CN111217654A - Palladium-catalyzed meta-arylation reaction and application thereof in synthesis of vemurafenib analogue - Google Patents
Palladium-catalyzed meta-arylation reaction and application thereof in synthesis of vemurafenib analogue Download PDFInfo
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- 238000006254 arylation reaction Methods 0.000 title claims abstract description 25
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 21
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical class CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims abstract description 14
- CYMDPTJBUBTWEY-UHFFFAOYSA-N 5-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound IC1=CN=C2NC=CC2=C1 CYMDPTJBUBTWEY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010499 C–H functionalization reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000000758 substrate Substances 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000654 additive Substances 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 6
- 150000001502 aryl halides Chemical class 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims abstract description 6
- -1 aromatic ring compound Chemical class 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- 230000008878 coupling Effects 0.000 claims abstract description 3
- 238000010168 coupling process Methods 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 9
- 238000004809 thin layer chromatography Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- HGFMFKSDOFFKRV-UHFFFAOYSA-N 8h-pyrano[2,3-h]quinoline Chemical group C1=CC=NC2=C(C=CCO3)C3=CC=C21 HGFMFKSDOFFKRV-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 5
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 5
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 4
- 229940071536 silver acetate Drugs 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- SKGRFPGOGCHDPC-UHFFFAOYSA-N 1-iodo-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(I)C=C1 SKGRFPGOGCHDPC-UHFFFAOYSA-N 0.000 claims description 3
- UDHAWRUAECEBHC-UHFFFAOYSA-N 1-iodo-4-methylbenzene Chemical compound CC1=CC=C(I)C=C1 UDHAWRUAECEBHC-UHFFFAOYSA-N 0.000 claims description 3
- ULMSEXZJAKWUQX-UHFFFAOYSA-N 5-iodo-1-(4-methylphenyl)sulfonylindole Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CC=C(I)C=C2C=C1 ULMSEXZJAKWUQX-UHFFFAOYSA-N 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 3
- 150000002848 norbornenes Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229940124530 sulfonamide Drugs 0.000 claims description 3
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 claims description 2
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical group CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims 6
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 2
- 239000001294 propane Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 229910052723 transition metal Inorganic materials 0.000 abstract description 5
- 150000003624 transition metals Chemical class 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000011261 inert gas Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- 230000005526 G1 to G0 transition Effects 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 7
- 230000000704 physical effect Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
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- 238000012544 monitoring process Methods 0.000 description 5
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- 238000003756 stirring Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241001120493 Arene Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 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
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- UHSMYBHUSYABFW-UHFFFAOYSA-N n-(2-oxo-1h-pyridin-3-yl)acetamide Chemical compound CC(=O)NC1=CC=CN=C1O UHSMYBHUSYABFW-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
Abstract
The invention relates to a palladium-catalyzed meta-arylation reaction and application thereof in synthesis of a vemurafenib analogue, which overcome the problems that byproducts are introduced in the reaction in the prior art, direct synthesis cannot be realized, and the production cost is high, realize direct C-H activation conversion of transition metal catalysis, and have the advantages of controllability, accuracy, high efficiency, no need of inert gas protection in the synthesis process, simple operation, low production cost and little environmental pollution. The technical scheme adopted by the invention is as follows: taking 0.25mmol of aromatic ring compound as a substrate, taking 10 mol% palladium acetate as a catalyst, taking 1-1.5 equivalents of norbornene as a medium, adding 3equiv of additive, adding 5-10 mol% of ligand, 1mL of benzotrifluoride and dichloroethane as a medium, coupling with 0.38mmol of aryl halide, and reacting at 80-120 ℃ for 12-24 h to obtain the 5-iodo-7-azaindole as a 5-position arylation product.
Description
The technical field is as follows:
the invention relates to a method for activating and converting meta-C-H, in particular to a palladium-catalyzed meta-arylation reaction and application thereof in synthesis of a vemurafenib analogue.
