CN108912059B - Synthetic method of nitrogenous heterocyclic inflammation inhibiting compound - Google Patents
Synthetic method of nitrogenous heterocyclic inflammation inhibiting compound Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The technical scheme and content of the invention relate to a synthetic method of a nitrogen-containing heterocyclic compound with obvious inflammation inhibition effect, which is shown in the following formula (7), and the synthetic method has the following route:
the synthesis method comprises the following steps: s1: reacting the compound of the formula (1) with the compound of the formula (2), and performing post-treatment after the reaction is finished to obtain a compound of the formula (3); s2: reacting a compound of the formula (3) with a compound of the formula (4) in an organic solvent under the action of a palladium catalyst, an organic ligand and an acidic additive, and performing post-treatment after the reaction to obtain a compound of the formula (5); s3: and (3) reacting the compounds of the above formula (5) and the above formula (6) in an organic solvent in the presence of potassium carbonate, and performing post-treatment after the reaction is finished to obtain the compound of the above formula (7). The synthesis method takes simple and easily-obtained raw materials as reactants, obtains the compound through three steps of reactions, and has good application prospect and research value.
Description
Technical Field
The invention relates to a synthetic method of a nitrogen-containing fused ring compound, in particular to a synthetic method of a nitrogen-containing heterocyclic ring inflammation inhibiting compound, belonging to the field of organic chemical synthesis.
Background
The nitrogen-containing heterocyclic compound generally has certain biological activity and unique property, thereby having wide application and research prospects in the fields of medicines, pesticides, organic luminescence and the like.
As one of nitrogen heterocyclic compounds, quinazoline compounds widely exist in various natural products, generally have good biological activity, such as weeding, sterilization, disinsection, antivirus, anti-inflammation, anti-hypertension, anti-spasm, anti-tumor, anti-malaria and anti-tuberculosis, and can also be applied to the technical field of organic luminescence, so that the quinazoline compounds have good application prospects and potentials in various fields of medicine, agriculture, metallurgy and the like.
Until now, scientists have found that the derivatives have excellent inhibitory effect on various disease pathogenic factors by applying the derivatives to various specific targets in the field of treatment. For example, it has been found in the prior art that 2-trichloromethyl-4-arylthioquinazoline derivatives have good antimalarial activity (see bioorg. med. chem. lett., 21, p 6003-substituted 6006, 2011), while some 4-heteroarylthioquinazoline derivatives have antiproliferative activity on some cancer cells (see bioorg. med. chem. lett., 17, p 2193-substituted 2196, 2007), and some quinazoline compounds have strong inhibitory effect on Epidermal Growth Factor Receptor (EGFR) and tyrosine kinase (EGFR-TK), and can be used for resisting cancer. Further, various quinazoline compounds have been marketed as drugs, such as prazosin, diuretic quinazolinone, raltitrexed, antimalarial, dichroine, gefitinib, and propoxymine.
Due to the wide application prospect and potential therapeutic effect of quinazoline compounds, the synthesis of corresponding compounds and the search and research of novel quinazoline compounds have become a research hotspot and focus of organic chemical synthesis.
For example, the preparation method of 2-arylquinazoline compounds can be divided into two types according to different reaction conditions: the first type is a catalytic cyclization reaction in which metal participates, and is mainly formed by cyclizing organic amine and corresponding aromatic aldehyde or amide compound by adopting transition metal palladium, copper and the like as catalysts. The second type is the use of strong oxidizers such as DDQ, MnO2And NaClO, etc. are deoxidized to form a ring.
For another example:
CN103242299A discloses the following novel quinazoline derivatives, preparation methods and uses thereof in organic electroluminescence:
the two compounds are respectively obtained by reacting 2- (4-bromobenzene) -4-phenylquinazoline with carbazole and diphenylamine through an Ullman reaction.
