CN116283972A - Preparation method of 3-substituted indolizine derivative - Google Patents
Preparation method of 3-substituted indolizine derivative Download PDFInfo
- Publication number
- CN116283972A CN116283972A CN202310238167.0A CN202310238167A CN116283972A CN 116283972 A CN116283972 A CN 116283972A CN 202310238167 A CN202310238167 A CN 202310238167A CN 116283972 A CN116283972 A CN 116283972A
- Authority
- CN
- China
- Prior art keywords
- reaction
- derivative
- substituted indolizine
- pyridine
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 3-substituted indolizine Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 91
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- YOCRKHKJFCWTHG-UHFFFAOYSA-N 2-[6-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC(C=2OCCN=2)=N1 YOCRKHKJFCWTHG-UHFFFAOYSA-N 0.000 claims abstract description 14
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims abstract description 11
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims abstract description 11
- 150000003222 pyridines Chemical class 0.000 claims abstract description 10
- 150000008062 acetophenones Chemical class 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical group CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012965 benzophenone Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000006056 electrooxidation reaction Methods 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 239000000376 reactant Substances 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 32
- 238000012512 characterization method Methods 0.000 description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 229910052799 carbon Inorganic materials 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 238000001308 synthesis method Methods 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 3
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical class BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 2
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 2
- 229940126650 Compound 3f Drugs 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 229940125796 compound 3d Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 1
- ARPWWLWXEUZAOO-UHFFFAOYSA-N 1h-tetracen-2-one Chemical compound C1=CC=C2C=C(C=C3C(CC(C=C3)=O)=C3)C3=CC2=C1 ARPWWLWXEUZAOO-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- SKFLCXNDKRUHTA-UHFFFAOYSA-N phenyl(pyridin-4-yl)methanone Chemical compound C=1C=NC=CC=1C(=O)C1=CC=CC=C1 SKFLCXNDKRUHTA-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The application discloses a preparation method for synthesizing 3-substituted indolizine derivatives by electrochemical oxidation. The preparation method is characterized in that a target product is obtained after a reaction by taking pyridine derivatives, acetophenone derivatives and maleic anhydride as reactants, nickel bromide as a catalyst, 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine as a ligand and N, N-Dimethylacetamide (DMA) as a solvent. The reaction raw materials and the solvent involved in the preparation method are all commercial products, and the price is low; the reaction condition is simple and mild, the yield is good, the atom utilization rate is high, the green chemistry characteristic is realized, and the sustainable development concept is met.
Description
Technical Field
The application belongs to the field of organic synthetic chemistry, and particularly relates to a preparation method of a 3-substituted indolizine derivative.
Background
The 3-substituted indolizine derivative is a compound with excellent biological activity and has wide application in the field of biological medicine. The existing methods for 3-substituted indolizine derivatives mainly comprise the following three types:
the method I adopts the ring closure reaction of triazole and alkyne, and the chemical reaction formula of the method is shown as a formula (1).
The method has the defects that the triazole derivative is rarely sold on the market and needs to be prepared in advance, two N atoms are removed in the reaction, the atom economy is poor, and the economic benefit is not high.
And II, through pyridine ylide self-cyclization reaction, the chemical reaction formula of the method is shown as a formula (2).
The disadvantage of this method is that pyridine ylide cannot be purchased directly in this reaction, requiring advanced preparation; dimethyl sulfate used in the reaction belongs to high-toxicity dangerous chemicals; meanwhile, the temperature needs to be changed in the reaction process, so that the operation becomes tedious, and the synthesis value of the reaction is influenced.
And thirdly, adopting pyridine derivatives, bromide and maleic anhydride to react, wherein the chemical reaction formula of the method is shown as a formula (3).
The method has the defects of using excessive oxidant, long reaction time (12-24 h) and high reaction temperature (60-120 ℃).
Disclosure of Invention
The invention aims to: the purpose of the application is to provide a simple and convenient 3-substituted indolizine derivative with easily available raw materials and a preparation method thereof, wherein the preparation method can greatly improve the atom economy and the step economy of the reaction, is beneficial to researching the pharmacological activity of the compound and is beneficial to protecting the environment.