Background art:
control of regioselectivity is a key issue for transition metal catalyzed C — H functionalization. When the substrate molecule contains multiple C-H, it is important to control the reaction site. There have been many examples of successful ortho-directed C-H functionalization catalyzed by transition metals Pd (II), Rh (III), Ru (II), Ir (III), etc. [ T.W. Lyons, et.al.chem.Rev.2010,110,1147], whereas relatively few transition metal-catalyzed meta C-H functionalisations have been reported. The mechanism can be roughly divided into three types: substrate control, catalyst control, and other factors. (1) Substrate control includes controlling the reaction to occur in the meta position using steric hindrance, electronic effects [ c.cheng, et al. science 2014,343,853] or a Directing Group (DG) of the substrate. Typical representatives of this strategy are the complement right and the pioti design of U-type template directing groups that pioneering the meta and para C-H activation of arenes [ D.Leow, et.al.Nature, 2012,486,518], other directing group strategies including meta C-H activation of carboxylic acids as traceless directing groups [ M.Font, et.al.chem.Commun.2017, 53,5584] and norbornene (norbomene: NBE) as transient directing groups [ X. -C.Wang, et.al.Nature 2015,519,334 ]. (2) Catalyst control includes Cu [ r.j.phipps, et.al.science 2009,323,1593] and Ru [ o.saidi, et.al.j.am.chem.soc.2011,133,19298] transition metal catalysts and sterically bulky ligand controlled meta C-H functionalization. (3) Other factors include Ir catalyzed meta-boronation as facilitated by hydrogen bonding between the substrate and the catalyst.
Inspired by the native and ortho tandem coupling reactions of aryl iodides cooperatively catalyzed by Pd and norbornene reported by Catellani et al [ m.catellani, et al.angelw.chem.int.ed.engl.1997, 36,119 ], recently, the combination of C-H bond activation promoted by a targeting group and Catellani reaction successfully achieved functionalization of C-H in the meta-position of aromatics. The problem group of Dongbin reported that arylation reaction of meta-position of aromatic hydrocarbon mediated by norbornene with tertiary amine as a directing group [ Z.Dong, et.al.J.am. chem.Soc.2015,137,5887 ]. The authors found that the "acetic acid cocktail" can significantly increase the reaction rate, acetic acid can dissociate the coordination of the directing group and Pd by protonation, acetate ions contribute to the deprotonation metallization process, both additions contribute to the insertion of olefins, and the pyridine 3-arylation product is obtained in good yield; ligands play a key role in this approach because they act synergistically with many targeting groups to promote C-H activation, yet avoid some potential side reactions. The project group of the remaining gold rights obtains good application in the arylation of indole and pyridine meta-position by optimizing the multifunctional ligand 3-acetamido-2-hydroxypyridine and utilizing norbornene as a transient medium [ P.Wang, et.al.J.am.chem.Soc.2016, 138,9269 ]
The 7-azaindole is used as a key member in an azaindole family, the skeleton of the 7-azaindole is widely present in core structural units of active natural products and drug molecules, and researches show that the compounds have important biological activities such as cancer resistance, antibiosis, diabetes resistance and the like, so that the pharmaceutical chemistry family usually uses the compounds containing the 7-azaindole skeleton as lead compounds to carry out structural modification and modification on the compounds, and searches for drugs with more ideal curative effects by analyzing the structure-activity relationship with targets.
The invention further improves and optimizes the rest reported meta-position arylation reaction [ P.Wang, et.al.J.am.chem.Soc. 2016,138,9269 ], adopts new ligands and solvents to realize the meta-position arylation reaction, and applies the method to 7-azaindole to realize the synthesis of the Verofinib analogue by a brand new method.
The invention content is as follows:
the invention aims to provide a palladium-catalyzed meta-position arylation reaction and application thereof in synthesis of a vemurafenib analogue, which overcome the problems that byproducts can be introduced in the reaction in the prior art, direct synthesis cannot be realized, and the production cost is high, realize direct C-H activation conversion of transition metal catalysis, and have the advantages of controllability, accuracy, high efficiency, no need of inert gas protection in the synthesis process, simple operation, low production cost and small environmental pollution.
In order to achieve the purpose, the invention adopts the technical scheme that:
a palladium-catalyzed meta-arylation reaction and application thereof in synthesis of a vemurafenib analogue are characterized in that: taking 0.25mmol of aromatic ring compound as a substrate, taking 10 mol% palladium acetate as a catalyst, taking 1-1.5 equivalents of norbornene as a medium, adding 3equiv of additive, adding 5-10 mol% of ligand, 1mL of benzotrifluoride and dichloroethane as a medium, coupling with 0.38mmol of aryl halide, and reacting at 80-120 ℃ for 12-24 h to obtain the 5-iodo-7-azaindole as a 5-position arylation product.
