CN114539234A - Synthesis method and application of C5-2-fatty amino pyrimidine azole compound - Google Patents
Synthesis method and application of C5-2-fatty amino pyrimidine azole compound Download PDFInfo
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Abstract
The application relates to the technical field of drug synthesis, in particular to a synthesis method and application of a C5-2-fatty amino pyrimidine azole compound, and provides a synthesis method of a C5-2-fatty amino pyrimidine azole compound, wherein the synthesis method comprises the step of synthesizing 5- (2-A-4- (R)2)‑6‑(R1) Pyrimidin-5-yl) -3-R4‑4‑R3Azole compounds as raw materials react with fatty amine under the action of inorganic base to perform amination reaction to obtain a target product 5- (3-R)4‑4‑R3Oxazol-5-yl) -4- (R2)‑6‑(R1)‑N‑R5The method is simple, the reaction time is short, the product is convenient to post-treat, no catalyst is needed, and the method is suitable for large-scale production.
Description
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a synthesis method and application of a C5-2-fatty amino pyrimidine azole compound.
Background
The pyrimidinamine compounds play an important role in clinical drugs, and currently, the 2-aminopyrimidine compounds have been reported to be widely applied in clinical medicine in related researches, such as: rosuvastatin (bioorg.med.chem.1997,5,437-444), gleevec (Nature Reviews Drug discovery.2002,1,493-502), and the potential application value of C5-2-aminopyrimidine compounds in clinical medicine are also concerned by many researchers, and related research results such as antimalarial drugs (pyrimethamine) (nature.2017,543,538-542), protein kinase inhibitors (MAPK4K inhibitors) (j.med.chem.2014,57,3484-3493) are obtained.
At present, the research on the synthetic method of the 2-aminopyrimidine compound has important research significance. Das A et al report a method for synthesizing C5-aryl-2-aminopyrimidine compounds, comprising the following steps: reacting 2-chloropyrimidine and primary amine in a solvent for 17 hours at 100 ℃ under the action of potassium fluoride to generate 2-aminopyrimidine; then 2-aminopyrimidine and aryl chloride are dissolved in 4-dioxane solution and react for 17 hours at 120 ℃ under the catalysis of palladium acetate and the action of silver carbonate, sodium carbonate and pyridine to generate C5-aryl-2-aminopyrimidine compounds (Chemical communications.2020,56), and the synthetic route is shown as follows;
and Smith S M et al also report the synthesis of 2-aminopyrimidine compounds by the amine synthesis of chloropyrimidine, with the specific steps: reacting 5-bromo-2, 4-dichloropyrimidine with chlorotrimethylsilane to produce 2, 4-dichloro-5- (trimethylsilyl) pyrimidine; then 2, 4-dichloro-5- (trimethylsilyl) pyrimidine and aromatic amine are reacted under the action of cesium carbonate and a catalyst to generate 4-chloro-5- (trimethylsilyl) pyrimidine 2-arylamine (Organic letters.2016,2180), and the synthetic route is shown as follows:
it can be seen that the synthesis method for synthesizing 2-aminopyrimidine compounds by combining amines of chloropyrimidine reported at present is complex, a catalyst is required to be used for catalytic reaction in the synthesis process, and the method for synthesizing by using the catalyst is low in efficiency, complex in reaction and not beneficial to large-scale preparation.
Disclosure of Invention
The application aims to provide a synthesis method and application of a C5-2-fatty amino pyrimidine azole compound, and aims to solve the problems that in the prior art, the synthesis method of the fatty amino pyrimidine azole compound needs to adopt a catalyst for reaction, so that the reaction is complex, and the mass preparation of products is not facilitated.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the application provides a method for synthesizing a C5-2-fatty amino pyrimidine azole compound, which comprises the following steps:
provides 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compounds, fatty amines, inorganic bases, organic solvents;
under the protection of inert gas, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compound, fatty amine and inorganic base are subjected to amination reaction in organic solvent to obtain 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5Pyrimidin-2-amines;
wherein A is selected from any one of chlorine, bromine and iodine;
R1、R2selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, ether group, saturated amine group, halogen;
R3、R4selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of the substituted alkyl groups of (1).
