CN115838351A - 4-alkyl-1, 4-dihydropyridine compound, and preparation method and application thereof - Google Patents
4-alkyl-1, 4-dihydropyridine compound, and preparation method and application thereof Download PDFInfo
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- CN115838351A CN115838351A CN202211555375.5A CN202211555375A CN115838351A CN 115838351 A CN115838351 A CN 115838351A CN 202211555375 A CN202211555375 A CN 202211555375A CN 115838351 A CN115838351 A CN 115838351A
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- alkyl
- arh
- compound
- dihydropyridine
- aryl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
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- 238000000034 method Methods 0.000 claims abstract description 43
- -1 anhydride compound Chemical class 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 9
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- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 7
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- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
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Abstract
The invention discloses a 4-alkyl-1, 4-dihydropyridine compound and a preparation method thereof, wherein the method takes an N-substituent enaminone compound or the N-substituent enaminone compound and an anhydride compound as raw materials, an ether compound as a solvent, the raw materials react under the condition of existence of a catalyst, an auxiliary agent and an oxidant at 60-120 ℃ in a nitrogen atmosphere, after the reaction is completed, a reaction product is extracted by ethyl acetate, a combined organic phase is collected and dried by anhydrous sodium sulfate, then the pressure reduction concentration is carried out, and a concentrate is separated and purified by silica gel column chromatography to obtain the 4-alkyl-1, 4-dihydropyridine compound; the method has the characteristics of mild reaction conditions, convenient operation, short synthetic route, novel synthetic method and the like, and the method has high yield, and the preliminary exploration of the inhibitory activity of PDE4 proves that the compounds have the application value in the anti-inflammatory aspect.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a 4-alkyl-1, 4-dihydropyridine derivative, a synthesis method thereof and application thereof as a PED4 inhibitor.
Background
Phosphodiesterases (PDEs) have the function of degrading intracellular second messengers such as cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), thereby terminating the biochemical role transduced by these second messengers. PDEs are a multigene large family, including more than 30 types of 11 types, and have the functions of different substrate specificities, enzyme kinetic characteristics, regulation and control characteristics and the like. PDEs are used as new therapeutic targets, attract extensive attention of a plurality of scholars, and become a research hotspot. The PDE4 is related to the hydrolysis of cAMP of various inflammatory cells, so that the selective PDE 4inhibitor can effectively inhibit immune and inflammatory cells, has certain efficacy on cAMP mediated airway smooth muscle relaxation and respiratory diseases such as asthma. Therefore, clinical studies of selective PDE 4inhibitors are receiving considerable attention.
The 1, 4-dihydropyridine compound is an important six-membered nitrogen heterocyclic compound and is widely used for treating cardiovascular diseases, toxic hepatitis, fatty liver and other diseases. The traditional method for synthesizing the 1, 4-dihydropyridine compound is mainly realized by Hantzsch reaction, and is a three-component condensation reaction of the 1, 3-dicarbonyl compound, aldehyde and ammonia water or ammonium salt, but the synthesis strategy has the defects of using strong ammonia water, insufficient structural diversity and the like (Lulingling, glowing, zhongpan and Yufuzhu. Organic chemistry, 2016,36 and 2858.). In recent years, some new 1, 4-dihydropyridine synthesis methods have been developed, such as Wan et al catalyzing the reaction with TMSCl in 2013, and through a recycling strategy of "by-product-intermediate-product", the reaction is fully utilized to the utmost extent, the atom economy is enhanced, and 1,4-DHPs with symmetrical structure are synthesized with high yield, but the aliphatic amine compounds of the reaction are not suitable for use, and the post-treatment is relatively complex (Wan, j. -p.; zhou, r.; liu, y.; cai, m.rsc adv.2013,3, 2477.); banafsheyazdanparast et al reported in 2014 that a novel 1, 4-dihydropyridine compound was efficiently prepared in good yield by a Hantzsch reaction using aldehyde, benzyl acetoacetate, and a catalytic amount of iron phosphate (III) under solvent-free conditions. (F.K. Behbahani, B.Yazdanapast.Arab.J.chem.2019.12, 1353-1357.). However, among many strategies for constructing 1, 4-dihydropyridine compounds, the carbon at the 4-position of 1, 4-dihydropyridine is achieved by a carbonyl compound having high chemical activity, and methods for achieving the carbon by other substrates have been rarely reported, regardless of the conventional Hantzsch reaction or the development of a new synthesis method.
On the other hand, ether compounds widely exist in nature and are often used as solvents in organic synthesis (such as tetrahydrofuran and dioxane), compared with alpha-C (sp) of N atom 3 ) Functionalization of the-H bond is extensively studied, alpha-C (sp) of the O atom 3 ) The H bond is more inert, its alpha-C (sp) 3 ) the-H bond is stable and not easy to activate, and most of the research at present mainly focuses on the alpha-C (sp) of ether 3 ) -an H-bond functionalized single bond. Considering that ether compounds are widely present in drugs and natural products with physiological activity and are cheap and easily available, the realization of high-efficiency conversion of ether through carbon-hydrogen bond functionalization has important significance. The research on constructing heterocyclic products by further introducing a series cyclization reaction for cutting off an ether C-O bond is less, and the research on the ether functionalization/cyclization reaction is deeply carried out, so that the method has important significance on organic chemistry and drug synthesis and also has great industrial prospect.
In summary, 1, 4-dihydropyridine compounds have been widely used in the field of medicine, and the synthesis methods are well-established, but the problems of complicated operation, preparation of prepared starting materials, limitation of substrates and the like still exist in the traditional Hantzsch reaction and some new synthesis methods, and particularly the 4-carbon construction strategy of 1, 4-dihydropyridine is still limited to the use of carbonyl compounds.
Disclosure of Invention
The invention provides a 4-alkyl-1, 4-dihydropyridine compound with a structural formula selected from the following formulas:
formula I, wherein R 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; n is selected from 1 and 2;
formula II wherein R 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; r 3 Is selected from aryl and alkyl, and n is selected from 1 and 2.
Another object of the present invention is to provide a process for producing the above-mentioned 4-alkyl-1, 4-dihydropyridine compound, wherein the ether compound is used as both the reaction solvent and the 4-carbon source of 1, 4-dihydropyridine, by efficiently cleaving O-C (sp) 3 ) Bond and C (sp) 3 ) -H bond, and highly efficient synthesis of 4-alkyl-1, 4-dihydropyridine derivatives, the compounds of formula I are prepared as follows:
adding an N-substituent enaminone compound 1 into a reactor, reacting at 60-120 ℃ in the presence of a catalyst, an auxiliary agent and an oxidant by taking an ether compound 2 as a solvent, monitoring the reaction process by thin-layer chromatography until the reaction is complete, extracting a reaction product for 2-3 times by using ethyl acetate, collecting and combining organic phases, drying the organic phases by using anhydrous sodium sulfate, then concentrating under reduced pressure, and separating and purifying a concentrate by using a silica gel column chromatography to obtain a target compound 4-alkyl-1, 4-dihydropyridine compound 3;
wherein R is 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; n is selected from 1 and 2.