The technical scheme is as follows: the present application provides a process for preparing 3-substituted indolizine derivatives, which is depicted in scheme 1,
wherein R is 1 A benzene ring selected from the group consisting of hydrogen, C1-C6 substituted or unsubstituted alkyl, ester, benzophenone, and one-side condensed with said pyridine ring; r is R 2 A benzene ring selected from hydrogen, halogen, C1-C6 alkoxy, and single-side condensed;
step 1, pyridine derivative structure as formula 1, acetophenone derivative structure as formula 2, nickel bromide, maleic anhydride, 2, 6-bis (4, 5-dihydro oxazol-2-yl) pyridine and reaction solvent are added into a reaction tube;
step 2, adding N, N-dimethylacetamide into a reaction tube, sealing the tube for reaction in a nitrogen atmosphere, and synthesizing to obtain a product mixture in one step;
and 3, extracting and filtering the product mixture obtained in the step 2 after the reaction in the step 3 is finished, and concentrating and separating the obtained filtrate to obtain the 3-substituted indolizine derivative with the structure shown in the formula 3.
The beneficial effects are that:
compared with the prior art, the application has the following beneficial effects:
one of the reaction raw materials of the method is acetophenone derivatives, which are bromoacetophenone derivatives in the past, and the reaction has difficulty because the C-H bond energy of acetophenone is larger than the bond energy of bromoacetophenone C-Br in terms of the reaction principle. Whereas acetophenone is cheaper and more abundant than the corresponding bromoacetophenone, such as: acetophenone (acetophenone): 30 yuan/100 ml, 2-bromoacetophenone: 190/100g; the preparation method provided by the application can enable the acetophenone derivatives to directly participate in the reaction, overcomes the reaction difficulty, and has more theoretical research value. In addition, from the economical point of view, the method greatly improves the atomic economy and the step economy of the reaction, is beneficial to environmental protection and accords with the green chemistry and the concept of double carbon.
The 3-substituted indolizine derivative prepared by the application has excellent biological activity and can be used for treating inflammation and cardiovascular diseases.
Drawings
FIG. 1 shows a spectrum characterization of compound 3a prepared in example 1 of the present application;
FIG. 2 shows a carbon spectrum characterization diagram of compound 3a prepared in example 1 of the present application;
FIG. 3 shows a spectrum characterization of compound 3b prepared in example 2 of the present application;
FIG. 4 shows a carbon spectrum characterization diagram of compound 3b prepared in example 2 of the present application;
FIG. 5 shows a spectrum characterization of compound 3c prepared in example 3 of the present application;
FIG. 6 shows a carbon spectrum characterization diagram of compound 3c prepared in example 3 of the present application;
FIG. 7 shows a spectrum characterization of compound 3d prepared in example 4 of the present application;
FIG. 8 shows a carbon spectrum characterization of compound 3d prepared in example 4 of the present application;
FIG. 9 shows a spectrum characterization of compound 3e prepared in example 5 of the present application;
FIG. 10 shows a carbon spectrum characterization diagram of compound 3e prepared in example 5 of the present application;
FIG. 11 shows a spectrum characterization of compound 3f prepared in example 6 of the present application;
FIG. 12 shows a carbon spectrum characterization diagram of compound 3f prepared in example 6 of the present application;
FIG. 13 is a graph showing a spectrum characterization of 3g of the compound prepared in example 7 of the present application;
FIG. 14 shows a carbon spectrum characterization chart of 3g of the compound prepared in example 7 of the present application;
FIG. 15 shows a spectrum characterization of compound 3h prepared in example 8 of the present application;
FIG. 16 shows a carbon spectrum characterization of compound 3h prepared in example 8 of the present application;
Detailed Description
The present application is further illustrated below in conjunction with specific embodiments, it being understood that these embodiments are provided only to illustrate the present application and not to limit the scope of the present application, and that various modifications of the present application, which are equivalent to those skilled in the art, after reading the present application, fall within the scope of the present application as defined in the appended claims.