Rupam Sarma et al ("Microwave-catalyzed synthesis of dihydroquinazolines", Green Chemistry,2011,13, 718-containing 722) reported a process in which an o-aminoarylketone, an aldehyde, and urea were reacted together with the assistance of microwaves to give a quinazoline compound, which has the following reaction formula:
in 2010, Fu et al synthesized a 2-substituted quinazoline compound using a ullmann coupling reaction model and more economical amide as a reaction substrate, with the following reaction formula:
dan ZHao et al ("powdered iodine-catalyzed present-component Synthesis of 2-arylauinazolines via amino of phenyl of C-H bonds of methyl", Advanced Synthesis & Catalysis,2015,357,339-344) disclose a method for preparing quinazoline compounds from o-aminoarylaldehydes, which has the following reaction formula:
CN102321075B discloses a method for preparing quinazoline derivatives of the following general formula (I) by reacting a compound of formula (II) with formula (III) and then with imidazole under catalysis of solid potassium carbonate:
CN103113311A discloses a preparation method of 2-arylquinazoline or 2-heteroarylquinazoline compound, which comprises reacting an arylaldehyde or heteroarylaldehyde with anthranilamide to obtain 2-arylquinazolinone or 2-heteroarylquinazolinone, and then reducing to obtain 2-arylquinazoline or 2-heteroarylquinazoline, wherein the reaction formula is as follows:
wu Zhang et al ("Synthesis of quinazoline Via CuO nanoparticles catalyzed aqueous coupling of aromatic alcohols and amines", Organic & molecular Chemistry,2014,12, 5752-:
wang et al use I2The di-substituted quinazoline compound is synthesized by taking 2-aminobenzophenone and benzylamine as raw materials and taking/TBHP as an oxidation system, and the reaction formula is as follows:
as described above, many novel quinazoline compounds and methods for synthesizing the same have been disclosed in the prior art, but there is still a need for further research and exploration in order to obtain more quinazoline compounds and study on methods for synthesizing the same, which is one of the research hotspots and focuses in the field of organic synthesis technology.
Disclosure of Invention
The present inventors have conducted intensive studies in order to find novel quinazoline compounds having pharmaceutical activities and methods for synthesizing the same, and as a result, have made extensive creative efforts, the present invention has been completed.
Specifically, the technical scheme and content of the invention relate to a synthesis method of a nitrogenous heterocyclic inflammation inhibiting compound shown in the following formula (7):
the synthetic method has the following route:
wherein R is1-R3Each independently selected from H, halogen, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkoxy group;
the synthesis method comprises the following steps:
s1: reacting the compound of the formula (1) with the compound of the formula (2), and performing post-treatment after the reaction is finished to obtain a compound of the formula (3);
s2: reacting a compound of the formula (3) with a compound of the formula (4) in an organic solvent under the action of a palladium catalyst, an organic ligand and an acidic additive, and performing post-treatment after the reaction to obtain a compound of the formula (5);
s3: and (3) reacting the compounds of the above formula (5) and the above formula (6) in an organic solvent in the presence of potassium carbonate, and performing post-treatment after the reaction is finished to obtain the compound of the above formula (7).
In the synthesis method of the present invention, the halogen is a halogen element, and may be, for example, F, Cl, Br, or I.
In the synthesis method of the present invention, the C1-C6Alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl, and the like.
In the synthesis method of the present invention, the C1-C6The meaning of alkoxy means C having the above meaning1-C6A group obtained by linking an alkyl group to an oxygen atom.
In the synthesis method of the present invention, the halogen C1-C6The meaning of alkyl is halogen having the above meaning with C having the above meaning1-C6Alkyl groups are connected to obtain the group.
In the synthesis method of the present invention, the halogen C1-C6The meaning of alkoxy is halogen having the above meaning and the above meaning C1-C6Alkoxy groups are connected to obtain the group.
The phenylamidophenyl substituted quinazoline compound shown in the formula (7) is a brand-new compound, and has a quinazoline ring and an active group amino group, so that more quinazoline compounds can be synthesized subsequently as described in the background technology, and the phenylamidophenyl substituted quinazoline compound has good application and development potentials and research values in multiple technical fields. The research of the inventor discovers that the compound and the intermediate thereof have obvious inflammation inhibition effect and good research prospect and application potential in the field of medicines.
Hereinafter, each technical feature in each step will be further described in detail, specifically as follows.
[ step S1]
In step S1, the molar ratio of the compound of formula (1) to the compound of formula (2) is 1:0.5 to 1.5, for example may be 1:0.5, 1:1 or 1: 1.5.
In step S1, the reaction temperature is 70-90 deg.C, and may be, for example, 70 deg.C, 80 deg.C, or 90 deg.C.
In step S1, the reaction time is 8 to 16 hours, and may be, for example, 8 hours, 10 hours, 12 hours, 14 hours, or 16 hours.