In a second aspect, the application provides a C5-2-fatty amino pyrimidine azole compound, wherein the C5-2-fatty amino pyrimidine azole compound is synthesized by a synthetic method of a C5-2-fatty amino pyrimidine azole compound.
In a third aspect, the application provides an application of a C5-2-fatty amino pyrimidine azole compound as a raw material for drug synthesis.
The first aspect of the application provides a method for synthesizing C5-2-fatty amino pyrimidine azole compounds, wherein in the method, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The azole compound and the fatty amine are used as reactants for reaction, and the nucleophilic ability of the amino in the fatty amine is promoted by the inorganic base, so that the reactants are subjected to amination reaction without the action of a catalyst to generate the C5-2-fatty amino pyrimidine azole compound. The reaction process does not need to use a catalyst for reaction, the synthesis method is simple, the preparation time is short, and the preparation method is convenient and safe, is beneficial to large-scale preparation, and enables the C5-2-fatty amino pyrimidine azole compound to be widely applied.
The C5-2-fatty amino pyrimidine azole compound provided by the second aspect of the application is synthesized by the provided synthesis method of the C5-2-fatty amino pyrimidine azole compound, and the obtained C5-2-fatty amino pyrimidine azole compound has high purity and excellent performance, and is suitable for wide application.
The C5-2-fatty amino pyrimidine azole compound provided by the third aspect of the application is used as a raw material for drug synthesis, and the reaction process of the provided synthesis method of the C5-2-fatty amino pyrimidine azole compound does not need to use a catalyst for reaction, so that the synthesis method is simple, the preparation time is short, the C5-2-fatty amino pyrimidine azole compound can be prepared in a large scale and in a short time, and the preparation method is suitable for being widely applied to the field of drug synthesis.
Detailed Description
In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In this application, the term "and/or" describes an association relationship of associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a alone, A and B together, and B alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the present application, "at least one" means one or more, "a plurality" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items. For example, "at least one (a), b, or c", or "at least one (a), b, and c", may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, and c may be single or plural, respectively.
It should be understood that, in various embodiments of the present application, the sequence numbers of the above-mentioned processes do not mean the execution sequence, some or all of the steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its function and inherent logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.
The terminology used in the embodiments of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in the examples of this application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weight of the related components mentioned in the description of the embodiments of the present application may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present application as long as it is scaled up or down according to the description of the embodiments of the present application. Specifically, the mass in the description of the embodiments of the present application may be in units of mass known in the chemical industry, such as μ g, mg, g, and kg.
The terms "first" and "second" are used for descriptive purposes only and are used for distinguishing purposes such as substances from one another, and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of embodiments of the present application. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature.
The compounds and derivatives thereof referred to in the examples of the present invention are named according to the IUPAC (International Union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, Ohio) naming system. Thus, the groups of compounds specifically mentioned in the examples of the present invention are illustrated and described as follows:
with respect to "hydrocarbon group," the minimum and maximum values of the carbon atom content in a hydrocarbon group are indicated by a prefix, e.g., the prefix (Ca-Cb) alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C1-C6) alkyl refers to alkyl groups containing one to six carbon atoms.
"alkoxy" refers to a straight or branched, monovalent, saturated aliphatic chain bonded to an oxygen atom and includes, but is not limited to, groups such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (Ca-Cb) alkoxy means any straight or branched, monovalent, saturated aliphatic chain having an alkyl group containing from "a" to "b" carbon atoms bonded to an oxygen atom.
"alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" means a straight or branched, monovalent, saturated aliphatic chain attached to at least one heteroatom, such as, but not limited to, methylaminoethyl or other similar groups.
"aryl" refers to a cyclic aromatic hydrocarbon including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or different. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b ] indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and the like.
