CN117567344A - Environment-friendly preparation method of compound containing chiral pyrrole skeleton - Google Patents

Environment-friendly preparation method of compound containing chiral pyrrole skeleton Download PDF

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CN117567344A
CN117567344A CN202311553311.6A CN202311553311A CN117567344A CN 117567344 A CN117567344 A CN 117567344A CN 202311553311 A CN202311553311 A CN 202311553311A CN 117567344 A CN117567344 A CN 117567344A
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reaction
reaction bottle
dissolving
pyrrole
adopting
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刘锴
曹沛
覃媛
高程海
刘永宏
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Guangxi University of Chinese Medicine
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Guangxi University of Chinese Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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

Abstract

The invention relates to the technical field of preparation of pyrrolyl derivatives, in particular to a green preparation method of a compound containing chiral pyrrolyl skeleton, which is characterized in that aiming at the reaction of an L-phenylalanine template compound and 2, 5-dimethoxy tetrahydrofuran (DMTMHF), water can be directly used as a green solvent, the pyrrole derivative can be obtained in high yield, the scheme is expanded, and the equivalent easy-to-prepare substitute 1, 4-succinyl aldehyde of DMTMHF is used as a starting material to react with L-phenylalanyl alcohol, so that the corresponding amino alcohol pyrrole derivative can be obtained through nearly complete quantitative conversion. The method has the advantages of mild reaction conditions, environment-friendly solvent as a reaction medium, nearly quantitative complete conversion, chiral center configuration maintenance, easy amplification and the like.