In step S1, the post-processing after the reaction is specifically as follows: after the reaction is finished, naturally cooling the reaction mixture to room temperature, adding a proper amount of deionized water, standing until the precipitation is complete, filtering out the precipitate, and fully drying by using an infrared lamp to obtain the compound of the formula (3).
The amount of the deionized water added can be suitably selected and determined, for example, as long as the precipitate can be completely precipitated, which can be determined by those skilled in the art after reading the present invention without any inventive work.
[ step S2]
In step S2, the palladium catalyst is palladium acetate (Pd (OAc)2) Palladium acetylacetonate (Pd (acac)2) Palladium chloride, tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Or palladium trifluoroacetate (Pd (TFA)2) Most preferably palladium acetate (Pd (OAc)2)。
In step S2, the organic ligand is any one of the following formulas L1-L6,
most preferably, the organic ligand is L1.
In step S2, the acidic additive is any one of p-toluenesulfonic acid monohydrate, acetic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or camphorsulfonic acid, preferably p-toluenesulfonic acid monohydrate or camphorsulfonic acid, and most preferably p-toluenesulfonic acid monohydrate.
In step S2, the organic solvent is any one of Tetrahydrofuran (THF), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol, 1, 4-dioxane, dichloromethane, cyclohexane or toluene, preferably toluene, dichloromethane or cyclohexane, and most preferably toluene.
The amount of the organic solvent is not strictly limited, and can be appropriately selected and determined by those skilled in the art according to actual conditions, for example, the amount is determined to facilitate the reaction and the post-treatment, and will not be described in detail herein.
In step S2, the molar ratio of the compound of formula (3) to the compound of formula (4) is 1:1.5-2.5, and may be, for example, 1:1.5, 1:2, or 1: 2.5.
In step S2, the molar ratio of the compound of formula (3) to the palladium catalyst is 1:0.02 to 0.1, and may be, for example, 1:0.02, 1:0.04, 1:0.06, 1:0.08, or 1: 0.1.
In step S2, the molar ratio of the compound of formula (3) to the organic ligand is 1:0.05-0.15, and may be, for example, 1:0.05, 1:0.1, or 1: 0.15.
In step S2, the molar ratio of the compound of formula (3) to the acidic additive is 1:8 to 12, and may be, for example, 1:8, 1:10, or 1: 12.
In step S2, the reaction temperature is 70 to 90 ℃ and may be, for example, 70 ℃, 80 ℃ or 90 ℃ without limitation.
In step S2, the reaction time is not particularly limited, and a suitable reaction time can be determined by, for example, detecting the residual amount of the starting material by liquid chromatography or TLC, and may be, for example, 16 to 28 hours, but is not limited to, for example, 16 hours, 20 hours, 24 hours, or 28 hours.
In step S2, the post-treatment after the reaction is finished may be specifically performedThe following were used: after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distilling under reduced pressure, eluting the residue by flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent), collecting the eluent and evaporating off the eluent to obtain the compound of formula (5).
Wherein, during the purification process of the silica gel flash column chromatography, the proper elution end point can be determined by TLC tracking monitoring.
[ step S3]
In step S3, the organic solvent is dichloromethane.
The amount of the organic solvent is not strictly limited, and can be appropriately selected and determined by those skilled in the art according to actual conditions, for example, the amount is determined to facilitate the reaction and the post-treatment, and will not be described in detail herein.
In step S3, the molar ratio of the compound of formula (5) to the compound of formula (6) is 1:0.8-1.2, and may be, for example, 1:085, 1:1, or 1: 1.2.
In step S3, the molar ratio of the compound of formula (5) to potassium carbonate is 1:0.8-1.2, which may be, for example, 1:0.8, 1:1 or 1: 1.2.
In step S3, the reaction temperature is room temperature.
In step S3, the reaction time is 3 to 7 hours, and may be, for example, 3 hours, 4 hours, 5 hours, 6 hours, or 7 hours.
In step S3, the post-processing after the reaction is specifically as follows: after the reaction was completed, the reaction mixture was washed with water and extracted twice with a sufficient amount of ethyl acetate, and the organic phases were combined, washed with water and washed with anhydrous Na2SO4Drying, distilling under reduced pressure, eluting the obtained residue by silica gel flash column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1 as an eluent), collecting the eluent and evaporating to remove the eluent, thereby obtaining the compound of the above formula (7).
