 A CN108707148 A CN 108707148A
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- racanisodamine
- resolving agent
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- tartaric acid
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- WTQYWNWRJNXDEG-UHFFFAOYSA-N (6-hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 3-hydroxy-2-phenylpropanoate Chemical compound CN1C(C2)CC(O)C1CC2OC(=O)C(CO)C1=CC=CC=C1 WTQYWNWRJNXDEG-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000000926 separation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000003287 optical effect Effects 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 18
- SDCAKSIYIYPDCB-UHFFFAOYSA-N CC(C(C(=O)O)(OC1=CC=CC=C1)C=O)(OC1=CC=CC=C1)C(=O)O Chemical compound CC(C(C(=O)O)(OC1=CC=CC=C1)C=O)(OC1=CC=CC=C1)C(=O)O SDCAKSIYIYPDCB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005194 fractionation Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 6
- 238000002953 preparative HPLC Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000013078 crystal Substances 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000012986 modification Methods 0.000 claims description 8
- 230000004048 modification Effects 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- -1 dichloromethane Alkane Chemical class 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 238000007689 inspection Methods 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- WTQYWNWRJNXDEG-LEOABGAYSA-N anisodamine Chemical compound C1([C@@H](CO)C(=O)O[C@@H]2C[C@H]3[C@@H](O)C[C@@H](C2)N3C)=CC=CC=C1 WTQYWNWRJNXDEG-LEOABGAYSA-N 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 244000144992 flock Species 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical class C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 241001248531 Euchloe <genus> Species 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 101000845012 Macrovipera lebetina Disintegrin lebein-1-alpha Proteins 0.000 description 1
- 101000845007 Macrovipera lebetina Disintegrin lebein-1-beta Proteins 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- ZZNMWGVMOBOREI-VQTJNVASSA-N chembl464952 Chemical compound C1([C@H]2OC=3C4=C(C=5C=CC(C)(C)OC=5C=3C(=O)[C@@H]2O)OC(C=C4)(C)C)=CC=CC=C1 ZZNMWGVMOBOREI-VQTJNVASSA-N 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 229960003210 hyoscyamine Drugs 0.000 description 1
- 229930005342 hyoscyamine Natural products 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of chiral separation methods of four isomers in Racanisodamine.The present invention using D or L- to methyldiphenyl formyl tartaric acid as resolving agent, using preparative HPLC joint chemical resolution method split Racanisodamine.This method reasonable design, practical, product yield is larger, and purity is high, obtained anisodamine four kinds of optical isomers 6R, 2'R,6R,2'S,6S,2'S,6S,2'The purity of R is all higher than 95%, is a kind of method of more effective four kinds of optical isomers of industrialized production anisodamine.This method is successfully realized the fractionation of four kinds of optical isomers, can be effectively reduced the fractionation cost of four kinds of optical isomers of anisodamine, and generate extensive social benefit, economic benefit is huge, has a extensive future.
Description
Technical field
The present invention relates to the chiral separation methods of four isomers in Racanisodamine, may be implemented to disappear by the method
Revolve the chiral resolution of four kinds of optical isomers in anisodamine.The invention belongs to pharmaceutical technology fields.
Background technology
Anisodamine can compete antagonism m receptor with acetylcholine, for treating smooth muscle spasm, neuralgia, fulminant type brain
Dyshaemia etc. caused by film inflammation, coccus meningitis, toxic dysentery and vasopasm.Racanisodamine is anisodamine
Composite (654-2), including four kinds of optical isomers, respectively 6R, 2'S,6S,2'R,6R,2'R,6S,2'S configurations.Have
Relevant animal is it is demonstrated experimentally that in the diastole effect power of isolated rat tracheae, 6S, 2'S isomers shows strongest medicine
Reason activity.And in isolated rat intestinal smooth muscle diastole effect, 6R, 2'S isomers shows strongest pharmacological activity.Cause
This, four kinds of optical isomers are separated by the method for chiral resolution by Racanisodamine, are carried out with single optical isomer
Medication can greatly improve Drug safety and validity.The patent application of Publication No. CN107991367A is attempted to adopt
The fractionation of four kinds of optical isomers of anisodamine is realized with capillary electrophoresis, but time-consuming since its method has, preparation amount
The defects of small, is only limitted to laboratory preparation, can not be suitable for industrialization large-scale production.
