CN113135872A - Chiral 4-hydroxymethyl-thiazolidine-3-imine and preparation method and application thereof - Google Patents
Chiral 4-hydroxymethyl-thiazolidine-3-imine and preparation method and application thereof Download PDFInfo
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of synthetic chemistry, and particularly relates to chiral 4-hydroxymethyl-thiazolidine-3-imine and a preparation method and application thereof. The chiral 4-hydroxymethyl-thiazolidine-3-imine is a novel thiazolidine framework compound and the compoundThe structural general formula is shown as formula (I):
the chiral 4-hydroxymethyl-thiazolidine-3-imine has excellent antiviral activity, can prevent virus infection, and has the capacity of resisting virus regeneration. The preparation method of chiral 4-hydroxymethyl-thiazolidine-3-imine not only solves the problem that the existing synthesis method of thiazolidine-3-imine is limited, but also overcomes the problem that the chiral 4-hydroxymethyl-thiazolidine-3-imine cannot be directly catalytically constructed in the field of chemical and pharmaceutical synthesis.
Description
Technical Field
The invention belongs to the technical field of synthetic chemistry, and particularly relates to chiral 4-hydroxymethyl-thiazolidine-3-imine and a preparation method and application thereof.
Background
The thiazolidine skeleton compound has attracted wide attention in the fields of medicinal chemistry, life science and chemistry and the like due to the application of the thiazolidine skeleton compound in the aspects of immunoregulation, insulin sensitization, improvement of carbohydrate metabolism and the like. Therefore, the new thiazolidine framework compound and the synthesis method thereof are provided, and the method has important significance for the development of the thiazolidine framework compound and the application and development thereof in the fields of chemistry, medicines and the like.
Disclosure of Invention
The invention aims to provide chiral 4-hydroxymethyl-thiazolidine-3-imine and a preparation method and application thereof, and aims to solve the technical problem that the synthesis and development of the existing thiazolidine framework compound are limited.
In order to achieve the above objects, in one aspect, the present invention provides chiral 4-hydroxymethyl-thiazolidin-3-imine, which has a general structural formula shown in formula (I):
wherein R is1And R2Each independently selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R3Is selected from any one of aryl, alkyl and hydrogen.
The chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the invention is a novel thiazolidine framework compound, is beneficial to the development of the type of the thiazolidine framework compound, and has a good application prospect.
In another aspect of the present invention, there is provided a method for preparing chiral 4-hydroxymethyl-thiazolidine-3-imine, comprising the steps of:
providing a first reactant, a second reactant and a chiral catalyst, wherein the structural formula of the first reactant is shown as a formula (II), and the structural formula of the second reactant is shown as a formula (III):
mixing the first reactant, the second reactant and the chiral catalyst in a solvent and carrying out asymmetric ring-opening reaction to obtain chiral 4-hydroxymethyl-thiazolidine-3-imine, wherein the structural formula of the chiral 4-hydroxymethyl-thiazolidine-3-imine is shown as a formula (I):
in the formulae (I), (II) and (III), R1And R2Each independently selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R3Is selected from any one of aryl, alkyl and hydrogen.
The preparation method of chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the invention not only solves the problem that the existing synthesis method of thiazolidine-3-imine is limited, but also overcomes the problem that the chiral 4-hydroxymethyl-thiazolidine-3-imine cannot be directly catalytically constructed in the field of chemical and pharmaceutical synthesis. The preparation method provided by the invention has the advantages of simple and practical operation, high yield, green and economical preparation process, environmental friendliness, easiness in industrialization and the like. In addition, the preparation method still effectively maintains the yield and stereoselectivity of the product after the scale is expanded to the level above gram, and has good application prospect in the fields of chemical synthesis and drug development.
In a final aspect of the invention, there is provided the use of chiral 4-hydroxymethyl-thiazolidin-3-imine for the preparation of an antiviral preparation.
The chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the invention has special molecular shape and spatial configuration, and the unique pharmaceutical properties thereof make the chiral 4-hydroxymethyl-thiazolidine-3-imine have great prospects in the aspect of new drug development. The cytotoxicity experiment shows that the compound has excellent antiviral activity, can prevent virus infection and has the capacity of resisting virus regeneration.
Drawings
FIG. 1 shows the cell morphology of chiral 4-hydroxymethyl-thiazolidin-3-imine treated Zika virus-infected A549 cells in example 1 of the present invention;
FIG. 2 shows the results of testing the degree of secretion of the RNA genome of Zika virus by RT-qPCR in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and technical effects of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described, and the embodiments described below are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art without any inventive step in connection with the embodiments of the present invention shall fall within the scope of protection of the present invention. Those whose specific conditions are not specified in the examples are carried out according to conventional conditions or conditions recommended by the manufacturer; the reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In the description of the present invention, the term "and/or" describing an association relationship of associated objects means that there may be three relationships, for example, a and/or B, may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the description of the present invention, "at least one" means one or more, "a plurality" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items. For example, "at least one (a), b, or c", or "at least one (a), b, and c", may each represent: a. b, c, a-b (i.e. a and b), a-c, b-c, or a-b-c, wherein a, b, and c can be single or multiple respectively.