An embodiment of the present application provides a method for preparing a 3-substituted indolizine derivative, which is depicted in scheme 1,
wherein R is 1 A benzene ring selected from the group consisting of hydrogen, C1-C6 substituted or unsubstituted alkyl, ester, benzophenone, and one-side condensed with said pyridine ring; r is R 2 A benzene ring selected from hydrogen, halogen, C1-C6 alkoxy, and single-side condensed;
step 1, pyridine derivative structure as formula 1, acetophenone derivative structure as formula 2, nickel bromide, maleic anhydride, 2, 6-bis (4, 5-dihydro oxazol-2-yl) pyridine and reaction solvent are added into a reaction tube;
step 2, adding N, N-dimethylacetamide into a reaction tube, sealing the tube for reaction in a nitrogen atmosphere, and synthesizing to obtain a product mixture in one step;
and 3, extracting and filtering the product mixture obtained in the step 2 after the reaction in the step 3 is finished, and concentrating and separating the obtained filtrate to obtain the 3-substituted indolizine derivative with the structure shown in the formula 3.
In one embodiment, the pyridine derivative has a chemical structure selected from any one of the following structural formulas:
in one embodiment, the acetophenone derivative has a chemical structure selected from any one of the following structural formulas:
in one embodiment, the 3-substituted indolizine derivative has a structural formula comprising:
in one embodiment, the reaction condition shown in the reaction formula 1 is that the reaction is carried out for 4 to 8 hours at normal temperature, and the reaction solvent is N, N-dimethylacetamide.
In one embodiment, the molar ratio of the pyridine derivative, the acetophenone derivative and the maleic anhydride added in the reaction of the reaction formula 1 is 1:1:1.
In one embodiment, the molar ratio of the pyridine derivative to the nickel bromide added in the reaction of equation 1 is 1:0.1.
In one embodiment, the molar ratio of the pyridine derivative added to the 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine in the reaction of equation 1 is 1:0.12.
In one embodiment, the preparation method further comprises a step of separating and purifying the product after the reaction is finished, wherein the step of separating and purifying is to concentrate the filtrate obtained by filtration in vacuum, and the obtained crude product is separated by column chromatography to obtain the 3-substituted indolizine derivative in a yellow solid shape.
In one embodiment, in step 3, the crude product obtained is separated by column chromatography to obtain a 3-substituted indolizine derivative as a yellow solid; wherein the yield of the 3-substituted indolizine derivative product is 62-80%.
Example 1
3a synthesis method: methyl isonicotinate (0.4 mmol), acetophenone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-diMethylacetamide solvent, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added respectively, after fully mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen, and air was purged), and reacted for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 83.7mg, yield: 75%. Mp:132-133 ℃. 1 H NMR(400MHz,CDCl 3 )δ：3.97(s,3H),6.76(d,J＝4.4Hz,1H),7.40(d,J＝4.4Hz,1H),7.45-.57(m,4H),7.81(dd,J＝8.4,1.6Hz,2H),8.32(d,J＝0.8Hz,1H),9.89(d,J＝7.2Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ185.4,165.7,140.3,137.8,131.4,129.1,128.3,127.9,126.9,124.9,124.1,121.6,112.5,106.0,52.5.
The results of the hydrogen spectrum characterization of the product 3a obtained by the reaction are shown in FIG. 1, and the results of the carbon spectrum characterization are shown in FIG. 2.
Example 2
3b synthesis method: methyl isonicotinate (0.4 mmol), 4-methoxyacetophenone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added respectively, after sufficiently mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen, and air was purged), and the reaction was carried out for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 98.9mg, yield: 80%. Mp:146-147 ℃. 1 H NMR(400MHz,CDCl 3 ):δ3.80(s,3H),3.97(s,3H),6.74(d,J＝4.4Hz,1H),7.00(d,J＝8.7Hz,2H),7.40-7.43(m,2H),7.83-7.85(m,2H),8.30(s,1H),9.82(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ185.3,165.7,162.4,136.4,132.8,131.2,127.7,126.2,124.0,121.6,113.6,112.5,105.6,55.3,52.4.
The results of the hydrogen spectrum characterization of the product 3b of the reaction are shown in fig. 3, and the results of the carbon spectrum characterization are shown in fig. 4.