The object of the present invention is to provide a kind of chiral separation methods of four isomers in Racanisodamine, pass through first
Racemic anisodamine is split as a pair and is configured as 6R, 2&apos by preparative high performance liquid chromatography (HPLC);S+6S,2'The isomers of R
654-2-A and a pair are configured as 6R, 2'R+6S,2'The isomers 654-2-B of S.Secondly, with the D/L of safety to methyldiphenyl first
Acyl tartaric acid is resolving agent, and is recrystallized by 3 times, carries out chemical resolution to 654-2-A and 654-2-B, finally obtains purity
Higher 6R, 2'S,6S,2'R,6R,2'R,6S,2'Tetra- kinds of anisodamine optical isomers of S.It can be real by the method for splitting
The chiral resolution of existing Racanisodamine, and can effectively save and split the time, production cost is reduced, industrial production is suitable for.
Invention content
The object of the present invention is to provide a kind of chiral separation methods of Racanisodamine, using preparative high-efficient liquid phase color
The method for composing joint chemical resolution, using the D/L of safety to methyldiphenyl formyl tartaric acid as resolving agent, acquisition purity higher mountain
Four kinds of optical isomers of hyoscyamine.The time is split to effectively save, production cost is reduced, to be suitable for industrial production.
In order to achieve the above object, present invention employs following technological means：
The chiral separation method of four isomers, includes the following steps in a kind of Racanisodamine of the present invention：
Step 1. Racanisodamine sample is completely dissolved with the aqueous solution containing 45% (v/v) methanol, and 0.22 μm excessively micro-
It is spare after the filter membrane of hole；
Step 2. detaches the Racanisodamine that step 1 obtains using preparative HPLC, respectively obtains racemic
Contain 6R, 2&apos in body 654-2-A and racemic modification 654-2-B, the racemic modification 654-2-A;S and 6S, 2'Two structures of R
Type contains 6R, 2&apos in the racemic modification 654-2-B;R and 6S, 2'Two configurations of S；
Step 3. is split as chemical resolution method 654-2-A by obtained by and 654-2-B, using D- to methyldiphenyl
Formyl tartaric acid or L- are resolving agent to methyldiphenyl formyl tartaric acid, and when being split to 654-2-A, the solvent system used is second
Nitrile：Methanol volume ratio=15:1；When being split to 654-2-B, the solvent system used after 24-48h, is respectively formed needle for ethyl alcohol
Shape crystallizes and crystalline particulate；
Step 4. is washed to crystallization is precipitated, and is filtered, is recrystallized 3 times；
Step 5. restores the crystal after four kinds of recrystallizations under ice bath with the sodium carbonate liquor of saturation, using isometric two
Chloromethanes extracts 3 times, and combining extraction liquid after solvent volatilizes, that is, has respectively obtained the optical isomer of four kinds of anisodamines.
The spatial configuration for synthesizing four isomers in anisodamine is as shown in Figure 1.
Wherein, it is preferred that the mobile phase that HPLC chromatogram separation uses in step 2 is the mixing of methanol, water and diethylamine
Solution, wherein methanol：Water：Volume ratio=45 of diethylamine:55:0.02；Chromatographic condition is：Detection wavelength 210nm, chromatographic column
For Agilent Prep C18 columns, 20 DEG C, sample size 1mL, flow velocity 5mL/min of column temperature.
Wherein, it is preferred that the fractionation of 654-2-A follows the steps below in step 3：Compound 654-2-A is taken to be dissolved in
In methanol, resolving agent D- is dissolved in acetonitrile methyldiphenyl formyl tartaric acid in methyldiphenyl formyl tartaric acid or L-, has waited for
654-2-A is mixed with resolving agent after fully dissolved, 30min is reacted under the conditions of 60 DEG C, generates white flock precipitate, filtering takes
Filtrate is placed under the conditions of being put into 4 DEG C, generates a large amount of white, needle-shaped crystals.