The first aspect of the embodiments of the present application provides a method for synthesizing a C5-2-fatty aminopyrimidine azole compound, including the following steps:
s01, providing 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compounds, fatty amines, inorganic bases, organic solvents;
s02, under the protection of inert gas, adding 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compound, fatty amine and inorganic base are subjected to amination reaction in organic solvent to obtain 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5Pyrimidin-2-amines;
wherein A is selected from any one of chlorine, bromine and iodine;
R1、R2selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedAny one of heteroaryl, aryloxy, heteroaryloxy, ether group, saturated amine group, and halogen;
R3、R4selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of the substituted alkyl groups of (1).
In the synthesis method of the C5-2-fatty amino pyrimidine azole compound provided by the first aspect of the embodiment of the application, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The azole compound and the fatty amine are used as reactants for reaction, and the nucleophilic ability of the amino in the fatty amine is promoted by the inorganic base, so that the reactants are subjected to amination reaction without the action of a catalyst to generate the C5-2-fatty amino pyrimidine azole compound. The reaction process does not need to use a catalyst for reaction, the synthesis method is simple, the preparation time is short, and the preparation method is convenient and safe, is beneficial to large-scale preparation, and enables the C5-2-fatty amino pyrimidine azole compound to be widely applied.
In step S01, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compounds, fatty amine, inorganic base and organic solvent.
In some embodiments, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The structural general formula of the azole compound is shown in formula I,
wherein X is selected from O or S;
y is selected from N, Z and is selected from C; or, Y is selected from C, Z is selected from N;
a is selected from any one of chlorine, bromine and iodine;
R1、R2selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Substituted alkyl, aryl, substituted aryl, heteroAny one of an aryl group, a substituted heteroaryl group, an aryloxy group, a heteroaryloxy group, an ether group, a saturated amine group, and a halogen;
R3、R4selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of the substituted alkyl groups of (1).
In some embodiments, R1、R2Selected from identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C1-C10Substituted alkyl groups of (1).
In some embodiments, R1Including but not limited to H, CH3-、CH3CH2-、CH3(CH2)n-、Ar-、CH3S-、CH3CH2S-、CH3(CH2)nS-、CH3O-、CH3CH2O-、CH3(CH2)nO-;R2Including but not limited to H, CH3-、CH3CH2-、CH3(CH2)n-、Ar-、CH3S-、CH3CH2S-、CH3(CH2)nS-、CH3O-、CH3CH2O-、CH3(CH2)nO-。
In some embodiments, R3、R4Selected from the same or different hydrogen, C1-C10Alkyl radical, C1-C10Heteroalkyl group, C1-C10Any of the substituted alkyl groups of (1).
In some embodiments, R3Including but not limited to H-, CH3-;R4Including but not limited to H-, CH3-。
In some embodiments, when X is selected from O and Y is selected from N, Z and C, the resulting 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The structural formula of the azole compound is shown as a formula I-1,
the reactants shown in formula I-1 are reacted to obtain the product C5-2-fatty amino pyrimidine isoxazole compound.
In some embodiments, when X is selected from O and Y is selected from C, Z selected from N, the resulting 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The structural formula of the azole compound is shown as a formula I-2,
the reaction is carried out by the reactant shown in the formula I-1, and the obtained product is the C5-2-fatty amino pyrimidine oxazole compound.
In some embodiments, when X is selected from S and Y is selected from N, Z and C, the resulting 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The structural formula of the azole compound is shown as a formula I-3,
the reactant shown in the formula I-3 is used for reaction, and the obtained product is the C5-2-fatty amino pyrimidine isothiazole compound.
In some embodiments, when X is selected from S and Y is selected from C, Z selected from N, the resulting 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The structural formula of the azole compound is shown as a formula I-4,
the reactant shown in the formula I-4 is used for reaction, and the obtained product is the C5-2-fatty amino pyrimidine thiazole compound.
In some embodiments, the fatty amine has the general structural formula shown in formula II,
R5-NH2
formula II;
wherein R is5Is selected from C1-C20Alkyl radical, C1-C20Any one of cycloalkyl, tetrahydro-2H-pyran-alkyl, tetrahydrofuran-alkyl, benzylamine, 1,2,3, 4-tetrahydronaphthylamine, aminoindan.
In some embodiments, tetrahydro-2H-pyran-alkyl is selected from any one of tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-ylmethyl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-pyran-2-ylmethyl.
In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.
In some embodiments, the tetrahydrofuran-alkyl is selected from any one of tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-ylmethyl, and tetrahydrofuran-2-ylmethyl.
In some embodiments, benzylamine is selected from any of α, α -dimethylbenzylamine, alpha-methylbenzylamine.
In some embodiments, the 1,2,3, 4-tetrahydronaphthylamine is selected from any one of 1,2,3, 4-tetrahydro-2-naphthylamine, 1,2,3, 4-tetrahydro-1-naphthylamine.
In some embodiments, the aminoindane is selected from any of 1-aminoindane, 2-aminoindane.
In some embodiments, the organic solvent comprises at least one of tetrahydrofuran, 1, 4-dioxane, methylene chloride, toluene; providing an organic solvent capable of reacting 5- (2-A-4- (R) as a reactant2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compounds and fatty amine are dissolved to react in the form of solution, so that reactants can be uniformly dispersed in the solution and the reaction is complete.
In some embodiments, the inorganic base comprises caustic soda, potassium hydroxideAt least one of barium, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, iron hydroxide, lead hydroxide, cobalt hydroxide, chromium hydroxide, zirconium hydroxide, nickel hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. Providing an inorganic base capable of promoting the nucleophilic ability of an amine group to react with an aliphatic amine and 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The azole compound is directly subjected to amination reaction, and a catalyst is not required to be added in the reaction process.
In step S02, under the protection of inert gas, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compound, fatty amine and inorganic base are subjected to amination reaction in organic solvent to obtain 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5Pyrimidin-2-amine.
The chemical reaction formula of step S02 is as follows:
in some embodiments, the inert gas is selected from at least one of nitrogen, helium, and argon, and is provided to ensure that no other impurity molecules are introduced during the reaction process, so that the obtained product has high purity.
In some embodiments, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The mol ratio of the azole compound to the fatty amine is 1: 0.7 to 5; by controlling the molar ratio of the two, the reaction rate is ensured to be fastest, and the reaction can be carried out under the condition of not needing a catalyst, so that a product with higher purity is generated.
In some embodiments, the temperature of the amination reaction is 75-120 ℃ and the time of the amination reaction is 2-6 hours. If the reaction temperature is too low, the reaction is not easy to occur, and the reaction speed is slow; if the reaction temperature is too high, more byproducts are generated in the reaction, so that the product is impure and is not beneficial to subsequent use. If the reaction time is too short, incomplete reaction of reactants is easily caused; if the reaction time is too long, the reaction efficiency will be low.
In some embodiments, the temperature of the amination reaction is selected from the group consisting of 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃.
In some embodiments, an oil bath or microwave treatment may be used during the amination reaction to achieve the reaction temperature.
In some embodiments, after performing the amination reaction, the method further comprises: extracting, washing, drying, filtering and purifying a product obtained by the reaction to obtain 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5Pyrimidin-2-amine.
In some embodiments, after the amination reaction is performed, the method further comprises: extracting the product obtained by the reaction with ethyl acetate, washing with saturated salt water for 3 times, collecting the ethyl acetate extract solution, drying with anhydrous sodium sulfate, filtering, and purifying by column chromatography with PE (polyethylene) EA (6: 1) to obtain 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5Pyrimidin-2-amine.
The second aspect of the embodiment of the application provides a C5-2-fatty amino pyrimidine azole compound, wherein the C5-2-fatty amino pyrimidine azole compound is synthesized by a synthesis method of a C5-2-fatty amino pyrimidine azole compound.
The C5-2-fatty amino pyrimidine azole compound provided by the second aspect of the embodiment of the application is synthesized by the provided synthesis method of the C5-2-fatty amino pyrimidine azole compound, and the obtained C5-2-fatty amino pyrimidine azole compound has high purity and excellent performance, and is suitable for wide application.
In some embodiments, 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5The structural general formula of the pyrimidine-2-amine is shown as a formula III,
wherein X is selected from O or S;
y is selected from N, Z and is selected from C; or, Y is selected from C, Z is selected from N;
R1、R2selected from identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, ether group, saturated amine group, halogen;
R3、R4selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of the substituted alkyl groups of (a);
R5is selected from C1-C20Alkyl radical, C1-C20Any one of cycloalkyl, tetrahydro-2H-pyran-alkyl, tetrahydrofuran-alkyl, benzylamine, 1,2,3, 4-tetrahydronaphthylamine, aminoindan.
The third aspect of the embodiments of the present application provides an application of a C5-2-fatty aminopyrimidine azole compound as a raw material for drug synthesis.
The C5-2-fatty amino pyrimidine azole compound provided by the third aspect of the embodiment of the application is used as a raw material for drug synthesis, and the reaction process of the provided synthesis method of the C5-2-fatty amino pyrimidine azole compound does not need to use a catalyst for reaction, so that the synthesis method is simple, the preparation time is short, the C5-2-fatty amino pyrimidine azole compound can be prepared in a large scale and in a short time, and the preparation method is suitable for being widely applied to the field of drug synthesis.
The following description will be given with reference to specific examples.
Example 1
When X is O, Y is N, Z is C, R2Is methoxy, R1,R3And R4When all are hydrogen, the raw material is 5- (2-chloro-4-methoxypyrimidin-5-yl) isoxazole; the aliphatic amine is selected from tert-butylamine; the inorganic base is selected from potassium carbonate; the organic solvent is selected from 1, 4-dioxane;
the synthesis method of the C5-2-aliphatic amino pyrimidine azole compound comprises the following steps:
adding 600mg (2.84mmol) of 5- (2-chloro-4-methoxypyrimidin-5-yl) isoxazole, 1.04g (14.2mmol) of tert-butylamine and 784mg (5.68mmol) of potassium carbonate into a 25mL reaction tube in sequence, adding 10mL of 1, 4-dioxane under the protection of inert gas, and reacting for two hours at the temperature of 100 ℃ by using microwaves; after the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine for 3 times, and the ethyl acetate extract was collected, dried over anhydrous sodium sulfate, filtered, and then subjected to column chromatography with PE: EA ═ 6:1 to obtain 400mg of the product. The product was a white solid with a purity of 95% and a yield of 54%, and the structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, with the results:1H NMR(400MHz,CDCl3)δ8.62(1H,s),8.24-8.22(1H,d),6.50-6.49(1H,d),4.07(3H,s),1.45(9H,s).MS(ESI):[M+H+]249.
example 2
When X is O, Y is N, Z is C, R2Is methoxy, R1,R3And R4When all are hydrogen, the raw material is 5- (2-chloro-4-methoxypyrimidin-5-yl) isoxazole; the aliphatic amine is selected from alpha, alpha-dimethylbenzylamine; the inorganic base is selected from potassium carbonate; the organic solvent is selected from 1, 4-dioxane;
the synthesis method of the C5-2-aliphatic amino pyrimidine azole compound comprises the following steps:
adding 5- (2-chloro-4-methoxypyrimidin-5-yl) isoxazole (19mmol), alpha-dimethylbenzylamine (20 mg) (15mmol) and potassium carbonate (52 mg (38mmol) in sequence into a 10mL reaction tube, adding 3mL of 1, 4-dioxane under the protection of inert gas, and reacting for two hours at 120 ℃ by microwave; after the reaction, ethyl acetate was used for extraction, saturated common salt was used for washing 3 times, an ethyl acetate extraction solution was collected, dried with anhydrous sodium sulfate, filtered, and subjected to column chromatography with PE: EA: 6:1 to obtain 7.6mg of a 5- (isoxazol-5-yl) -4-methoxy-N- (2-phenylprop-2-yl) pyrimidin-2-amine product as a white solid with a purity of 95% and a yield of 16.2%, and the structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, with the results that: 1H NMR (400MHz, CDCl 3). delta.8.64 (1H, s),8.22-8.21(1H, d),7.47-7.43(2H, M),7.32-7.30(2H, M),7.23-7.19(1H, M),6.43-6.42(1H, d),3.50(3H, s),1.86(6H, s). MS (ESI): M + H + ]310.
Example 3
When X is O, Y is N, Z is C, R2Is methoxy, R1And R3Are all hydrogen, R4When the methyl is adopted, the raw material is 5- (2-chloro-4-methoxypyrimidin-5-yl) -3-methylisoxazole; the aliphatic amine is selected from cyclohexylamine hydrochloride; the inorganic base is selected from potassium carbonate; the organic solvent is selected from 1, 4-dioxane;
the synthesis method of the C5-2-aliphatic amino pyrimidine azole compound comprises the following steps:
to a 10mL reaction tube were added 40mg (18mmol) of 5- (2-chloro-4-methoxypyrimidin-5-yl) -3-methylisoxazole, 19mg (14mmol) of cyclohexylamine hydrochloride, and 49mg (36mmol) of potassium carbonate in this order, and under an inert gas atmosphere, 3mL of 1, 4-dioxane was added and reacted at 100 ℃ for 6 hours. After the reaction is finished, extracting with ethyl acetate, washing with saturated salt water for 3 times, collecting ethyl acetate extract solution, drying with anhydrous sodium sulfate, filtering, and then performing column chromatography with PE: EA (6: 1) to obtain 16mg of N-cyclohexyl-4-methoxy-5- (3-methylisoxazol-5-yl) pyrimidine-2-amine product which is white solid with the purity of 95% and the yield of 40%, wherein the structure of the obtained product is confirmed by mass spectrometry and nuclear magnetic resonance, and the result is that: 1H NMR (400MHz, CDCl3), delta 8.67(1H, s),8.39-8.35(1H, d),6.58-6.53(1H, d),4.06(3H, s),3.45-3.41(1H, M),2.43(3H, s),2.07-2.02(2H, M),1.78-1.63(4H, M),1.41-1.34(4H, M) MS (ESI) [ M + H + ] 289).
Example 4
When X is O, Y is N, Z is C, R2Is methoxy, R1And R4Is hydrogen, R3When the methyl is adopted, the raw material is 5- (2-chloro-4-methoxypyrimidin-5-yl) -4-methylisoxazole; the aliphatic amine is selected from tetrahydro-2H-pyran triamine; the inorganic base is selected from potassium carbonate; the organic solvent is selected from 1, 4-dioxane;
to a 10mL reaction tube were added 40mg (18mmol) of 5- (2-chloro-4-methoxypyrimidin-5-yl) -4-methylisoxazole, 14mg (14mmol) of tetrahydro-2H-pyranotriamine and 49mg (36mmol) of potassium carbonate in this order, and 3mL of 1, 4-dioxane was added under an inert gas atmosphere and reacted at 100 ℃ for 6 hours. After the reaction is finished, extracting with ethyl acetate, washing with saturated common salt for 3 times, collecting ethyl acetate extraction solution, drying with anhydrous sodium sulfate, filtering, and then performing column chromatography with PE: EA (6: 1) to obtain 20mg of 4-methoxy-5- (4-methylisoxazol-5-yl) -N- (tetrahydro-2H-pyran-3-yl) pyrimidine-2-amine product which is white solid, has the purity of 95% and the yield of 50%, and the structure of the obtained product is confirmed by mass spectrometry and nuclear magnetic resonance, and the result is that: 1H NMR (400MHz, CDCl 3). delta.8.65 (1H, s),8.40-8.35(1H, d),6.58-6.52(1H, d),4.08(3H, s),3.86-3.63(4H, M),2.71-2.60(1H, M),2.52(3H, s)1.90-1.63(4H, M). MS (ESI): M + H + ]291.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (10)
1. A method for synthesizing C5-2-fatty amino pyrimidine azole compounds is characterized by comprising the following steps:
provides 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compounds, fatty amines, inorganic bases, organic solvents;
under the protection of inert gas, 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compound, fatty amine and inorganic base are subjected to amination reaction in organic solvent to obtain 5- (3-R)4-4-R3Oxazol-5-yl) -4- (R2)-6-(R1)-N-R5Pyrimidin-2-amine;
wherein A is selected from any one of chlorine, bromine and iodine;
the R is1、R2Selected from the same or different hydrogen, C1-C20Alkyl radical, C1-C20Heteroalkyl group, C1-C20Any of substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, ether group, saturated amine group, halogen;
the R is3、R4Selected from the same or different hydrogen, C1-C20Alkyl radical、C1-C20Heteroalkyl group, C1-C20Any of the substituted alkyl groups of (1).