The compound of formula ii is prepared as follows:
adding an N-substituent enaminone compound 1 and an anhydride compound 4 into a reactor, reacting at 60-120 ℃ in the presence of a catalyst, an auxiliary agent and an oxidant by taking an ether compound 2 as a solvent in a nitrogen atmosphere, monitoring the reaction process by thin-layer chromatography until the reaction is complete, extracting the reaction product for 2-3 times by using ethyl acetate, collecting and combining organic phases, drying by using anhydrous sodium sulfate, then concentrating under reduced pressure, and separating and purifying the concentrate by using a silica gel column chromatography to obtain a target compound 4-alkyl-1, 4-dihydropyridine compound 5;
wherein R is 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; r 3 Selected from aryl, alkyl; n is selected from 1 and 2.
The catalyst is ferrous chloride, ferric chloride, ferrous sulfate, palladium chloride, copper chloride, cobalt chloride, chromium chloride or nickel chloride hexahydrate, and the molar ratio of the N-substituted enaminone compound 1 to the catalyst is 1.1-5.
The oxidant is di-tert-butyl peroxide (DTBP), di-tert-butyl peroxydicumyl, tert-butyl perbenzoate, tert-butyl hydroperoxide, hydrogen peroxide, dibenzoyl peroxide, cumene hydroperoxide, m-chloroperoxybenzoic acid or potassium persulfate, and the molar ratio of the N-substituted enaminone compound 1 to the oxidant is 1.5-4.
The auxiliary agent is tetrafluoroboric acid, perchloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or sulfuric acid, and the molar ratio of the N-substituted enaminone compound 1 to the auxiliary agent is 1.
The ether compound is tetrahydrofuran, tetrahydrothiophene, hydropyran or oxepane.
Another object of the present invention is to use the above-mentioned 4-alkyl-1, 4-dihydropyridine derivatives in the preparation of PDE4 inhibitors.
Compared with the prior art, the invention has the following advantages:
1. the invention uses widely-existing, cheap and easily-obtained ether compounds as a 4-position carbon source for constructing the 1, 4-dihydropyridine ring, introduces non-carbonyl compounds into the construction of the 1, 4-dihydropyridine ring for the first time, is not only beneficial to the development of novel 1, 4-dihydropyridine compounds, but also is beneficial to providing a new idea for the development of a new strategy of the 1, 4-dihydropyridine;
2. the invention provides two preparation methods of 4-alkyl-1, 4-dihydropyridine derivatives, which are beneficial to the structural diversity synthesis of the 4-alkyl-1, 4-dihydropyridine derivatives;
3. the 4-alkyl-1, 4-dihydropyridine compound has PDE4 inhibition effect and potential for being developed into anti-inflammatory drugs;
the synthetic method has the characteristics of simplicity, high efficiency, simplicity and convenience in operation, environmental friendliness, high yield and the like, and is favorable for industrial production.
Drawings
FIG. 1 is a single crystal structural diagram of Compound 3 a.
Detailed Description
The present invention is further illustrated in detail by the following examples, but the scope of the present invention is not limited thereto, and the reagents in the examples are all conventional commercially available reagents or reagents prepared by conventional methods unless otherwise specified; the structure of the product in the following examples was confirmed by nmr, high resolution mass spectrometry and single crystal diffraction testing of representative products;
example 1:
adding N-substituent enaminone 1a (0.5 mmol), di-tert-butyl peroxide (DTBP, 0.5 mmol), ferrous chloride (0.4 mmol), and HBF into a thick-wall reaction tube at 80 deg.C under nitrogen atmosphere 4 (0.5 mmol), adding 3mL of Tetrahydrofuran (THF) 2a, reacting under magnetic stirring, monitoring the reaction by TLC until the N-substituent enaminone reacts completely, cooling the reaction mixture to room temperature, adding saturated sodium bicarbonate solution, extracting with ethyl acetate for three times, collecting and combining upper organic solvents, adding anhydrous sodium sulfate for drying, concentrating the dried organic layer, and finally performing silica gel column chromatography separation on the concentrate, wherein the solvent used for the column chromatography separation is a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 5:
the morphology, melting point, nuclear magnetic, high resolution mass spectral data for product 3a from example 1 are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.2, yellow solid 85mg, yield 81%, melting point =160-162 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.67–7.65(m,4H,ArH),7.53–7.50(m,2H,ArH),7.46–7.44(m,4H,ArH),7.38–7.36(m,2H,ArH),7.25(s,2H,C＝CH),7.08–7.07(m,2H,ArH),4.66(t,J＝5.3Hz,1H,C–CH),3.72(t,J＝6.4Hz,2H,OCH 2 ),1.76–1.72(m,2H,C–CH 2 ),1.68–1.63(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝194.9,194.9,143.3,141.4,141.4,139.3,139.3,131.8,131.8,130.5,130.5,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,127.1,121.5,121.5,119.2,119.2,61.5,32.3,30.2,28.8；HRMS(TOF ES+):m/z calcd for C 28 H 25 NO 3 [(M+H) + ]424.1907, found,424.1906. Single crystal structure of Compound 3a see FIG. 1.
Example 2: this example is prepared by the same procedure as example 1, except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (4-methoxyphenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism, and high resolution mass spectrometry data of 3b prepared in this example are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.15, yellow solid 92.9mg, yield 77%, melting point =137-139 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝7.71–7.69(m,4H,ArH),7.41–7.40(m,2H,ArH),7.34–7.33(m,2H,ArH),7.27–7.26(m,3H,ArH+C＝CH),7.05–7.03(m,4H ArH),4.42–4.39(m,2H,C–CH 2 ),3.82(s,6H,OCH 3 ),3.35–3.34(m,1H,C–CH),1.51–1.46(m,4H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝193.9,193.9,162.3,162.3,143.4,140.0,140.0,131.6,131.6,131.2,131.2,131.2,131.2,130.5,130.5,130.5,130.5,126.8,121.3,121.3,119.2,119.2,114.3,114.3,61.5,55.8,55.8,32.6,31.0,28.9；HRMS(TOF ES+):m/z calcd for C 30 H 29 NO 5 [(M+H) + ],484.2118,found,484.2120.
example 3 this example was prepared by the same procedure as in example 1 except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (4-ethylphenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3c are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.1, yellow solid 99mg, yield 83%, melting point =169-171 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝7.62(d,J＝7.8Hz,4H,ArH),7.41(t,J＝7.8Hz,2H,ArH),7.34–7.31(m,6H,ArH),7.28–7.26(m,1H,ArH),7.25(s,2H,C＝CH),4.42(q,J＝4.9Hz,2H,C–CH 2 ),3.37–3.35(m,1H,C–CH),2.66(q,J＝7.6Hz,4H,ArCH 2 ),1.53–1.45(m,4H,C–CH 2 ),1.19(t,J＝7.7Hz,6H,CH 3 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝194.6,194.6,148.0,148.0,143.3,140.8,140.8,136.7,136.7,130.5,130.5,129.2,129.2,129.2,129.2,128.4,128.4,128.4,128.4,127.0,121.6,121.6,119.1,119.1,61.5,32.5,30.5,28.9,28.5,28.5,15.7,15.7；HRMS(TOF ES+):m/zcalcd for C 32 H 33 NO 3 [(M+H) + ],480.2533,found,480.2534.