Wherein, during the purification process of the silica gel flash column chromatography, the proper elution end point can be determined by TLC tracking monitoring.
As described above, the invention provides a nitrogen-containing heterocyclic compound with inflammation inhibitory activity and a synthesis method thereof, wherein the nitrogen-containing heterocyclic compound is a brand-new compound, has a quinazoline ring, an active group amino group and the like, can be used for synthesizing more quinazoline compounds in a subsequent step, and has an obvious inflammation inhibitory effect on the compound and an intermediate thereof, so that the compound has good application and development potential and research value in multiple technical fields.
Drawings
FIG. 1 is a graph showing the inhibitory effect of the compound K1-K2 of the present invention on IL-6.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
Example 1
The reaction route is as follows:
the method specifically comprises the following steps:
s1: adding 100mmol of the compound of the above formula (1) and 50mmol of the compound of the above formula (2) to a reaction vessel, and reacting at 70 ℃ for 16 hours;
after the reaction was completed, the reaction mixture was naturally cooled to room temperature, an appropriate amount of deionized water was added, and the mixture was allowed to stand until the precipitation was completed, and the precipitate was filtered off and sufficiently dried by an infrared lamp, thereby obtaining the compound of the above formula (3) as a white solid with a yield of 92.8%.
1H NMR(500MHz,DMSO-d6)δ8.46(s,1H),8.24(d,J＝8Hz,1H), 8.12(d,J＝7.5Hz,1H),7.93-7.98(m,2H),7.86(d,J＝8Hz,1H), 7.75-7.82(m,2H),7.66(t,J＝7.5Hz,1H)。
S2: adding 100mmol of the compound of the above formula (3), 150mmol of the compound of the above formula (4), 10mmol of palladium acetate, 5mmol of organic ligand L1 and 1200mmol of p-toluenesulfonic acid monohydrate to an appropriate amount of organic solvent toluene at room temperature, then stirring and heating to 70 ℃ and stirring at the temperature for reaction for 28 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distillation under reduced pressure, and flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent) of the residue, collecting the eluent and evaporating off the eluent, to obtain the compound of formula (5) above as a yellow solid, which was named as K1, with a yield of 89.5%.
Melting point: 147 ℃ and 148 ℃.
1H NMR(500MHz,DMSO-d6)δ8.56(d,J＝8.5Hz,1H),8.11(d,J ＝8.5Hz,1H),8.02(d,J＝8.5Hz,1H),7.97(t,J＝7.5Hz,1H),7.84-7.86 (m,2H),7.61-7.65(m,4H),7.49(s,2H),7.20(t,J＝8.5Hz,1H),6.87(d, J＝8.5Hz,1H),6.64(t,J＝7.5Hz,1H)。
S3: adding 100mmol of the compound of the formula (5), 80mmol of the compound of the formula (6) and 120mmol of potassium carbonate into a proper amount of an organic solvent dichloromethane in a reaction vessel, and stirring for reaction at room temperature for 3 hours;
after the reaction was completed, the reaction mixture was washed with water and extracted twice with a sufficient amount of ethyl acetate, and the organic phases were combined, washed with water and washed with anhydrous Na2SO4Drying, distillation under reduced pressure, and eluting the obtained residue by flash column chromatography on silica gel (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1 as an eluent), collecting the eluent and evaporating the eluent to obtain the compound of the above formula (7) as a light yellow solid, which is named as K2, with a yield of 98.6%.
Melting point: 188-189 ℃.
1H NMR(500MHz,DMSO-d6)δ13.52(s,1H),8.77-8.81(m,2H), 8.09-8.15(m,3H),7.97(d,J＝7.5Hz,2H),7.89(d,J＝7Hz,2H),7.79(t, J＝7.5Hz,1H),7.60-7.71(m,5H),7.49(t,J＝8Hz,2H),7.33(t,J＝7.5 Hz,1H)。
Example 2
The reaction scheme is the same as example 1.
The method specifically comprises the following steps:
s1: adding 100mmol of the compound of the above formula (1) and 150mmol of the compound of the above formula (2) to a reaction vessel, and reacting at 90 ℃ for 8 hours;
after the reaction was completed, the reaction mixture was naturally cooled to room temperature, an appropriate amount of deionized water was added, and the mixture was allowed to stand until the precipitation was completed, and the precipitate was filtered off and sufficiently dried by an infrared lamp, thereby obtaining the compound of the above formula (3) as a white solid with a yield of 92.4%.
