CN1740181A - New pirkle-type chiral fixed phase and its prepn process - Google Patents
New pirkle-type chiral fixed phase and its prepn process Download PDFInfo
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- CN1740181A CN1740181A CN 200510046924 CN200510046924A CN1740181A CN 1740181 A CN1740181 A CN 1740181A CN 200510046924 CN200510046924 CN 200510046924 CN 200510046924 A CN200510046924 A CN 200510046924A CN 1740181 A CN1740181 A CN 1740181A
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Abstract
The present invention is new Pirkle-type chiral fixed phase and its preparation process. The process adopts R-(+)-1, 1'-binaphthyl-2, 2'-diamine as initial material and prepares the target product through two reaction steps. The Pirkle-type chiral fixed phase has in its molecular structure both electron donor binaphthyl radical and electron acceptor 3, 5-dinitro benzoyl radical, has several sites capable of generating hydrogen bond effect with analyte and can generate certain spatial stereo chemical effect. The Pirkle-type chiral fixed phase is important one with wide application range and has excellent separation effect. The two-step reaction process has total yield up to 42.24 %, simple reaction line, easy operation and easy application in industrial production.
Description
Technical field:
The present invention relates to the chiral separation technical field, exactly it is a kind of new Pirkle type chiral stationary phase and preparation method.
Background technology:
Chirality is an essential characteristic of living things system, biomacromolecule as the vital movement important foundation, all have the chirality feature as protein, polysaccharide, carrier, acceptor, nucleic acid and enzyme etc., and the pharmacological action of chiral antipode drugs be by and body in strict chirality coupling and molecular recognition between the macromole realize.In many cases, there is significant difference in a pair of enantiomorph of compound pharmacologically active, metabolic process, metabolic rate and toxicity etc. in vivo.Therefore the separation determination of chiral drug to pharmacokinetics process in the body of research chiral drug, is determined pharmacokinetic parameters, pharmacology and toxicological effect mechanism, and chiral drug quality control etc. is all significant.
The high performance liquid phase chiral chromatography is the important tool of chiral drug research, is that use is the most extensive at present, one of effective means.Its separate drug enantiomorph is divided into indirect method and direct method.The former claims the chiral reagent derivatization method again, and the latter can be divided into chirality moving phase additive method and chiral stationary phase method.The chiral stationary phase method is because direct, quick, effective, easy, and capacity is big, is more suitable in the preparation scale chromatogram, therefore has more development prospect.
Pirkle type chiral stationary phase is present usage quantity maximum, the important chiral stationary phase of a class that applicable surface is the widest, but they mostly are single π-alkali type (bringing electron substituent group) chiral stationary phase (as Naphthylleucine) or π-acid type (band electron-withdrawing substituent) chiral stationary phase (as Pirkle-1J, α-Burke-2 etc.), can only be used for π-e-acceptor compound or π-electron donor compound Separation of Enantiomers.At present, existing have π-(as Whelk-0, ULMO), all obtained separating effect preferably for the chiral stationary phase of electronics and π-electron-withdrawing group simultaneously.Therefore, actively the development Pirkle type chiral stationary phase that effectively has a mixed type function is a significant problem.
Summary of the invention:
The object of the invention provides a kind of new Pirkle type chiral stationary phase and preparation method.
The preparation method of this chiral stationary phase is as described below:
To react initial thing R-(+)-1,1 '-binaphthylyl-2,2 '-diamines are dissolved in an amount of methylene dichloride, add triethylamine, under the room temperature nitrogen protection, the dichloromethane solution of 3,5 dinitrobenzoylchloride are splashed in the mixing solutions in the above-mentioned stirring.Drip and finish, the mixture heating up that obtains refluxed 10 hours.After the cooling, reaction mixture is with 2mol/L hydrochloric acid soln washing (100ml * 3), and organic layer is through anhydrous magnesium sulfate drying, and solvent evaporated obtains product N-[2 '-amino-[1,1 '] naphthyl naphthalene-2-through the silica gel column chromatography separation]-3, the 5-dinitrobenzamide.It is dissolved in the methylene dichloride, under the room temperature nitrogen protection, slowly splashes into 3-(triethoxy is silica-based) propyl group isocyanate solution and triethylamine.Drip and finish, the mixture heating up that obtains refluxed 10 hours.After the cooling, reaction mixture is with 2mol/L hydrochloric acid soln washing (100ml * 3), and organic layer is through anhydrous magnesium sulfate drying, solvent evaporated obtains product N-[2 '-(3-propyl group urea)-[1,1 through the silica gel column chromatography separation, ] naphthyl naphthalene-2-]-3, the 5-dinitrobenzamide.Silica gel (Regis Rexchrom, 5 μ m) and toluene are added in the flask, reflux, the moisture in mixture is removed fully.With N-[2 '-(3-propyl group urea)-[1,1 '] naphthyl naphthalene-2-]-3, the 5-dinitrobenzamide adds wherein, and the entire reaction mixture heating up refluxed 72 hours.Resulting silica gel after filtration, with toluene, ethyl acetate, methyl alcohol, acetone, ether and normal hexane wash successively.Silica gel is dissolved in an amount of methyl alcohol, and homogenization uses the slurry packing machine of Alltech HPLC that it is tamped to stainless HPLC void column then.