The aromatic ring compound comprises acetamido-substituted aromatic hydrocarbon.
Aryl halides include iodobenzene, 4-methyl iodobenzene, 4-trifluoromethyl iodobenzene, 4-methoxy-iodobenzene, N-p-methylbenzenesulfonyl 5-iodoindole, 5-iodo-7 azaindole or 3-acyl-5-iodo-7-azaindole.
The norbornenes include norbornene or 2-oxycarbonyl norbornene.
The ligand is pyranoquinoline, pyridine, pyridone or quinoline.
The solvent is chlorobenzene, dichloroethane, toluene, DMSO, acetonitrile or DCE.
The additive is silver trifluoromethanesulfonate, silver acetate or silver carbonate.
The method for preparing the aromatic ring-based tandem C-H activation synthesis of the vemurafenib analogue by using the 7-azaindole 5-position arylation product 5-iodo-7-azaindole is characterized in that: the subsequent treatment process comprises the following steps: accurately weighing 0.25mmol of the prepared 5-iodo-7-azaindole, 0.38mmol of N- (3-5-difluoro-4-formylphenyl) propyl-1-sulfonamide, 3equiv of potassium carbonate and methanol in sequence at room temperature; and sequentially adding the measured reactants into a 25mL pressure-resistant pipe filled with magnetons, sealing the pressure-resistant pipe, stirring on a magnetic stirrer at room temperature, slowly heating to 108 ℃, and monitoring the reaction process by using thin-layer chromatography. Stopping the reaction after 12 hours under the pressure of 0.1MPa, cooling to room temperature, removing redundant solvent by using a rotary evaporator, separating residues by using column chromatography, and purifying and separating products by using 300-400-mesh silica gel as a stationary phase and using mixed solvents of ethyl acetate and petroleum ether in different proportions as eluents.
Compared with the prior art, the invention has the following advantages and effects:
1. the invention introduces guide groups (acetyl and amido) into a substrate, and realizes the arylation reaction with 7-azaindole through the activation of serial C-H bonds catalyzed by Pd under the action of transient medium of norbornene to construct the core skeleton of a drug molecule.
2. Meanwhile, on the premise of the prepared core framework, Vemurafenib analogue is synthesized by series C-H activation for the first time; the reaction process can be carried out in an air atmosphere without inert gas protection, and the synthesis process is simple to operate; shortening the reaction steps and having great potential application prospect.
3. After the reaction, the intermediate is further structurally modified, so that the high-efficiency synthesis of the drug and the drug-like molecules is realized, and more potential antitumor drugs can be screened out. Provides diversification and huge cost advantage for drug design and implementation, and enriches drug compound libraries.
The specific implementation mode is as follows:
in order to further understand the present invention, the following examples are further illustrated, which are only used for explaining the present invention and are not to be construed as limiting the scope of the present invention.
Aromatic hydrocarbons are used as a substrate, palladium acetate is used as a catalyst, norbornene is used as a medium, pyridone is used as a ligand (5 mol% -20 mol%) norbornene (1equiv-1.5equiv) is used as a medium, silver acetate is used as an additive, the aromatic hydrocarbons and aryl halides are coupled, the reaction is carried out for 12-24 hours at the temperature of 80-120 ℃, and a 7-azaindole 5-position arylation product is obtained through subsequent treatment.
The reaction equation is as follows:
specific examples are as follows.
Example 1
Accurately weighing acetylamino-substituted aromatic hydrocarbon (0.25mmol,0.25mmol88mg), 4-methyl iodobenzene (0.38mmol,0.38mmol83mg), pyranoquinoline (10 mol%, 10 mol% 5g), palladium acetate (10 mol%, 6g), (10 mol%), silver acetate (3equiv,3equiv 125g), 2-oxycarbonyl norbornene (1.5equiv,)1.5equiv and trifluorotoluene (2.0mL) in this order at room temperature; and sequentially adding the measured reactants into a 25mL pressure-resistant pipe filled with magnetons, sealing the pressure-resistant pipe, stirring on a magnetic stirrer at room temperature, slowly heating to 90 ℃, and monitoring the reaction process by using thin-layer chromatography. The reaction was stopped after 20h at 0.1MPa, cooled to room temperature, the mixture was extracted with diethyl ether (10 mL. times.3), the organic phases were combined, excess solvent was removed by rotary evaporator, the residue was chromatographed using column chromatography, the product was purified using 300 mesh silica gel as the stationary phase and a mixed solvent of ethyl acetate and petroleum ether in different proportions as the eluent.