example 4 this example was prepared according to the same procedure as example 1 except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (4-fluorophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3d are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.1, yellow solid 85mg, yield 74%, melting point =177-179 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝7.78–7.75(m,4H,ArH),7.41(t,J＝7.9Hz,2H,ArH),7.36–7.31(m,7H,ArH),7.27(s,2H,C＝CH),4.41–4.39(m,2H,C–CH 2 ),3.37–3.35(m,1H,C–CH),1.53–1.45(m,4H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝193.6,193.6,164.3(J C–F ＝248.9Hz),164.3(J C–F ＝248.9Hz),143.2,141.3,135.8(J C–F ＝2.9Hz),135.8(J C–F ＝2.9Hz),131.6(J C–F ＝8.9Hz),131.6(J C–F ＝8.9Hz),131.6(J C–F ＝8.9Hz),131.6(J C–F ＝8.9Hz),130.4,130.4,130.4,130.4,127.0,121.5,121.5,119.0,116.0(J C–F ＝21.7Hz),116.0(J C–F ＝21.7Hz),116.0(J C–F ＝21.7Hz),116.0(J C–F ＝21.7Hz),61.4,32.4,30.4,28.8；HRMS(TOF ES+):m/z calcd for C 28 H 23 F 2 NO 3 [(M+Na) + ],482.1538,found,482.1536.
example 5 this example was prepared according to the same procedure as example 1 except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (4-chlorophenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3e are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.1, yellow solid 96.9mg, yield 79%, melting point =194-196 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝7.61(d,J＝8.3Hz,4H,ArH),7.43–7.37(m,6H,ArH),7.30(d,J＝7.5Hz,1H,ArH),7.20(s,2H,C＝CH),7.08(d,J＝7.9Hz,2H,ArH),4.61(t,J＝5.4Hz,1H,C–CH),3.70(t,J＝6.4Hz,2H,C–CH 2 ),1.73–1.69(m,2H,C–CH 2 ),1.65–1.60(m,2H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝194.4,194.4,142.4,140.3,140.3,137.1,137.1,137.0,137.0,129.8,129.8,129.5,129.5,129.5,129.5,128.4,128.4,128.4,128.4,126.7,120.6,120.6,119.7,119.7,62.1,32.1,29.4,28.1；HRMS(TOF ES+):m/z calcd for C 28 H 23 Cl 2 NO 3 [(M+H) + ],492.1128,found,492.1130.
example 6 this example was prepared according to the same procedure as example 1 except that the N-substituted enaminoketone compound 1a was 3- (phenylamino) -1- (2-bromophenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3f are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.2, yellow solid 107mg, yield 74%, melting point =95-97 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.61–7.60(m,2H,ArH),7.39–7.34(m,4H,ArH),7.32–7.29(m,4H,ArH),7.25(d,J＝7.5Hz,1H,ArH),7.01–6.99(m,2H,ArH),6.96(s,2H,C＝CH),4.62(t,J＝4.6Hz,1H,C–CH),3.76(t,J＝6.4Hz,2H,C–CH 2 ),1.85–1.81(m,2H,C–CH 2 ),1.79–1.75(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝193.6,193.6,142.8,142.8,142.7,140.6,140.6,133.3,133.3,130.8,130.8,130.2,130.2,128.8,128.8,127.4,127.4,127.3,121.3,121.3,120.4,120.4,119.5,119.5,62.8,31.4,28.7,28.3；HRMS(TOF ES+):m/z calcd for C 28 H 24 Br 2 NO 3 [(M+H) + ],580.0177,found,580.0117.
example 7 this example was prepared by the same procedure as in example 1, except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (4-nitrophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of 3g of the obtained product are as follows:
V petroleum ether /V Ethyl acetate ＝4:1,R f =0.15, yellow solid 105mg, yield 82%, melting point =163-165 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝7.67(d,J＝7.2Hz,4H,ArH),7.56(t,J＝7.4Hz,2H,ArH),7.50(q,J＝7.3Hz,4H,ArH),7.41–7.37(m,2H,ArH),7.30–7.29(m,1H,ArH),7.24(s,2H,C＝CH),4.46–4.41(m,2H,C–CH 2 ),3.38–3.36(m,1H,C–CH),1.55–1.49(m,4H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝194.9,194.9,143.3,141.4,141.4,139.3,139.3,131.8,131.8,130.5,130.5,129.0,129.0,129.0,129.0,129.0,129.0,129.0,129.0,127.1,121.5,121.5,119.2,119.2,61.5,33.3,30.2,28.8；HRMS(TOF ES+):m/z calcd for C 28 H 23 N 3 O 7 [(M+H) + ],514.1609,found,514.1606.
example 8 this example was prepared by the same procedure as in example 1 except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (4-methanesulfonylphenyl) -2-propen-1-one;
the obtained product has the following 3h structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data:
V petroleum ether /V Ethyl acetate ＝8:1,R f =0.1, yellow solid 123.1mg, yield 85%, melting point =181-183 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝8.04(d,J＝8.0Hz,4H,ArH),7.92(d,J＝8.0Hz,4H,ArH),7.43–7.38(m,4H,ArH),7.32(s,2H,C＝CH),7.29(t,J＝7.2Hz,1H,ArH),4.43(t,J＝5.1Hz,2H,C–CH 2 ),3.28(s,6H,S–CH 3 ),1.58–1.54(m,2H,C–CH 2 ),1.52–1.46(m,2H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝193.6,193.6,143.7,143.7,143.1,143.1,142.6,130.4,130.4,130.4,130.4,129.7,129.7,129.7,129.7,127.7,127.7,127.7,127.7,127.4,122.0,122.0,119.0,119.0,61.4,43.8,43.8,32.3,30.0,28.7；HRMS(TOF ES+):m/z calcd for C 30 H 29 NO 7 S 2 [(M+H) + ],580.1458,found,580.1459.
example 9 this example was prepared in the same manner as in example 1 except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (4-biphenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3i are as follows:
V petroleum ether /V Ethyl acetate ＝8:1,R f =0.1, yellow solid 81.9mg, yield 57%, melting point =231-233 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.77–7.76(m,4H,ArH),7.68(d,J＝8.0Hz,4H,ArH),7.64–7.62(m,4H,ArH),7.48(t,J＝7.6Hz,4H,ArH),7.39(q,J＝8.6,8.2Hz,4H,ArH),7.33(s,2H,C＝CH),7.25(d,J＝7.7Hz,1H,ArH),7.13(d,J＝8.3Hz,2H,ArH),4.71(t,J＝5.3Hz,1H,C–CH),3.75(t,J＝6.4Hz,2H,C–CH 2 ),1.80–1.76(m,2H,C–CH 2 ),1.72–1.67(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝194.5,194.5,143.8,143.8,142.7,140.3,140.3,139.7,139.7,137.5,137.5,129.8,129.8,128.9,128.9,128.9,128.9,128.6,128.6,128.6,128.6,127.7,127.7,126.9,126.9,126.9,126.9,126.8,126.8,126.8,126.8,126.5,120.7,120.7,120.0,120.0,62.2,32.3,29.6,28.3；HRMS(TOF ES+):m/z calcd for C 40 H 33 NO 3 [(M+H) + ],576.2533,found,576.2534.
example 10 this example was prepared by the same procedure as in example 1, except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (2-naphthyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3j are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.15, yellow solid 118mg, yield 90%, melting point =193-195 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝8.36(s,2H,ArH),8.16(d,J＝8.0Hz,2H,ArH),8.06(d,J＝8.5Hz,2H,ArH),8.02(d,J＝8.0Hz,2H,ArH),7.80(d,J＝8.4Hz,2H,ArH),7.66–7.61(m,4H,ArH),7.43(s,2H,C＝CH),7.36–7.35(m,4H,ArH),7.23–7.21(m,1H,ArH),4.58(d,J＝5.7Hz,1H,C–CH),4.51–4.49(m,1H,C–CH 2 ),1.69–1.66(m,2H,C–CH 2 ),1.64–1.59(m,2H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝194.9,194.9,143.2,141.6,141.6,136.6,136.6,134.6,134.6,132.6,132.6,130.4,130.4,129.6,129.6,129.3,129.3,128.7,128.7,128.3,128.3,128.1,128.1,127.3,127.3,127.0,125.8,125.8,121.4,121.4,119.5,119.5,61.6,32.7,30.4,29.0；HRMS(TOF ES+):m/zcalcd for C 36 H 30 NO 3 [(M+H) + ],524.2220,found,524.2219.
