CN114105989A - Preparation method and application of iodo-pyrrolotriazine amine compound - Google Patents
Preparation method and application of iodo-pyrrolotriazine amine compound Download PDFInfo
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- -1 iodo-pyrrolotriazine amine compound Chemical class 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 32
- 150000007513 acids Chemical class 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 12
- VSPXQZSDPSOPRO-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical class NC1=NC=NN2C=CC=C12 VSPXQZSDPSOPRO-UHFFFAOYSA-N 0.000 claims abstract description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 235000009518 sodium iodide Nutrition 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- JJHHIJFTHRNPIK-UHFFFAOYSA-N Diphenyl sulfoxide Chemical compound C=1C=CC=CC=1S(=O)C1=CC=CC=C1 JJHHIJFTHRNPIK-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000002777 nucleoside Substances 0.000 claims description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 150000002496 iodine Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 claims description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 3
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 3
- 229940107816 ammonium iodide Drugs 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 40
- ZEBGLCLVPCOXIV-UHFFFAOYSA-N 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound NC1=NC=NN2C(I)=CC=C12 ZEBGLCLVPCOXIV-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000000758 substrate Substances 0.000 description 10
- 239000007810 chemical reaction solvent Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 230000026045 iodination Effects 0.000 description 7
- 238000006192 iodination reaction Methods 0.000 description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940071870 hydroiodic acid Drugs 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001924 cycloalkanes Chemical class 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BOUIZPWBFIVJPD-UHFFFAOYSA-N 3h-1,2,4-triazin-4-amine Chemical compound NN1CN=NC=C1 BOUIZPWBFIVJPD-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The application discloses a preparation method and application of iodo-pyrrolotriazine amine compounds, wherein the method at least comprises the following steps: and adding pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compounds into a reaction system I containing iodized salt, sulfoxide compounds and acidic compounds, and reacting to obtain the iodo-pyrrolo-triazine amine compounds. The preparation method provided by the application has the advantages of simple and easily-obtained raw materials, no transition metal, mild reaction conditions, simple post-treatment, high yield and the like.
Description
Technical Field
The application relates to a preparation method and application of iodo-pyrrolotriazine amine compounds, belonging to the field of organic synthesis.
Background
Organic iodides are widely applied in the fields of medicine preparation, natural product synthesis, new material preparation and the like, and the preparation of organic iodides by directly forming C-I bonds from C-H bonds through a green iodination method is more favored.
At present, nucleoside drugs are important drugs clinically used for treating viral infection, tumor and AIDS, and nearly 50 percent of antiviral drugs used are nucleoside drugs. Pyrrolotriazine amine compounds are often contained in the skeleton of nucleoside drugs, such as kinase inhibitors, ridciclovir, protease inhibitors and the like, and play an important role in the research and development of related drugs.
Iodo-pyrrolotriazine amines are important synthetic fragments for synthesizing pyrrolotriazine amine antiviral drug skeletons, and are expensive, such as 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine, which is 23000 yuan per kilogram. Aiming at the defects of the existing method for directly synthesizing iodo-pyrrolo-triazine amine derivatives, the research starts from cheaper chemical raw materials, develops a green and convenient iodination method for synthesizing iodo-pyrrolo-triazine amine fragments, and hopefully innovates from the source and provides a better iodination method.
At present, very few documents are reported for the synthesis of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine. The existing iodination method is to prepare a target compound by reacting pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine with stoichiometric amount of NIS (N-iodosuccinimide), but after the reaction is finished, a stoichiometric by-product is generated, the separation and purification of the target product are difficult, and the reaction is not green enough. Therefore, development of a novel iodination technique which is green and convenient is expected.
Disclosure of Invention
According to one aspect of the application, a preparation method of iodo-pyrrolotriazine amine compounds is provided, the reaction hardly generates byproducts, and only a simple quenching operation is needed after the reaction is finished, and the target products can be obtained by slightly purifying the products. The method has the advantages of environmental protection, high atom economy, simple and convenient post-treatment and suitability for mass production, can well improve the iodination method for synthesizing the iodo-pyrrolotriazine amine derivatives, can be innovated from the source, and can reduce the synthesis cost of raw material fragments.