2. The method for synthesizing C5-2-fatty amino pyrimidine azole compound according to claim 1, wherein the 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3The structural general formula of the azole compound is shown in formula I,
wherein X is selected from O or S;
y is selected from N, Z and is selected from C; or Y is selected from C and Z is selected from N.
3. The method for synthesizing C5-2-fatty amino pyrimidine azole compounds according to claim 1, wherein the fatty amine has a general structural formula shown in formula II,
R5-NH2
formula II;
wherein, R is5Is selected from C1-C20Alkyl radical, C1-C20Any one of cycloalkyl, tetrahydro-2H-pyran-alkyl, tetrahydrofuran-alkyl, benzylamine, 1,2,3, 4-tetrahydronaphthylamine, aminoindan.
4. A method of synthesising a C5-2-fatty aminopyrimidine azole compound as claimed in claim 3 wherein the tetrahydro-2H-pyran-alkyl is selected from any of tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-ylmethyl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-pyran-2-ylmethyl; and/or the presence of a gas in the gas,
the tetrahydrofuran-alkyl is selected from any one of tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-ylmethyl and tetrahydrofuran-2-ylmethyl; and/or the presence of a gas in the gas,
the benzylamine is selected from any one of alpha, alpha-dimethylbenzylamine and alpha-methylbenzylamine; and/or the presence of a gas in the atmosphere,
the 1,2,3, 4-tetrahydronaphthylamine is selected from any one of 1,2,3, 4-tetrahydro-2-naphthylamine and 1,2,3, 4-tetrahydro-1-naphthylamine; and/or the presence of a gas in the gas,
the aminoindan is selected from any one of 1-aminoindan and 2-aminoindan.
5. The method for synthesizing C5-2-fatty aminopyrimidine azole compounds according to claim 1, wherein the organic solvent comprises at least one of tetrahydrofuran, 1, 4-dioxane, dichloromethane, and toluene; and/or the presence of a gas in the atmosphere,
the inorganic base comprises at least one of caustic soda, potassium hydroxide, barium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, ferric hydroxide, lead hydroxide, cobalt hydroxide, chromium hydroxide, zirconium hydroxide, nickel hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; and/or the presence of a gas in the gas,
the inert gas is at least one of nitrogen, helium and argon.
6. The method for synthesizing C5-2-fatty amino pyrimidine azole compound according to claim 1,
the R is1、R2Selected from identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C1-C10Substituted alkyl of (a); and/or the presence of a gas in the atmosphere,
the R is3、R4Selected from the same or different hydrogen, C1-C10Alkyl radical, C1-C10Heteroalkyl group, C1-C10Any of the substituted alkyl groups of (1).
7. The method for synthesizing C5-2-fatty amino pyrimidine azole compound according to any one of claims 1 to 3, wherein the 5- (2-A-4- (R)2)-6-(R1) Pyrimidin-5-yl) -3-R4-4-R3Azole compound and the compoundThe molar ratio of the fatty amine is 1: 0.7 to 5.
8. The method for synthesizing C5-2-fatty amino pyrimidine azole compound according to any claim 1 to 3, wherein the temperature of the amination is 75 to 120 ℃ and the time of the amination is 2 to 6 hours.
9. A C5-2-fatty amino pyrimidine azole compound, characterized in that the C5-2-fatty amino pyrimidine azole compound is synthesized by the method for synthesizing the C5-2-fatty amino pyrimidine azole compound according to any one of claims 1 to 8.
10. Use of a C5-2-fatty aminopyrimidine azole compound according to claim 9 as a starting material for the synthesis of a medicament.
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