CN115340553A - Pyrimido [1,2-b ] indazole derivative and preparation method and application thereof - Google Patents
Pyrimido [1,2-b ] indazole derivative and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- GFGFXJMTIXGYHF-UHFFFAOYSA-N pyrimido[1,2-b]indazole Chemical class C1=CC=NC2=C3C=CC=CC3=NN21 GFGFXJMTIXGYHF-UHFFFAOYSA-N 0.000 title claims description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- -1 3-aminoindazole compound Chemical class 0.000 claims abstract description 35
- 239000011968 lewis acid catalyst Substances 0.000 claims abstract description 10
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims abstract description 7
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 3
- 239000011790 ferrous sulphate Substances 0.000 claims description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- HWUPLUNLNUHIQZ-UHFFFAOYSA-N copper;trifluoromethanesulfonic acid Chemical compound [Cu].OS(=O)(=O)C(F)(F)F.OS(=O)(=O)C(F)(F)F HWUPLUNLNUHIQZ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 239000003054 catalyst Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 150000002473 indoazoles Chemical class 0.000 abstract 3
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000012043 crude product Substances 0.000 description 13
- YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 238000002390 rotary evaporation Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UEEJHVSXFDXPFK-UHFFFAOYSA-O N-dimethylethanolamine Chemical compound C[NH+](C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-O 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- GXSJBTNGASSDOQ-UHFFFAOYSA-N 2-phenylpyrimido[1,2-b]indazole Chemical class c1ccc(cc1)-c1ccn2nc3ccccc3c2n1 GXSJBTNGASSDOQ-UHFFFAOYSA-N 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 102000010909 Monoamine Oxidase Human genes 0.000 description 4
- 108010062431 Monoamine oxidase Proteins 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- TXQAZWIBPGKHOX-UHFFFAOYSA-N 1H-indol-3-amine Chemical compound C1=CC=C2C(N)=CNC2=C1 TXQAZWIBPGKHOX-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 1
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 1
- HUDYANRNMZDQGA-UHFFFAOYSA-N 1-[4-(dimethylamino)phenyl]ethanone Chemical compound CN(C)C1=CC=C(C(C)=O)C=C1 HUDYANRNMZDQGA-UHFFFAOYSA-N 0.000 description 1
- HHAISVSEJFEWBZ-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=C(C(F)(F)F)C=C1 HHAISVSEJFEWBZ-UHFFFAOYSA-N 0.000 description 1
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 description 1
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 1
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 238000002841 anti-cancer assay Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
- C07J71/0052—Nitrogen only at position 16(17)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a pyrimido [1,2-b ]]Indazole derivatives, and a preparation method and application thereof, wherein the preparation method comprises the following steps: reacting a 3-aminoindazole compound shown as a formula (II), a ketone compound shown as a formula (III) and an N, N-dimethyl amine compound shown as a formula (IV) under the action of a Lewis acid catalyst at a certain reaction temperature for a period of time, and purifying to obtain pyrimido [1,2-b ] shown as a formula (I)]Indazoles;
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a pyrimido [1,2-b ] indazole derivative, and a preparation method and application thereof.
Background
The pyrimido [1,2-B ] indazole derivatives are azatricyclo compounds with wide pharmacological activity, and the compounds containing the parent nucleus of the structure show good biological activity in the aspects of cancer resistance, anti-inflammation, antifungal, monoamine oxidase B (MAO-B) resistance and the like. For example, pyrimido [1,2-b ] indazole derivatives were found to have good activity against A-549 cells and better activity than etoposide in vitro anticancer activity evaluation (Synthesis and structure-activity relationships of novel pyrimida [1,2-b ] azoles as potential anticancer agents, available A-549 cells lines, bioorg.Med.Chem.Lett.,2007,17, 3445-3453). In addition, pyrimido [1,2-B ] indazole derivatives selectively inhibit MAO-B subtypes in a reversible and competitive manner, are non-toxic to S-SH5Y cells, and are potentially useful as anti-Parkinson drugs (Pyrimido [1,2-B ] indole derivatives: selective inhibitors of human monoamine oxidase B with neuropathic activity, euro.J.Med.Chem.2021,209, 112911). Based on the wide application prospect of the compounds in the field of medicine, the design and preparation of novel pyrimido [1,2-b ] indazole derivatives are concerned by more and more researchers.