The present application envisages the use of HI (hydroiodic acid)/DMSO instead of NIS.
The application provides a green and convenient iodination method for preparing a key intermediate iodo-pyrrolotriazine amine compound for synthesizing nucleoside drugs. The method uses simple and easily-obtained raw materials, and has the characteristics of mild reaction conditions, no participation of transition metals, simple post-treatment, high product yield and the like.
According to a first aspect of the present application, there is provided a process for the preparation of iodopyrrolotriazinamines, said process comprising at least:
and adding pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compounds into a reaction system I containing iodized salt, sulfoxide compounds and acidic compounds, and reacting to obtain the iodo-pyrrolo-triazine amine compounds.
Optionally, the pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound is selected from at least one of compounds having the structural formula shown in formula I:
in the formula I, R1、R2、R3、R4、R5Independently selected from hydrogen, halogen, nitro, substituted acyl, C1-C10Alkyl of (C)2-C10Alkenyl of, C6-C10Aryl of (C)4-C10Heteroaryl of (A), C2-C10Alkynyl of (2), substituted C2-C10Alkenyl of (a), substituted C1-C10Alkyl, substituted C2-C10At least one of alkynyl groups of (a);
the substituent of the substituted acyl is selected from C1-C3Alkyl group of (1).
Alternatively, said substituted C2-C10The substituents in the alkenyl group of (A) are selected from C1-C3Alkyl groups of (a);
said substituted C1-C10The substituents in the alkyl group of (A) are selected from C6-C10Aryl of (a);
said substituted C2-C10The substituent in the alkynyl group of (A) is selected from C1-C10Alkyl group of (1).
Alternatively, the pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound is selected from compounds having the formula shown in formula I-1:
optionally, the iodo-pyrrolotriazine amine compound is selected from at least one compound having a structural formula shown in formula II:
alternatively, in formula II, R1、R2、R3、R4、R5Independently selected from hydrogen, halogen, nitro, substituted acyl, C1-C10Alkyl of (C)2-C10Alkenyl of, C6-C10Aryl of (C)4-C10Heteroaryl of (A), C2-C10Alkynyl of (2), substituted C2-C10Alkenyl of (a), substituted C1-C10Alkyl, substituted C2-C10At least one of alkynyl groups of (a);
the substituent of the substituted acyl is selected from C1-C3Alkyl group of (1).
Alternatively, said substituted C2-C10The substituents in the alkenyl group of (A) are selected from C1-C3Alkyl groups of (a);
said substituted C1-C10The substituents in the alkyl group of (A) are selected from C6-C10Aryl of (a);
said substituted C2-C10The substituent in the alkynyl group of (A) is selected from C1-C10Alkyl group of (1).
Optionally, the iodopyrrolotriazine amine compound is selected from any one of compounds having a structural formula shown below:
optionally, the iodine salt is selected from at least one of sodium iodide, potassium iodide, ammonium iodide, tetrabutylammonium iodide.
Optionally, the sulfoxide compound is at least one selected from the group consisting of diethyl sulfoxide, dimethyl sulfoxide, thionyl chloride and diphenyl sulfoxide.
Optionally, the acidic compound is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid.
Preferably, the acidic compound is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, concentrated hydrochloric acid, concentrated sulfuric acid, and acetic acid.
Optionally, the reaction system 1 further comprises a solvent; the solvent is at least one selected from toluene, acetonitrile, tetrahydrofuran, anisole, 1, 4-dioxane, dibutyl ether, diphenyl ether, ethyl acetate, tetrahydrofuran, water and dichloromethane.
Optionally, in the reaction system I, the molar ratio of the iodine salt to the acidic compound to the sulfoxide compound is 1: 1-5: 1-10.
Preferably, in the reaction system I, the molar ratio of the iodide salt to the acidic compound to the sulfoxide compound is 1.0 to (1.0-3.0).