It should be understood that the weight of the related components mentioned in the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, it is within the scope of the disclosure that the content of the related components is scaled up or down according to the embodiments of the present invention. Specifically, the weight described in the embodiments of the present invention may be a unit of mass known in the chemical field such as μ g, mg, g, kg, etc.
In addition, unless the context clearly uses otherwise, an expression of a word in the singular is to be understood as including the plural of the word. The terms "comprises" or "comprising" are intended to specify the presence of stated features, quantities, steps, operations, elements, portions, or combinations thereof, but are not intended to preclude the presence or addition of one or more other features, quantities, steps, operations, elements, portions, or combinations thereof.
The embodiment of the invention provides chiral 4-hydroxymethyl-thiazolidine-3-imine, which has a structural general formula shown in a formula (I):
wherein R is1And R2Each independently selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R3Is selected from any one of aryl, alkyl and hydrogen.
The chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the embodiment of the invention is a novel thiazolidine framework compound, is beneficial to the development of the type of the thiazolidine framework compound, and has a good application prospect.
"alkyl" refers to a chain of groups including, but not limited to, groups such as methyl, ethyl, multi-carbon straight and branched chains.
"aryl" refers to a cyclic aromatic group including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused-ring heterocyclic aromatic group in which one or more carbon atoms have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur.
"substituted" means that one or more hydrogen atoms within a group can be independently replaced with the same or different substituent.
"functional group" refers to an atom or group of atoms that determines the chemical nature of an organic compound.
In some embodiments, R1And/or R2And/or R3The aryl in (b) may be monocyclic aryl or polycyclic aryl (such as fused-ring aralkyl), and is specifically selected from at least one of phenyl, phenanthryl, anthryl, acenaphthenyl, fluorenyl, pyrenyl and fluoranthenyl.
In some embodiments, R1And/or R2And/or R3The heteroaryl group in (1) may be a five-membered heterocyclic group, a six-membered heterocyclic group, a benzene-condensed heterocyclic group (a benzene ring is condensed with a heterocyclic ring), a condensed heterocyclic group (several heterocyclic rings are condensed), and specifically at least one selected from the group consisting of a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolyl group, a benzothienyl group, a benzofuryl group, a benzopyrazolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzoxazolyl group, a quinolyl group, an isoquinolyl group and a purinyl group.
In some embodiments, R1And/or R2The substituent in the substituted aryl group in (1) is at least one selected from fluorine, chlorine, bromine, iodine, cyano, alkyl, halogenated alkyl, alkenyl, alkynyl, nitro, mercapto, alkyl ester group, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy and cycloalkylalkyl, that is, any one of the above substituents may be a mono-substituted aryl group, or at least one of the above substituents may be a multi-substituted aryl group, and the substituents may be the same or different. Wherein the heterocyclic group may be C3-C10Heterocycloalkyl of (A), C3-C10Heterocycloalkenyl or C of3-C10The heterocyclic alkynyl group of (a); cycloalkyl may be C3-C20A cycloalkyl group of (a).
In some embodiments, R1And/or R2The substituent in the substituted heteroaryl group in (1) is selected from at least one of fluorine, chlorine, bromine, iodine, cyano, alkyl, halogenated alkyl, alkenyl, alkynyl, nitro, mercapto, alkyl ester group, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclic alkyl, cycloalkyl, aryloxy, heteroaryloxy and cycloalkylalkyl, that is, any one of the above substituents may be a mono-substituted heteroaryl group, or at least one of the above substituents may be a multi-substituted heteroaryl group, and the substituents may be the same or different.
In some embodiments, R1And/or R2And/or R3The alkyl group in (A) is selected from C1-C20Alkyl group of (1).
In some embodiments, R1And/or R2The alkyl group having a functional group in (1) is at least one selected from the group consisting of an alkoxy group, an alkylthio group, an aminoalkoxy group, a silyl ether alkyl group, an alkyl ester group, an arylalkyl group, a heteroarylalkyl group, and a cycloalkyl group; wherein alkoxy may be C1-C20Alkoxy, alkylthio or may be C1-C20The alkylthio group of (a) is,
in some embodiments, R1And/or R2The alkenyl in (A) is selected from C2-C20Alkenyl groups of (a).
In some embodiments, R1And/or R2Alkynyl in (A) is selected from C2-C20Alkynyl group of (1).
Preferably, R1Selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R2Selected from aryl or alkyl, R3Selected from alkyl or hydrogen. In some embodiments, R1Is substituted phenyl 4-fluorophenyl, 2-furyl or 3-triisopropylsiloxypropane.
Through the selection of the above substituents, a plurality of different embodiments can be obtainedChiral 4-hydroxymethyl-thiazolidine-3-imine with a structure, wherein the more typical chiral 4-hydroxymethyl-thiazolidine-3-imine compounds comprise a compound Ia, a compound Ib, a compound Ic and a compound Id, and the structural formula of the compound Ia is shown in the specification
The structural formula of the compound Ib is
The structural formula of the compound Ic is
The compound Id has the structural formula
The chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the embodiment of the invention can be prepared by the following preparation method.