Example 3
3c synthesis method: methyl isonicotinate (0.4 mmol), 2-naphthaceneone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added respectively, after sufficiently mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen, and air was purged), and reacted for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 92.1mg, yield: 70%. Mp:158-159 ℃. 1 H NMR(400MHz,CDCl 3 ):δ3.96(s,3H),6.78(d,J＝4.4Hz,1H),7.46-7.50(m,2H),7.56-7.63(m,2H),7.91-7.98(m,4H),8.32(d,J＝9.2Hz,2H),9.92(d,J＝7.2Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ185.1,165.6,137.6,137.3,134.7,132.4,129.9,129.1,128.2,127.9,127.8,127.7,127.1,126.7,125.6,124.8,124.2,121.6,112.5,106.0,52.5.
The results of the hydrogen spectrum characterization of the product 3c obtained by the reaction are shown in fig. 5, and the results of the carbon spectrum characterization are shown in fig. 6.
Example 4
The synthesis method of 3 d: 4-benzoylpyridine (0.4 mmol), acetophenone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added, respectively, after sufficiently mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen, and air was purged), and reacted for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 101.4mg, yield: 78%. Mp:143-144℃. 1 H NMR(400MHz,CDCl 3 ):δ6.76(d,J＝4.8Hz,1H),7.41(dd,J＝7.2,2.0Hz,2H),7.49-7.64(m,6H),7.82-7.84(m,4H),8.02(s,1H),9.94(d,J＝7.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ194.3,185.3,140.1,137.4,137.0,132.6,131.5,131.4,129.7,129.1,128.5,128.3,128.1,126.9,124.1,122.6,113.1,106.4.
The results of the 3d hydrogen spectrum of the product of the reaction are shown in FIG. 7, and the results of the carbon spectrum are shown in FIG. 8.
Example 5
3e, the synthesis method comprises the following steps: pyridine (0.4 mmol), 4-chloroacetophenone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added, respectively, after sufficiently mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen, and air was purged), and the reaction was carried out for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 69.4mg, yield: 68%. Mp:121-122 ℃. 1 H NMR(400MHz,CDCl 3 ):δ6.55(d,J＝4.8Hz,1H),6.98(td,J＝7.2,0.8Hz,1H),7.22(td,J＝7.6,1.2Hz,1H),7.30(d,J＝4.4Hz,1H),7.46(d,J＝8.4Hz,2H),7.57(d,J＝8.8Hz,1H),7.76(d,J＝8.4Hz,2H),9.94(d,J＝7.2Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ182.9,139.7,139.1,137.0,130.3,128.9,128.4,126.6,124.5,122.3,118.8,114.0,102.8.
The results of the hydrogen spectrum characterization of the product 3e obtained by the reaction are shown in FIG. 9, and the results of the carbon spectrum characterization are shown in FIG. 10.
Example 6
3f synthesis method: isoquinoline (0.4 mmol), acetophenone (0.4 mmol) and were added to the reaction tubeMaleic anhydride (0.4 mmol), 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added respectively, after thoroughly mixing, a reaction apparatus was assembled (the reaction tube was filled with nitrogen, and air was purged), and reacted for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 67.2mg, yield: 62%. Mp:138-139 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.06(d,J＝4.4Hz,1H),7.11(d,J＝7.6Hz,1H),7.32(d,J＝4.4Hz,1H),7.48-7.57(m,5H),7.73(dd,J＝7.2,1.6Hz,1H),7.84-7.87(m,2H),8.16-8.20(m,1H),9.61(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ185.4,140.6,136.9,131.0,129.1,128.9,128.2,128.0,127.6,126.9,126.0,125.8,124.6,123.6,113.4,101.9.
The results of the hydrogen spectrum characterization of the product 3f obtained by the reaction are shown in fig. 11, and the results of the carbon spectrum characterization are shown in fig. 12.