Optionally, the reaction conditions are: the reaction temperature is 50-120 ℃; the reaction time is 6-58 h.
Alternatively, the upper temperature limit of the reaction is independently selected from 120 ℃, 110 ℃, 100 ℃, 90 ℃, 80 ℃, 70 ℃, 60 ℃, and the lower temperature limit is independently selected from 50 ℃, 110 ℃, 100 ℃, 90 ℃, 80 ℃, 70 ℃, 60 ℃.
Alternatively, the upper time limit of the reaction II is independently selected from 58h, 48h, 38h, 28h, 18h and 8h, and the lower time limit is independently selected from 6h, 48h, 38h, 28h, 18h and 8 h.
Optionally, the method comprises at least:
(1) stirring raw materials containing an iodide salt, a sulfoxide compound, an acidic compound and a solvent at 50-120 ℃ for 0-8 h to obtain a system I;
(2) and adding pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compounds into the system I, and reacting to obtain the iodo-pyrrolo-triazine amine compounds.
Optionally, the molar ratio of the pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compound to the iodine salt to the acidic compound to the sulfoxide compound is 1: 1-4: 1-8: 1-12.
Optionally, the method also comprises the steps of extracting and removing the solvent after the reaction.
According to the second aspect of the present application, there is also provided an iodopyrrolotriazine amine compound selected from at least one iodopyrrolotriazine amine compound prepared according to the above-described method.
According to the third aspect of the application, the iodo-pyrrolotriazine amine compound prepared by the method and the application of the iodo-pyrrolotriazine amine compound in the synthesis of nucleoside drugs are also provided.
As a specific embodiment, the method for preparing iodopyrrolotriazine amine compounds comprises the following steps:
1) adding an iodide salt and a sulfoxide compound into a reaction solvent, adding an acidic compound into the reaction solvent, and stirring the mixture for 0 to 8 hours at a temperature of between 50 and 120 ℃ to obtain a system I;
2) adding reactant pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compound into the system I, heating to 50-120 ℃ after closing or opening a reaction system, reacting for 6-58 hours, cooling, quenching, separating into an organic layer and a water layer, neutralizing the water layer with an acidic solution, extracting with an organic solvent, and removing the organic solvent to obtain a target product.
In this application, C1～C10Refers to the number of carbon atoms involved. The carbon atom of the "substituted alkyl group" or "substituted aryl group" is not limited to the number of carbon atoms contained in the alkyl group or the aryl group itself, but is not the number of carbon atoms after the substitution. Such as C1～C10The substituted alkyl group of (1) is an alkyl group having 1 to 10 carbon atoms, at least one hydrogen atom being substituted by a substituent.
In the present application, an "alkyl group" is a group formed by losing any one hydrogen atom on the molecule of an alkane compound. The alkane compound comprises straight-chain alkane, branched-chain alkane, cycloalkane and cycloalkane with branched chain.
In the present application, an "alkenyl group" is a group formed by losing any one hydrogen atom on the molecule of an olefin compound. The olefin compound includes linear olefin, branched olefin, cyclic olefin, and cyclic olefin with branched chain.
In the present application, "aryl" is a group formed by losing one hydrogen atom on an aromatic ring on an aromatic compound molecule; such as p-tolyl, formed by toluene losing the hydrogen atom para to the methyl group on the phenyl ring.
In the present application, an "alkynyl group" is a group formed by losing any one hydrogen atom on the molecule of an alkyne compound. The alkyne compound includes a straight-chain alkyne, a branched-chain alkyne, a cycloalkyne, and a cycloalkyne with a branch.
In the present application, halogen means F, Cl, Br, I.
In the present application, "heteroaryl" is a group formed by losing any one of the hydrogen atoms on an aromatic ring on an aromatic compound (abbreviated as a heteroaromatic compound) having O, N, S heteroatoms in the aromatic ring; such as quinoline ring, pyridine ring, pyrimidine ring, and quinoline group, pyridine group, and pyrimidine group formed by losing any hydrogen atom.