The NMR data were the same as for the compound of formula (3) in step S1 of example 1.
S2: adding 100mmol of the compound shown in the formula (3), 250mmol of the compound shown in the formula (4), 2mmol of palladium acetate, 15mmol of organic ligand L1 and 800mmol of p-toluenesulfonic acid monohydrate into an appropriate amount of organic solvent toluene at room temperature, and then stirring and heating to 90 ℃ and stirring at the temperature for reaction for 16 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distillation under reduced pressure, and flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent), collecting the eluent and evaporating off the eluent to obtain said compound of formula (5) as a yellow solid in 88.9% yield.
The melting point and nuclear magnetic characterization data were the same as those for the compound of formula (5) in step S2 of example 1.
S3: adding 100mmol of the compound shown in the formula (5), 120mmol of the compound shown in the formula (6) and 80mmol of potassium carbonate into a proper amount of an organic solvent dichloromethane in a reaction vessel, and stirring for reaction at room temperature for 7 hours;
after the reaction was completed, the reaction mixture was washed with water and extracted twice with a sufficient amount of ethyl acetate, and the organic phases were combined, washed with water and washed with anhydrous Na2SO4Drying, distilling under reduced pressure, eluting the obtained residue by silica gel flash column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1 as an eluent), collecting the eluent and evaporating off the eluent, thereby obtaining the compound of formula (7) as a light yellow solid with a yield of 98.8%.
The melting point and nuclear magnetic characterization data were the same as those for the compound of formula (7) in step S3 of example 1.
Example 3
The reaction scheme is the same as example 1.
The method specifically comprises the following steps:
s1: adding 100mmol of the compound of formula (1) and 100mmol of the compound of formula (2) to a reaction vessel, and reacting at 80 ℃ for 12 hours;
after the reaction was completed, the reaction mixture was naturally cooled to room temperature, an appropriate amount of deionized water was added, and the mixture was allowed to stand until the precipitation was completed, and the precipitate was filtered off and sufficiently dried by an infrared lamp to complete, thereby obtaining the compound of formula (3) as a white solid with a yield of 92.3%.
The NMR data were the same as for the compound of formula (3) in step S1 of example 1.
S2: adding 100mmol of the compound shown in the formula (3), 200mmol of the compound shown in the formula (4), 6mmol of palladium acetate, 10mmol of organic ligand L1 and 1000mmol of p-toluenesulfonic acid monohydrate into an appropriate amount of organic solvent toluene at room temperature, and then stirring and heating to 80 ℃ and stirring at the temperature for reaction for 22 hours;
after the reaction is finished, naturally cooling the reaction system to room temperature, washing the reaction system by using saturated potassium carbonate aqueous solution, adding ethyl acetate for extraction for three times, combining organic phases, and using anhydrous Na2SO4Drying, distillation under reduced pressure, and flash column chromatography on silica gel (16: 1 by volume mixture of petroleum ether and ethyl acetate as eluent), collecting the eluent and evaporating off the eluent, to obtain said compound of formula (5) as a yellow solid in 89.4% yield.
The melting point and nuclear magnetic characterization data were the same as those for the compound of formula (5) in step S2 of example 1.
S3: adding 100mmol of the compound shown in the formula (5), 100mmol of the compound shown in the formula (6) and 100mmol of potassium carbonate into a proper amount of an organic solvent dichloromethane in a reaction vessel, and stirring for reaction at room temperature for 5 hours;
after the reaction was completed, the reaction mixture was washed with water and extracted twice with a sufficient amount of ethyl acetate, and the organic phases were combined, washed with water and washed with anhydrous Na2SO4Drying, distilling under reduced pressure, eluting the obtained residue by silica gel flash column chromatography (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1 as an eluent), collecting the eluent and evaporating off the eluent, thereby obtaining the compound of formula (7) as a light yellow solid with a yield of 98.9%.
The melting point and nuclear magnetic characterization data were the same as those for the compound of formula (7) in step S3 of example 1.
Some technical features in step S2 are considered below to make an inventive selection of the most preferable conditions, specifically as follows.
Examination of technical characteristics in step S2
Investigation of the catalyst
Comparative examples S201 to S203: except that the catalyst palladium acetate in step S2 was replaced with palladium acetylacetonate (Pd (acac)2) Otherwise, the other operations were not changed, so that examples 1 to 3 were repeated to obtain comparative examples S201 to S203 in this order.