It splashes into speed to want strict control when adding 3,5 dinitrobenzoylchloride solution, and its slow as far as possible adding is under agitation reacted in the initial thing.
Be reflected under the condition that triethylamine exists and just can carry out smoothly.
Under the reflux condition, reaction just can be carried out smoothly, can carry out in 10 hours fully.
Byproduct of reaction can separate by silica gel column chromatography, and product can reach satisfied productive rate.
Formula I
Have π-give electronics (binaphthylyl) and π-electrophilic (3 in the present invention's (formula I) the structure simultaneously; the 5-dinitrobenzoyl) group; and have a plurality of can with the site (NH of analyte generation interaction of hydrogen bond; C=O); also can produce certain space multistory chemical action, can be used for separating multiple chiral compound enantiomer.
The present invention has been successfully used to separate the amides (N-acyl-1-aryl-1-aminoalkane) with aromatic group and the compound that contains dinitrobenzoyl, and (N-(3; 5-dinitrobenzoyl)-and α-amino amides) enantiomorph; the effectively interaction of π-π Subjective and Objective between compound and the stationary phase; interaction of hydrogen bond between the corresponding hydrogen bond site in amide group and the stationary phase structure in the compound structure, and space behavior is proved to be to realize the main separation mechanism of chiral recognition.
Advantage of the present invention is, this stationary phase not only can be used for π-e-acceptor compound but also can be used for π-electron donor compound Separation of Enantiomers, for the separation determination of chiral compound enantiomer provides a kind of new valid approach.Reaction scheme of the present invention is simple, and processing ease is convenient to industrialization.
Embodiment:
Embodiment 1:
With R-(+)-1,1 '-binaphthylyl-2,2 '-diamines 1.21g (4.26mmol) is dissolved in the 100ml methylene dichloride, adds triethylamine 0.59ml (4.26mmol), and this mixing solutions places the two neck round-bottomed flasks of 250ml; 3,5 dinitrobenzoylchloride (DNB-Cl) 0.98g (4.26mmol) is dissolved in the 80ml methylene dichloride, under the room temperature nitrogen protection, slow as far as possible the splashing in the mixing solutions in the above-mentioned stirring of this solution.Drip and finish, the mixture heating up that obtains refluxed 10 hours.After the cooling, reaction mixture is with 2mol/L hydrochloric acid soln washing (100ml * 3), and organic layer is through anhydrous magnesium sulfate drying, solvent evaporated, product separates through silica gel column chromatography, red powder shape solid 1.79g, warp
1The H-NMR conclusive evidence is N-[2 '-amino-[1,1 '] naphthyl naphthalene-2-]-3,5-dinitrobenzamide, yield: 88%.
Its 1.79g (3.74mmol) is dissolved in the 100ml methylene dichloride, under the room temperature nitrogen protection, slowly splashes into 3-(triethoxy is silica-based) propyl group isocyanate solution 0.92ml (3.74mmol) and triethylamine 0.52ml (3.74mmol).Drip and finish, the mixture heating up that obtains refluxed 10 hours.After the cooling, reaction mixture is with 2mol/L hydrochloric acid soln washing (100ml * 3), and organic layer is through anhydrous magnesium sulfate drying, solvent evaporated, product separates through silica gel column chromatography, yellow powder shape solid (3) 1.3g, warp
1H-NMR conclusive evidence is N-[2 '-(3-propyl group urea)-[1,1 '] naphthyl naphthalene-2-]-3,5-dinitrobenzamide, yield: 48%.