The physical properties and characterization data of the obtained compounds are as follows:
white solid:1H NMR(500MHz,acetone-d6)δ9.55(br,1H,N-H),7.63 (d,J＝2.0Hz,1H),7.54(d,J＝8.0Hz,2H),7.47(dd,J＝7.5,1.8Hz, 1H),7.33(m,1H),7.28(d,J＝8.5Hz,1H),7.26(d,J＝8.5Hz,2H), 3.98(s,2H),2.35(s,3H).
13C NMR(125MHz,acetone-d6)δ169.59,139.62,138.63,137.62,136.92, 135.21,134.82,131.63,130.32,129.51,127.34,126.31,41.42,19.30.
example 2
Accurately weighing, in order, acetamido-substituted aromatic hydrocarbon (0.25mmol,0.25mmol88mg), 4-trifluoromethyl iodobenzene (0.38mmol,0.38mmol103mg), pyranoquinoline (10 mol% ), palladium acetate (10 mol%, 10 mol% 6g), silver triflate (3equiv,3equiv193g), 2-oxycarbonyl norbornene (1.5equiv,) and chlorobenzene (2.0mL) at room temperature; and sequentially adding the measured reactants into a 25mL pressure-resistant pipe filled with magnetons, sealing the pressure-resistant pipe, stirring on a magnetic stirrer at room temperature, slowly heating to 110 ℃, and monitoring the reaction process by using thin-layer chromatography. Stopping the reaction after 22h under 0.1MPa, cooling to room temperature, extracting the mixture with diethyl ether (10mL multiplied by 3), combining organic phases, removing excessive solvent by using a rotary evaporator, separating residues by using column chromatography, and purifying and separating the product by using 300-400 mesh silica gel as a stationary phase and using a mixed solvent of ethyl acetate and petroleum ether in different proportions as an eluent.
The physical properties and characterization data of the obtained compounds are as follows:
brown solid:1H NMR(500MHz,acetone-d6)δ9.59(br,1H,N-H),7.88 (d,J＝8.0Hz,2H),7.79(d,J＝8.2Hz,2H),7.73(d,J＝1.5Hz,1H), 7.58(dd,J＝8.0,2.0Hz,1H),7.43(m,3H),7.36(d,J＝7.5Hz,1H), 4.03(s,2H).
13C NMR(125MHz,acetone-d6)δ169.43,145.42,138.60,137.98,135.28, 131.89,130.05,129.43(q,J＝32Hz),128.13,126.83,126.58(q,J＝ 4.0Hz),125.51(q,J＝270Hz),41.28.
19F NMR(376MHz,acetone-d6)δ-56.02(t,J＝21Hz,3F),-62.11(s, 3F),-143.61--143.25(m,4F).
example 3
Acetylamino-substituted aromatic hydrocarbon (0.25mmol,0.25mmol88mg), N-p-toluenesulfonyl-5-iodoindole (0.38mmol,0.38mmol151mg), pyranoquinoline (10 mol%, 10 mol% 5g), palladium acetate (10 mol%, 10 mol% 6g), silver carbonate (3equiv,3equiv207g), norbornene (3equiv,3equiv71g) and dichloroethane (2.0mL) were accurately weighed in this order at room temperature, and the progress of the reaction was monitored by thin layer chromatography. The reaction was stopped after 15h at 0.1MPa, cooled to room temperature, the mixture was extracted with diethyl ether (10 mL. times.3), the organic phases were combined, excess solvent was removed by rotary evaporator, the residue was chromatographed using column chromatography, the product was purified using 400 mesh silica gel as the stationary phase and a mixed solvent of ethyl acetate and petroleum ether in different proportions as the eluent.
The physical properties and characterization data of the obtained compounds are as follows:
white solid:1H NMR(500MHz,acetone-d6)δ9.54(br,1H,N-H),8.07 (d,J＝8.5Hz,1H),7.89(d,J＝8.0Hz,2H),7.83(d,J＝1.0Hz,1H), 7.73(d,J＝3.5Hz,1H),7.64(d,J＝1.0Hz,1H),7.63(dd,J＝8.8, 1.2Hz,1H),7.54(m,1H),7.49(dd,J＝7.5,1.5Hz,1H),7.37(d,J ＝8.0Hz,2H),7.29(d,J＝7.5Hz,1H),6.84(d,J＝4.0Hz,1H),3.99 (s,2H),2.40(s,3H).
13C NMR(125MHz,acetone-d6)δ169.52,146.44,139.71,137.26,137.03, 136.05,135.02,134.88,132.56,131.68,130.95,130.04,128.23,127.76, 126.76,124.58,120.35,114.59,110.36,41.42,21.41.
example 4
Acetylamino-substituted aromatic hydrocarbon (0.25mmol,0.25mmol88mg), 5-iodo-7-azaindole (0.38mmol,0.38mmol92mg), pyranoquinoline (10 mol%, 10 mol% 5g), palladium acetate (10 mol%, 10 mol% 6g), silver carbonate (3equiv,3equiv207g), norbornene (3equiv,71g3equiv) and dichloroethane (2.0mL) were accurately weighed in this order at room temperature, and the progress of the reaction was monitored by thin layer chromatography. The reaction was stopped after 15h at 0.1MPa, cooled to room temperature, the mixture was extracted with diethyl ether (10 mL. times.3), the organic phases were combined, excess solvent was removed by rotary evaporator, the residue was chromatographed using column chromatography, the product was purified using 300 mesh silica gel as the stationary phase and a mixed solvent of ethyl acetate and petroleum ether in different proportions as the eluent.
The physical properties and characterization data of the obtained compounds are as follows:
white solid:1H NMR(500MHz,acetone-d6)δ12.51(br,1H,N-H),9.54 (br,1H,N-H),8.07(s,1H),7.83(d,J＝1.0Hz,1H),7.73(d,J＝3.5 Hz,1H),7.64(d,J＝1.0Hz,1H),7.63(m,1H),7.54(m,1H),7.49(dd, J＝7.5,1.5Hz,1H),6.84(d,J＝4.0Hz,1H),3.99(s,2H).
13C NMR(125MHz,acetone-d6)δ169.52,146.44,139.71,137.26,136.05, 135.02,134.88,132.56,131.68,130.04,127.76,126.76,124.58,114.59, 110.36,41.42.
example 5
Acetylamino-substituted aromatic hydrocarbon (0.25mmol,88mg0.25mmol), 3-acyl-5-iodo-7-azaindole (0.38mmol, 197mg mmol), pyranoquinoline (10 mol%, 10 mol% 5g), palladium acetate (10 mol%, 10 mol% 6g), silver carbonate (3equiv,3equiv207g), norbornene (3equiv,71g, 3equiv), and dichloroethane (2.0mL) were accurately weighed in this order at room temperature, and the progress of the reaction was monitored by thin layer chromatography. Stopping the reaction after 15h under 0.1MPa, cooling to room temperature, extracting the mixture with diethyl ether (10mL multiplied by 3), combining organic phases, removing excessive solvent by using a rotary evaporator, separating residues by using column chromatography, and purifying and separating the product by using 300-400 mesh silica gel as a stationary phase and using a mixed solvent of ethyl acetate and petroleum ether in different proportions as an eluent.
The physical properties and characterization data of the obtained Vemurafenib analogues are as follows:
white solid:1H NMR(500MHz,acetone-d6)δ12.54(br,1H,N-H),9.54 (br,1H,N-H),8.07(d,J＝8.5Hz,1H),7.89(d,J＝8.0Hz,2H),7.83 (d,J＝1.0Hz,1H),7.73(d,J＝3.5Hz,1H),7.64(d,J＝1.0Hz,1H), 7.63(dd,J＝8.8,1.2Hz,1H),7.54(m,1H),7.49(dd,J＝7.5,1.5Hz, 1H),7.37(d,J＝8.0Hz,2H),7.29(d,J＝7.5Hz,1H),7.04(m,1H), 7.01(m,1H),3.99(s,2H),3.10(t,J＝2.4,2H),1.87(m,2H),1.21(t, J＝2.4,2H).
13C NMR(125MHz,acetone-d6)δ196.24,169.52,152.03,151.81,146.44, 139.71,137.26,137.03,136.05,135.02,134.88,132.56,131.68,130.95, 130.04,129.65,128.23,127.76,126.76,124.58,123.63,120.35,114.59, 112.31,110.36,62.31,41.42,21.41,19.68,14.32.
the application of the products of the above examples to a process for preparing vemurafenib analogs is illustrated by the following two examples:
example 6
Accurately weighing the above prepared 5-iodo-7-azaindole (0.25mmol, 61mg), N- (3-5-difluoro-4-formylphenyl) propyl-1-sulfonamide (0.38mmol, 100mg), potassium carbonate (3equiv,3equiv104g), and methanol (1.0ml) in this order at room temperature; and sequentially adding the measured reactants into a 25mL pressure-resistant pipe filled with magnetons, sealing the pressure-resistant pipe, stirring on a magnetic stirrer at room temperature, slowly heating to 108 ℃, and monitoring the reaction process by using thin-layer chromatography. Stopping the reaction after 12 hours under the pressure of 0.1MPa, cooling to room temperature, removing redundant solvent by using a rotary evaporator, separating residues by using column chromatography, and purifying and separating products by using 300-400-mesh silica gel as a stationary phase and using mixed solvents of ethyl acetate and petroleum ether in different proportions as eluents.
The physical properties and characterization data of the obtained compounds are as follows:
yellow solid: 1H NMR (400MHz, CDCl)3):δ＝12.53(s,1H),8.62(dd,J ＝7.4Hz,J＝1.6Hz,1H),8.13(td,J＝8.6Hz,J＝2.6Hz,1H),7.33 (dd,J＝7.9Hz,J＝1.6Hz,1H),6.83(dd,J＝7.6Hz,J＝1.8Hz,1H), 6.73(dd,J＝7.8Hz,J＝1.9Hz,1H),6.53(m,1H),6.16(s,1H),3.10 (t,J＝4.6Hz,2H),1.69(m,2H),0.97(t,J＝4.6Hz,3H)ppm；
HRMS(APCI):[M+H]+(C17H16N3O2SI):calcd m/z 506.9925,found:506.9926。
Example 7
Accurately weighing 3-hydroxy 5-iodo-7-azaindole (0.25mmol, 122mg), dichlorodicyanobenzoquinone (0.5mmol, 114mg), and dioxane (1.0ml) at room temperature; and sequentially adding the measured reactants into a 25mL pressure-resistant pipe filled with magnetons, sealing the pressure-resistant pipe, stirring on a magnetic stirrer at room temperature, slowly heating to 100 ℃, and monitoring the reaction process by using thin-layer chromatography. Stopping the reaction after 12 hours under the pressure of 0.1MPa, cooling to room temperature, removing redundant solvent by using a rotary evaporator, separating residues by using column chromatography, and purifying and separating products by using 300-400-mesh silica gel as a stationary phase and using mixed solvents of ethyl acetate and petroleum ether in different proportions as eluents.
The physical properties and characterization data of the obtained compounds are as follows:
yellow solid: 1H NMR (400MHz, CDCl)3):δ＝12.53(s,1H),8.68(dd,J ＝7.6Hz,J＝1.6Hz,1H),8.18(td,J＝8.6Hz,J＝2.6Hz,1H),7.35(dd, J＝7.9Hz,J＝1.6Hz,1H),6.83(dd,J＝7.6Hz,J＝1.8Hz,1H),6.73 (dd,J＝7.8Hz,J＝1.9Hz,1H),6.53(m,1H),3.15(t,J＝4.6Hz,2H), 1.89(m,2H),1.27(t,J＝4.6Hz,3H)ppm；
HRMS(APCI):[M+H]+(C17H14F2N3O3SI):calcd m/z 504.9769,found: 504.9768。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, modifications and decorations can be made without departing from the core technology of the present invention, and the modifications and decorations shall also fall within the scope of the patent protection of the present invention. Any changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
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