Comparative examples S204 to S206: the procedures were not changed except for replacing the catalyst palladium acetate with palladium chloride in step S2, respectively, to thereby repeat examples 1 to 3, and comparative examples S204 to S206 were obtained in this order.
Comparative examples S207 to S209: except that the catalyst palladium acetate in step S2 was replaced with tris (dibenzylideneacetone) dipalladium (Pd) respectively2(dba)3) Otherwise, the other operations were not changed, so that examples 1 to 3 were repeated to obtain comparative examples S207 to S209 in this order.
Comparative examples S210 to S212: except that the catalyst palladium acetate in step S2 was replaced with palladium trifluoroacetate (Pd (TFA))2) Otherwise, the other operations were not changed, so that examples 1 to 3 were repeated to obtain comparative examples S210 to S212 in this order.
The results are shown in Table 1 below (wherein the product yield refers to the yield of compound (5) in step S2).
TABLE 1
For example, in the case of comparative examples S201 to S203, the product yield of S201 is 52.4%, the product yield of S202 is 52.9%, and the product yield of S203 is 52.3%, and the rest and the expressions in the following tables have similar correspondence, and thus are not repeated herein.
It follows that slight variations in the effect for the catalyst in step S2 can result, for example in a significant reduction in yield when palladium trifluoroacetate is used, albeit highly similar to palladium acetate. This demonstrates the unpredictability and non-obvious effect of catalyst selection on species.
Investigation of organic ligands
Examples 1-3 were repeated except that organic ligand L1 was replaced with the other organic ligands in Table 2 below, respectively, and the organic ligands used, the example correspondences, and the product yields are shown in Table 2 below (where the product yields refer to the yield of compound (5) in step S2).
TABLE 2
It follows that L1 is most preferred for organic ligands, while other organic ligands all have a significant reduction in effect; it can also be seen that even with very similar L2-L3, there is a significant reduction in the effect, whereas L5 does not even give a product, which demonstrates that the choice of organic ligands is not obvious.
Examination of acidic additives
Comparative examples S219 to S221: examples 1 to 3 were repeated except that the p-toluenesulfonic acid monohydrate in step S2 was replaced with acetic acid, respectively, to obtain comparative examples S219 to S221 in this order.
Comparative examples S222 to S224: examples 1 to 3 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with trifluoroacetic acid, respectively, to obtain comparative examples S222 to S224 in this order.
Comparative examples S225 to S227: examples 1 to 3 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with benzoic acid, respectively, to obtain comparative examples S225 to S227 in this order.
Comparative examples S228 to S230: examples 1 to 3 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with methanesulfonic acid, respectively, to obtain comparative examples S228 to S230 in this order.
Comparative examples S231 to S233: examples 1 to 3 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with trifluoromethanesulfonic acid, respectively, to obtain comparative examples S231 to S233 in this order.
Comparative examples S234 to S236: examples 1 to 3 were repeated except that p-toluenesulfonic acid monohydrate in step S2 was replaced with camphorsulfonic acid, respectively, to obtain comparative examples S234 to S236.
The results are shown in Table 3 below (wherein the product yield refers to the yield of compound (5) in step S2).
TABLE 3
NR indicates no product detected.
It follows that slight variations in the acidic additive in step S2 can result in significant changes in effect, for example in the case of benzoic acid, which, although highly similar to p-toluenesulfonic acid monohydrate, still does not give a product. This demonstrates the unpredictability of the choice of the acid additive in kind and non-obvious in effect.
Investigation of organic solvents
Examples 1 to 3 were repeated except that the organic solvent toluene was replaced with the other organic solvents shown in Table 4 below, respectively, and the organic solvents used, the correspondence among examples, and the product yields are shown in Table 4 below (wherein the product yield refers to the yield of the compound (5) in step S2).
TABLE 4
It follows that toluene is most preferred for the organic solvent, while other organic solvents all have a significant reduction in effectiveness, even failing to yield the product, which demonstrates that the choice of organic solvent is not obvious.