Correspondingly, the embodiment of the invention also provides a preparation method of chiral 4-hydroxymethyl-thiazolidine-3-imine, which comprises the following steps:
s1, providing a first reactant, a second reactant and a chiral catalyst, wherein the structural formula of the first reactant is shown as a formula (II), and the structural formula of the second reactant is shown as a formula (III):
s2, mixing the first reactant, the second reactant and the chiral catalyst in a solvent and carrying out asymmetric ring opening reaction to obtain chiral 4-hydroxymethyl-thiazolidine-3-imine, wherein the structural formula of the chiral 4-hydroxymethyl-thiazolidine-3-imine is shown as the formula (I):
in the formulae (I), (II) and (III), R1And R2Are respectively independentIs selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R3Is selected from any one of aryl, alkyl and hydrogen.
The preparation method of chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the embodiment of the invention not only solves the problem that the existing synthesis method of thiazolidine-3-imine is limited, but also overcomes the problem that the chiral 4-hydroxymethyl-thiazolidine-3-imine cannot be directly catalytically constructed in the field of chemical and pharmaceutical synthesis. The preparation method provided by the embodiment of the invention has the advantages of simple and practical operation, high yield, green and economic preparation process, environmental friendliness, easiness in industrialization and the like. In addition, the preparation method still effectively maintains the yield and stereoselectivity of the product after the scale is expanded to the level above gram, and has good application prospect in the fields of chemical synthesis and drug development.
Specifically, in S1, the structural formula of the first reactant is shown as formula (II), which is a nitrogen-substituted 3-amino oxa-four-membered ring; the structural formula of the second reactant is shown as the formula (III), and the second reactant is isothiocyanate substituted by different substituents. In the structural formulas shown in the formulas (II) and (III), R1、R2And R3The specific choices are as described above, and are not described herein again; wherein R is2Aryl, substituted aryl or alkyl groups are preferred.
In some embodiments, the chiral catalyst is a chiral phosphoric acid catalyst, and specifically may be selected from at least one of a binaphthyl-based chiral phosphoric acid catalyst (structural formula shown in formula (IV)), an octahydrobinaphthyl-based chiral phosphoric acid catalyst (structural formula shown in formula (V)), a spiro-skeleton-based chiral phosphoric acid catalyst (structural formula shown in formula (VI)):
in the structural formula of the chiral phosphoric acid catalyst, a substituent R4Can be monocyclic aryl or polycyclic aryl (such as fused ring aromatic hydrocarbon group) or silicon group, and is selected from phenyl, 2,4, 6-tricyclohexylphenylAt least one of isopropylphenyl, 3, 5-bistrifluoromethylphenyl, phenanthryl, anthracenyl, fluorenyl, pyrenyl, naphthyl, pentafluorophenyl and triphenylsilyl.
It should be noted that, taking a chiral phosphoric acid catalyst based on a spiro skeleton as an example, an (S) -type chiral phosphoric acid catalyst having a structural formula shown in formula (VI) or an (R) -type chiral phosphoric acid catalyst having a similar skeleton may be used, and a product obtained by catalysis of the (R) -type chiral phosphoric acid catalyst is a stereo configuration opposite to that of a product obtained by catalysis of the (S) -type chiral phosphoric acid catalyst; other chiral phosphoric acid catalysts of the formula are similar and are not described in detail herein.
Preferably, the chiral phosphoric acid catalyst is (S) -SPINOL-9-Anthracene-OH, and the structural formula is as follows:
in S2, the first reactant and the second reactant are dissolved in a solvent, and asymmetric ring opening reaction is carried out under the catalysis condition of a chiral phosphoric acid catalyst, so that high-optical-purity chiral 4-hydroxymethyl-thiazolidine-3-imine can be directly obtained through catalysis. In some embodiments, the asymmetric ring opening reaction has a molar ratio of the first reactant to the second reactant of 1 (0.9 to 1.3), preferably 1:1.1, at which complete conversion of the first reactant can be achieved.
In some embodiments, the chiral phosphoric acid catalyst is present in an amount of 0.5 to 10 mole%, preferably 5 mole%, based on the first reactant, and the molar ratio of the chiral phosphoric acid catalyst is such that complete conversion of the reactants is ensured in a shorter reaction time without increasing the molar ratio. Lowering the molar ratio will extend the reaction time and may result in a decrease in the enantioselectivity of the product.
In some embodiments, a enantioselective additive is added to improve the enantioselectivity of the reaction product in the step of performing the asymmetric ring opening reaction under the catalysis condition of the chiral phosphoric acid catalyst by dissolving the first reactant and the second reactant in a solvent. In some embodiments, the pairsThe enantioselective additive is Lewis acid additive, and can be selected from at least one of ferric chloride, zinc chloride, cupric chloride, cuprous chloride, cupric bromide, cuprous bromide, cerium chloride, chromium chloride, silver trifluoroacetate, aluminum trichloride, aluminum tribromide, yttrium trichloride, and yttrium trichloride hexahydrate, preferably aluminum tribromide (AlBr)3) Or yttrium trichloride hexahydrate (YCl)3﹒6H2O)。
Further, in the asymmetric ring opening reaction, the molar amount of the enantioselective additive accounts for 1% -20% of the molar amount of the first reactant, and if the molar amount of the enantioselective additive is too high or too low, the enantioselectivity of the product is reduced.