Wherein, it is preferred that the molar ratio of the addition of resolving agent and 654-2-A to be split are 1.5：1.
Wherein, it is preferred that the fractionation of 654-2-B follows the steps below in step 3：Compound 654-2-B is taken to be dissolved in
In ethanol solution, resolving agent D- is dissolved in ethyl alcohol methyldiphenyl formyl tartaric acid in methyldiphenyl formyl tartaric acid or L-,
654-2-B is mixed with resolving agent until completely dissolved, reacts 30min under the conditions of 60 DEG C, is filtered, filtrate is put at 4 DEG C and protects
It deposits, generates a large amount of granular crystals.
Wherein, it is preferred that the molar ratio of the addition of resolving agent and 654-2-B to be split are 1.5：1.
Wherein, it is preferred that in step 4, the acicular crystal filtering obtained after 654-2-A is split washs this with pure acetonitrile
Crystallization 2 times, gained crystal is recrystallized 3 times under pure acetonitrile system；The crystalline particulate mistake obtained after 654-2-B is split
Filter, washs the crystallization 2 times with absolute ethyl alcohol, gained crystal is recrystallized 3 times under absolute ethyl alcohol system.
Compared to the prior art, the beneficial effects of the invention are as follows：
The present invention using D or L- to methyldiphenyl formyl tartaric acid as resolving agent, using preparative HPLC combine chemical resolution
Method splits Racanisodamine.This method reasonable design, practical, product yield is larger, and purity is high, obtained anisodamine
Four kinds of optical isomers 6R, 2'R,6R,2'S,6S,2'S,6S,2'The purity of R is all higher than 95%, is a kind of more effective work
The method that industry metaplasia produces four kinds of optical isomers of anisodamine.This method is successfully realized the fractionation of four kinds of optical isomers, energy
It is effectively reduced the fractionation cost of four kinds of optical isomers of anisodamine, and generates extensive social benefit, economic benefit is huge,
It has a extensive future.
Description of the drawings
Fig. 1 is the structure for synthesizing four kinds of optical isomers in anisodamine；
Fig. 2 is the HPLC chromatogram (210nm) of 654-2-A, 654-2-B and Racanisodamine；
Fig. 3 is the chiral HPLC chromatogram (210nm) of 654-2-A；
Fig. 4 is the chiral HPLC chromatogram (210nm) of 654-2-B.
Specific implementation mode
Disclosed herein is a kind of method for splitting of Racanisodamine, those skilled in the art can use for reference present disclosure,
It is suitably modified technological parameter.In particular, it should be pointed out that all similar substitutions and modifications are for a person skilled in the art
It will be apparent that they are considered as being included in the present invention.The method of the present invention and application are carried out by preferred embodiment
Or else description, related personnel obviously can be detached from the content of present invention, spirit and scope carry out method described herein and application
It changes or suitably changes and combine, to realize and apply the technology of the present invention.
The chiral resolution of four isomers in 1 Racanisodamine of embodiment
1, the preparation of sample
Racanisodamine sample (sample concentration：It is 100mg/mL) completely molten with the aqueous solution containing 45% (v/v) methanol
It solves, it is spare after 0.22 μm of miillpore filter excessively.
2, HPLC chromatogram detaches
Mobile phase：The mixed solution of methanol, water and diethylamine, wherein methanol：Water：Volume ratio=45 of diethylamine:
55:0.02。
Chromatographic condition：Detection wavelength 210nm, chromatographic column are Agilent Prep C18 columns (250mm × 9.4mm), column temperature
20 DEG C, sample size 1mL, flow velocity 5mL/min.
Isolated product is subjected to HPLC analyses, analysis condition is：Mobile phase methanol：Water：Diethylamine volume ratio is
50:50:0.02, chromatographic column be cosmosil MS-II C18 columns, 35 DEG C, Detection wavelength 210nm of column temperature, 10 μ L of sampling volume,
Flow velocity 1mL/min, analysis result are as shown in Figure 2.The yield for the 654-2-A (purity 97.8%) being wherein prepared is
The yield of 51.2%, 654-2-B (purity 97.2%) are 39.4%.
