CN105749890A - Chiral stationary phase prepared by taking cinchonidine-boc-amide as chiral selector as well as preparation method and application thereof - Google Patents

Chiral stationary phase prepared by taking cinchonidine-boc-amide as chiral selector as well as preparation method and application thereof Download PDF

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Publication number
CN105749890A
CN105749890A CN201610078456.9A CN201610078456A CN105749890A CN 105749890 A CN105749890 A CN 105749890A CN 201610078456 A CN201610078456 A CN 201610078456A CN 105749890 A CN105749890 A CN 105749890A
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chiral
stationary phase
cinchonidine
benzoyl
selector
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张毅军
陈娜
张裕平
荆树科
马晶晶
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Henan Institute of Science and Technology
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Henan Institute of Science and Technology
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/29—Chiral phases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2220/00—Aspects relating to sorbent materials
    • B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
    • B01J2220/52—Sorbents specially adapted for preparative chromatography
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a chiral stationary phase prepared by taking cinchonidine-boc-amide as a chiral selector as well as a preparation method and application thereof. The method is used for preparing a UPHLC chiral stationary phase with maximum pressure endurance of 1300bar, and the UPHLC chiral stationary phase is used for UHPL chiral separation. The chiral selector is catalyzed with azodiisobutyronitrile by use of a one-pot method, then is covalently bound to the surface of mercaptopropyl derivation full-porous spherical silica, and 1-hexene is utilized for endcapping, so that the chiral stationary phase for ultrahigh-pressure liquid chromatography chiral separation is successfully prepared; bonding of the chiral selector and endcapping of the stationary phase are finished by virtue of the one-pot method, so that the preparation efficiency is improved; the prepared chiral stationary phase is used for ultrahigh-pressure liquid chromatography chiral separation of 12 types of acidic amino acid derivative enantiomers and displaying favorable chiral separation capability.

Description

Solid with the chirality that cinchonidine-t-butylcarbamate is prepared for chiral selector Determine phase and its preparation method and application
Technical field
The present invention relates to chiral separation technology, be specifically related to select for chirality with cinchonidine-t-butylcarbamate Chiral stationary phase of son preparation and its preparation method and application.
Background technology
Have the compound of chirality refer to have in kind with mirror image can not the compound of completely overlapped character, containing chirality medicine Thing, Chiral pesticide, chirality organic synthesis intermediate, chiral environmental pollutants etc..Compound containing a chiral centre has A pair enantiomer, the equal amount of mixture of this pair enantiomer constitutes a racemic modification.Chiral drug is generally with racemic modification Form medication.A pair enantiomer of chiral drug has different metabolism behaviors and physiologic effect in human body, usual one different Structure body has good curative effect (excellent isomer), and another is invalid even has strong side effect, toxicity (carcinogenic, teratogenecity) Deng effect (bad isomer).So further investigate the property of each isomer after Chiral Separation should be opened for chiral drug Matter, and with the excellent isomer medication of chiral purity.
In numerous chiral separation methods, high performance liquid chromatography (High Performance Liquid Chromatography, HPLC) Chiral Stationary Phases is most widely used chiral chromatogram technology general, most successful.It is applicable to HPLC Chiral stationary phase (Chiral Stationary Phase, CSP) of a great variety, have shiploads of merchandiseization to originate simultaneously.It is applicable to The chiral stationary phase of HPLC is typically to be coated by chiral selector or be bonded to the surface system of 3-10 micron grain size spherical silica gel Standby, the rustless steel chromatograph column internal diameter of filling is usually 4.6-10mm, and a length of 15-25cm, disengaging time is from several minutes to number Ten minutes.Do not have any CSP can meet the needs of all Chiral Separation in practical study work, in the urgent need to exploitation The new CSP with high separability energy.
Ultrahigh pressure liquid phase chromatograph i.e. Ultra Performance Liquid Chromatography (Ultra High Performance Liquid Chromatography, UHPLC) it is that modern liquid chromatography separates the latest developments analyzing science and technology.UHPLC is by reducing fixing phase The particle diameter of filler (to sub-2 microns), less internal diameter chromatographic column (usually 2.1mm internal diameter), relatively shorter chromatogram column length (5cm or 10cm length), high flow rate (the highest 5ml/min) obtain higher post effect and shorten analysis time.UHPLC chromatographic column needs superelevation Pressure (being up to 1300bar) drive flowing phase.The UHPLC chromatographic column of commercial source only has C18, is not bonded at present SiO2On achirality post.