In some embodiments, the asymmetric ring opening reaction is at room temperature and for a reaction time of 1h to 6 h.
In some embodiments, the solvent used to dissolve the first reactant and the second reactant is selected from Mesitylene (Mesitylene), benzene (Ph), Xylene (Xylene), nitrobenzene (PhNO)2) n-Hexane (Hexane), Tetrahydrofuran (THF), 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), trichloromethane (CHCl)3) Tetrachloromethane (CCl)4) Chlorobenzene (PhCl), fluorobenzene (PhF), toluene (PhMe) and trifluorotoluene (PhCF)3) At least one of (1).
In one embodiment, 0.2mmol of the nitrogen-substituted 3-aminooxatetracyclic ring (i.e., the first reactant) is dissolved in 10.0mL of toluene as a solvent and placed at ambient temperature (22 ℃). 0.01mmol of chiral phosphoric acid catalyst (S) -SPINOL-9-Anthracene-OH and 0.02mmol of enantioselective additive were added to the reaction solution and stirred at room temperature for 10 minutes. Then 0.21mmol of isothiocyanate (i.e. the second reactant) was added to the reaction mixture and kept stirring at room temperature for 1 hour, and the reaction was confirmed by Thin Layer Chromatography (TLC), and after completion of the reaction, high yield, high optical purity chiral 4-hydroxymethyl-thiazolidin-3-imine was obtained by column chromatography, the specific reaction formula is as follows:
the embodiment of the invention also provides application of chiral 4-hydroxymethyl-thiazolidine-3-imine in preparation of an antiviral preparation.
The chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the embodiment of the invention has a special molecular shape and a special spatial configuration, and the unique pharmaceutical properties of the chiral 4-hydroxymethyl-thiazolidine-3-imine make the chiral 4-hydroxymethyl-thiazolidine-3-imine have great prospects in the aspect of new drug development. The cytotoxicity experiment shows that the compound has excellent antiviral activity, can prevent virus infection and has the capacity of resisting virus regeneration.
Specifically, the chiral 4-hydroxymethyl-thiazolidine-3-imine provided by the embodiment of the invention can be used for preparing at least one of a preparation for preventing viruses, a preparation for treating viral infection and a preparation for inhibiting virus regeneration.
In order to clearly understand the details and operation of the above-described embodiments of the present invention by those skilled in the art and to clearly show the advanced performance of chiral 4-hydroxymethyl-thiazolidin-3-imine and the preparation and use thereof in the examples of the present invention, the above-described technical solutions are illustrated by the following examples.
Example 1
This example provides a specific chiral 4-hydroxymethyl-thiazolidin-3-imine (Ia)
The preparation method comprises the following steps:
(11) providing a first compound and a second compound, and R in the first compound1Is 4-fluorophenyl, R3A 3-aminooxatetracyclic ring being hydrogen, R in the second reactant2Is 3, 5-bistrifluoromethylphenyl isothiocyanate, yttrium trichloride hexahydrate (YCl)3·6H2O) is an additive;
(12) the 3-aminooxatetracyclic ring (36.2mg,0.2mmol) was dissolved in toluene (10.0mL) solvent at room temperature, the chiral phosphoric acid catalyst (6.6mg,0.01mmol) and the enantioselective additive (6.1mg,0.02mmol) were added and the reaction was stirred at room temperature for 10 min. Then, 3, 5-bistrifluoromethylphenyl isothiocyanate (57.0mg,0.21mmol) was added to the reaction mixture in this order, followed by stirring at room temperature for 1 hour, and the reaction equation was as follows:
(13) the reaction solution was removed by low-pressure rotary evaporation and then directly subjected to silica gel column chromatography to obtain 82.4mg of the objective product Ia as a colorless oily liquid, with a calculated yield of 91%.
To confirm that the purified compound was indeed the target product to be produced in this example, the obtained product was analyzed by measuring the specific rotation, measuring the ee value by high performance liquid chromatography, and nuclear magnetic resonance. The assay of the test is as follows:
(14) specific optical rotation [ alpha ] measured at 22 ℃ on D line]D 22:-48.4(c＝1.0,CHCl3)。
(15) The high performance liquid chromatography is used for analyzing the esterified derivative to determine the ee value: chiral column Daicel
An OD-H column; 5% hexanes of i-PrOH; 1.0 mL/min; retention time 16.5min (minor),19.1min (major). The calculated result was 94% ee.
(16) Hydrogen, carbon, infrared and high resolution mass spectra of nmr analysis.
1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.44(s,2H),7.38-7.34(m,2H),7.11-7.07(m,2H),5.07(d,J＝15.6Hz,1H),4.52(d,J＝15.6Hz,1H),3.90-3.86(m,1H),3.82(dd,J1＝11.2Hz,J2＝6.0Hz,1H),3.71(dd,J1＝11.2Hz,J2＝3.6Hz,1H),3.28-3.26(m,2H),2.07(brs,1H)ppm.