example 11 this example was prepared by the same procedure as in example 1, except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (benzo [ d ] dioxole) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3k are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.2, yellow solid 105mg, yield 82%, melting point =150-152 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝7.44(t,J＝7.7Hz,2H,ArH),7.37(d,J＝7.9Hz,2H,ArH),7.31–7.28(m,5H,ArH),7.23(s,2H,C＝CH),7.02(d,J＝8.0Hz,2H,ArH),6.13(s,2H,OCH 2 ),6.12(s,2H,OCH 2 ),4.40–4.39(m,1H,C–CH),3.36(d,J＝5.8Hz,2H,C–CH 2 ),1.51–1.44(m,4H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝193.4,193.4,150.6,150.6,148.0,148.0,143.3,140.3,140.3,133.4,133.4,130.4,130.4,126.9,124.6,124.6,121.4,121.4,119.0,119.0,108.9,108.9,108.4,108.4,102.2,102.2,61.5,32.6,30.9,28.9；HRMS(TOF ES+):m/z calcd for C 30 H 26 NO 7 [(M+H) + ],512.1704,found,512.1704.
example 12 this example is prepared by the same procedure as example 1 except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1-styryl-2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3l are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.1, yellow solid 82mg, yield 69%, melting point =127-129 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.75(s,1H,C＝CH),7.72(s,1H,C＝CH),7.67(s,2H,C＝CH),7.60–7.59(m,4H,ArH),7.54–7.51(m,4H,ArH),7.40–7.35(m,9H,ArH+C＝CH),7.27(s,1H,C＝CH),7.24(s,1H,C＝CH),4.58(t,J＝5.1Hz,1H,C–CH),3.70(t,J＝6.5Hz,2H,C–CH 2 ),1.65–1.61(m,2H,C–CH 2 ),1.59–1.54(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝187.7,187.7,143.4,142.6,142.6,137.6,137.6,135.1,135.1,130.2,130.2,130.2,130.2,128.9,128.9,128.9,128.9,128.3,128.3,128.3,128.3,127.3,121.8,121.8,121.5,121.5,120.8,120.8,62.8,33.1,29.2,28.1；HRMS(TOF ES+):m/z calcd for C 32 H 30 NO 3 [(M+H) + ],476.2220,found,476.2218.
example 13 this example is prepared by the same procedure as in example 1, except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1- (2-furyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3m are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.1, yellow solid 81.6mg, yield 81%, melting point =171-173 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝8.05(s,2H,C＝CH),7.58(s,2H,C＝CH),7.52–7.49(m,2H,ArH),7.37–7.36(m,1H,ArH),7.27(s,2H,C＝CH),7.21(d,J＝3.5Hz,2H,C＝CH),6.55–6.54(m,2H,ArH),4.60(t,J＝5.2Hz,1H,C–CH),3.67(t,J＝6.4Hz,2H,C–CH 2 ),1.66–1.63(m,2H,C–CH 2 ),1.60–1.56(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝179.8,179.8,153.3,153.3,145.3,145.3,143.5,139.5,139.5,130.2,130.2,126.9,121.3,121.3,119.2,119.2,117.5,117.5,112.0,112.0,62.6,32.7,29.3,28.3；HRMS(TOF ES+):m/z calcd for C 24 H 21 NO 5 [(M+H) + ],404.1492,found,404.1493.
example 14 this example is prepared by the same procedure as in example 1, except that the N-substituent enaminone compound 1a is 3- (phenylamino) -1-cyclopropyl-2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3n are as follows:
V petroleum ether /V Ethyl acetate ＝10:1,R f =0.15, yellow solid 50mg, yield 57%, melting point =136-138 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.66(s,2H,C＝CH),7.48(t,J＝7.9Hz,2H,ArH),7.35–7.32(m,3H,ArH),4.33(d,J＝4.3Hz,1H,C–CH),3.67–3.65(m,2H,C–CH 2 ),2.04(d,J＝19.6Hz,2H,C–CH),1.50–1.49(m,4H,C–CH 2 ),1.14–1.11(m,2H,C–CH 2 ),1.08–1.06(m,2H,C–CH 2 ),0.90–0.84(m,4H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝198.0,198.0,143.5,137.0,137.0,130.1,130.1,126.8,126.8,121.4,121.4,120.8,62.7,33.2,28.9,28.0,15.9,15.9,10.7,10.7,10.6,10.6；HRMS(TOF ES+):m/z calcd for C 22 H 25 NO 3 [(M+H) + ],352.1907,found,352.1909.
example 15 this example is prepared by the same procedure as in example 1, except that the N-substituent enaminone compound 1a is 3- (4-methoxyphenylamino) -1-phenyl-2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3o are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.1, yellow solid 93mg, yield 82%, melting point =190-192 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.64(d,J＝7.5Hz,4H,ArH),7.50(t,J＝7.4Hz,2H,ArH),7.44(d,J＝7.5Hz,4H,ArH),7.14(s,2H,C＝CH),7.02(d,J＝8.8Hz,2H,ArH),6.87(d,J＝8.9Hz,1H,ArH),4.65(t,J＝5.2Hz,1H,C–CH),3.78(s,3H,ArOCH 3 ),3.72(t,J＝6.4Hz,2H,C–CH 2 ),1.75–1.71(m,2H,C–CH 2 ),1.68–1.65(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝195.2,195.2,158.5,141.6,141.6,139.2,139.2,136.4,131.2,131.2,128.6,128.6,128.6,128.6,128.5,128.5,128.5,128.5,123.1,123.1,119.7,119.7,115.1,115.1,62.6,55.6,32.7,29.5,28.6；HRMS(TOF ES+):m/z calcd for C 29 H 28 NO 4 [(M+H) + ],454.2013,found,454.2013.
example 16 this example is prepared by the same procedure as in example 1, except that the N-substituent enaminone compound 1a is 3- (4-chlorophenylamino) -1-phenyl-2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3p are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.15, 85mg of yellow solid, 79% yield, melting point =207-209 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.66–7.65(m,4H,ArH),7.54–7.51(m,2H,ArH),7.46(t,J＝7.5Hz,4H,ArH),7.34–7.32(m,2H,ArH),7.18(s,2H,C＝CH),7.02(d,J＝8.8Hz,2H,ArH),4.65(t,J＝5.3Hz,1H,C–CH),3.71(t,J＝6.4Hz,2H,C–CH 2 ),1.75–1.71(m,2H,C–CH 2 ),1.67–1.63(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝195.2,195.2,141.5,140.3,140.3,139.0,139.0,132.4,131.4131.4,130.2,130.2,128.6,128.6,128.6,128.6,128.5,128.5,128.5,128.5,122.3,122.3,120.6,120.6,62.5,32.6,29.8,28.6；HRMS(TOF ES+):m/z calcd for C 28 H 25 ClNO 3 [(M+H) + ],458.1517,found,458.1518.