For the preparation of pyrimido [1,2-b ] indazole derivatives, they are generally synthesized by condensation of 3-aminoindazole with α, β -unsaturated ketones or 1, 3-diketones:
the pyrimido [1,2-b ] indazole compound prepared by the method can only introduce aromatic groups at the 3-position or the 2, 4-position of a pyrimidine ring, and the product structure is single; recently, researchers have utilized photocatalytic methods to prepare 2-aryl substituted pyrimido [1,2-b ] indazoles (controlled site-selective chemistry of 2-and 4-substituted pyrimidines [1,2-b ] indole from 3-aminoindole and ynals, J.org.chem.2021,86, 9107-9116) from 3-aminoindazole and alkynal.
However, the alkynylaldehyde used in the method is not easy to obtain and needs to be prepared in two steps, the used catalyst bis (triphenylphosphine) palladium chloride is expensive, and the used solvent dichloromethane is a highly toxic solvent and is harmful to the environment; in addition, the two-step preparation method requires column chromatography for separation and purification, and is not suitable for industrial production.
Therefore, the development of a high-efficiency green preparation method with cheap and easily-obtained raw materials, low catalyst price and wide substrate universality is significant when the method is used for preparing pyrimido [1,2-b ] indazole derivatives.
Disclosure of Invention
The invention provides a preparation method of pyrimido [1,2-b ] indazole derivatives, which has the advantages of simple and easily-obtained raw materials, low catalyst price and wide substrate universality.
A pyrimido [1,2-b ] indazole derivative has a structure shown in a formula (I):
wherein,
R 1 is H or halogen or C 1-3 Alkyl, said halogen and C 1-3 Alkyl is optionally substituted by 1,2 or 3R a Substitution;
R 2 is aryl, heteroaryl or C 1-6 Alkyl, said aryl or heteroaryl being optionally substituted with 1 to 5 substituents; said C 1-6 Alkyl is optionally substituted by 1,2 or 3R b Substitution;
R 3 is H, C 1-3 Alkyl or aryl, said C 1-3 Alkyl or phenyl optionally substituted by 1,2 or 3R c Substitution;
R a 、R b 、R c are respectively and independently H, F, cl, br, I, C 1-6 Alkyl, cycloalkyl.
Preferably, the pyrimido [1,2-b ] indazole derivative has the following structure:
more preferably, the structural formula of the pyrimido [1,2-b ] indazole derivative is one of the following formulas:
experimental results show that the pyrimido [1,2-b ] indazole derivative obtained by the invention has certain antitumor activity.
The invention also provides a preparation method of the pyrimido [1,2-b ] indazole derivative, which comprises the following steps:
reacting a 3-aminoindazole compound shown in a formula (II), a ketone compound shown in a formula (III) and an N, N-dimethyl amine compound shown in a formula (IV) for a period of time at a certain reaction temperature under the action of a Lewis acid catalyst, and purifying to obtain a pyrimido [1,2-b ] indazole compound shown in a formula (I);
wherein,
R 1 is H or halogen or C 1-3 Alkyl, said halogen and C 1-3 Alkyl is optionally substituted by 1,2 or 3R a Substitution;
R 2 is aryl, heteroaryl or C 1-6 Alkyl, said aryl or heteroarylThe substituent is 1-5, the 1-5 substituents are respectively and independently H, F, cl, br, I and NO 2 、NMe 2 Me, OMe, et, t-Bu or CF3; said C 1-6 Alkyl is optionally substituted by 1,2 or 3R b Substitution;
R 3 is H, C 1-3 Alkyl or aryl, said C 1-3 Alkyl or aryl optionally substituted by 1,2 or 3R c Substitution;
R a 、R b 、R c are respectively and independently H, F, cl, br, I, C 1-6 Alkyl or cycloalkyl.