13C NMR(100MHz,CDCl3)δ163.5,161.1(d,J＝3.7Hz),152.7,132.8(d,J＝3.2Hz),132.0(q,J＝32.8Hz),129.4(d,J＝8.0Hz),123.4(q,J＝271.1Hz),122.5,116.3(t like,J＝3.9Hz),115.8(d,J＝21.5Hz),61.9,61.0,48.1,29.1ppm.
19F NMR(376.5MHz,CDCl3)δ-62.9ppm.
IR(thin film)2932,1595,1511,1367,1278,1227,1133,888,844,694cm-1.
HRMS(CI+)Calcd for C19H16F7N2OS[M+H]+:453.0872,Found:453.0874.
Example 2
This example provides a specific chiral 4-hydroxymethyl-thiazolidin-3-imine (Ib)
The preparation method comprises the following steps:
(21) providing a first compound and a second compound, and R in the first compound1Is 3-triisopropylsiloxanyl, R3An N-substituted 3-aminooxatetracyclic ring being hydrogen, R in the second reactant2Is 3, 5-bistrifluoromethylphenyl isothiocyanate, yttrium trichloride hexahydrate (YCl)3·6H2O) is an additive;
(22) the 3-aminooxatetracyclic ring (60.3mg,0.2mmol) was dissolved in toluene (10.0mL) solvent at room temperature, the chiral phosphoric acid catalyst (6.6mg,0.01mmol) and the enantioselective additive (6.1mg,0.02mmol) were added and the reaction was stirred at room temperature for 10 min. Then 3, 5-bistrifluoromethylphenyl isothiocyanate (57.0mg,0.21mmol) was added to the reaction mixture in this order, followed by stirring for reaction for 1 hour;
(23) the reaction solution is removed by low-pressure rotary evaporation, and is directly used for silica gel column chromatography to obtain 99.5mg of target product Ib colorless oily liquid, and the calculated yield is 87%.
To confirm that the purified compound was indeed the target product to be produced in this example, the obtained product was analyzed by measuring the specific rotation, measuring the ee value by high performance liquid chromatography, and nuclear magnetic resonance. The assay of the test is as follows:
(24) specific optical rotation [ alpha ] measured at 22 ℃ on D line]D 22:+7.7(c＝1.0,CHCl3)。
(25) Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 1% hexanes of i-PrOH; 1.0 mL/min; the retention time is 8.3min (major) and 8.8min (minor). The calculated result was 86% ee.
(26) Hydrogen, carbon, infrared and high resolution mass spectra of nmr analysis.
1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.35(s,2H),3.99-3.96(m,1H),3.89-3.82(m,2H),3.80-3.73(m,3H),3.31-3.22(m,3H),2.03(brs,1H),1.84-1.70(m,2H),1.64-1.59(m,2H),1.12-1.03(m,21H)ppm.
13C NMR(100MHz,CDCl3)δ160.1,153.2,131.9(q,J＝32.8Hz),123.4(q,J＝271.1Hz),122.5,116.0(t,J＝3.7Hz),62.8,62.2,61.0,45.1,30.1,29.2,23.9,18.0,11.9ppm.
19F NMR(376.5MHz,CDCl3)δ-62.9ppm.
IR(thin film)3386,2935,1618,1587,1490,1213,1141,1062,922,746cm-1.
HRMS(CI+)Calcd for C25H39F6N2O2SSi[M+H]+:573.2406,Found:573.2427.
Example 3
This example provides a specific chiral 4-hydroxymethyl-thiazolidin-3-imine (Ic)
The preparation method comprises the following steps:
(31) providing a first compound and a second compound, and R in the first compound1Is 2-furyl, R3An N-substituted 3-aminooxatetracyclic ring being hydrogen, R in the second reactant2Isothiocyanate, aluminum tribromide (AlBr), being 3-trifluoromethylphenyl3) Is an additive;
(32) the 3-aminooxatetracyclic ring (30.6mg,0.2mmol) was dissolved in toluene (10.0mL) solvent at room temperature, the chiral phosphoric acid catalyst (6.6mg,0.01mmol) and the enantioselective additive (5.4mg,0.02mmol) were added and the reaction was stirred at room temperature for 10 min. Then 3-trifluoromethylphenyl isothiocyanate (42.7mg,0.21mmol) was added to the reaction mixture in this order, followed by stirring for reaction for 6 hours;
(33) the reaction solution was directly subjected to silica gel column chromatography to give 66.2mg of the objective product Ic as a colorless oily liquid, with a calculated yield of 93%.
To confirm that the purified compound was indeed the target product to be produced in this example, the obtained product was analyzed by measuring the specific rotation, measuring the ee value by high performance liquid chromatography, and nuclear magnetic resonance. The assay of the test is as follows:
(34) specific optical rotation [ alpha ] measured at 22 ℃ on D line]D 22:-54.9(c＝1.0,CHCl3)。
(35) Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 10% hexanes of i-PrOH; 1.0 mL/min; retention time 6.9min (major),7.7min (minor). The calculated result was 94% ee.