Description

Environment-friendly preparation method of compound containing chiral pyrrole skeleton
Technical Field
The invention relates to the technical field of preparation of pyrrolyl derivatives, in particular to a green preparation method of a compound containing a chiral pyrrole skeleton.
Background
Most of pyrrole derivatives have remarkable biological activity, are used as important intermediates related to natural products and heterocyclic compounds, such as vitamin B12, bile pigment, heme, chlorophyll, alkaloid and the like, contain pyrrole fragments, and many compounds synthesized to contain pyrrole rings show certain antibacterial, antiviral and antitumor biological activities. Pyrrole derivatives having chiral substitution on the nitrogen atom often show important biological activities, and therefore pyrrole is a very potential unit in derivatization modifications and alterations highly correlated with their activities.
Pyrrole units have been of interest as active fragments in the field of peptidomimetics, natural products and heterocyclic compounds. In recent years, a number of Lewis acids, such as Ti (Oi-Pr), have been reported 4 、ZrOCl 2 ·8H 2 O、Sc(OTf) 3 、Bi(NO 3 ) 3 ·5H 2 O、ZrCl 4 、BiCl 3 /SiO 2 、InCl 3 、FeCl 3 The catalytic Paal-Knorr cyclization reaction of primary amine and 1, 4-diketone has certain defects such as harsh reaction conditions, poor substrate applicability, easy substitution side reaction on heterocyclic mother nucleus and the like. Therefore, there is a need to explore a reaction with mild, high efficiency and high selectivity to synthesize N-substituted pyrrole derivatives.
The chiral amino acid and amino alcohol protected by the pyrrolyl and the derivatives thereof are widely applied to the fields of chemistry, biology and pharmacy. This type of optically pure primary amine has mostly difficult solubility problems in conventional solvents and, because of epimerization of the chiral centers, its pyrrole group protection usually needs to be carried out in a non-miscible water/halogen-containing organic solvent two-phase system, which is acid-catalyzed under heating to produce pyrrole derivatives while extraction into the organic phase occurs to reduce or avoid epimerization of the chiral centers.
However, using conventional acid/base buffer systems, yields are low, time consuming and lengthy, and the products generally require cumbersome column chromatography purification.
Disclosure of Invention
In view of the above, the present application provides a green preparation method of a compound containing a chiral pyrrole skeleton, which has the advantages of mild reaction conditions, green solvent as a reaction medium, near quantitative complete conversion, chiral center configuration maintenance, easy amplification and the like.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a green preparation method of a compound containing a chiral pyrrole skeleton, which comprises the following steps:
taking a reaction bottle, putting the reaction bottle into a magnetic stirrer, dissolving L-phenylalanine/L-phenylalaninol into pure water to obtain a template substrate, putting the template substrate into the reaction bottle, dropwise and slowly adding gamma-dicarbonyl compound or an equivalent thereof into the reaction bottle by adopting a pipetting gun, sealing the reaction bottle, heating the reaction bottle to 90-100 ℃, reacting for 0.5-4h, cooling the product to room temperature, centrifuging the reaction bottle for 4-6min at 8000r/min, dissolving the centrifuged product by adopting a solvent, washing the centrifuged product by adopting water, drying the organic phase by adopting anhydrous sodium sulfate, and removing the solvent by adopting a rotary evaporator to obtain a pyrrole protection crude product, namely the finished pyrrole derivative (compound containing chiral pyrrole skeleton).
In the invention, the reaction bottle is a reaction bottle with a cover and a volume of 5 ml.
In the present invention, further, the solvent is ethyl acetate or chloroform.
In the present invention, the template substrate is obtained by dissolving L-phenylalanine in pure water.
In the present invention, further, the γ -dicarbonyl compound or an equivalent thereof is 2, 5-dimethoxy tetrahydrofuran.
In the invention, the template substrate is obtained by dissolving L-phenylalaninol in pure water.
In the present invention, further, the gamma-dicarbonyl compound or an equivalent thereof is an aqueous 1, 4-butanedialdehyde solution.
In the invention, further, the 1, 4-butanedial aqueous solution is obtained by the following method: dissolving 2, 5-dimethoxy tetrahydrofuran in pure water, adding amberlyst-732 resin with a catalytic amount of 10wt%, heating to 70 ℃, volatilizing generated methanol in an open mouth for 3.5-4.5 hours, cooling to room temperature, and filtering to remove the resin to obtain 1, 4-succinaldehyde aqueous solution for standby.
In the present invention, further, the aqueous 1, 4-succinaldehyde solution has a pH of 6.5 to 7.
The pure water is specifically ultrapure water.
The invention has at least the following beneficial effects:
the invention takes pure water phase as medium, has mild reaction condition, chiral center configuration maintenance and easy amplification; solves the problems of low yield, long time consumption and complicated column chromatography purification reaction of the product existing in the traditional acid/alkali buffer system.