Summary of the invention
In order to solve the deficiencies in the prior art, the invention provides with cinchonidine-t-butylcarbamate as chirality Select chiral stationary phase of son preparation and its preparation method and application.
The technical scheme is that and prepare chirality admittedly with cinchonidine-t-butylcarbamate for chiral selector The method determining phase, comprises the following steps: step one successively, prepares mercapto propyl group derivatization full porous spherical silica gel；Step 2, by pungent Clothianadin-t-butylcarbamate chiral selector is bonded to mercapto propyl group derivatization full porous spherical silica gel to be prepared chirality and fixes Phase.
Further improvement of the present invention includes:
Described step one specifically includes: accurately weigh the full porous spherical silica gel of 5.0g a diameter of 1.1-1.9 micron, adds In the round-bottomed flask of 100ml, add 60ml dry toluene, water knockout drum and nitrogen protection device, magnetic agitation, backflow are installed Azeotropic water removing 3 hours；Reaction unit is cooled to room temperature, removes water knockout drum, add 10ml derivatization reagent 3-mercapto propyl group three second TMOS, installs nitrogen protection device, magnetic agitation, back flow reaction 72 hours；Post processing: centrifuge washing product, makes successively With dry toluene, methanol, ether, normal hexane each 60ml washing, often step centrifugal rotational speed is 5000rpm, and centrifugation time is 10min； End product is vacuum dried 24 hours under the conditions of 60 DEG C.
Described step 2 specifically includes: in 100ml round-bottomed flask, adds 0.27g cinchonidine-tert-butylamino formic acid Ester chiral selector, 0.40g a diameter of 1.1-1.9 micron mercapto propyl group derivatization full porous spherical silica gel, 27.0mg azo two is different Butyronitrile, 40ml anhydrous chloroform, nitrogen protection device, magnetic agitation, back flow reaction 12 hours are installed；Reaction unit is cooled to room Temperature, adds sealing reagent 0.27ml 1-hexene, 27.0mg azodiisobutyronitrile, installs nitrogen protection device, magnetic agitation, returns Stream reaction 12 hours；Post processing: centrifuge washing product, uses each 60ml of anhydrous chloroform, methanol, ether, normal hexane to wash successively, Often step is centrifugal, and rotating speed is 5000rpm, and the time is 10min；Last product chiral stationary phase is vacuum dried 24 under the conditions of 60 DEG C Hour.
Ultrahigh pressure liquid phase chromatograph chiral stationary phase (CSP) preparation flow is as follows:
。
Another object of the present invention is to provide a kind of ultrahigh pressure liquid phase chromatograph chiral column, utilize high-pressure homogenization, with chlorine Imitate as homogenate and displacement fluid, under 12000psi pressure condition, the chiral stationary phase that method described above prepares is inserted internal diameter 2.1mm, length 50mm rustless steel chromatograph void column pipe in, obtain the chiral column that can use on ultrahigh-pressure liquid chromatograph.
Described a kind of ultrahigh pressure liquid phase chromatograph chiral column, before use so that it is under 1ml/min flow conditions, use second Alcohol rushes post 10min, then uses flowing to balance 10min under setting chromatographic condition.
Present invention also offers a kind of ultrahigh pressure liquid phase chromatograph chiral column chirality prepared according to above-mentioned method to fix Phase,.
Invention further provides the chirality prepared with cinchonidine-t-butylcarbamate for chiral selector solid Fixed application in ultrahigh pressure liquid phase chromatograph chiral separation.
Described application, its chiral separation sample is the aminoacid of band blocking group on amino, in acidity, specifically includes: N-dansyl-DL-phenylalanine (S1), N-benzoyl-DL-methionine (S2), N-benzoyl-DL-LEUCINE (S3), N-benzoyl-DL-phenylalanine (S4), N-benzoyl-DL-Alanine (S5), N-benzoyl-DL-valine (S6), N-(3,5-dinitrobenzoyl)-DL-LEUCINE (S7), N-(3,5-dinitrobenzoyl)-DL-phenylalanine (S8), N-(3,5-dinitro benzoyl)-DL-serine (S9), N-(3,5-dinitro benzoyl)-DL-methionine (S10), N-(3, 5-dinitro benzoyl)-DL-Alanine (S11) and N-(dinitrophenyl group)-DL-LEUCINE (S12).
Described application, the chromatographic condition of ultrahigh-pressure liquid chromatograph is: under rp mode, and flowing is second by volume mutually Nitrile: the mixed solution of 0.1M ammonium acetate solution=80:20, adjusts pH value to be 6.0 with acetic acid, and flow velocity is 3.0ml/min, column temperature 20 DEG C, sample size is 0.5 microlitre, detects wavelength 254nm；Under polar organic solvent pattern, flowing is mutually for the first mixed by volume Alcohol: acetic acid: triethylamine=98:2:0.2, flow velocity is 2.5ml/min, column temperature 20 DEG C, and sample size is 0.5 microlitre, detects wavelength 254nm。
It is contemplated that prepare the UHPLC chiral stationary phase of the highest pressure 1300bar and for UHPLC chiral separation.Adopt With " one kettle way " by chiral selector, it is catalyzed with azodiisobutyronitrile, is covalently bound to the full porous spherical of mercapto propyl group derivatization On Silica Surface, and utilize 1-hexene sealing, be successfully prepared and be applicable to the chirality of ultrahigh pressure liquid phase chromatograph chiral separation and fix Phase.
The bonding of chiral selector and the sealing " one kettle way " of fixing phase complete, and improve preparation efficiency.The chirality of preparation Fixing phase, for the acid chiral amino acid derivative enantiomer of ultrahigh pressure liquid phase chromatograph chiral separation 12 kinds, demonstrates good Chiral Separation Ability.Under selected chromatographic separation condition, most of acid chiral amino acid derivative enantiomer can be at one point Baseline separation (separating degree Rs ＞ 1.5) is obtained in about clock.Some aobvious acid chirality ammonia can be successfully separated at about one minute Base acid derivative enantiomer, for solving in the process of producing product such as chiral drug, Chiral pesticide, chirality organic synthesis intermediate Chiral Separation problem there is important value.
Being evaluated by UHPLC chiral separation, result shows that prepared UHPLC CSP has good chiral Recognition energy Power, can separate acid chiral amino acid derivative, can be applicable to amino acid derivativges enantiomer and analyzes and produce Quality control.
Accompanying drawing explanation
Fig. 1 is that under polarity flowing facies model, N-(3,5-dinitro benzoyl)-DL-serine (S8) chirality on CSP is divided From result.
Fig. 2 is N-under rp mode (3,5-dinitro benzoyl)-DL-serine (S8) chirality separating resulting on CSP.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is elaborated.
Embodiment 1
In 100ml round-bottomed flask, it is initially charged 9.0mmol cinchonidine (Cinchonine, CD, 98.5%, 2.69g)； Add 60ml dry toluene, water knockout drum and nitrogen protection device, magnetic agitation, backflow azeotropic water removing 1 hour are installed.Will reaction Device is cooled to room temperature, removes water knockout drum, adds 10.0mmol derivatization reagent t-butylisocyanate (97%, 1.17ml), Add 3 catalyst dibutyltin dilaurylate, nitrogen protection device, magnetic agitation, back flow reaction 4 hours are installed.Post processing: Removing solvent toluene first by Rotary Evaporators, add 60ml normal hexane the most in the crude product, under room temperature condition, magnetic force stirs Mix overnight, sand core funnel sucking filtration, use a small amount of normal hexane washed product, drain, finally utilize hexamethylene for recrystallization solvent, warp Recrystallization operation purified product, 60 DEG C are vacuum dried 24 hours, obtain chiral selector cinchonidine-tert-butylamino after purification Formic acid esters (tert-BuCCD):
13C NMR(101MHz,CDCl3)δ153.82(s),150.08(s),148.66(s),146.26(s),141.96 (s),130.39(s),129.16(s),126.80(s),126.80(s),123.68(s),118.77(s),114.49(s), 73.34(s),59.90(s),56.64(S),50.73(s),42.40(s),39.88(s),28.94(s),27.83(s),27.67 (s),24.38(s).
Embodiment 2
The preparation of the full porous spherical silica gel that 3-mercapto propyl group derivatization is sub-, accurately weighs 5.0g a diameter of 1.1-1.9 micron Full porous spherical silica gel, join in the round-bottomed flask of 100ml, add 60ml dry toluene, water knockout drum and nitrogen are installed Protection device, magnetic agitation, backflow azeotropic water removing 3 hours.Reaction unit is cooled to room temperature, removes water knockout drum, add 10ml Derivatization reagent 3-mercaptopropyltriethoxysilane, installs nitrogen protection device, magnetic agitation, back flow reaction 72 hours.Rear place Reason: centrifuge washing product, uses each 60ml of dry toluene, methanol, ether, normal hexane to wash successively, and often step centrifugal rotational speed is 5000rpm, centrifugation time is 10min.End product is vacuum dried 24 hours under the conditions of 60 DEG C.
Embodiment 3
Chiral stationary phase and the preparation of chiral column, described step 2 specifically includes: in 100ml round-bottomed flask, adds 0.27g cinchonidine-t-butylcarbamate chiral selector, 0.40g a diameter of 1.1-1.9 micron mercapto propyl group derivatization is complete Porous spherical silica gel, 27.0mg azodiisobutyronitrile, 40ml anhydrous chloroform, nitrogen protection device, magnetic agitation are installed, backflow is anti- Answer 12 hours；Reaction unit is cooled to room temperature, adds sealing reagent 0.27ml 1-hexene, 27.0mg azodiisobutyronitrile, peace Dress nitrogen protection device, magnetic agitation, back flow reaction 12 hours；Post processing: centrifuge washing product, use successively anhydrous chloroform, The each 60ml of methanol, ether, normal hexane washs, and often step is centrifugal, and rotating speed is 5000rpm, and the time is 10min；Last product chirality Fixing vacuum drying 24 hours under the conditions of 60 DEG C.
Utilize high-pressure homogenization, with chloroform as homogenate with displacement fluid, will be with above-mentioned side under 12000psi pressure condition The chiral stationary phase that method prepares is inserted in the rustless steel chromatograph void column pipe of internal diameter 2.1mm, length 50mm, and obtaining can be at superelevation hydraulic fluid The chiral column used on chromatography.Before use so that it is use ethanol to rush post 10min, then under 1ml/min flow conditions Flowing is used to balance 10min under setting chromatographic condition.
Embodiment 4
The chiral stationary phase prepared with cinchonidine-t-butylcarbamate for chiral selector is at ultrahigh pressure liquid phase color Application in spectrum chiral separation.Its chiral separation sample is the aminoacid of band blocking group on amino, in acidity, specifically includes: N-dansyl-DL-phenylalanine (S1), N-benzoyl-DL-methionine (S2), N-benzoyl-DL-LEUCINE (S3), N-benzoyl-DL-phenylalanine (S4), N-benzoyl-DL-Alanine (S5), N-benzoyl-DL-valine (S6), N-(3,5-dinitrobenzoyl)-DL-LEUCINE (S7), N-(3,5-dinitrobenzoyl)-DL-phenylalanine (S8), N-(3,5-dinitro benzoyl)-DL-serine (S9), N-(3,5-dinitro benzoyl)-DL-methionine (S10), N-(3, 5-dinitro benzoyl)-DL-Alanine (S11) and N-(dinitrophenyl group)-DL-LEUCINE (S12).Its chemical constitution Formula is as follows:
The chromatographic condition of ultrahigh-pressure liquid chromatograph is: the chromatographic condition of ultrahigh-pressure liquid chromatograph is: under rp mode, Flowing be acetonitrile by volume mutually: the mixed solution of 0.1M ammonium acetate solution=80:20, is 6.0 with acetic acid tune pH value, flow velocity For 3.0ml/min, column temperature 20 DEG C, sample size is 0.5 microlitre, detects wavelength 254nm；Under polar organic solvent pattern, flow phase Methanol for mixing by volume: acetic acid: triethylamine=98:2:0.2, flow velocity is 2.5ml/min, column temperature 20 DEG C, and sample size is 0.5 microlitre, detects wavelength 254nm.
12 kinds of acid chiral amino acid derivative chirality separating resultings on chiral stationary phase see table 1 respectively.Wherein color Spectrum parameter: t, retention time；α, separation factor；Rs, separating degree.
Table 1 12 derived from amino acid thing hands on 1.9 microns of cinchonidines-t-butylcarbamate UHPLC CSP Property separating resulting
1:Mobile phase:ACN:0.1M CH3COONH4=80:20 (v/v), pH=6.0,3.0ml/min, 254nm, 20℃,0.5μl.
2:Mobile phase:MeOH:CH3COOH:(CH3CH2)3N=98:2:0.2 (v/v/v), 2.5ml/min, 254nm,20℃,0.5μl.
Embodiment 5
As it is shown in figure 1, N-(3,5-dinitro benzoyl)-DL-serine (S8) is at CSP left-hand seat under polarity flowing facies model Property separating resulting, wherein flow phase: MeOH:CH3COOH:(CH3CH2)3N=98:2:0.2 (v/v/v), flow velocity 2.5ml/min, Detection wavelength 254nm, 20 DEG C, sample size 0.5 μ l.The chromatographic condition of ultrahigh-pressure liquid chromatograph is with embodiment 4.
Embodiment 6
As in figure 2 it is shown, N-(3,5-dinitro benzoyl)-DL-serine (S8) chiral separation on CSP under rp mode As a result, wherein mobile phase A CN:0.1M CH3COONH4=80:20 (v/v), pH=6.0, flow velocity 3.0ml/min, detect wavelength 254nm, 20 DEG C, sample size 0.5 μ l.The chromatographic condition of ultrahigh-pressure liquid chromatograph is with embodiment 4.
It is contemplated that prepare the UHPLC chiral stationary phase of the highest pressure 1300bar and for UHPLC chiral separation.Adopt With " one kettle way " by chiral selector, it is catalyzed with azodiisobutyronitrile, is covalently bound to mercapto propyl group derivatization full porous spherical silicon On glue surface, and utilize 1-hexene sealing, be successfully prepared the chiral stationary phase being applicable to ultrahigh pressure liquid phase chromatograph chiral separation.
The bonding of chiral selector and the sealing " one kettle way " of fixing phase complete, and improve preparation efficiency.The chirality of preparation Fixing phase, for the acid chiral amino acid derivative enantiomer of ultrahigh pressure liquid phase chromatograph chiral separation 12 kinds, demonstrates good Chiral Separation Ability.Under selected chromatographic separation condition, most of acid chiral amino acid derivative enantiomer can be at one point Baseline separation (separating degree Rs ＞ 1.5) is obtained in about clock.Some aobvious acid chirality ammonia can be successfully separated at about one minute Base acid derivative enantiomer, for solving in the process of producing product such as chiral drug, Chiral pesticide, chirality organic synthesis intermediate Chiral Separation problem there is important value.
Being evaluated by UHPLC chiral separation, result shows that prepared UHPLC CSP has good chiral Recognition energy Power, can separate acid chiral amino acid derivative, can be applicable to amino acid derivativges enantiomer and analyzes and produce Quality control.
The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described.The technology of the industry Personnel, it should be appreciated that the present invention is not restricted to the described embodiments, simply illustrating this described in above-described embodiment and description The principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, and these become Change and improvement both falls within scope of the claimed invention.Claimed scope by appending claims and Equivalent defines.

Claims (9)

1. the method preparing chiral stationary phase with cinchonidine-t-butylcarbamate for chiral selector, it is characterised in that Comprise the following steps successively: step one, prepare mercapto propyl group derivatization full porous spherical silica gel；Step 2, by cinchonidine-tertiary fourth Aminocarbamic acid ester chiral selector is bonded to mercapto propyl group derivatization full porous spherical silica gel and prepares chiral stationary phase.
The most according to claim 1 prepare chirality with cinchonidine-t-butylcarbamate for chiral selector and fix The method of phase, it is characterised in that described step one specifically includes: accurately weigh the full porous of 5.0g a diameter of 1.1-1.9 micron Spherical silica gel, joins in the round-bottomed flask of 100ml, adds 60ml dry toluene, installs water knockout drum and nitrogen protection device, Magnetic agitation, backflow azeotropic water removing 3 hours；Reaction unit is cooled to room temperature, removes water knockout drum, add 10ml derivatization reagent 3-mercaptopropyltriethoxysilane, installs nitrogen protection device, magnetic agitation, back flow reaction 72 hours；Post processing: centrifuge washing Product, uses each 60ml of dry toluene, methanol, ether, normal hexane to wash successively, and often step centrifugal rotational speed is 5000rpm, time centrifugal Between be 10min；End product is vacuum dried 24 hours under the conditions of 60 DEG C.
The most according to claim 1 prepare chirality with cinchonidine-t-butylcarbamate for chiral selector and fix The method of phase, it is characterised in that described step 2 specifically includes: in 100ml round-bottomed flask, adds 0.27g cinchonidine-uncle Butyl carbamate chiral selector, 0.40g a diameter of 1.1-1.9 micron mercapto propyl group derivatization full porous spherical silica gel, 27.0mg azodiisobutyronitrile, 40ml anhydrous chloroform, nitrogen protection device, magnetic agitation, back flow reaction 12 hours are installed；Will be anti- Answer device to be cooled to room temperature, add sealing reagent 0.27ml 1-hexene, 27.0mg azodiisobutyronitrile, nitrogen protection dress is installed Put, magnetic agitation, back flow reaction 12 hours；Post processing: centrifuge washing product, uses anhydrous chloroform, methanol, ether, just successively The each 60ml of hexane washs, and often step is centrifugal, and rotating speed is 5000rpm, and the time is 10min；Last product chiral stationary phase is at 60 DEG C Under the conditions of be vacuum dried 24 hours.
4. a ultrahigh pressure liquid phase chromatograph chiral column, it is characterised in that utilize high-pressure homogenization, with chloroform as homogenate with replacement Liquid, inserts internal diameter 2.1mm, length by the chiral stationary phase prepared with method described in claim 1 under 12000psi pressure condition In the rustless steel chromatograph void column pipe of degree 50mm, obtain the chiral column that can use on ultrahigh-pressure liquid chromatograph.
A kind of ultrahigh pressure liquid phase chromatograph chiral column the most according to claim 4, it is characterised in that use at described chiral column Before so that it is use ethanol to rush post 10min under 1ml/min flow conditions, then use flowing flat under setting chromatographic condition Weighing apparatus 10min.
6. a ultrahigh pressure liquid phase chromatograph chiral column chiral stationary phase, it is characterised in that in accordance with the method for claim 1 Prepare.
7. the chiral stationary phase prepared with cinchonidine-t-butylcarbamate for chiral selector is in ultrahigh pressure liquid phase chromatograph Application in chiral separation.
Application the most according to claim 7, it is characterised in that chiral separation sample is the amino of band blocking group on amino Acid, in acidity, specifically includes: N-dansyl-DL-phenylalanine, N-benzoyl-DL-methionine, and N-benzoyl- DL-LEUCINE, N-benzoyl-DL-phenylalanine, N-benzoyl-DL-Alanine, N-benzoyl-DL-valine, N- (3,5-dinitrobenzoyl)-DL-LEUCINE, N-(3,5-dinitrobenzoyl)-DL-phenylalanine, N-(3,5-dinitros Base benzoyl)-DL-serine, N-(3,5-dinitro benzoyl)-DL-methionine, N-(3,5-dinitro benzoyl)-DL-third Propylhomoserin and N-(dinitrophenyl group)-DL-LEUCINE.
Application the most according to claim 7, it is characterised in that the chromatographic condition of ultrahigh-pressure liquid chromatograph is: anti-phase mould Under formula, flowing be acetonitrile by volume mutually: the mixed solution of 0.1M ammonium acetate solution=80:20, with acetic acid tune pH value is 6.0, flow velocity is 3.0ml/min, column temperature 20 DEG C, and sample size is 0.5 microlitre, detects wavelength 254nm；Polar organic solvent pattern Under, flowing is mutually for the methanol mixed by volume: acetic acid: triethylamine=98:2:0.2, and flow velocity is 2.5ml/min, column temperature 20 DEG C, Sample size is 0.5 microlitre, detects wavelength 254nm.
CN201610078456.9A 2016-02-04 2016-02-04 Chiral stationary phase prepared by taking cinchonidine-boc-amide as chiral selector as well as preparation method and application thereof Pending CN105749890A (en)

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Cited By (1)

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CN107474018A (en) * 2017-09-30 2017-12-15 台州市大鹏药业有限公司 A kind of preparation method of high activity nitrile bacterium azoles

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