(36) Hydrogen, carbon, infrared and high resolution mass spectra of nmr analysis.
1H NMR(400MHz,CDCl3)δ7.39-7.35(m,2H),7.29(d,J＝7.6Hz,1H),7.21(s,1H),7.13(d,J＝8.0Hz,1H),6.36(d,J＝1.6Hz,2H),4.98(d,J＝16.0Hz,1H),4.48(d,J＝15.6Hz,1H),3.91-3.82(m,2H),3.72(dd,J1＝10.8Hz,J2＝3.2Hz,1H),3.19-3.18(m,2H),2.42(brs,1H)ppm.
13C NMR(100MHz,CDCl3)δ160.1,151.9,150.5,142.3,131.1(q,J＝32.1Hz),129.3,125.4,124.2(q,J＝270.7Hz),119.7(t,J＝3.9Hz),119.1(q,J＝3.7Hz),110.6,108.8,62.1,61.0,41.7,28.9ppm.
19F NMR(376.5MHz,CDCl3)δ-62.5ppm.
IR(thin film)3450,2951,1890,1437,1327,1262,1163,1124,1069,901,803,743cm-1.
HRMS(CI+)Calcd for C16H16F3N2O2S[M+H]+:357.0885,Found:357.0882.
Example 4
This example provides a specific chiral 4-hydroxymethyl-thiazolidin-3-imine (Id)
The preparation method comprises the following steps:
(41) providing a first compound and a second compound, and R in the first compound1Is 2-furyl, R3An N-substituted 3-aminooxatetracyclic ring being hydrogen, R in the second reactant2Isothiocyanate, aluminum tribromide (AlBr), being 2-trifluoromethyl-4-fluorophenyl3) Is an additive;
(42) the 3-aminooxatetracyclic ring (30.6mg,0.2mmol) was dissolved in toluene (10.0mL) solvent at room temperature, the chiral phosphoric acid catalyst (6.6mg,0.01mmol) and the enantioselective additive (5.4mg,0.02mmol) were added and the reaction was stirred at room temperature for 10 min. Then 2-trifluoromethyl-4-fluorophenyl isothiocyanate (59.2mg,0.21mmol) was added to the reaction mixture in this order, followed by stirring for 6 hours;
(43) the reaction solution was directly subjected to silica gel column chromatography to obtain 80.2mg of the objective product Id as a colorless oily liquid, with a calculated yield of 92%.
To confirm that the purified compound was indeed the target product to be produced in this example, the obtained product was analyzed by measuring the specific rotation, measuring the ee value by high performance liquid chromatography, and nuclear magnetic resonance. The assay of the test is as follows:
(44) specific optical rotation [ alpha ] measured at 22 ℃ on D line]D 22:-75.4(c＝1.0,CHCl3)。
(45) Determination of ee value by high performance liquid chromatography: chiral column Daicel
An AD-H column; 10% hexanes of i-PrOH; 1.0 mL/min; retention time 6.7min (major),7.7min (minor). The calculated result was 88% ee.
(46) Hydrogen, carbon, infrared and high resolution mass spectra of nmr analysis.
1H NMR(400MHz,CDCl3)δ7.70(d,J＝2.4Hz,1H),7.52(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.38(t,J＝1.2Hz,1H),6.90(d,J＝8.4Hz,1H),6.36(d,J＝1.2Hz,2H),4.92(d,J＝16.0Hz,1H),4.54(d,J＝15.6Hz,1H),3.93-3.87(m,2H),3.75-3.70(m,1H),3.24-3.22(m,2H),2.12(brs,1H)ppm.
13C NMR(100MHz,CDCl3)δ159.7,150.5,149.0,142.2,135.2,129.3(q,J＝5.5Hz),124.52(q,J＝29.6Hz),124.45,123.2(q,J＝272.0Hz),115.0,110.7,108.9,62.3,61.0,41.7,29.0ppm.
19F NMR(376.5MHz,CDCl3)δ-61.9ppm.
IR(thin film)3450,2935,1620,1480,1404,1308,1131,1050,889,828,747cm-1.
HRMS(CI+)Calcd for C16H14BrF3N2O2S[M]+:433.9911,Found:433.9907.
Example 5
The chiral 4-hydroxymethyl-thiazolidin-3-imine compounds obtained in examples 1 to 4 were used to test antiviral efficacy. Human lung cancer cell group a549 was very sensitive to infection by ZIKA virus (ZIKA), and was used in this experiment. First through CC50The experiments tested the magnitude of the toxicity of the chiral 4-hydroxymethyl-thiazolidine-3-imine compounds obtained in examples 1-4 on cells.
The virus culture method comprises the following steps: human a549 lung cancer cell (
CCL-185TM) To Du's medium (DMEM) was added 10% Fetal Bovine Serum (FBS) and 100U/mL penicillin and streptomycin. The cells were cultured in a 10cm dish at 37 ℃ in 5% CO2The thin-layer constant-temperature incubator. When the cell culture reached about 90% of the confluent cell monolayer, Zika virus (Zika virus, PRVABC59 strain, GenBank accession No. KU501215.1) was infected at an MOI of 1. In DM containing 2% FBSAfter 72 hours incubation in EM, the culture broth was collected and aliquoted and stored at-80 ℃. Viral titers were then determined using the 50% tissue culture infectious dose (TCID50) method.