example 17 this example is prepared by the same procedure as example 1 except that the N-substituent enaminone compound 1a is 3- (4-bromophenylamino) -1-phenyl-2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3q are as follows:
V petroleum ether /V Acetic acid ethyl ester ＝5:1,R f =0.1, yellow solid 98mg, yield 79%, melting point =213-215 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.66–7.64(m,4H,ArH),7.54–7.51(m,2H,ArH),7.48–7.44(m,6H,ArH),7.18(s,2H,C＝CH),6.95(d,J＝8.7Hz,2H,ArH),4.64(t,J＝5.3Hz,1H,C–CH),3.70(t,J＝6.4Hz,2H,C–CH 2 ),1.74–1.71(m,2H,C–CH 2 ),1.66–1.61(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝195.2,195.2,142.0,140.2,140.2,139.0,139.0,133.2,133.2,131.5,131.5,128.6,128.6,128.6,128.6,128.5,128.5,128.5,128.5,122.5,122.5,120.7,120.7,120.1,62.5,32.6,29.8,28.6；HRMS(TOF ES+):m/z calcd for C 28 H 25 BrNO 3 [(M+H) + ],502.1012,found,502.1011.
example 18 this example is prepared by the same procedure as in example 1, except that the N-substituted enaminone compound 1a is 3- (4-hydroxyphenylamino) -1-phenyl-2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3r are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.2, yellow solid 98mg, yield 85%, melting point =163-165 ℃; 1 H NMR(600MHz,DMSO–d 6 ):δ＝9.78(s,1H,ArOH),7.66–7.64(m,4H,ArH),7.57(t,J＝7.3Hz,2H,ArH),7.51(t,J＝7.5Hz,4H,ArH),7.14(d,J＝8.4Hz,2H,ArH),7.09(s,2H,C＝CH),6.77(d,J＝8.6Hz,2H,ArH),4.47–4.43(m,2H,C–CH 2 ),3.41–3.39(m,1H,C–CH),1.54–1.49(m,4H,C–CH 2 )； 13 C NMR(150MHz,DMSO–d 6 ):δ＝194.5,194.5,156.9,142.4,142.4,139.4,139.4,135.3,131.7,131.7,129.0,129.0,129.0,129.0,128.8,128.8,128.8,128.8,123.8,123.8,118.4,118.4,116.7,116.7,61.5,32.4,29.9,28.9；HRMS(TOF ES+):m/z calcd for C 28 H 26 NO 4 [(M+H) + ],440.1856,found,440.1853.
example 19 this example is prepared by the same procedure as in example 1, except that the N-substituted enaminone compound 1a is 3-cyclohexyl-1-phenyl-2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3s are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.15, yellow56mg of a colored solid, 52% yield, melting point =171-173 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.60–7.59(m,4H,ArH),7.52(t,J＝7.3Hz,2H,ArH),7.45(t,J＝7.5Hz,4H,ArH),7.27(s,2H,C＝CH),4.58(t,J＝5.0Hz,1H,C–CH),3.69(t,J＝6.1Hz,2H,C–CH 2 ),3.08–3.05(m,1H,N–CH),1.86–1.85(m,2H,C–CH 2 ),1.82–1.80(m,2H,C–CH 2 ),1.65–1.56(m,6H,C–CH 2 ),1.29–1.23(m,4H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝195.0,195.0,141.2,141.2,139.6,139.6,130.9,130.9,128.6,128.6,128.6,128.6,128.4,128.4,128.4,128.4,118.4,118.4,63.7,62.6,32.6,32.4,32.4,29.7,28.4,25.4,25.4,24.8；HRMS(TOF ES+):m/z calcd for C 28 H 32 NO 3 [(M+H) + ],430.2377,found,430.2378.
example 20 this example was prepared according to the same procedure as in example 1 except that Tetrahydrofuran (THF) 2a was replaced with oxepane;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3t are as follows:
V petroleum ether /V Ethyl acetate ＝4:1,R f =0.1, yellow solid 63mg, yield 57%, melting point =182-184 ℃; 1 H NMR(600MHz,CDCl 3 ):δ＝7.67–7.65(m,4H,ArH),7.52–7.50(m,2H,ArH),7.46–7.44(m,4H,ArH),7.38–7.35(m,2H,ArH),7.24–7.23(m,3H,ArH+C＝CH),7.08–7.07(m,2H,ArH),4.66(t,J＝5.3Hz,1H,C–CH),3.61(t,J＝6.5Hz,2H,C–CH 2 ),1.70–1.67(m,2H,C–CH 2 ),1.62–1.58(m,2H,C–CH 2 ),1.48–1.43(m,2H,C–CH 2 )； 13 C NMR(150MHz,CDCl 3 ):δ＝195.3,195.3,143.1,140.8,140.8,139.2,139.2,131.3,131.3,130.1,130.1,128.6,128.6,128.6,128.6,128.5,128.5,128.5,128.5,126.8,121.0,121.0,120.4,120.4,62.7,35.8,32.6,30.5,21.4；HRMS(TOF ES+):m/z calcd for C 29 H 28 NO 3 [(M+H) + ],438.2064,found,438.2064.
example 21:
adding N-substituent enaminone compound 1a (0.4 mmol), di-tert-butyl dicumyl peroxide (DCP, 1.2 mmol), ferrous chloride (0.4 mmol), acetic anhydride 4a (2.4 mmol) and 3mL Tetrahydrofuran (THF) 2a into a thick-walled reaction tube under a nitrogen atmosphere at 80 ℃, reacting under magnetic stirring, monitoring the reaction by TLC until N-substituent enaminone 1a reacts completely, cooling the reaction mixture to room temperature, adding saturated sodium bicarbonate solution, extracting the organic solvent ethyl acetate three times, collecting and combining the upper organic solvents, adding anhydrous sodium sulfate for drying, concentrating the dried organic layer, and finally carrying out silica gel column chromatography on the concentrate, wherein the solvent adopted for column chromatography is a mixed solvent of petroleum ether and ethyl acetate (volume ratio is 5), so as to obtain the target compound 4-alkyl-1, 4-dihydropyridine compound 5a, and the general formula is as follows:
the morphology, melting point, nuclear magnetism, high resolution mass spectrometry data for product 5a obtained in example 21 are as follows:
V petroleum ether /V Acetic acid ethyl ester ＝5:1,R f =0.5, yellow solid 68mg, yield 71%, melting point =115-117 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.69(d,J＝7.6Hz,4H,ArH),7.59–7.57(m,2H,ArH),7.53–7.50(m,4H,ArH),7.43–7.40(m,2H,ArH),7.33–7.32(m,2H,ArH),7.29–7.28(m,3H,ArH+C＝CH),4.46(t,J＝5.2Hz,1H,C-CH),4.00(t,J＝6.5Hz,2H,C-CH 2 ),1.94(s,3H,C-CH 3 ),1.69–1.62(m,2H,C-CH 2 ),1.58–1.55(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,170.9,143.2,141.7,141.7,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.7,118.7,64.5,31.9,29.9,24.5,21.2；HRMS(TOF ES + ):m/zcalcd for C 30 H 27 NO 4 [(M+H) + ],466.2013,found,466.2017.
example 22: this example is prepared by the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (4-methoxyphenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5b are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, yellow solid 76mg, yield 72%, melting point =137-139 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.70(d,J＝8.3Hz,4H,ArH),7.43–7.40(m,2H,ArH),7.36–7.35(m,2H,ArH),7.27–7.26(m,3H,ArH+C＝CH),7.04(d,J＝8.2Hz,5H,ArH),4.42(t,J＝5.4Hz,1H,C-CH),3.96(t,J＝6.5Hz,2H,C-CH 2 ),3.82(s,6H,ArOCH 3 ),1.91(s,3H,C-CH 3 ),1.63–1.60(m,2H,C-CH 2 ),1.54–1.50(m,2H,CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝193.8,193.8,170.9,162.4,162.4,143.3,140.4,140.4,131.5,131.5,131.2,131.2,131.2,131.2,130.4,130.4,126.9,121.4,121.4,118.6,118.6,114.3,114.3,114.3,114.3,64.44,55.85,55.85,32.10,30.64,24.61,21.16；HRMS(TOF ES + ):m/z calcd for C 32 H 31 NO 6 [(M+H) + ],526.2224,found,526.2238.
example 23: this example is prepared by the same procedure as example 21 except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (4-ethylphenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5c are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, yellow solid 63mg, yield60 percent, and the melting point =134-136 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.63(d,J＝7.8Hz,4H,ArH),7.43–7.41(m,2H,ArH),7.35(d,J＝7.8Hz,6H,ArH),7.29-7.27(m,3H,C＝CH+ArH),4.44(t,J＝5.9Hz,1H,C-CH),3.98(t,J＝6.4Hz,2H,C-CH 2 ),2.69–2.65(m,4H,C-CH 2 ),1.93(s,3H,C-CH 3 ),1.67–1.60(m,2H,C-CH 2 ),1.57–1.52(m,2H,C-CH 2 ),1.20(t,J＝7.6Hz,6H,C-CH 3 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.6,194.6,170.9,148.0,148.0,143.3,141.2,141.2,136.7,136.7,130.5,130.5,130.5,130.5,129.2,129.2,129.2,129.2,128.4,128.4,128.4,128.4,127.1,121.7,121.7,118.6,118.6,64.5,32.0,30.2,28.5,24.6,21.2,15.7；HRMS(TOF ES + ):m/z calcd for C 34 H 35 NO 4 [(M+H) + ],520.2614,found,520.2625.
example 24: this example was prepared according to the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (4-fluorophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5d are as follows:
V petroleum ether /V Acetic acid ethyl ester ＝5:1,R f =0.5, 65mg of yellow solid, 65% yield, melting point =127-129 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.78–7.76(m,4H,ArH),7.41–7.28(m,11H,ArH+C＝CH),4.43–4.41(m,1H,C-CH),3.98–3.96(m,2H,C-CH 2 ),1.92(s,3H,C-CH 3 ),1.63–1.61(m,2H,CH 2 ),1.55–1.53(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝193.6,193.6,170.9,164.3(J C-F ＝249.5Hz),164.3(J C-F ＝249.5Hz),143.2,141.7,141.7,135.7,131.7(J C-F ＝9.0Hz),131.7(J C-F ＝9.0Hz),131.7(J C-F ＝9.0Hz),131.7(J C-F ＝9.0Hz),130.40,130.40,130.40,130.40,127.1,121.6,121.6,118.5,118.5,116.0(J C-F ＝21.6Hz),116.0(J C-F ＝21.6Hz),116.0(J C-F ＝21.6Hz),116.0(J C-F ＝21.6Hz),64.4,31.9,30.0,24.5,21.2；HRMS(TOF ES + ):m/z calcd for C 30 H 25 Cl 2 NO 4 [(M+H) + ],502.1824,found,502.1831.
example 25: this example was prepared by the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (4-chlorophenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5e are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, yellow solid 59mg, yield 56%, melting point =153-155 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.73(d,J＝7.9Hz,4H,ArH),7.58–7.57(m,4H,ArH),7.43–7.39(m,2H,ArH),7.33(s,2H,C＝CH),7.31–7.30(m,1H,ArH),4.43–4.42(m,1H,C-CH),4.00–3.98(m,2H,C-CH 2 ),1.94(s,3H,C-CH 3 ),1.69–1.61(m,2H,C-CH 2 ),1.61–1.50(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝193.6,193.6,170.9,143.1,142.0,142.0,137.9,137.9,136.6,130.6,130.9,130.9,130.9,130.9,130.4,130.4,129.1,129.1,129.1,129.1,127.2,121.7,121.7,118.5,118.5,64.4,31.8,29.9,24.5,21.2；HRMS(TOF ES + ):m/z calcd for C 30 H 25 Cl 2 NO 4 [(M+H) + ],534.1233,found,534.1238.
example 26: this example is prepared by the same procedure as example 21 except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (2-naphthyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5e are as follows:
V petroleum ether /V Ethyl acetate ＝3:1,R f =0.5, yellow solid 66mg, yield 58%, melting point =175-177 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝8.34(s,2H,ArH),8.14–8.13(m,2H,ArH),8.05–7.99(m,4H,ArH),7.78(d,J＝8.5Hz,2H,ArH),7.65–7.55(m,4H,ArH),7.43(s,2H,ArH),7.36–7.34(m,4H,ArH+C＝CH),7.22–7.20(m,1H,ArH),4.57–4.55(m,1H,C–CH),4.05(t,J＝6.6Hz,2H,C-CH 2 ),1.92(s,3H,C-CH 3 ),1.79–1.72(m,2H,C-CH 2 ),1.68–1.64(m,2H,C-CH 2 ).； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,171.0,143.2,141.9,136.6,136.6,134.6,134.6,132.6,132.6,130.4,130.4,130.4,129.6,129.6,129.3,129.3,128.7,128.7,128.3,128.3,128.1,128.1,127.4,127.4,127.0,125.8,125.8,121.5,121.5,121.5,119.0,119.0,64.6,32.2,30.1,24.7,21.2；HRMS(TOF ES + ):m/z calcd for C 38 H 31 NO 4 [(M+H) + ],566.2326,found,566.2333.
example 27: this example is prepared by the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (phenylamino) -1- (2-furyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5f are as follows:
V petroleum ether /V Ethyl acetate ＝4:1,R f =0.5, 53mg of yellow solid, 59% yield, melting point =130-132 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.99(d,J＝8.9Hz,4H,C＝CH),7.59–7.57(m,2H,C＝CH),7.54–7.51(m,2H,ArH),7.38–7.35(m,3H,ArH+C＝CH),6.76–6.67(m,2H,C＝CH),4.36–7.34(m,1H,C–CH),3.93–3.91(m,2H,C-CH 2 ),1.90(s,3H,C-CH 3 ),1.56-1.50(m,2H,C-CH 2 ),1.49–1.44(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝179.9,179.9,170.8,152.3,152.3,147.4,147.4,143.4,139.9,139.9,130.5,130.5,127.1,121.6,121.6,118.5,118.5,117.8,117.8,112.6,112.6,64.4,32.0,29.9,24.4,21.1；HRMS(TOF ES + ):m/z calcd for C 26 H 23 NO 6 [(M+H) + ],446.1598,found,446.1604.