Example 7
3g of synthesis method: isoquinoline (0.4 mmol), 4-methoxyacetophenone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added, respectively, after sufficiently mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen, and air was purged), and reacted for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 78.3mg, yield: 65%. Mp:182-183 ℃. 1 H NMR(400MHz,CDCl 3 ):δ3.89(s,3H),7.00(d,J＝8.8Hz,2H),7.03(d,J＝4.4Hz,1H),7.09(d,J＝7.6Hz,1H),7.31(d,J＝4.4Hz,1H),7.53-7.57(m,2H),7.70(dd,J＝8.4,1.6Hz,1H),7.85(d,J＝8.4Hz,2H),8.16(d,J＝7.2Hz,1H),9.53(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ184.4,162.2,136.4,133.1,131.5,128.8,127.7,127.6,126.9,125.6,125.2,124.9,123.5,113.4,113.1,101.6,55.4.
The reaction product 3g hydrogen spectrum is shown in figure 13 and the carbon spectrum is shown in figure 14.
Example 8
The synthesis method for 3h comprises the following steps: quinoline (0.4 mmol), acetophenone (0.4 mmol) and maleic anhydride (0.4 mmol) were added to the reaction tube, 4mL of N, N-dimethylacetamide solvent was added, then 0.04mmol of nickel bromide and 0.048mmol of 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine were added, respectively, after thoroughly mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen, and air was purged), and reacted for 6 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 75.7mg, yield: 70%. Mp:92-93 ℃. 1 H NMR(400MHz,CDCl 3 ):δ6.55(d,J＝4.4Hz,1H),7.20(d,J＝4.4Hz,1H),7.38-7.43(m,3H),7.48-7.54(m,3H),7.61(t,J＝7.6Hz,1H),7.71(dd,J＝8.0,1.2Hz,1H),8.06(dd,J＝8.0,1.2Hz,2H),8.17(d,J＝8.4Hz,1H). 13 C NMR(100MHz,CDCl 3 ):δ184.3,139.5,139.5,133.7,132.1,130.1,128.9,128.5,128.5,128.1,128.1,125.7,125.0,124.6,120.1,117.8,104.1.
The results of the 3h hydrogen spectrum of the product of the reaction are shown in FIG. 15, and the results of the carbon spectrum are shown in FIG. 16.
The above is only a preferred embodiment of the present application, and the protection scope of the present application is not limited to the above embodiment, and all technical solutions belonging to the concept of the present application belong to the protection scope of the present application. It should be noted that modifications and adaptations to those skilled in the art without departing from the principles of the present application are intended to be within the scope of the present application.
Claims (10)
1. A preparation method of a 3-substituted indolizine derivative is characterized in that the preparation method is shown in a route shown in a reaction formula 1,
wherein R is 1 A benzene ring selected from the group consisting of hydrogen, C1-C6 substituted or unsubstituted alkyl, ester, benzophenone, and one-side condensed with said pyridine ring; r is R 2 A benzene ring selected from hydrogen, halogen, C1-C6 alkoxy, and single-side condensed;
step 1, pyridine derivative structure as formula 1, acetophenone derivative structure as formula 2, nickel bromide, maleic anhydride, 2, 6-bis (4, 5-dihydro oxazol-2-yl) pyridine and reaction solvent are added into a reaction tube;
step 2, adding N, N-dimethylacetamide into a reaction tube, sealing the tube for reaction in a nitrogen atmosphere, and synthesizing to obtain a product mixture in one step;
and 3, extracting and filtering the product mixture obtained in the step 2 after the reaction in the step 3 is finished, and concentrating and separating the obtained filtrate to obtain the 3-substituted indolizine derivative with the structure shown in the formula 3.
2. The method for producing a 3-substituted indolizine derivative according to claim 1, wherein the chemical structure of the pyridine derivative is selected from any one of the following structural formulas:
3. the method for preparing 3-substituted indolizine derivatives according to claim 1, characterized in that the chemical structure of the acetophenone derivatives is selected from any one of the following structural formulas:
4. the method for producing a 3-substituted indolizine derivative according to claim 1, wherein the structural formula of the 3-substituted indolizine derivative comprises:
5. the method for producing a 3-substituted indolizine derivative according to claim 1, wherein the reaction condition shown in the reaction formula 1 is a reaction at normal temperature for 4 to 8 hours, and the reaction solvent is N, N-dimethylacetamide.
6. The method for producing a 3-substituted indolizine derivative according to claim 1, wherein a molar ratio of the pyridine derivative, the acetophenone derivative and the maleic anhydride added in the reaction represented by the reaction formula 1 is 1:1:1.