The cytotoxicity test method comprises the following steps: the cytotoxicity of the chiral 4-hydroxymethyl-thiazolidin-3-imine compound obtained in examples 1 to 4 was determined by the MTT method [3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide ]. A549 cells were seeded overnight in 96-well plates (104 cells per well). The chiral 4-hydroxymethyl-thiazolidine-3-imine compounds obtained in examples 1 to 4 were diluted 5-fold in a medium containing 2% fetal bovine serum. Cells were treated with diluted compounds separately and cultured for an additional 48 hours. The medium was replaced with 0.5mg/mL MTT medium and incubation was continued for 4 hours. MTT solution was removed from the wells and formazan crystals were dissolved in DMSO. Formazan crystals were measured for absorbance at 550nm and the reference wavelength was 690 nm. Cell viability was determined in triplicate for three independent experiments. The CC50 value was calculated and the results are shown in Table 1.
As can be seen from Table 1, the chiral 4-hydroxymethyl-thiazolidine-3-imine compounds obtained in examples 1 to 4 all showed relatively low cytotoxicity.
TABLE 1 results of cytotoxicity experiments
Subsequently, the ability of the chiral 4-hydroxymethyl-thiazolidin-3-imine compounds obtained in examples 1 to 4 to combat Zika virus infection of cells was measured by observing the degree of cytopathic effect of Zika virus at a multiplicity of infection of 0.1 after 45 hours of infection of the cells. The cytopathic effect (CPE) experimental method comprises the following steps: a549 cells were seeded in 24-well plates and cultured overnight in 10% -FBS DMEM in an incubator. After removal of the medium, the cells were either not infected with (mock group) or with ZIKA with MOI 0.1 and incubated in DMEM containing 2% FBS for 45 hours. Images of cell morphology were collected and recorded using a phase contrast microscope, a CCD camera and a computer, and the results are shown in fig. 1. As can be seen from FIG. 1, the chiral 4-hydroxymethyl-thiazolidin-3-imine compounds obtained in example 1, example 3 and example 4 showed a stronger resistance to Zika virus infection, whereas in the untreated control group, the cells were almost dead due to Zika virus infection.
The RNA level of the corresponding secreted virions in the medium was then further measured and the viral RNA isolation procedure was: a549 cells were cultured overnight in 24-well plates. Cells were first treated with various concentrations of the chiral 4-hydroxymethyl-thiazolidin-3-imine compound obtained in examples 1-4 for 2 hours, and then infected with ZIKA having an MOI of 0.1 and incubated for 44 hours. 4 replicates were set for each concentration. 500L of medium was collected to isolate virion RNA. Virion RNA was isolated using TRIzol reagent (Ambion, Life, Technologies), and 8uL of whole RNA was taken and cDNA was synthesized by using promi-ii reverse transcriptase (Promega) as per the instructions. Quantitative reverse transcription polymerase chain reaction (RT-qPCR): real-time fluorescent quantitative PCR (RT-qPCR) was performed using SYBR Green Mix (Life Technologies) on an Applied Biosystems QuantStudio 3Real-time PCR system. RT-qPCR was performed using the following primer pairs ZIKV, 5-TGCCCAACACAAGGTGAAGC-3 '(forward) and 5-ACTGACAGCATTATCCGGTACTC-3' (reverse). The target fragment is amplified by reverse transcription at 50 deg.C for 30 min; initial activation of HotStar Taq DNA polymerase for 15 min at 95 ℃; the following four steps are circulated for 45 times: 94 ℃ for 10 seconds, 56 ℃ for 30 seconds, and 72 ℃ for 30 seconds. Melting point analysis was performed by slowly raising the temperature (0.1 ℃/s) to 95 ℃ at the end of the amplification cycle, with the results shown in figure 2, where the data are expressed as mean ± standard deviation (n ═ 3);. p <0.05, vs untreated zika virus infected groups; p <0.01, control untreated Zika virus infected groups. As can be seen from FIG. 2, the chiral 4-hydroxymethyl-thiazolidine-3-imine compounds obtained in example 1, example 3 and example 4 can greatly reduce the RNA concentration of secreted virus particles by 80% or even more than 90%, and the results further illustrate that the compounds have strong virus regeneration inhibition effect and are potential drug molecule candidates with antiviral ability.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The structural general formula of the chiral 4-hydroxymethyl-thiazolidine-3-imine is shown as the formula (I):
wherein R is1And R2Each independently selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R3Is selected from any one of aryl, alkyl and hydrogen.