example 28: this example is prepared by the same procedure as in example 21, except that the N-substituted enaminone compound 1a is 3- (3, 4,5 trimethoxyphenylamino) -1- (4-nitrophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of 5g of the obtained product are as follows:
V petroleum ether /V Ethyl acetate ＝4:1,R f =0.5, 50mg of yellow solid, 48% yield, melting point =135-137 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.71–7.69(s,4H,ArH),7.56–7.49(m,6H,ArH),7.22(s,2H,C＝CH),6.68–7.66(m,2H,ArH),4.43–4.45(m,1H,C–CH),3.40–3.38(s,2H,C-CH 2 ),3.72(s,6H,ArOCH 3 ),3.58(s,3H,ArOCH 3 ),1.92(s,3H,C-CH 3 ),1.66–1.64(m,2H,C-CH 2 ),1.57–1.55(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,170.9,153.9,153.9,153.9,142.4,142.4,139.6,139.2,136.7,131.9,131.9,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,118.1,118.1,100.5,100.5,64.5,60.5,56.7,56.7,32.0,30.0,24.6,21.2；HRMS(TOF ES + ):m/zcalcd for C 31 H 30 NO 5 [(M+H) + ],556.2330,found,556.2333
example 29: this example is prepared by the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (4-methylphenylamino) -1- (4-nitrophenyl) -2-propen-1-one;
the obtained product has 5h structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, yellow solid 63mg, yield 66%, melting point =127-129 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.66–7.65(m,4H,ArH),7.57–7.55(m,2H,ArH),7.51–7.49(m,4H,ArH),7.20–7.18(m,6H,ArH+C＝CH),4.44–4.42(m,1H,C–CH),4.00–4.38(m,2H,C-CH 2 ),2.24(s,3H,ArCH 3 ),1.92(s,3H,C-CH 3 ),1.65–1.63(m,2H,CH 2 ),1.56–1.54(m,2H,CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,170.9,142.0,142.0,140.9,139.2,139.2,136.8,131.8,131.8,130.8,130.8,130.0,130.0,130.0,130.0,128.8,128.8,128.8,128.8,121.7,121.7,118.4,118.4,64.5,31.9,29.8,24.5,21.2,20.8；HRMS(TOF ES + ):m/z calcd for C 31 H 29 NO 4 [(M+H) + ],480.2169,found,480.2186.
example 30: this example is prepared by the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (4-N, N-dimethylphenylamino) -1- (4-nitrophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5i are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5,yellow liquid, yield 46%, 1 H NMR(600MHz,DMSO-d 6 )δ＝7.65–7.61(m,4H,ArH),7.54(d,J＝7.6Hz,2H,ArH),7.50–7.47(m,4H,ArH),7.12–7.09(m,4H,ArH+C＝CH),6.67(d,J＝8.5Hz,2H,ArH),4.44–4.43(m,1H,C–CH),4.00(t,J＝6.5Hz,2H,CH 2 ),2.84(s,6H,N-CH 3 ),1.94(s,3H,C-CH 3 ),1.66–1.64(m,2H,C-CH 2 ),1.57–1.53(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.7,194.7,170.9,149.8,142.9,142.9,139.4,139.4,132.7,131.6,131.6,128.5,128.5,128.5,128.5,128.9,128.9,128.9,128.9,123.2,123.2,117.8,117.8,113.3,113.3,64.5,40.6,40.6,31.9,29.6,24.5,21.2；HRMS(TOF ES + ):m/z calcd for C 31 H 29 NO 5 [(M+H) + ],496.2118,found,496.2122.
example 31: the preparation process of this example is the same as that of example 21, except that the N-substituted enaminone compound 1a is 3- (4-chloroanilino) -1- (4-nitrophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5j are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, 64mg of yellow solid, 64% yield, melting point =135-137 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.69(d,J＝7.5Hz,4H,ArH),7.59–7.56(m,2H,ArH),7.51–7.49(m,4H,ArH),7.44–7.44(m,2H,ArH),7.37–7.36(m,2H,ArH),7.25(s,2H,C＝CH),4.55–4.30(m,1H,C–CH),3.99–3.97(m,2H,C-CH 2 ),1.92(s,3H,C-CH 3 ),1.68–1.60(m,2H,C-CH 2 ),1.57–1.53(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,170.9,142.1,141.4,141.4,139.1,139.1,131.9,131.9,131.3,130.2,130.2,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,123.5,123.5,118.8,118.8,64.4,31.9,29.9,24.5,21.2；HRMS(TOF ES + ):m/z calcd for C 30 H 26 ClNO 4 [(M+H) + ],500.1623,found,500.1630.
example 32: this example is prepared by the same procedure as example 21 except that the N-substituted enaminone compound 1a is 3- (4-bromophenylamino) -1- (4-nitrophenyl) -2-propen-1-one;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5k are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, 50mg of yellow solid, 46% yield, melting point =133-135 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.69(d,J＝7.4Hz,4H,ArH),7.60–7.57(m,4H,ArH),7.52–7.50(m,4H,ArH),7.32(d,J＝8.4Hz,2H,ArH),7.26(s,2H,C＝CH),4.45–4.43(m,1H,C–CH),4.00–3.97(m,2H,C-CH 2 ),1.93(s,3H,C-CH 3 ),1.72–1.59(m,2H,C-CH 2 ),1.56–1.54(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,170.9,142.5,141.3,141.3,139.1,139.1,133.2,133.2,131.9,131.9,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,123.8,123.8,119.5,118.9,118.9,64.4,31.8,29.9,24.5,21.2；HRMS(TOF ES + ):m/z calcd for C 30 H 26 BrNO 4 [(M+H) + ],544.1118,found,544.1112.
example 33: this example is prepared by the same procedure as example 21, except that the N-substituted enaminone compound 1a is 3- (4-methoxybenzylamino) -1- (4-nitrophenyl) -2-propen-1-one;
the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of 5l of the obtained product are as follows:
V petroleum ether /V Ethyl acetate ＝6:1,R f =0.5, 45mg of yellow solid, 44% yield, melting point =114-116 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.56–7.55(m,2H,ArH),7.48–7.47(m,8H,ArH),7.17(d,J＝8.1Hz,2H,ArH),7.12(s,2H,C＝CH),6.95(d,J＝8.1Hz,2H,ArH),4.64(s,2H,C-CH 2 ),4.31(t,J＝5.2Hz,1H,C–CH),3.90(t,J＝6.5Hz,2H,C-CH 2 ),3.75(s,3H,ArOCH 3 ),1.93(s,3H,C-CH 3 ),1.49–1.42(m,2H,CH 2 ),1.40–1.37(m,2H,CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.3,194.3,170.8,159.4,144.3,144.3,139.6,139.6,131.5,131.5,129.5,129.5,129.3,128.8,128.8,128.8,128.8,128.7,128.7,128.7,128.7,116.6,116.6,114.6,114.6,64.5,56.5,55.6,31.8,29.4,24.4,21.1；HRMS(TOF ES + ):m/z calcd for C 32 H 31 NO 5 [(M+H) + ],510.2275,found,510.2281.
example 34: the preparation process of this example is the same as that of example 21, except that acetic anhydride is replaced with chloroacetic anhydride;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5m are as follows:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, yellow solid 51mg, yield 51%, melting point =119-121 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.69–7.67(m,4H,ArH),7.61–7.54(m,2H,ArH),7.52–7.49(m,4H,ArH),7.42–7.36(m,3H,ArH),7.33–7.29(m,2H,ArH),7.25(s,2H,C＝CH),4.46–4.42(m,1H,C–CH),4.33–4.29(m,2H,C-CH 2 ),4.14–4.09(m,2H,C-CH 2 ),1.69–1.64(m,2H,C-CH 2 ),1.59–1.55(m,2H,C-CH 2 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,167.9,143.2,141.8,141.8,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.7,118.7,66.2,41.6,31.9,29.8,24.4；HRMS(TOF ES + ):m/z calcd for C 30 H 26 ClNO 4 [(M+H) + ],500.1623,found,500.1626.
example 35: this example is prepared by the same procedure as example 21 except that acetic anhydride is replaced with propionic anhydride;
the structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 5n are as follows:
V petroleum ether /V Acetic acid ethyl ester ＝5:1,R f =0.5, 58mg of yellow solid, 61% yield, melting point =130-132 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.68(d,J＝7.5Hz,4H,ArH),7.58–7.56(m,2H,ArH),7.52–7.49(m,4H,ArH),7.40(t,J＝7.7Hz,2H,ArH),7.31(d,J＝7.9Hz,2H,ArH),7.28–7.26(m,2H,ArH+C＝CH),4.45(t,J＝5.1Hz,1H,C–CH),4.01(t,J＝6.4Hz,2H,C-CH 2 ),2.21(q,J＝7.5Hz,2H,C-CH 2 ),1.67–1.63(m,2H,C-CH 2 ),1.58–1.54(m,2H,C-CH 2 ),0.94(t,J＝7.5Hz,3H,C-CH 3 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,174.1,143.2,141.7,141.7,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.7,118.7,64.3,31.7,29.9,27.3,24.6,9.5；HRMS(TOF ES + ):m/z calcd for C 31 H 29 NO 4 [(M+H) + ],480.2169,found,480.2173.
example 36: this example was prepared by the same procedure as example 21 except that acetic anhydride was replaced with isobutyric anhydride;
the obtained product 5o has the following structure, form, melting point, nuclear magnetism and high-resolution mass spectrum data:
V petroleum ether /V Ethyl acetate ＝5:1,R f =0.5, 59mg of yellow solid, 60% yield, melting point =148-150 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ＝7.67(d,J＝7.4Hz,4H,ArH),7.58–7.56(m,2H,ArH),7.51–7.49(m,4H,ArH),7.42–7.39(m,2H,ArH),7.31–7.30(m,2H,ArH),7.28–7.25(m,3H,ArH+C＝CH),4.45(t,J＝5.2Hz,1H,C-CH),4.02(t,J＝6.2Hz,2H,C-CH 2 ),2.43–2.42(m,1H,C-CH),1.67–1.63(m,2H,C-CH 2 ),1.60–1.50(m,2H,C-CH 2 ),0.98(d,J＝7.0Hz,C-CH 3 )； 13 C NMR(150MHz,DMSO-d 6 )δ＝194.8,194.8,176.6,143.2,141.8,141.8,139.2,139.2,131.8,131.8,130.5,130.5,129.0,129.0,129.0,129.0,128.9,128.9,128.9,128.9,127.2,121.6,121.6,118.6,118.6,64.2,33.6,31.6,29.9,24.5,19.2,19.2；HRMS(TOF ES + ):m/z calcd for C 30 H 26 ClNO 4 [(M+H) + ],494.2326,found,494.2332.
PDE4 inhibiting Effect of the Compounds of the examples
The compounds of the present invention were tested for PDE4 inhibitory activity by reference to the procedure in "pretreated Coumarins: natural phosphorus vesterase-4 inhibitors from Toddalia asiatica.J.Nat.Prod.2014,77,955-962", the results of which are shown in Table 1.
The results of the inhibitory activity of two representative 1, 4-dihydropyridine compounds, 3o and 5a, on phosphodiesterase 4 are: the inhibition rates in the concentration of 10 mu M are respectively 61.12 percent and 69.76 percent, and the 4-alkyl-1, 4-dihydropyridine compound of the invention has inhibitory activity on PDE 4; the inhibition rates in the concentration of 1.0 mu M are respectively 8.51 percent and 16.21 percent, and are lower than the inhibition rate (59.21 percent) of the positive control drug Rolipram;
TABLE 1
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, and such changes and modifications are within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. 4-alkyl-1, 4-dihydropyridine compounds of the structural formulae i, ii:
formula I, wherein R 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; n is selected from 1 and 2;
formula II wherein R 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; r 3 Is selected from aryl and alkyl, and n is selected from 1 and 2.
2. A process for preparing a 4-alkyl-1, 4-dihydropyridine compound as claimed in claim 1, characterized in that: adding an N-substituent enaminone compound 1 into a reactor, reacting at 60-120 ℃ in the presence of a catalyst, an auxiliary agent and an oxidant by taking an ether compound 2 as a solvent, monitoring the reaction process by thin-layer chromatography until the reaction is complete, extracting a reaction product for 2-3 times by using ethyl acetate, collecting and combining organic phases, drying the organic phases by using anhydrous sodium sulfate, then concentrating under reduced pressure, and separating and purifying a concentrate by using a silica gel column chromatography to obtain a 4-alkyl-1, 4-dihydropyridine compound 3;
wherein R is 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; n is selected from 1 and 2.
3. A process for preparing a 4-alkyl-1, 4-dihydropyridine compound as claimed in claim 1, characterized in that: adding an N-substituent enaminone compound 1 and an anhydride compound 4 into a reactor, reacting at 60-120 ℃ in the presence of a catalyst, an auxiliary agent and an oxidant by taking an ether compound 2 as a solvent in a nitrogen atmosphere, monitoring the reaction process by thin-layer chromatography until the reaction is complete, extracting the reaction product for 2-3 times by using ethyl acetate, collecting and combining organic phases, drying by using anhydrous sodium sulfate, then concentrating under reduced pressure, and separating and purifying the concentrate by using a silica gel column chromatography to obtain a 4-alkyl-1, 4-dihydropyridine compound 5;
wherein R is 1 Selected from aryl, heterocycle, alkyl; r 2 Selected from aryl, heterocycle, alkyl; r 3 Selected from aryl, alkyl; n is selected from 1 and 2.
4. The process for producing a 4-alkyl-1, 4-dihydropyridine compound according to claim 2 or 3, characterized in that: the catalyst is ferrous chloride, ferric chloride, ferrous sulfate, palladium chloride, copper chloride, cobalt chloride, chromium chloride or nickel chloride hexahydrate, and the molar ratio of the N-substituted enaminone compound 1 to the catalyst is 1.1-5.
5. The process for producing a 4-alkyl-1, 4-dihydropyridine compound according to claim 2 or 3, characterized in that: the oxidant is di-tert-butyl peroxide, di-tert-butyl dicumyl peroxide, tert-butyl perbenzoate, tert-butyl hydroperoxide, hydrogen peroxide, dibenzoyl peroxide, cumyl hydroperoxide, m-chloroperoxybenzoic acid or potassium persulfate, and the molar ratio of the N-substituted enaminone compound 1 to the oxidant is 1.
6. The process for producing a 4-alkyl-1, 4-dihydropyridine compound according to claim 2 or 3, characterized in that: the auxiliary agent is tetrafluoroboric acid, perchloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or sulfuric acid, and the molar ratio of the N-substituted enaminone compound 1 to the auxiliary agent is 1.
7. The process for producing a 4-alkyl-1, 4-dihydropyridine compound according to claim 2 or 3, characterized in that: the ether compound is tetrahydrofuran, tetrahydrothiophene, hydropyran or oxepane.
8. Use of a 4-alkyl-1, 4-dihydropyridine compound according to claim 1 in the preparation of a PED4 inhibitor.
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