3,654-2-A (6R, 2&apos in Racanisodamine;S+6S,2'R separation)；
The culture of crystal：It takes compound 654-2-A (21.71mg) to be dissolved in 100 μ l methanol, splits acid D- to methyldiphenyl
Formyl tartaric acid 41.18mg is dissolved in 1.5mL acetonitriles, until completely dissolved mixes the two, is reacted under the conditions of 60 DEG C
30min generates a little white flock precipitate, and filtering takes filtrate.48h is placed under the conditions of being put into 4 DEG C, generates a large amount of white needles
Crystallization.Crystallization is filtered, the crystallization 2 times is washed with pure acetonitrile.
The processing of crystal：After gained crystal is recrystallized 3 times under the pure acetonitrile systems of 300 μ L, takes this crystal a small amount of, be put in
In EP pipes, sodium carbonate liquor is added under ice bath, blows and beats repeatedly entirely molten to crystal.It is extracted 3 times with isometric dichloromethane.Liquid separation takes
Go out dichloromethane layer, sample number into spectrum is 654-2-A1 after solvent is drained by combining extraction liquid.Sample is dissolved in 500 μ L methanol
In, 0.22 μm of filter membrane is crossed, takes subsequent filtrate in case HPLC analysis detections.Similarly, separately using resolution reagent L- to methyldiphenyl formyl
Tartaric acid can obtain the anisodamine of another configuration, number 654-2-A2, using chiral chromatographic column to obtaining in the same way
Two samples carry out HPLC detections.HPLC analysis conditions are n-hexane：Ethyl alcohol：Diethylamine volume ratio is 90：10：0.1, chromatography
Column type number：Daicel Chiral celOX-H (5 μm), flow velocity：1mL/min, column temperature：35 DEG C, analysis result is as shown in Figure 3.
4,654-2-B (6R, 2&apos in Racanisodamine;R+6S,2'S separation)；
The formation of crystal：It takes compound 654-2-B (21.71mg) to be dissolved in 700 μ l ethanol solutions, acid L- will be split to first
Base dibenzoyl tartaric acid 41.20mg, which is dissolved in 100 μ l ethyl alcohol, until completely dissolved mixes the two, is reacted under the conditions of 60 DEG C
30min, filtering.Filtrate is put into preserve at 4 DEG C there are a large amount of granular crystals afterwards for 24 hours, and crystallization is filtered, is washed with absolute ethyl alcohol
The crystallization 2 times.
The processing of crystal：After gained crystal is recrystallized 3 times under 300 μ L absolute ethyl alcohol systems, takes this crystal a small amount of, put
In EP pipes, sodium carbonate liquor is added under ice bath, blows and beats repeatedly entirely molten to crystal.It is extracted 3 times with isometric dichloromethane.Liquid separation
Take out dichloromethane layer, combining extraction liquid.After solvent is drained by sample number into spectrum be 654-2-B1.After dichloromethane volatilizes,
Sample is dissolved in 500 μ L methanol, 0.22 μm of filter membrane is crossed, takes subsequent filtrate in case HPLC analysis detections.Similarly, using resolution reagent
L- is to methyldiphenyl formyl tartaric acid, in the same way, can obtain the anisodamine of another configuration, number 654-2-B2 is utilized
Above-mentioned chiral chromatographic column and analysis condition carry out HPLC detections to sample, and analysis result is as shown in Figure 4.
Four kinds of optical isomers 654-2-A1,654-2-A2,654-2-B1,654- of Racanisodamine obtained above
Absolute configuration and purity corresponding to 2-B2 is as shown in table 1.