The beneficial effects that this application can produce include:
1) according to the method provided by the application, the 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compound can be prepared by directly taking an iodonium salt, a sulfoxide compound, an acidic compound and a pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compound as raw materials;
2) the method provided by the application has the advantages of simple and easily obtained raw materials, low price, stability, mild reaction conditions, simple post-treatment and high yield.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
The raw materials in the examples of the present application were all purchased commercially, unless otherwise specified.
In the examples, the qualitative analysis of the product was carried out using a Variani NOVA model 400MHz NMR spectrometer from Warran, USA.
The yield of the target product in the application is calculated by adopting the following method:
the yield of the target product is equivalent to the mass of the target product actually obtained/the mass of the target product theoretically obtained × 100%.
Example 1
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
0.5mmol (1.0equiv) of sodium iodide, 1.5mmol (1.5equiv) of diphenyl sulfoxide and toluene (as a solvent) are added into a reaction bottle, hydrochloric acid (2.5equiv.) is added under stirring, and then the reaction bottle is placed in a 30 ℃ oil bath and stirred for 1.0 h. Then, 0.5mmol (1.0equiv, substrate concentration is 0.05M) of pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine is added thereto, the mixture is heated to 65 ℃, the reaction is detected until the raw materials are completely consumed, the mixture is cooled to room temperature and then quenched, extracted by ethyl acetate, dried, and the solvent is removed by distillation under reduced pressure to obtain a crude product of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine, and the yield of the target product is calculated to be 52%.
1H NMR(400MHz，DMSO-d6)δ7.91(s，1H)，7.79(br s，2H)，6.97(d，J＝4.4Hz，1H)，6.80(d，J＝4.4Hz，1H).13C NMR(101MHz，DMSO-d6)δ155.7，149.2，118.8，118.2，104.4，71.9.MS m/z＝260.9[M+H].
Example 2
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the reaction solvent was changed to acetonitrile (to a substrate concentration of 0.05M) to obtain a yield of the objective product of 63%.
Example 3
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the reaction solvent was changed to tetrahydrofuran (to a substrate concentration of 0.05M), and the yield of the objective product was: and 47 percent.
Example 4
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1 except for changing the reaction solvent to 1, 4-dioxane (to a substrate concentration of 0.05M), the yield of the objective product: 56 percent.
Example 5
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the reaction solvent was changed to water (substrate concentration was 0.05M), and the yield of the objective product was: 23 percent.
Example 6
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, except for changing the reaction solvent, which was methylene chloride (to make the substrate concentration 0.05M), the yield of the objective product: and 69 percent.
Example 7
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the reaction solvent was changed to ethyl acetate (substrate concentration was 0.05M), yield of the objective product: 73 percent.
Example 8
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the reaction solvent was changed to DMSO (so that the substrate concentration was 0.05M), and the yield of the objective product was: 74 percent.
Example 9
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only sodium iodide was changed to potassium iodide (1.0equiv), yield of the objective product: 66 percent.
Example 10
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only sodium iodide was changed to tetrabutylammonium iodide (1.0equiv), yield of the objective product: 76 percent.
Example 11
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only sodium iodide was changed to cesium iodide (1.0equiv), the yield of the objective product was: and 47 percent.
Example 12
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only sodium iodide was changed to ammonium iodide (1.0equiv), yield of the objective product: 67% white solid.
Example 13
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only the reaction temperature was changed to 50 ℃, the yield of the objective product: 0 percent.
Example 14
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only the reaction temperature was changed to 75 ℃, yield of the objective product: 49 percent.
Example 15
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only the reaction temperature was changed to 100 ℃, and the yield of the objective product: 42 percent.
Example 16
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only the reaction temperature was changed to 120 ℃, the yield of the objective product: 23 percent.
Example 17
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only the acid was changed to sulfuric acid (2.5equiv), yield of the objective product: 66 percent.