Specifically, the application comprises two types of products, namely, aiming at an L-phenylalanine template compound, the reaction is designed to be carried out with 2, 5-dimethoxy tetrahydrofuran (DMTF), water can be directly used as a green solvent, and pyrrole derivatives can be obtained in high yield. The two types of products are easy to amplify, crude products can be obtained by simple treatment, and the NMR spectrum purity is extremely high, so that complicated column chromatography is avoided, the existing substrate is expanded, and the yield is superior to that of the traditional double-phase reflux and exogenous acid catalytic system.
The crude product obtained after centrifugation is the final product, and is directly sent to nuclear magnetism inspection and analysis, the purity is mostly better, and the initial raw material is nearly quantitatively and completely converted.
Drawings
FIG. 1 is a schematic diagram of the protection product of L-phenylalanine pyrrole 13 C NMR crude spectrum control;
FIGS. 2-3 are spectral data of nuclear magnetic resonance analysis of representative analogs;
FIG. 4 is a schematic representation of a representative analog reaction acquisition process.
Detailed Description
In order that the above objects, features and advantages of the invention will be readily understood, a more particular description of the invention will be rendered by reference to the appended drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit or scope of the invention, which is therefore not limited to the specific embodiments disclosed below.
Example 1:
Clauson-Kaas pyrrole cyclization reaction scheme (DMTDF)
The embodiment provides a green preparation method of a compound containing a chiral pyrrole skeleton, which comprises the following steps:
taking a reaction bottle with a cover, placing the reaction bottle with a volume of 5ml into a magnetic stirring rod, dissolving L-phenylalanine (16.5 mg,0.1mol,1.0 equiv.) into ultrapure water (300 mu L, about 20 times of volume) to obtain a template substrate, placing the template substrate into the reaction bottle, dropwise and slowly adding 2, 5-dimethoxy tetrahydrofuran (DMTF, 13.9mg,13.0 mu L,1.05 equiv.) into the reaction bottle by using a pipette, generally without nitrogen protection, heating to 90 ℃ after sealing, monitoring the reaction progress according to TLC, nearly completely converting the reaction progress into a target product after the reaction (0.1 mmol scale) is finished, purifying the product by cooling the product to room temperature, centrifuging the product for 5min under 8000r/min, washing the centrifuged product by using water after dissolving the centrifuged product by using ethyl acetate or chloroform, drying an organic phase by using sodium sulfate, and removing the solvent by using a rotary evaporator to obtain a pyrrole protection crude product, namely the finished pyrrole derivative.
Example 2:
Paal-Knorr pyrrole cyclization reaction scheme (1, 4-butanedialdehyde)
The embodiment provides a green preparation method of a compound containing a chiral pyrrole skeleton, which comprises the following steps:
(1) Preparation of 1, 4-butanedial aqueous solution: dissolving 2, 5-dimethoxy tetrahydrofuran (DMTDF, 1.0g,37.8 mmol) in ultrapure water (2.5 mL), adding amberlyst-732 resin with a catalytic amount of 10wt%, heating to 70 ℃, volatilizing generated methanol in an open mouth, cooling to room temperature after 3.5-4.5 hours, and filtering to remove the resin to obtain 1, 4-succinaldehyde water solution for later use; the aqueous 1, 4-butanedial solution has a pH of about 7;
(2) Preparation of pyrrole derivatives: taking a reaction bottle with a cover, the volume of which is 5ml, putting the reaction bottle into a magnetic stirring rod, dissolving L-phenylalaninol (13.7 mg,0.1mol,1.0 equiv.) into ultrapure water (300 mu L, about 20 times of volume) to obtain a template substrate, putting the template substrate into the reaction bottle, dropwise adding 1, 4-succinyl aldehyde (0.11 mol,1.1 equiv.) into the reaction bottle by adopting a pipetting gun, generally without nitrogen protection, heating to 100 ℃ after sealing, monitoring the reaction progress according to TLC, nearly completely converting the reaction into a target product after the reaction (0.1 mmol scale) is finished, purifying the oily precipitate by cooling the product to room temperature, centrifuging the reaction product for 5min at 8000r/min, washing the centrifuged product by adopting ethyl acetate or chloroform, drying the organic phase by adopting anhydrous sodium sulfate, and removing the solvent by adopting a rotary evaporator to obtain a pyrrole protection crude product, namely the pyrrole derivative.
1. Applicants have conducted a control of the reaction conditions based on examples 1-2, which also included the addition of a citric acid catalyzed control group, i.e., the addition of the corresponding desired catalytic amount before the reactants begin to stir.
Coarse weight: the organic phase is dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure or naturally dried, and a portion of the sample may be mixed with trace amounts of residual moisture and other impurities.
Crude yield: the crude yield was calculated according to: the weight of the pure product is calculated according to the actual crude product weight/target product theory obtained by 100 percent x target product experiment.
The crude weight and yield are summarized in Table 1 under different reaction conditions:
TABLE 1
As can be seen from the results in Table 1, the pyrrole derivatives obtained by the method of the present application have a high purity, the starting materials are almost quantitatively and completely converted, and the pure water phase is used as a medium, the reaction conditions are mild, the chiral center configuration is maintained, the complicated column chromatography is avoided, and the yield is superior to that of the conventional biphasic reflux and exogenous acid (such as citric acid) catalytic system.
As shown in fig. 1, the 13C NMR crude spectrum control, the L-phenylalanine pyrrole protected product only needs to be purified by simple centrifugation, the reaction temperature is set to 90 ℃, ca=citric acid. Wherein 0.75% CA,1h (Entry 1); 0.75% CA,30min (Entry 2); 0.75% CA,15min (Entry 3); 0.3% CA,30min (Entry 4); 0.1% CA,30min (Entry 5); 0.05% CA,30min (Entry 6); 0.01% CA,30min (Entry 7); 0% CA,30min (Entry 8); 0% CA,15min (Entry 9). As can be seen from FIG. 1, the reaction is complete in 30 minutes with 0.1mmol of starting material in the absence of an exogenous catalyst, the actual yield is not significantly different from that of acid catalysis, and the addition of an acidic reagent generally has side effects affecting the chiral center. At the same time, the scale of 24.2mmol is enlarged, the heating time is about 1 hour, the true crude yield is not obviously reduced, and the scheme is fully proved to be suitable for industrial production application (the data are shown in the table 1).
The present application proposes a novel N-glycosylation mechanism similar to that of natural carbohydrates according to actual reaction, and preliminary conjecture is to undergo a self-driven catalytic path. The reaction principle is as follows:
weak H of water and amino acid self-free + Under the combined action of the two, the initial reaction energy barrier is obviously reduced to 9.4kcal/mol, so that nucleophilic attack of N-containing fragment on 2, 5-dimethoxy tetrahydrofuran (DMTLF) is promoted, and the elimination of methanol (acetal partial hydrolysis) is accompanied. Then H-migration to obtain N, O-acetal, and hydrolysis ring opening of furan unit under the assistance of ortho-carboxyl to obtain imine salt. The following 1, 3-H-migration generates more stable enamine, then methanol is removed through further hydrolysis, hemiacetal is obtained through intramolecular cyclization, and the pyrrole protected end product is obtained after dehydration and aromatization.
The reaction process is as follows:
two representative compounds of the present application, two analog chemical structures, related spectroscopic data:
(1) (S) 3-phenyl-2- (1H-pyrrol-1-yl) propionic acid
1 H NMR(500MHz，CDCl 3 )δ H 7.25-7.21(m，3H)，7.02(dd，J＝7.6，1.9Hz，2H)，6.70(t，J＝2.1Hz，2H)，6.16(t，J＝2.1Hz，2H)，4.78(dd，J＝9.3，5.8Hz，1H)，3.45(dd，J＝14.0，5.8Hz，1H)，3.29(dd，J＝14.0，9.4Hz，1H)。
13 C NMR(126MHz，CDCl 3 )δ C 175.21，136.27，128.92，128.73，127.25，120.36，109.00，63.53，39.15。
The above data are described in Angew.chem.int.ed.2015, 54, 11516-11520; org.lett.2019, 21, 8957-8961; the standard spectra of the compounds in adv. Synth. Catalyst.2020, 362, 424-429 were identical.
(2) (S) 3-phenyl-2- (1H-pyrrol-1-yl) 1-propanol
1 H NMR(500MHz，CDCl 3 )δ H 7.27-7.19(m，3H)，7.04(d，J＝7.0Hz，2H)，6.70(t，J＝2.2Hz，2H)，6.17(t，J＝2.1Hz，2H)，4.19(quintet，J＝6.2Hz，1H)，3.81(d，J＝5.9Hz，2H)，3.06(dd，J＝7.3，3.6Hz，2H)。
13 C NMR(126MHz，CDCl 3 )δ C 137.72，128.98，128.64，126.79，119.36，108.54，65.41，63.64,38.71。
The above data are in agreement with standard spectrum controls for compounds in document chem. Eur. J.2020, 26, 8951-8957.
(3) (S) methyl 3-hydroxy-2- (1H-pyrrol-1-yl) propionate
1 H NMR(500MHz，CDCl 3 )δ6.77(t，J＝2.1Hz，2H)，6.22(t，J＝2.2Hz，2H)，4.80-4.74(m，1H)，4.16(dd，J＝11.6，5.8Hz，1H)，4.07(dd，J＝11.7，6.8Hz，1H)，3.77(s，3H)。
13 C NMR(126MHz，CDCl 3 )δ169.91，120.59，109.37，63.55，63.25，52.95。
The above data are in agreement with standard spectra of compounds in literature Tetrahedron Lett.2006, 47, 799-801.
The reaction process of the two representative compounds is shown in FIG. 4.
(4) (S) 3-hydroxy-2- (1H-pyrrol-1-yl) propionic acid
1 H NMR(500MHz，D 2 O)δ6.87(t，J＝2.1Hz，2H)，6.22(t，J＝2.1Hz，2H)，4.70(dd，J＝9.0，4.5Hz，1H)，4.17-4.04(m，1H)，1.93(d，J＝2.1Hz，1H)。
13 C NMR(126MHz，D 2 O) δ 176.13, 120.93, 107.75, 66.03, 62.57 (trace residual solvent).
The above data can be deduced from direct control analysis with methyl ester derivatives, as they differ only in the methylated fragments.
Figures 1-3 are spectral data of nuclear magnetic resonance analysis of compounds, and as can be seen from figures 1-3, the spectral data are consistent with known pyrrole derivatives, demonstrating the versatility of the scheme of the present application.
The scope of the present invention includes chiral fragment-containing primary amines (amino acids/alcohols or structural analogues, derivatives thereof), gamma-dicarbonyl compounds or equivalents thereof (aldehydes/or substituted ketones) suitable for use in the unique reaction principles and green solvent systems described above.
The above examples merely represent a few embodiments of the present invention, which are described in more detail and are not to be construed as limiting the scope of the present invention.

Claims (9)

1. A green preparation method of a compound containing a chiral pyrrole skeleton, which is characterized by comprising the following steps:
taking a reaction bottle, putting the reaction bottle into a magnetic stirrer, dissolving L-phenylalanine/L-phenylalaninol into pure water to obtain a template substrate, putting the template substrate into the reaction bottle, dropwise and slowly adding gamma-dicarbonyl compound or an equivalent thereof into the reaction bottle by adopting a pipetting gun, sealing the reaction bottle, heating the reaction bottle to 90-100 ℃, reacting for 0.5-4h, cooling the product to room temperature, centrifuging the reaction bottle for 4-6min at 8000r/min, dissolving the centrifuged product by adopting a solvent, washing the centrifuged product by adopting water, drying the organic phase by adopting anhydrous sodium sulfate, and removing the solvent by adopting a rotary evaporator to obtain a pyrrole protection crude product, namely a finished pyrrole derivative.
2. The method of claim 1, wherein the reaction flask is a capped reaction flask having a volume of 5 ml.
3. The method of claim 1, wherein the solvent is ethyl acetate or chloroform.
4. The method of claims 1-2, wherein the template substrate is obtained by dissolving L-phenylalanine in pure water.
5. The method of claim 4, wherein the gamma dicarbonyl compound or equivalent thereof is 2, 5-dimethoxy tetrahydrofuran.
6. The method of claims 1-2, wherein the template substrate is obtained by dissolving L-phenylalaninol in pure water.
7. The method of claim 6, wherein the gamma-dicarbonyl compound or equivalent thereof is an aqueous 1, 4-butanedial solution.
8. The method of claim 7, wherein the aqueous 1, 4-succinaldehyde solution is obtained by: dissolving 2, 5-dimethoxy tetrahydrofuran in pure water, adding amberlyst-732 resin with a catalytic amount of 10wt%, heating to 70 ℃, volatilizing generated methanol in an open mouth for 3.5-4.5 hours, cooling to room temperature, and filtering to remove the resin to obtain 1, 4-succinaldehyde aqueous solution for standby.
9. The method of claim 8, wherein the aqueous 1, 4-succinaldehyde solution has a pH of 6.5 to 7.0.
CN202311553311.6A 2023-11-21 2023-11-21 Environment-friendly preparation method of compound containing chiral pyrrole skeleton Pending CN117567344A (en)

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