The yield and purity result of four stereoisomers in 1 654-2 of table
| Number | Configuration | Purity |
| 654-2-A1 | 6S,2'R | 98.3% |
| 654-2-A2 | 6R,2'S | 97.5% |
| 654-2-B1 | 6R,2'R | 95.3% |
| 654-2-B2 | 6S,2'S | 98.6% |
Claims (7)
1. the chiral separation method of four isomers in a kind of Racanisodamine, which is characterized in that include the following steps：
Step 1. Racanisodamine sample is completely dissolved with the aqueous solution containing 45% (v/v) methanol, crosses 0.22 μm of micropore filter
It is spare after film；
Step 2. detaches the Racanisodamine that step 1 obtains using preparative HPLC, respectively obtains racemic modification
Contain 6R, 2&apos in 654-2-A and racemic modification 654-2-B, the racemic modification 654-2-A;S and 6S, 2'Two configurations of R,
Contain 6R, 2&apos in the racemic modification 654-2-B;R and 6S, 2'Two configurations of S；
Step 3. is split as chemical resolution method 654-2-A by obtained by and 654-2-B, using D- to methyldiphenyl formyl
Tartaric acid or L- are resolving agent to methyldiphenyl formyl tartaric acid, and when being split to 654-2-A, the solvent system used is acetonitrile：
Methanol volume ratio=15:1；When being split to 654-2-B, the solvent system used is ethyl alcohol, after 24-48h, is respectively formed needle-shaped knot
Brilliant and crystalline particulate；
Step 4. is washed to crystallization is precipitated, and is filtered, is recrystallized 3 times；
Step 5. restores the crystal after four kinds of recrystallizations under ice bath with the sodium carbonate liquor of saturation, using isometric dichloromethane
Alkane extracts 3 times, and combining extraction liquid after solvent volatilizes, that is, has respectively obtained the optical isomer of four kinds of anisodamines.
2. the method as described in claim 1, which is characterized in that in step 2 the HPLC chromatogram mobile phase that uses of separation for methanol,
The mixed solution of water and diethylamine, wherein methanol：Water：Volume ratio=45 of diethylamine:55:0.02；Chromatographic condition is：Inspection
Wavelength 210nm is surveyed, chromatographic column is Agilent Prep C18 columns, 20 DEG C, sample size 1mL, flow velocity 5mL/min of column temperature.
3. the method as described in claim 1, which is characterized in that the fractionation of 654-2-A follows the steps below in step 3：
Compound 654-2-A is taken to be dissolved in methanol, by resolving agent D- to methyldiphenyl formyl tartaric acid or L- to methyldiphenyl formyl wine
Stone acid is dissolved in acetonitrile, until completely dissolved mixes 654-2-A with resolving agent, and 30min is reacted under the conditions of 60 DEG C, is generated white
Color flocculent deposit, filtering, takes filtrate, is placed under the conditions of being put into 4 DEG C, generate a large amount of white, needle-shaped crystals.
4. method as claimed in claim 3, which is characterized in that mole of the addition of resolving agent and 654-2-A to be split
Than being 1.5：1.
5. the method as described in claim 1, which is characterized in that the fractionation of 654-2-B follows the steps below in step 3：
Compound 654-2-B is taken to be dissolved in ethanol solution, by resolving agent D- to methyldiphenyl formyl tartaric acid or L- to methyldiphenyl first
Acyl tartaric acid is dissolved in ethyl alcohol, until completely dissolved mixes 654-2-B with resolving agent, reacts 30min, mistake under the conditions of 60 DEG C
Filter, filtrate are put at 4 DEG C and preserve, and generate a large amount of granular crystals.
6. method as claimed in claim 5, which is characterized in that mole of the addition of resolving agent and 654-2-B to be split
Than being 1.5：1.
7. the method as described in claim 1, which is characterized in that in step 4, the acicular crystal that is obtained after 654-2-A is split
Filtering, washs the crystallization 2 times with pure acetonitrile, gained crystal is recrystallized 3 times under pure acetonitrile system；After 654-2-B is split
Obtained crystalline particulate filtering, washs the crystallization 2 times with absolute ethyl alcohol, gained crystal is recrystallized under absolute ethyl alcohol system
3 times.
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