Example 18
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only hydrochloric acid was changed to phosphoric acid (2.5equiv), yield of the objective product: 61 percent.
Example 19
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only hydrochloric acid was changed to hydrobromic acid (2.5equiv), yield of the objective product: 60 percent.
Example 20
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only hydrochloric acid was changed to hydroiodic acid (2.5equiv), yield of the objective product: 70 percent.
Example 21
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only diphenyl sulfoxide was changed to diethyl sulfoxide (1.5equiv), yield of the objective product: 72 percent.
Example 22
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only diphenyl sulfoxide was changed to dimethyl sulfoxide (1.5equiv), yield of the objective product: 71 percent.
Example 23
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only diphenyl sulfoxide was changed to thionyl chloride (1.5equiv), the yield of the objective product: 0 percent.
Example 24
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
As in example 1, only diphenyl sulfoxide was changed to diethyl sulfoxide (1.5equiv), yield of the objective product: 33 percent.
Example 25
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only sodium iodide in the reaction was removed, the hydrochloric acid in the reaction was changed to hydroiodic acid (2.5equiv), and the yield of the objective product was: 68 percent.
Example 26
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the molar ratio of pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound, iodide salt, acidic compound and sulfoxide compound in the reaction is 1: 1, and the yield of the target product is: 35 percent.
Example 27
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the molar ratio of pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound, iodide salt, acidic compound and sulfoxide compound in the reaction is 1: 4: 8: 12, and the yield of the objective product is: 75 percent.
Example 28
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
In the same manner as in example 1, only the molar ratio of pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound, iodide salt, acidic compound and sulfoxide compound in the reaction is 1: 2: 4: 6, and the yield of the target product is: 71 percent.
Example 29
Preparation of 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazine-4-benzamide
0.5mmol (1.0equiv) of sodium iodide, 1.5mmol (1.5equiv) of diphenyl sulfoxide and toluene (as a solvent) are added into a reaction bottle, hydrochloric acid (2.5equiv.) is added under stirring, and then the reaction bottle is placed in a 30 ℃ oil bath and stirred for 1.0 h. Then, 0.5mmol (1.0equiv, substrate concentration is 0.05M.) of pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-benzamide is added, the mixture is heated to 65 ℃, the reaction is detected until the raw materials are completely consumed, the mixture is cooled to room temperature and quenched, extracted by ethyl acetate, dried, and the solvent is removed by reduced pressure distillation to obtain a crude product, namely 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazine-4-benzamide, and the yield of the target product is calculated to be 56%.
1H NMR(300MHz，DMSO-d6)：d＝8.05(s，1H)，7.94(dd，J＝8.2and 7.8Hz，1H)，7.66-7.47(m，4H)，7.31(dd，J＝3.9and 4.6Hz，1H)，7.10ppm(s，1H)；13C NMR(75MHz，DMSO-d6)：d＝172.0，146.9，133.9，133.1，132.9，129.3，129.0，128.6，128.5，123.7，121.0，106.7ppm；MS：calcd for C13H9IN4O([M+H]+)364.98，found 364.98.
Example 30
Preparation of 9-methyl-7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine
Adding 0.5mmol (1.0equiv) of sodium iodide, 1.5mmol (1.5equiv) of diphenyl sulfoxide and toluene (as a solvent) into a reaction bottle, adding 2.5equiv hydrochloric acid under stirring, and then placing the reaction bottle in a 30 ℃ oil bath and stirring for 0.0-1.0 h. Then, 0.5mmol (1.0equiv, so that the substrate concentration is 0.05M.) of 9-methylpyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine is added into the mixture, then the mixture is heated to 65 ℃, the reaction is detected until the raw materials are completely consumed, the mixture is cooled to room temperature and quenched, extracted by ethyl acetate and dried, the solvent is removed by reduced pressure distillation to obtain a crude product, namely 9-methyl 7-iodopyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine, and the yield of the target product is calculated to be 62%.