7. The method for producing a 3-substituted indolizine derivative according to claim 1, wherein a molar ratio of the pyridine derivative to the nickel bromide added in the reaction shown in the reaction formula 1 is 1:0.1.
8. The method for producing a 3-substituted indolizine derivative according to claim 1, wherein a molar ratio of the pyridine derivative to the 2, 6-bis (4, 5-dihydro-oxazol-2-yl) pyridine added in the reaction represented by the reaction formula 1 is 1:0.12.
9. The method for preparing 3-substituted indolizine derivatives according to claim 1, further comprising a step of separating and purifying the product after the reaction, wherein the step of separating and purifying is to concentrate the filtrate obtained by filtration in vacuum, and the obtained crude product is separated by column chromatography to obtain the 3-substituted indolizine derivatives as yellow solid.
10. The process for producing a 3-substituted indolizine derivative according to claim 1, characterized in that: in the step 3, the obtained crude product is separated by column chromatography to obtain a yellow solid 3-substituted indolizine derivative; wherein the yield of the 3-substituted indolizine derivative product is 62-80%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310238167.0A CN116283972A (en) | 2023-03-08 | 2023-03-08 | Preparation method of 3-substituted indolizine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310238167.0A CN116283972A (en) | 2023-03-08 | 2023-03-08 | Preparation method of 3-substituted indolizine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116283972A true CN116283972A (en) | 2023-06-23 |
Family
ID=86779218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310238167.0A Pending CN116283972A (en) | 2023-03-08 | 2023-03-08 | Preparation method of 3-substituted indolizine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116283972A (en) |
-
2023
- 2023-03-08 CN CN202310238167.0A patent/CN116283972A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114644614A (en) | Preparation method of levo-nicotine | |
| CN108558635B (en) | Preparation method of 3-aryl propiolic acid and 3-aryl propiolic acid ester compound | |
| CN112457339B (en) | Synthetic method of pyrrole [1,2-a ] quinoxaline derivative | |
| CN111808023B (en) | Method for preparing 3-aryl isoquinoline derivative | |
| CN116283972A (en) | Preparation method of 3-substituted indolizine derivative | |
| CN110204533B (en) | Preparation method of 4- (isochromen-1-yl) isoquinoline derivative | |
| JPS6046104B2 (en) | Method for producing butene derivatives | |
| CN115772157B (en) | Preparation method of 2-alkoxyindole compound | |
| CN107915653B (en) | Method for preparing amide by catalyzing ester and amine to react | |
| CN107353245B (en) | A kind of synthetic method of quinolines | |
| CN113912609B (en) | Preparation method of natural alkaloid tryptanthrin and derivatives thereof | |
| CN110606829A (en) | Method for synthesizing 4-substituted quinoline derivative under palladium catalysis | |
| CN106928119B (en) | A kind of preparation method of 5- cyano -3- (4- chlorobutyl)-indoles | |
| CN112661667B (en) | Preparation method of trifluoroacetamidine | |
| CN111018779B (en) | 2- (3-isoquinolyl) -ethyl propionate derivative and synthetic method thereof | |
| CN115010707A (en) | Process for preparing quinolopyrrole derivatives | |
| CN110372724B (en) | Preparation method of levofloxacin cycloate | |
| CN108586340B (en) | Synthesis method of 3-acyl hydrogenated azepine compound | |
| CN109836374B (en) | Environment-friendly preparation method of vitamin B6 | |
| CN111592481A (en) | Preparation method of polysubstituted pyrroline compound | |
| CN110655485A (en) | Preparation method of N-substituted indolone | |
| CN111100085A (en) | Preparation method of 3-aryl-2H-benzo [ β ] [1,4] benzoxazine-2-one compound | |
| CN115286568B (en) | Preparation method of 2-hydroxy-4-trifluoromethyl pyridine | |
| CN117418244A (en) | Preparation method for synthesizing 1, 2, 3 full-substituted indolizine derivative by electrochemical oxidation | |
| CN108794470B (en) | 6-hydrazino-1H-pyrazolo [3,4-b ] pyridine and synthesis method of downstream product thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |