CN111978448A - Ureido-modified (S) -2-ethynylpyrrolidine and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a novel (S) -2-ethynylpyrrolidine derivative and a preparation method and application thereof. N-tert-butyloxycarbonyl- (S) -2-prolinaldehyde is used as a reaction substrate, a novel ureido modified acetylene monomer is efficiently synthesized through two-step organic reaction, and then a spiral chain polymer is obtained through coordination polymerization. The reaction route is simple and convenient to design, and the used raw materials are economical and practical. The monomer can be suitable for various polymerization modes, and the polymerization conditions are mild. The polymer is prepared into a chiral stationary phase of a high performance liquid chromatography by a coating method, and the enantioselective resolution is realized on various racemic compounds.
Description
Technical Field
The invention belongs to the field of chiral resolution of high performance liquid chromatography, and particularly relates to a novel chiral stationary phase poly [ (S) -2-ethynylpyrrolidine ] derivative, a preparation method thereof and chiral resolution performance thereof.
Background
The FDA required in 1992 that newly developed chiral drugs must provide a complete file of the individual enantiomeric pharmacology and pharmacokinetics, which stimulated the study and development of chiral drugs. It is speculated that 95% of drugs will be chiral by 2020. Apart from the pharmaceutical field, stereochemistry has important implications in the fields of development of pharmaceuticals and agrochemicals, food additives, fragrances, and Chiral contamination (Imran Ali and Hassan Absoul-Enein, Chiral polutants: Distribution, perception and Analysis by Chromatography and Capillary Electrophoresis, Wiley,2004: 7). Therefore, how to obtain high-purity single-enantiomer chiral compounds with high efficiency becomes a focus of attention of researchers.
In the field of chromatographic resolution, High Performance Liquid Chromatography (HPLC) has the advantages of high column capacity, high-efficiency rapid qualitative and quantitative analysis, convenience, simplicity, wide solute application range and the like, and occupies a dominant position in the field of laboratory and industrial scale enantiomer resolution (Satinder Ahuja, Chiral separation by Chromatography, Oxford University Press,2004: 34). Whether the enantiomeric purities of various structural types can be rapidly, accurately and broadly determined; whether the elution order of two enantiomers of the chiral compound with similar structure is unchanged can be ensured, and absolute configuration information is directly provided; whether a chiral stationary phase with high enantioselectivity, high column capacity and preparation and separation capability can be obtained is the basic requirement for a high-efficiency chiral stationary phase. However, for hundreds of products that have already been commercialized, there is still no product that can satisfy the above three basic requirements at the same time.
Disclosure of Invention
The invention aims to provide a helical poly ((S) -2-ethynylpyrrolidine), which can be used as a novel chiral stationary phase, realizes high-efficiency stereoselective resolution on various racemic molecules and enriches the existing stationary phase system.
The helical poly ((S) -2-ethynylpyrrolidine) provided by the invention is a polymer (namely, polyacetylene containing carbamido side group) formed by the repeating unit shown in the formula I;
In the formula I, R is selected from any one of the following groups:
the spiro poly ((S) -2-ethynylpyrrolidine) has a number average molecular weight of more than 30000, in particular 38000-148000, more in particular 48000, 75000, 147000, 68000, 39000, 78000, 60000, 62000, 87000, 120000 and 38000.
Another object of the present invention is to provide a process for the preparation of a polymer 9 of formula I, comprising the steps of:
1) uniformly mixing a compound (N-tert-butyloxycarbonyl- (S) -2-prolinaldehyde) shown as a formula II-1, a diazo compound and an inorganic base in a solvent for reaction to obtain a compound shown as a formula II-2 after the reaction is finished;
2) reacting a compound (N-tert-butyloxycarbonyl- (S) -2-ethynylpyrrolidine) shown in a formula II-2 with inorganic acid in a solvent, uniformly mixing a solid obtained after the reaction, organic amine and isocyanate in the solvent to react b, and obtaining a compound shown in a formula II-3 after the reaction; wherein R in the formula II-3 is as defined in the formula I;
3) and (2) uniformly mixing the compound (N-aromatic carbamoyl- (S) -2-ethynylpyrrolidine) shown in the formula II-3 with organic amine and a metal organic compound in a solvent for reaction, and obtaining the helical poly ((S) -2-ethynylpyrrolidine) shown in the formula I after the reaction is finished.
In the above method, the solvent is selected from any one of: anhydrous methanol, anhydrous dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, petroleum ether, water, n-hexane and isopropanol;
The method, in step 1), the inorganic base is selected from at least one of the following: anhydrous potassium carbonate, sodium bicarbonate; the diazo compound is (1-diazo-2-oxopropyl) phosphonic acid dimethyl ester;
the molar ratio of the compound shown as the formula II-1 to the diazo compound in the step 1) is less than 1:1.05, and specifically can be 1: 1.2.
In the step 1), the reaction conditions of the reaction are as follows: stirring for 20h at 0-30 ℃ under nitrogen atmosphere.
In the method, the inorganic acid in the step 2) is a hydrogen chloride-dioxane solution;
the organic base in the step 2) is triethylamine; the isocyanate is selected from at least one of the following: 3, 5-bis (trifluoromethyl) phenyl isocyanate, 3, 5-bischlorophenyl isocyanate, 4-chlorophenyl isocyanate, 3-chloro-4-methylphenyl isocyanate, 3-chloro-5-methylphenyl isocyanate, phenyl isocyanate, 4-methyl isocyanate, 4-tert-butyl isocyanate, 3, 5-bismethyl isocyanate, (R) - α -methylbenzyl isocyanate, and (S) - α -methylbenzyl isocyanate.
The molar ratio of the compound shown in the formula II-2 to the inorganic acid is less than 1:1.2, and specifically can be 1: 5.
The molar ratio of the compound shown as the formula II-2 to the isocyanate is less than 1:1.1, and specifically can be 1: 1.2.
The molar ratio of the compound shown as the formula II-2 to triethylamine is less than 1:1.5, and specifically can be 1: 3.
In the step 2), the reaction conditions of the reaction a are as follows: stirring for 0.5-2h at room temperature;
the reaction conditions of the reaction b are as follows: stirring at 0-30 deg.C for more than 5 hr.
In the method, the metal organic compound in the step 3) is chloronorbornadiene rhodium dimer.
The organic amine in the step 3) is triethylamine;
the molar ratio of the compound (N-aromatic carbamoyl- (S) -2-ethynylpyrrolidine) shown in the formula II-3 to the organic amine and the metal organic compound is 100-50: 0.2-1: 1, and specifically can be 50:1: 1.
In the step 3), the reaction conditions of the reaction are as follows: stirred at room temperature for 20h under nitrogen atmosphere.
More specifically, the preparation method of the compound shown in the formula I comprises the following steps:
adding the compound shown in the formula II-1, anhydrous potassium carbonate and dimethyl (1-diazo-2-oxopropyl) phosphonate into anhydrous methanol, reacting at 0-25 ℃ for 20h, filtering to obtain filtrate, performing rotary evaporation to remove the solvent, and performing column chromatography separation to obtain a product shown in the formula II-2;
adding the compound shown in the formula II-2 into a hydrogen chloride-dioxane solution, adding anhydrous dichloromethane and triethylamine after the reaction is finished, slowly dropwise adding a dichloromethane solution of isocyanate in an ice water bath, and heating to room temperature for reacting for 24 hours after the dropwise adding is finished. Adding water into the obtained mixture, stirring, extracting with dichloromethane, rotary evaporating to remove dichloromethane to obtain crude product, and separating by column chromatography to obtain product shown in formula II-3;
Adding the compound shown in the formula II-3 into tetrahydrofuran in a nitrogen atmosphere, dropwise adding a tetrahydrofuran-triethylamine mixed solution of chloronorbornadiene rhodium dimer, reacting for 24 hours at 30 ℃, and precipitating in anhydrous methanol to obtain a polymer product shown in the formula I.
The above-mentioned monomer for preparing the spiro poly ((S) -2-ethynylpyrrolidine) of formula I, i.e., the compound of formula II-3 (ureido-modified acetylene monomer), also belongs to the protection scope of the present invention.
The application of the helical poly ((S) -2-ethynylpyrrolidine) shown in formula I as the chiral stationary phase in chiral resolution also belongs to the protection scope of the invention.
Specifically, the method comprises the following steps: dissolving the helical poly ((S) -2-ethynylpyrrolidine) in the formula I in a proper amount of tetrahydrofuran, uniformly dispersing in mesoporous silica gel, and loading a silica gel stationary phase into a stainless steel chromatographic column by using an automatic column loading machine to be used as chiral HPLC to resolve nine racemic molecules in the formula IV.
The invention selects N-tert-butyloxycarbonyl- (S) -2-prolinaldehyde as a reaction substrate, efficiently synthesizes novel ureido modified acetylene monomers through two-step organic reaction, and obtains a spiral chain polymer through coordination polymerization. The reaction route is simple and convenient to design, and the used raw materials are economical and practical. The monomer can be suitable for various polymerization modes, and the polymerization conditions are mild. Meanwhile, the helical poly ((S) -2-ethynylpyrrolidine) provided by the invention can be used as a novel chiral stationary phase, realizes high-efficiency stereoselective resolution on various racemic molecules, and enriches the existing stationary phase system. Compared with the traditional commercialized polysaccharide stationary phase, the chiral stationary phase prepared by the method breaks through the highest resolution coefficient compared with the resolution of metal complex racemic compounds, and realizes new resolution record.
Drawings
FIG. 1 is a reaction scheme showing the preparation of a spiro poly ((S) -2-ethynylpyrrolidine) of formula I according to the present invention.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of N-t-butoxycarbonyl- (S) -2-ethynylpyrrolidine (formula II-2) synthesized in example 1;
FIGS. 3 to 13 are NMR hydrogen spectra of N-arylcarbamoyl- (S) -2-ethynylpyrrolidine (formula II-3) synthesized in example 2;
FIGS. 14-24 are NMR spectra of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ] (formula I) synthesized in example 3;
FIG. 25 is a UV-visible absorption and circular dichroism spectrum of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ] (formula I);
FIG. 26 is a chiral HPLC resolution spectrum of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ].
Detailed Description
The present invention is described below with reference to specific embodiments, but the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The isocyanate in the following examples is selected from any one of the following: 3, 5-bis (trifluoromethyl) phenyl isocyanate, 3, 5-bischlorophenyl isocyanate, 4-chlorophenyl isocyanate, 3-chloro-4-methylphenyl isocyanate, 3-chloro-5-methylphenyl isocyanate, phenyl isocyanate, 4-methyl isocyanate, 4-tert-butyl isocyanate, 3, 5-bismethyl isocyanate, (R) - α -methylbenzyl isocyanate, and (S) - α -methylbenzyl isocyanate.
Example 1: synthesis of N-tert-Butoxycarbonyl- (S) -2-ethynylpyrrolidine
The preparation method comprises the following steps: a250 mL three-neck flask is replaced by nitrogen atmosphere, 100mL of anhydrous methanol, 28.00g of anhydrous potassium carbonate, 20.00g of N-tert-butyloxycarbonyl- (S) -2-prolinaldehyde and 25.00g of dimethyl (1-diazo-2-oxopropyl) phosphonate are sequentially added, and the mixture is stirred and reacted for 20 to 24 hours in an ice water bath or at room temperature. The resulting mixture was filtered to remove insoluble material, the filtrate was rotary evaporated to remove solvent and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v ═ 1:5) as developing solvent) to give 17.10g of product in 87% yield.
FIG. 2 is a nuclear magnetic characterization of N-tert-butoxycarbonyl- (S) -2-ethynylpyrrolidine (said formula II-2) showing that a new shock absorption peak at 2.3ppm appears, indicating that the reaction successfully converted the aldehyde group of the substrate to ethynyl;
Example 2: synthesis of N-aromatic carbamoyl- (S) -2-ethynylpyrrolidine
The preparation method comprises the following steps: a150 mL single-neck flask was charged with 40mL of a dioxane solution of 4M hydrogen chloride and 4.00g of N-t-butoxycarbonyl- (S) -2-ethynylpyrrolidine, and after stirring for 2 hours, 35mL of anhydrous dichloromethane and 7mL of triethylamine were added thereto and the mixture was stirred in an ice-water bath. An appropriate amount of isocyanate (1.2-1.5equiv) was dissolved in 10mL of dichloromethane and slowly added dropwise. After the dropwise addition, the temperature is raised to room temperature and the reaction is continued for 20 to 24 hours. The reaction was quenched by the addition of 100ml of water, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate. The inorganic salt is removed by filtration, the filtrate is rotated to evaporate the solvent, and the crude product is purified by column chromatography (ethyl acetate/petroleum ether (v/v ═ 1: 1-10) as developing agent) to obtain 4.40g of product with 80% yield.
FIGS. 3-13 are nuclear magnetic representations of N-aromatic carbamoyl- (S) -2-ethynylpyrrolidine (described in formula II-3), in which the acetylene peak at 2.3ppm remained, while the aromatic ring nuclear magnetic peak in the range of 7.0-8.0 ppm appeared, and the new peak at 6.8ppm was attributed to the urea-bonded amino hydrogen nuclear magnetic peak, indicating that the reaction successfully modified the urea group on the monomer without destroying other chemical structures.
Example 3: synthesis of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ]
The preparation method comprises the following steps: a100 mL Schlenk tube was purged with nitrogen, and 20mL of anhydrous tetrahydrofuran and 2.50g of N-arylcarbamoyl- (S) -2-ethynylpyrrolidine were sequentially added thereto, followed by stirring and adding 1.5mL of triethylamine and 2mL of a tetrahydrofuran solution of chloronorbornadiene rhodium dimer. The system is reacted for 24 hours at a constant temperature of 30 ℃. After the reaction is finished, 10mL of tetrahydrofuran is added into the diluted solution in the reaction system, the polymer solution is slowly dripped into methanol to precipitate out a polymer, and the filtered product is dried in vacuum to obtain 2.1-2.4g of the product with the yield of 83-92%. The number average molecular weight of the resulting polymer is between 38000 and 148000.
FIGS. 14-24 are nuclear magnetic representations of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ] (said formula I) with the disappearance of the acetylene peak at 2.3ppm and the appearance of a new peak at 6.1ppm, attributable to hydrogen in the polymer backbone, indicating that the polymerization conditions successfully achieved polymerization of the monomer without entrapment of unreacted monomer in the polymer.
Example 4:
in this example, a preparation method and resolution conditions of poly [ N-aromatic carbamoyl- (S) -2-ethynylpyrrolidine ] coating stationary phase HPLC are as follows:
The preparation method comprises the following steps: a50 ml single neck round bottom flask was charged with appropriate amounts of anhydrous tetrahydrofuran and 0.50g of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ] in sequence to effect complete dissolution. Dripping several drops of tetrahydrofuran solution of polymer into the mesoporous silica gel, beating to disperse the solution uniformly, and rotary evaporating to remove the solvent. The above operation was repeated until the tetrahydrofuran solution was completely dropped, and the coated stationary phase was loaded on a stainless steel column (25 cm. times.0.2 cm) using an automatic column loader, and the eluent was a mixed solvent of n-hexane-isopropyl alcohol (95/5 or 90/10, v/v) at a flow rate of 0.1mL/min at 25 ℃. And (3) taking the n-hexane solution of the racemic compound of the formula IV as a sample to be tested, and injecting the sample to finish the enantiomer resolution test. The theoretical plate number of all chiral stationary phases is between 1400-2500.
FIG. 25 is a graph showing the spectrum of poly [ N-arylcarbamoyl- (S) -2-ethynylpyrrolidine ] (formula I), the absorption peak of the conjugated main chain of the polymer is at 330-350nm, the absorption peak of the side group is within 230-280nm, and both absorption regions show obvious Cotton effect, which shows that the chiral amplification process is realized after the polymerization of the chiral monomer, and the main chain and the side group have regular chiral arrangement.
FIG. 26 is a chiral resolution spectrum of pVII (said formula I) on cobalt acetylacetonate (said formula IV, Rac-5), under which a chiral stationary phase can be found to achieve baseline separation resolution of cobalt acetylacetonate racemic compound, indicating that this series of stationary phases has excellent chiral resolution capability.
Table 1 resolution results using different polymers (n-hexane/isopropanol 90/10, v/v)
aThe test condition of the polymer stationary phase is pure hexane mobile phase.
Table 2 resolution results using different polymers (n-hexane/isopropanol 95/5, v/v)
Claims (10)
1. A spiro poly ((S) -2-ethynylpyrrolidine), which is a polymer composed of repeat units of formula I;
in the formula I, R is selected from any one of the following groups:
the number average molecular weight of the spiro poly ((S) -2-ethynylpyrrolidine) is more than 30000.
2. A spiro poly ((S) -2-ethynylpyrrolidine), according to claim 1, wherein: the number average molecular weight of the spiro poly ((S) -2-ethynylpyrrolidine) is 38000-148000.
3. A method for preparing spiro poly ((S) -2-ethynylpyrrolidine) of formula I, comprising the steps of:
1) uniformly mixing a compound shown as a formula II-1, a diazo compound and inorganic base in a solvent for reaction to obtain a compound shown as a formula II-2;
2) Reacting a compound shown as a formula II-2 with inorganic acid in a solvent, uniformly mixing the obtained solid, organic amine and isocyanate in the solvent after the reaction is finished, and reacting b to obtain a compound shown as a formula II-3; wherein R in the formula II-3 is as defined in the formula I;
3) uniformly mixing a compound shown as a formula II-3, organic amine and a metal organic compound in a solvent for reaction to obtain helical poly ((S) -2-ethynylpyrrolidine) shown as a formula I after the reaction is finished;
4. the production method according to claim 3, characterized in that: the solvent is selected from any one of the following: anhydrous methanol, anhydrous dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, petroleum ether, water, n-hexane, and isopropanol.
5. The production method according to claim 3 or 4, characterized in that: in the step 1), the inorganic base is selected from at least one of the following: anhydrous potassium carbonate, anhydrous sodium sulfate, sodium chloride, sodium bicarbonate; the diazo compound is (1-diazo-2-oxopropyl) phosphonic acid dimethyl ester;
the molar ratio of the compound shown as the formula II-1 to the diazo compound is less than 1: 1.05;
in the step 1), the reaction conditions of the reaction are as follows: stirring for more than 4h at 0-30 ℃ in nitrogen atmosphere.
6. The production method according to any one of claims 3 to 5, characterized in that: in the step 2), the inorganic acid is a hydrogen chloride-dioxane solution;
in the step 2), the organic base is triethylamine;
in the step 2), the isocyanate is selected from at least one of the following: 3, 5-bis (trifluoromethyl) phenyl isocyanate, 3, 5-bischlorophenyl isocyanate, 4-chlorophenyl isocyanate, 3-chloro-4-methylphenyl isocyanate, 3-chloro-5-methylphenyl isocyanate, phenyl isocyanate, 4-methyl isocyanate, 4-tert-butyl isocyanate, 3, 5-bismethyl isocyanate, (R) - α -methylbenzyl isocyanate, and (S) - α -methylbenzyl isocyanate;
the molar ratio of the compound shown as the formula II-2 to the inorganic acid is less than 1: 1.2.
The molar ratio of the compound shown as the formula II-2 to the isocyanate is less than 1: 1.1.
The molar ratio of the compound shown as the formula II-2 to triethylamine is less than 1: 1.5.
In the step 2), the reaction conditions of the reaction a are as follows: stirring for 0.5-2h at room temperature;
the reaction conditions of the reaction b are as follows: stirring at 0-30 deg.C for more than 5 hr.
7. The production method according to any one of claims 3 to 6, characterized in that: in the step 3), the metal organic compound is chloronorbornadiene rhodium dimer;
The organic amine in the step 3) is triethylamine;
the molar ratio of the compound shown as the formula II-3 to the organic amine and the metal organic compound is 100-50: 0.2-1: 1;
in the step 3), the reaction conditions of the reaction are as follows: stirring was carried out under nitrogen atmosphere at room temperature for 20 h.
8. A compound represented by formula II-3:
in the formula II-3, R is selected from any one of the following groups:
9. use of a helical poly ((S) -2-ethynylpyrrolidine) according to claim 1 or 2 as a chiral stationary phase in chiral resolution.
10. Use according to claim 9, characterized in that: the racemic molecule adopted in the chiral resolution is selected from any one of the following:
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