1H NMR(400MHz，DMSO-d6)δ7.91(s，1H)，7.79(br s，2H)，6.97(d，J＝4.4Hz，1H)，6.80(d，J＝4.4Hz，1H)，1.6(s，3H).13C NMR(101MHz，DMSO-d6)δ155.7，149.2，118.8，118.2，104.4，71.9，12.1.MS m/z＝273.0[M+H].
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (10)
1. A method for preparing iodo-pyrrolotriazine amine compounds, characterized in that the method at least comprises:
and adding pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compounds into a reaction system I containing iodized salt, sulfoxide compounds and acidic compounds, and reacting to obtain the iodo-pyrrolo-triazine amine compounds.
2. The method according to claim 1, wherein the pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound is at least one compound having a structural formula represented by formula I:
in the formula I, R1、R2、R3、R4、R5Independently selected from hydrogen, halogen, nitro, substituted acyl, C1-C10Alkyl of (C)2-C10Alkenyl of, C6-C10Aryl of (C)4-C10Heteroaryl of (A), C2-C10Alkynyl of (2), substituted C2-C10Alkenyl of (a), substituted C1-C10Alkyl, substituted C2-C10At least one of alkynyl groups of (a);
the substituent of the substituted acyl is selected from C1-C3Alkyl group of (1).
3. The method of claim 2, wherein said substituted C is2-C10The substituents in the alkenyl group of (A) are selected from C1-C3Alkyl groups of (a);
said substituted C1-C10The substituents in the alkyl group of (A) are selected from C6-C10Aryl of (a);
said substituted C2-C10The substituent in the alkynyl group of (A) is selected from C1-C10Alkyl group of (1).
4. The process according to claim 2, wherein the pyrrolo [2, 1-F ] [1, 2, 4] triazin-4-amine compound is selected from compounds having the formula shown in formula I-1:
5. the method according to claim 1, wherein the iodopyrrolotriazinylamine compound is at least one compound selected from the group consisting of compounds having a formula represented by formula II:
6. the method according to claim 5, wherein the iodopyrrolotriazinylamine compound is selected from any one of compounds having a structural formula shown below:
7. the method according to claim 1, wherein the iodine salt is at least one selected from the group consisting of sodium iodide, potassium iodide, ammonium iodide, tetrabutylammonium iodide, and cesium iodide.
8. The production method according to claim 1, wherein the sulfoxides are at least one selected from the group consisting of diethyl sulfoxide, dimethyl sulfoxide, thionyl chloride and diphenyl sulfoxide;
preferably, the acidic compound is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid;
preferably, the reaction system I also contains a solvent; the solvent is at least one selected from toluene, acetonitrile, tetrahydrofuran, anisole, 1, 4-dioxane, dibutyl ether, diphenyl ether, ethyl acetate, tetrahydrofuran, water and dichloromethane;
preferably, in the reaction system I, the molar ratio of the iodide salt to the acidic compound to the sulfoxide compound is 1: 1-5: 1-10;
preferably, the reaction conditions are: the reaction temperature is 50-120 ℃; the reaction time is 6-58 h;
preferably, the method comprises at least:
(1) stirring raw materials containing an iodide salt, a sulfoxide compound, an acidic compound and a solvent at 50-120 ℃ for 0-8 h to obtain a system I;
(2) adding pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compounds into the system I, and reacting to obtain the iodo-pyrrolo-triazine amine compounds;
preferably, the molar ratio of the pyrrolo [2, 1-F ] [1, 2, 4] triazine-4-amine compound to the iodine salt to the acidic compound to the sulfoxide compound is 1: 1-4: 1-8: 1-12;
preferably, the method also comprises the steps of extracting and removing the solvent after the reaction.
9. Iodo-pyrrolotriazine amine compound, characterized in that it is selected from at least one iodo-pyrrolotriazine amine compound prepared according to the method of any one of claims 1 to 8.
10. Iodo-pyrrolotriazinamines prepared according to any one of claims 1 to 8, or iodo-pyrrolotriazinamines according to claim 9, for use in the synthesis of nucleoside drugs.
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