Drug activity assay
The experimental procedure was as follows:
1. preparing broth, namely fixing the volume of 0.5g of peptone, 0.25g of NaCl, 3g of soluble starch and 0.15g of beef extract to 50ml by using sterilized water;
2. filtering the broth with a 0.22 μm filter membrane to obtain a filtered broth;
3. injecting 5ml of broth into abdominal cavity of ICR male mouse (purchased from Experimental animal center of Wenzhou university of medicine) with weight of 18-22g, killing ICR male mouse 72h later, and separating to obtain primary macrophage;
4. the isolated primary cells were resuspended by centrifugation and plated into six-well plates (5X 10 per well)5Individual cells), then 2ml of 1640 complete medium (Gibco) was added to each well and the cells were cultured at a volume concentration of 5% CO237 ℃ in a cell culture box;
5. replacing fresh 1640 culture medium 4-6 hours after the cells adhere to the wall;
6. 24 hours after the cells were attached, the medium was replaced again with fresh 1640 medium, 10nM of the compound of the invention was added to each well, followed by 0.5mg/ml of LPS (Sigma-Aldrich) and incubation continued for 24 hours;
7. cell culture media was collected and IL-6 levels in the media were measured and normalized by determining total protein concentration, expressed as a percentage of LPS (i.e., in% ordinate), following the instructions for the mouse IL-6 enzyme-linked immunosorbent assay (ELISA) kit purchased from eBioscience Inc.
The result is shown in figure 1, and it can be seen that the compound K2 and the intermediate compound K1 both have obvious inhibition effect on IL-6, wherein the anti-inflammatory effect of K2 is further superior to that of K1, so that the compound has more excellent anti-inflammatory activity, and has good research prospect and application potential in the field of medicines.
In conclusion, the invention provides a synthetic method of a nitrogen-containing heterocyclic compound with an inflammation inhibition effect, the compound has obvious anti-inflammatory activity and good research prospect and application potential in the field of medicines, the synthetic method takes simple and easily-obtained raw materials as reactants, the nitrogen-containing heterocyclic compound is obtained through three-step reaction, and the synthetic method has good application prospect and research value.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should also be understood that various alterations, modifications and/or variations can be made to the present invention by those skilled in the art after reading the technical content of the present invention, and all such equivalents fall within the protective scope defined by the claims of the present application.
Claims (8)
1. A method for synthesizing a nitrogen-containing heterocyclic compound represented by the following formula (7):
the synthetic method has the following route:
wherein R is1-R3Each independently selected from H, halogen, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkoxy group;
the synthesis method comprises the following steps:
s1: reacting the compound of the formula (1) with the compound of the formula (2), and performing post-treatment after the reaction is finished to obtain a compound of the formula (3);
s2: reacting a compound of the formula (3) with a compound of the formula (4) in an organic solvent under the action of a palladium catalyst, an organic ligand and an acidic additive, and performing post-treatment after the reaction to obtain a compound of the formula (5);
s3: reacting the compounds of the above formula (5) and the above formula (6) in an organic solvent in the presence of potassium carbonate, and performing post-treatment after the reaction is finished to obtain a compound of the above formula (7);
in step S2, the palladium catalyst is any one of palladium acetate, palladium acetylacetonate, palladium chloride, tris (dibenzylideneacetone) dipalladium, or palladium trifluoroacetate;
in step S2, the organic ligand is of the formula L1,
in step S2, the acidic additive is p-toluenesulfonic acid monohydrate;
in step S2, the organic solvent is toluene.
2. The method of synthesis of claim 1, wherein: in step S2, the palladium catalyst is palladium acetate.
3. The method of synthesis of claim 1, wherein: in step S2, the molar ratio of the compound of formula (3) to the compound of formula (4) is 1: 1.5-2.5.
4. The method of synthesis of claim 1, wherein: in step S2, the molar ratio of the compound of formula (3) to the palladium catalyst is 1:0.02 to 0.1.
5. The method of synthesis of claim 1, wherein: in step S2, the molar ratio of the compound of formula (3) to the organic ligand is 1: 0.05-0.15.
6. The method of synthesis of claim 1, wherein: in step S2, the molar ratio of the compound of formula (3) to the acidic additive is 1: 8-12.
7. The method of synthesis of claim 1, wherein: in step S3, the molar ratio of the compound of formula (5) to the compound of formula (6) is 1: 0.8-1.2.
8. The method of synthesis according to any one of claims 1 to 7, wherein: in step S3, the molar ratio of the compound of formula (5) to potassium carbonate is 1: 0.8-1.2.
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