2. The chiral 4-hydroxymethyl-thiazolidin-3-imine according to claim 1, wherein the aryl group is selected from at least one of phenyl, phenanthryl, anthracenyl, acenaphthenyl, fluorenyl, pyrenyl, fluoranthenyl; and/or
The heteroaryl is selected from at least one of pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl, benzofuryl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl and purinyl; and/or
The substituent in the substituted aryl is selected from at least one of fluorine, chlorine, bromine, iodine, cyano, alkyl, halogenated alkyl, alkenyl, alkynyl, nitro, sulfydryl, alkyl ester group, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclic alkyl, cycloalkyl, aryloxy, heteroaryloxy and cycloalkylalkyl; and/or
The substituent in the substituted heteroaryl is selected from at least one of fluorine, chlorine, bromine, iodine, cyano, alkyl, halogenated alkyl, alkenyl, alkynyl, nitro, sulfydryl, alkyl ester group, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclic alkyl, cycloalkyl, aryloxy, heteroaryloxy and cycloalkylalkyl; and/or
The alkyl is selected from C1-C20Alkyl groups of (a); and/or
The alkyl containing functional groups is selected from at least one of alkoxy, alkylthio, amino alkoxy, silyl ether alkyl, alkyl ester group, aryl alkyl, heteroaryl alkyl and cycloalkyl; and/or
The alkenyl is selected from C2-C20Alkenyl of (a); and/or
The alkynyl is selected from C2-C20Alkynyl group of (1).
3. The chiral 4-hydroxymethyl-thiazolidin-3-imine of claim 1 or 2, wherein the chiral 4-hydroxymethyl-thiazolidin-3-imine comprises at least one of compound Ia, compound Ib, compound Ic and compound Id, compound Ia having the formula
The structural formula of the compound Ib is
The structural formula of the compound Ic is
The structural formula of the compound Id is
4. The preparation method of chiral 4-hydroxymethyl-thiazolidine-3-imine is characterized by comprising the following steps:
providing a first reactant, a second reactant and a chiral catalyst, wherein the structural formula of the first reactant is shown as a formula (II), and the structural formula of the second reactant is shown as a formula (III):
mixing the first reactant, the second reactant and the chiral catalyst in a solvent and carrying out asymmetric ring-opening reaction to obtain chiral 4-hydroxymethyl-thiazolidine-3-imine, wherein the structural formula of the chiral 4-hydroxymethyl-thiazolidine-3-imine is shown as a formula (I):
in the formulae (I), (II) and (III), R1And R2Each independently selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl containing functional group, alkenyl and alkynyl, R3Is selected from any one of aryl, alkyl and hydrogen.
5. The process for preparing chiral 4-hydroxymethyl-thiazolidine-3-imine according to claim 4, wherein the molar ratio of the first reactant to the second reactant in the asymmetric ring-opening reaction is 1 (0.9-1.3); and/or
In the asymmetric ring-opening reaction, the molar weight of the chiral catalyst accounts for 0.5-10% of that of the first reactant; and/or
The reaction temperature of the asymmetric ring-opening reaction is room temperature, and the reaction time is 1-6 h; and/or
The chiral catalyst is a chiral phosphoric acid catalyst.
6. The process for preparing chiral 4-hydroxymethyl-thiazolidin-3-imine according to claim 4 or 5, wherein a enantioselective additive is added in the step of mixing the first reactant, the second reactant and the chiral catalyst in a solvent and performing an asymmetric ring opening reaction.
7. The method of preparing chiral 4-hydroxymethyl-thiazolidin-3-imine according to claim 6, wherein the enantioselective additive is a Lewis acid catalyst; and/or
The molar amount of the enantioselective additive is 1-20% of the molar amount of the first reactant.
8. The method for preparing chiral 4-hydroxymethyl-thiazolidine-3-imine according to claim 4 or 5, wherein the chiral phosphoric acid catalyst is at least one selected from the group consisting of a chiral phosphoric acid catalyst based on a spiro skeleton, a chiral phosphoric acid catalyst based on binaphthyl, and a chiral phosphoric acid catalyst based on octahydrobinaphthyl; the Lewis acid catalyst is at least one selected from ferric chloride, zinc chloride, copper chloride, cuprous chloride, cupric bromide, cuprous bromide, cerium chloride, chromium chloride, silver trifluoroacetate, aluminum trichloride, aluminum tribromide, yttrium trichloride and yttrium trichloride hexahydrate.
9. The method for preparing chiral 4-hydroxymethyl-thiazolidine-3-imine according to claim 4 or 5, wherein the solvent is selected from at least one of toluene, mesitylene, tetrachloromethane, chlorobenzene, fluorobenzene, benzene, xylene, nitrobenzene, n-hexane, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, trichloromethane, trifluorotoluene.
10. Use of a chiral 4-hydroxymethyl-thiazolidin-3-imine according to any of claims 1 to 3 or a chiral 4-hydroxymethyl-thiazolidin-3-imine obtained by a process for the preparation of a chiral 4-hydroxymethyl-thiazolidin-3-imine according to any of claims 4 to 9 for the preparation of an antiviral preparation.
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| CN106892877A (en) * | 2017-02-27 | 2017-06-27 | 北京师范大学 | A kind of 2 substituted imido thiazolidine compounds and its synthetic method |
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| US6353006B1 (en) * | 1999-01-14 | 2002-03-05 | Bayer Corporation | Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents |
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