The reaction process is as follows:
the pyrimido [1,2-b ] indazole compound shown in the formula (I) is prepared by a one-pot method, and the yield can reach 85 percent at most; compared with the prior art, the method has the advantages that the used starting raw materials are simple in structure, cheap and easily available, the catalyst is low in price, the use of a heavy metal catalyst is eliminated, and the heavy metal pollution in medical chemicals is avoided from the source; the substrate has wide applicability, and has good application value and potential social and economic benefits.
Preferably, said R is 1 And R 3 When both are H, the R 2 Not being unsubstituted aryl, 4-CH 3 、4-O-CH 3 4-Cl and 4-Br substituted phenyl.
Optionally, the Lewis acid catalyst is cupric chloride, ferric chloride, zinc chloride, nickel chloride, ferrous sulfate, cuprous bromide or copper trifluoromethanesulfonate.
Optionally, the molar ratio of the 3-aminoindazole compound shown in the formula (II), the ketone compound shown in the formula (III), the N, N-dimethyl amine compound shown in the formula (IV) and the Lewis acid catalyst is 1-3.
Optionally, the molar ratio of the 3-aminoindazole compound shown in the formula (II), the ketone compound shown in the formula (III), the N, N-dimethyl amine compound shown in the formula (IV) and the Lewis acid catalyst is 1-2-20.
Furthermore, the molar ratio of the 3-aminoindazole compound shown in the formula (II), the ketone compound shown in the formula (III), the N, N-dimethyl amine compound shown in the formula (IV) and the Lewis acid catalyst is 1.
Optionally, the purifying comprises: extracting the obtained reaction liquid by ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, removing the solvent by rotary evaporation to obtain a crude product, and recrystallizing the crude product by ethyl acetate/petroleum ether.
Optionally, the reaction temperature is 20-140 ℃, and the reaction time is 1-30 h.
Optionally, the reaction temperature is 120-140 ℃, and the reaction time is 25-30 h.
Further, the reaction temperature was 140 ℃ and the reaction time was 30 hours.
The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds are referred to by the supplier's catalog name.
Compared with the prior preparation method, the invention has at least one of the following beneficial effects:
(1) The preparation method takes a simple compound which is cheap and easy to obtain as a starting raw material, takes ferric chloride which is cheap as a catalyst, and obtains the pyrimido [1,2-b ] indazole derivative through one-step reaction, and the atom economy is high.
(2) The used catalyst has low price, the dosage can be reduced to 20mol%, no other solvent is used, and the generated three wastes are relatively less; is environment-friendly and accords with the green chemical concept.
(3) The purification process is simple and meets the requirement of industrial production.
(4) The reaction substrate has wide universality, and the product has rich and various structures and better application value.
Detailed Description
The technical solutions of the present application will be described clearly and completely with reference to the embodiments of the present application, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
Example 1: preparation of 2-phenylpyrimidino [1,2-b ] indazoles (Ia)
3-aminoindazole (133mg, 1mmol), acetophenone (120mg, 1mmol), N-dimethylethanolamine (1.8g, 20mmol) and iron chloride (32mg, 0.2mmol) were added to a closed-tube reactor and stirred at 140 ℃ for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give the crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2-phenylpyrimidino [1,2-b ] indazole (Ia) as a yellow solid 199mg, m.p.: 139.5-140.7 ℃, yield: 79 percent.
Ia structural formula is:
1 H NMR(400MHz,CDCl 3 ):δ8.97(d,J＝7.2Hz,1H),8.38(d,J＝8.4Hz,1H),8.24-8.19(m,2H),7.83(d,J＝8.8Hz,1H),7.68-7.61(m,2H),7.59-7.48(m,3H),7.31(t,J＝8.0Hz,1H). 13 C NMR(101MHz,CDCl 3 ):δ152.9,151.6,143.8,137.0,133.9,130.5,130.2,129.2,127.3,121.2,121.0,116.3,113.9,109.0.ESI-MS:m/z[M+H] + 246.
example 2: preparation of 2- (4-methyl) phenyl pyrimido [1,2-b ] indazole (Ib)
3-aminoindazole (133mg, 1mmol), p-toluoylene (134mg, 1mmol), N-dimethylethanolamine (1.8g, 20mmol) and copper chloride (27mg, 0.2mmol) were added to a closed-tube reactor, and a reaction was stirred at 140 ℃ for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give a crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-methyl) phenylpyrimidino [1,2-b ] indazole (Ib) as a yellow solid 182mg, melting point: 157.7-158.9 ℃, yield: 75 percent.
Ib has a structural formula:
1 H NMR(400MHz,CDCl 3 ):δ8.96(d,J＝7.2Hz,1H),8.37(d,J＝8.4Hz,1H),8.12(d,J＝8.0Hz,2H),7.82(d,J＝8.8Hz,1H),7.66–7.61(m,2H),7.35(d,J＝8.0Hz,2H),7.30(t,J＝7.2Hz,1H),2.45(s,3H). 13 C NMR(101MHz,CDCl 3 ):δ153.1,151.9,143.9,140.9,134.3,133.9,130.1,130.0,127.2,121.3,120.8,116.2,113.9,108.8,21.6.ESI-MS:m/z[M+H] + 260.
example 3: preparation of 2- (4-methoxy) phenyl pyrimido [1,2-b ] indazole (Ic)
3-aminoindazole (133mg, 1mmol), p-oxyacetophenone (150mg, 1mmol), N-dimethylethanolamine (1.8g, 20mmol) and cuprous bromide (29mg, 0.2mmol) were added to a closed-tube reactor and stirred at 140 ℃ for reaction for 30 hours, and after completion of the TLC detection reaction, the reaction was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give the crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-methoxy) phenylpyrimidino [1,2-b ] indazole (Ic) as a yellow solid 184mg, melting point: 167.7-168.9 ℃, yield: 70 percent.
Ic is of the formula:
1 H NMR(400MHz,CDCl 3 ):δ8.90(d,J＝7.2Hz,1H),8.35(d,J＝8.4Hz,1H),8.17(d,J＝8.8Hz,2H),7.80(d,J＝8.8Hz,1H),7.61(t,J＝7.6Hz,1H),7.57(d,J＝7.6Hz,1H),7.28(t,J＝7.6Hz,1H),7.04(d,J＝8.8Hz,2H),3.89(s,3H). 13 C NMR(101MHz,CDCl 3 )δ161.6,152.6,151.8,143.7,133.7,129.9,129.5,128.7,121.1,120.5,116.1,114.5,113.7,108.3,55.5.ESI-MS:m/z[M+H] + 276.
example 4: preparation of 2- (4-dimethylamino) phenylpyrimidino [1,2-b ] indazole (Id)
3-aminoindazole (133mg, 1mmol), 4-dimethylaminoacetophenone (163mg, 1mmol), N-dimethylethanolamine (1.8g, 20mmol) and ferrous sulfate (31mg, 0.2mmol) were added to a closed-tube reactor, and the reaction was stirred at 140 ℃ for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give a crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-dimethylamino) phenylpyrimidino [1,2-b ] indazole (Id) as a yellow solid, 95mg, mp: 156.7-157.9 ℃, yield: 35 percent.
Id is of the formula:
1 H NMR(400MHz,CDCl 3 ):δ8.85(d,J＝7.4Hz,1H),8.34(d,J＝8.4Hz,1H),8.14(d,J＝8.8Hz,2H),7.78(d,J＝8.8Hz,1H),7.59(t,J＝7.6Hz,1H),7.56(d,J＝7.6Hz,1H),7.25(t,J＝7.4Hz,1H),6.81(d,J＝8.8Hz,2H),3.07(s,6H). 13 C NMR(101MHz,CDCl 3 )δ153.5,151.9,151.8,143.9,133.5,129.7,128.4,124.3,121.2,120.1,115.9,113.5,112.0,108.0,40.2.HRMS(ESI):calcd.for C 18 H 17 N 4 +[M+H] + 289.1448；found 289.1444.
example 5: preparation of 2- (4-chloro) phenyl pyrimido [1,2-b ] indazole (Ie)
3-aminoindazole (133mg, 1mmol), p-chloroacetophenone (155mg, 1mmol), N-dimethylethanolamine (1.8g, 20mmol) and zinc chloride (20mg, 0.2mmol) were added to a closed-tube reactor and stirred at 140 ℃ for reaction for 30 hours, and after completion of the TLC detection reaction, the reaction was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give a crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-chloro) phenylpyrimidino [1,2-b ] indazole (Ie) as a yellow solid of 182mg melting point: 136.6-137.8 ℃, yield: 66 percent.
Ie has the structural formula:
1 H NMR(400MHz,CDCl 3 ):δ8.99(d,J＝7.2Hz,1H),8.37(d,J＝8.4Hz,1H),8.18(d,J＝8.4Hz,2H),7.84(d,J＝8.8Hz,1H),7.71–7.60(m,2H),7.53(d,J＝8.4Hz,2H),7.33(t,J＝7.2Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ152.0,151.3,143.6,136.6,135.4,133.9,130.2,129.3,128.4,121.1,116.3,113.8,108.5.ESI-MS:m/z[M+H] + 280.
example 6: preparation of 2- (4-bromo) phenyl pyrimido [1,2-b ] indazole (If)
3-aminoindazole (133mg, 1mmol), p-bromoacetophenone (200mg, 1mmol), N-dimethylethanolamine (1.8g, 20mmol) and copper trifluoromethanesulfonate (72mg, 0.2mmol) were added to a closed-tube reactor, and stirred at 140 ℃ for reaction for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give a crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-bromo) phenylpyrimidino [1,2-b ] indazole (If) as a yellow solid, 220mg, melting point: 148.9-149.9 ℃, yield: 61 percent.
If structural formula is:
1 H NMR(400MHz,CDCl 3 ):δ9.00(d,J＝7.2Hz,1H),8.37(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,2H),7.84(d,J＝8.8Hz,1H),7.71-7.55(m,4H),7.32(t,J＝8.4Hz,1H). 13 C NMR(101MHz,CDCl 3 ):δ152.0,151.6,143.8,135.9,134.0,132.4,130.3,128.8,125.2,121.3,121.2,116.4,114.0,108.6.ESI-MS:m/z[M+H] + 324.
example 7: preparation of 2- (4-trifluoromethyl) phenylpyrimidino [1,2-b ] indazole (Ig)
3-aminoindazole (133mg, 1mmol), p-trifluoromethylacetophenone (189mg, 1mmol), N-dimethylethanolamine (180mg, 2mmol), ferric chloride (32mg, 0.2mmol) and DMF (2 mL) were added to a closed-tube reactor, stirred at 140 ℃ for reaction for 30 hours, and after the completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give a crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-trifluoromethyl) phenylpyrimidino [1,2-b ] indazole (Ig) as a yellow solid 158mg, melting point: 158.9-159.9 ℃, yield: and 55 percent.
The Ig structural formula is:
1 H NMR(400MHz,CDCl 3 ):δ9.02(d,J＝7.2Hz,1H),8.39(d,J＝8.4Hz,1H),8.34(d,J＝8.4Hz,2H),7.86(d,J＝8.8Hz,1H),7.81(d,J＝8.4Hz,2H),7.35(t,J＝7.4Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ152.0,150.7,143.6,140.2,133.9,131.9(q,J＝32.6Hz),130.3,127.4,126.0(q,J＝32.6Hz),124.0(q,J＝271Hz),121.3,121.0,116.4,114.0,108.7.HRMS(ESI):calcd.for C 17 H 11 F 3 N 3 + [M+H] + 314.0900；found 314.0891.
example 8: preparation of 2- (Naphthalen-1-yl) phenyl pyrimido [1,2-b ] indazole (Ih)
3-aminoindazole (133mg, 1mmol), 1-acetonaphthone (170mg, 1mmol), N-dimethylethanolamine (180mg, 2mmol), ferric chloride (32mg, 0.2mmol) and DMSO (2 mL) were added to a closed-tube reactor, stirred at 140 ℃ for reaction for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give a crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (4-trifluoromethyl) phenylpyrimidino [1,2-b ] indazole (Ih) as a yellow solid 198mg, m.p.: 156.0-158.0 ℃, yield: 65 percent. The structural formula of Ih is:
1 H NMR(400MHz,CDCl 3 ):δ9.07(d,J＝7.2Hz,1H),8.40(d,J＝8.4Hz,1H),8.34–8.31(m,1H),8.01(d,J＝8.4Hz,1H),7.98–7.93(m,1H),7.89(d,J＝8.8Hz,1H),7.81(d,J＝7.2Hz,1H),7.69–7.52(m,5H),7.34(t,J＝8.0Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ155.0,151.9,143.6,136.1,134.1,133.5,130.8,130.2,130.1,128.7,128.3,127.2,126.4,125.4,125.2,121.1,121.0,116.3,113.8,113.6.HRMS(ESI):calcd.for C 20 H 14 N 3 + [M+H] + 296.1182；found 296.1178.
example 9: preparation of 2- (pyridin-2-yl) phenyl pyrimido [1,2-b ] indazoles (Ii)
3-aminoindazole (133mg, 1mmol), 2-acetylpyridine (189mg, 1mmol), N, N-tetramethylethylenediamine (2.32g, 20mmol) and ferric chloride (32mg, 0.2mmol) were added to a closed-tube reactor, and the reaction was stirred at 140 ℃ for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give the crude product which was recrystallized from ethyl acetate/petroleum ether to give the desired 2- (pyridin-2-yl) phenylpyrimidino [1,2-b ] indazole (Ii) as a yellow solid 155mg, melting point: 156.0-158.0 ℃, yield: 54 percent.
Ii has the structural formula:
1 H NMR(400MHz,CDCl 3 ):δ9.03(d,J＝7.2Hz,1H),8.74–8.71(m,2H),8.43(d,J＝7.6Hz,1H),8.39(d,J＝8.0Hz,1H),7.91(td,J＝8.0,1.2Hz,1H),7.87(d,J＝8.4Hz,1H),7.65(t,J＝7.2Hz,1H),7.39(dd,J＝5.6,7.2Hz,1H),7.35(t,J＝7.6Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ154.1,151.9,151.8,149.40,143.4,137.1,133.8,130.0,124.7,121.6,121.1,121.0,116.4,114.0,109.3.HRMS(ESI):calcd.for C 15 H 11 N 4 + [M+H] + 247.0978；found 247.0975.
examples 10 to 26:
3-aminoindazole (1 mmol), aromatic or aliphatic ketone (1 mmol), N-dimethylethanolamine (1.8mg, 20mmol) and iron chloride (32mg, 0.2mmol) were added to a closed-tube reactor and stirred at 140 ℃ for reaction for 30 hours, and after completion of the TLC detection reaction, the reaction system was cooled to room temperature, 10mL of water was added, and extracted 2 times with ethyl acetate (10 mL). Drying an organic phase by using anhydrous sodium sulfate, removing the solvent by rotary evaporation to obtain a crude product, recrystallizing the crude product by using ethyl acetate/petroleum ether to obtain the required phenyl pyrimido [1,2-b ] indazole (I), wherein the reaction formula is shown as the following formula; the product formula and yield are shown in table 1.
TABLE 1
Results of biological Activity test
Lung cancer cell strain A-549 and liver cancer Bel-7402 inhibitor
8 compounds (Ia, ic, id, ih, ij, in, it, iu) were selected to evaluate the ability of the compounds of the present application to inhibit lung cancer A-549 and liver cancer Bel-7402. The method comprises calculating the inhibition rate of the substance on the growth of cancer cells, and half the inhibition IC by CCK-8 method 50 The values were calculated using the Logit method. The experiment is repeated for 2-3 times, and the average IC of multiple experiments is calculated 50 The value serves as the final indicator of the inhibition capacity. The results are shown in Table 2.
TABLE 2
| Compound (I) | IC 50 for A549(μmol/L) | IC 50 for Bel-7402(μmol/L) |
| Ia | 203 | 220 |
| Ic | 85 | 63 |
| Ih | 254 | 146 |
| Ij | 82 | 99 |
| In | 94 | 126 |
| Ip | 41 | 48 |
| It | 11 | 22 |
| Iu | 34 | 31 |
The above-mentioned embodiments only express several embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, and these are all within the scope of protection of the present application. Therefore, the protection scope of the present patent application shall be subject to the appended claims.
Claims (10)
1. A process for preparing a pyrimido [1,2-b ] indazole derivative, comprising:
reacting a 3-aminoindazole compound shown in a formula (II), a ketone compound shown in a formula (III) and an N, N-dimethyl amine compound shown in a formula (IV) for a period of time at a certain reaction temperature under the action of a Lewis acid catalyst, and purifying to obtain a pyrimido [1,2-b ] indazole compound shown in a formula (I);
wherein,
R 1 is H or halogen or C 1-3 Alkyl, said C 1-3 Alkyl is optionally substituted by 1,2 or 3R a Substitution;
R 2 is aryl, heteroaryl or C 1-6 Alkyl, said aryl or heteroaryl being optionally substituted with 1-5 substituents, said 1-5 substituents each being independently H, F, cl, br, I, NO 2 、NMe 2 Me, OMe, et, t-Bu or CF3; said C 1-6 Alkyl is optionally substituted by 1,2 or 3R b Substitution;
R 3 is H, C 1-3 Alkyl or aryl, said C 1-3 Alkyl or aryl optionally substituted by 1,2 or 3R c Substitution;
R a 、R b 、R c are respectively and independently H, F, cl, br, I, C 1-6 Alkyl or cycloalkyl.
2. The method of claim 1, wherein the Lewis acid catalyst is selected from the group consisting of cupric chloride, ferric chloride, zinc chloride, nickel chloride, ferrous sulfate, cuprous bromide, and cupric trifluoromethanesulfonate.
3. The preparation method according to claim 1, wherein the molar ratio of the 3-aminoindazole compound represented by formula (II), the ketone compound represented by formula (III), the N, N-dimethylamine compound represented by formula (IV) and the Lewis acid catalyst is 1 to 3.
4. The preparation method according to claim 1, wherein the molar ratio of the 3-aminoindazole compound represented by the formula (II), the ketone compound represented by the formula (III), the N, N-dimethylamine compound represented by the formula (IV) and the Lewis acid catalyst is 1.
5. The method according to claim 1, wherein the reaction temperature is 20 to 140 ℃ and the reaction time is 1 to 30 hours.
6. The method according to claim 1, wherein the reaction temperature is 120 to 140 ℃ and the reaction time is 25 to 30 hours.
7. A pyrimido [1,2-b ] indazole derivative is characterized by having a structure shown in a formula (I):
wherein R is 1 Is H or halogen or C 1-3 Alkyl radical, said C 1-3 Alkyl is optionally substituted by 1,2 or 3R a Substitution;
R 2 is aryl, heteroaryl or C 1-6 Alkyl, said aryl or heteroaryl being optionally substituted with 1-5 substituents, said 1-5 substituents each being independently H, F, cl, br, I, NO 2 、NMe 2 Me, OMe, et, t-Bu or CF3; said C 1-6 Alkyl is optionally substituted by 1,2 or 3R b Substitution;
R 3 is H, C 1-3 Alkyl or aryl, said C 1-3 Alkyl or aryl optionally substituted by 1,2 or 3R c Substitution;
R a 、R b 、R c are respectively and independently H, F, cl, br, I, C 1-6 Alkyl or cycloalkyl.
8. The pyrimido [1,2-b ] indazole derivative of claim 7, having the structural formula one of:
9. the pyrimido [1,2-b ] indazole derivative of claim 7, having the structural formula one of:
10. use of a pyrimido [1,2-b ] indazole derivative according to any one of claims 7-9 for the preparation of a medicament for the prevention or treatment of tumors.
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