Silica gel 4.5g (Regis Rexchrom, 5 μ m) and toluene 100ml are added in the flask, reflux, the moisture in mixture is removed fully.With N-[2 '-(3-propyl group urea)-[1,1 '] naphthyl naphthalene-2-]-3,5-dinitrobenzamide 1.3g (1.79mmol) adds wherein, and the entire reaction mixture is heated and refluxed 72 hours.Resulting silica gel after filtration, with toluene, ethyl acetate, methyl alcohol, acetone, ether and normal hexane wash successively.Silica gel is dissolved in an amount of methyl alcohol, and homogenization uses the slurry packing machine of Alltech HPLC it to be tamped to stainless HPLC void column (4.6mm * 250mm) then.
Claims (6)
1, new Pirkle type chiral stationary phase; it is characterized in that: have π-in the molecular structure simultaneously to electronics both binaphthylyl and π-electrophilic both 3; 5-dinitrobenzoyl group; have a plurality of can with the site (NH of analyte generation interaction of hydrogen bond; C=O); can produce certain space multistory chemical action, structural formula is suc as formula I.
Formula I
2; a kind of preparation method of new Pirkle type chiral stationary phase as claimed in claim 1; it is characterized in that: its preparation technology is as follows: will react initial thing R-(+)-1; 1 '-binaphthylyl-2; 2 '-diamines is dissolved in an amount of methylene dichloride; add triethylamine; under the room temperature nitrogen protection; with 3; the dichloromethane solution of 5-dinitrobenzoyl chloride splashes in the mixing solutions in the above-mentioned stirring; drip and finish; the mixture heating up that obtains refluxed 10 hours; after the cooling; reaction mixture is with 2mol/L hydrochloric acid soln washing (100ml * 3); organic layer is through anhydrous magnesium sulfate drying; solvent evaporated; obtain product N-[2 '-amino-[1 through the silica gel column chromatography separation; 1 '] naphthyl naphthalene-2-]-3; the 5-dinitrobenzamide; it is dissolved in the methylene dichloride; under the room temperature nitrogen protection; slowly splash into 3-(triethoxy is silica-based) propyl group isocyanate solution and triethylamine; drip and finish; the mixture heating up that obtains refluxed 10 hours; after the cooling; reaction mixture is with 2mol/L hydrochloric acid soln washing (100ml * 3); organic layer is through anhydrous magnesium sulfate drying; solvent evaporated; obtain product N-[2 '-(3-propyl group urea)-[1 through the silica gel column chromatography separation; 1 '] naphthyl naphthalene-2-]-3, the 5-dinitrobenzamide is with silica gel (Regis Rexchrom; 5 μ m) and toluene add in the flask; reflux, the moisture in mixture is removed fully, with N-[2 '-(3-propyl group urea)-[1; 1 '] naphthyl naphthalene-2-]-3; the 5-dinitrobenzamide adds wherein, and the entire reaction mixture heating up refluxed 72 hours, and resulting silica gel after filtration; with toluene; ethyl acetate, methyl alcohol, acetone; ether and normal hexane wash successively; silica gel is dissolved in an amount of methyl alcohol, and homogenization uses the slurry packing machine of Alltech HPLC that it is tamped to stainless HPLC void column then.
3, the preparation method of new Pirkle type chiral stationary phase according to claim 2, it is characterized in that: add 3, it splashes into speed to want strict control during 5-dinitrobenzoyl chloride solution, its slow as far as possible adding is under agitation reacted in the initial thing, because react initial thing R-(+)-1,1 '-binaphthylyl-2, two amino group character of 2 '-diamines are identical, so be easy to form N-[1,1 '] naphthyl naphthalene-[2,2 ']-3,5-dinitrobenzamide by product causes the productive rate of needed product on the low side.
4, the preparation method of new Pirkle type chiral stationary phase according to claim 2 is characterized in that: under the condition that triethylamine exists, reaction just can be carried out smoothly.
5, the preparation method of new Pirkle type chiral stationary phase according to claim 2, it is characterized in that: above-mentioned reaction still can not be carried out at ambient temperature in 48 hours; Under the reflux condition, reaction can be carried out in 10 hours fully.
6, the preparation method of new Pirkle type chiral stationary phase according to claim 2, it is characterized in that: byproduct of reaction can separate by silica gel column chromatography, and product can reach satisfied productive rate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110652975A (en) * | 2019-11-18 | 2020-01-07 | 昆明医科大学 | (S) -BIONL derivative CSP filler and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110652975A (en) * | 2019-11-18 | 2020-01-07 | 昆明医科大学 | (S) -BIONL derivative CSP filler and preparation method and application thereof |
| CN110652975B (en) * | 2019-11-18 | 2021-10-26 | 昆明医科大学 | (S) -BINOL derivative CSP filler and preparation method and application thereof |
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