CN114874221A - RIP2 kinase inhibitor intermediate and synthetic method thereof - Google Patents
RIP2 kinase inhibitor intermediate and synthetic method thereof Download PDFInfo
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- 101001109137 Homo sapiens Receptor-interacting serine/threonine-protein kinase 2 Proteins 0.000 title claims abstract description 23
- 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 title claims abstract description 23
- 101000733257 Homo sapiens Rho guanine nucleotide exchange factor 28 Proteins 0.000 title claims abstract description 21
- 229940043355 kinase inhibitor Drugs 0.000 title claims abstract description 19
- 239000003757 phosphotransferase inhibitor Substances 0.000 title claims abstract description 19
- 238000010189 synthetic method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- -1 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol Chemical group 0.000 claims abstract description 14
- 238000001308 synthesis method Methods 0.000 claims abstract description 10
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- 239000003960 organic solvent Substances 0.000 claims description 26
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- 238000000034 method Methods 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 13
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- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 6
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
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- 239000000203 mixture Substances 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 12
- 239000002994 raw material Substances 0.000 abstract description 5
- OELYMZVJDKSMOJ-UHFFFAOYSA-N 4-bromo-1h-pyrazol-5-amine Chemical compound NC1=NNC=C1Br OELYMZVJDKSMOJ-UHFFFAOYSA-N 0.000 abstract description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
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- ORXJMBXYSGGCHG-UHFFFAOYSA-N dimethyl 2-methoxypropanedioate Chemical compound COC(=O)C(OC)C(=O)OC ORXJMBXYSGGCHG-UHFFFAOYSA-N 0.000 description 3
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- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
The invention relates to an RIP2 kinase inhibitor intermediate and a synthesis method thereof, wherein the RIP2 kinase inhibitor intermediate is 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol, and is prepared by taking 3-amino-4-bromopyrazole as a starting material and performing three-step reactions of cyclization, chlorination and demethylation. The synthesis method provided by the invention is simple and convenient to operate, low in cost, easy to obtain raw materials, high in yield, low in production cost and suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to an intermediate of an RIP2 kinase inhibitor and a synthesis method thereof.
Background
Receptor-interacting protein kinase 2(RIP2) belongs to the RIP family and is distributed in a variety of tissues. RIP2 interacts with enough proteins, participates in signal transduction of multiple receptors, exerts physiological functions, is considered to be an important adaptor molecule of innate immunity, adaptive immunity and apoptosis signal pathways, and plays an important role in various diseases such as inflammation, tumor, autoimmune disease and the like.
Based on the important biological mechanism of action for RIP2 kinase, patent WO2016/042087 discloses a series of macrocyclic pyrazolopyrimidine compounds having nanomolar inhibitory activity against RIP2 kinase. Another patent US 2021/0163499 discloses a series of RIP2 kinase inhibitors having a pyrazolopyrimidine structure. 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol is an important intermediate for a plurality of RIP2 kinase inhibitors including the above patent, and no synthetic method thereof is reported in the literature at present.
Disclosure of Invention
The invention provides a preparation method of an intermediate 3-bromo-5-chloropyrazole [1,5-a ] pyrimidine-6-ol of an RIP2 kinase inhibitor, which is prepared by taking 3-amino-4-bromopyrazole as an initial raw material through three steps of cyclization, chlorination and demethylation.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a method for synthesizing an RIP2 kinase inhibitor intermediate, comprising the steps of:
dissolving a compound with a structure shown in a formula I in a certain amount of organic solvent, adding dimethyl methoxymalonate and alkali, reacting at a certain temperature, adding water for dilution after the reaction is finished, adjusting the pH value to acidity, and filtering to obtain brown solid, namely the compound with the structure shown in a formula II;
dissolving the compound with the structure shown in the formula II in an organic solvent or reacting the compound with a halogen donor under a certain condition without the solvent, and after the reaction is completed, dropwise adding the reaction liquid into ice water to obtain brown solid, namely the compound with the structure shown in the formula III;
dissolving the structural compound shown in the formula III in an organic solvent, adding a demethylating reagent, after the reaction is finished, evaporating reaction liquid by rotary evaporation, adding water for dilution, adjusting the pH value to be alkaline, washing the organic solvent, adjusting the pH value of a water phase to be acidic, and obtaining a light yellow solid, namely the structural compound shown in the formula IV, namely the RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazole [1,5-a ] pyrimidine-6-ol;
wherein the synthetic route of the 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol is as follows:
in some embodiments of the present invention, in the first step, the organic solvent used for dissolving the compound having a structure represented by formula I comprises any one or a mixture of two or more of dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
Preferably, in the first step, the organic solvent used for dissolving the structural compound shown in formula I is any one of N, N-dimethylformamide and dimethyl sulfoxide.
In some embodiments of the present invention, in the first step, the amount of the organic solvent used for dissolving the compound having the structure represented by formula I is 3 to 10 times by volume of the mass of the compound having the structure represented by formula I.
Preferably, in the first step, the amount of the organic solvent used for dissolving the compound having the structure shown in formula I is 5 to 10 times of the mass of the compound having the structure shown in formula I.
In some embodiments of the present invention, in the first step, the amount of dimethyl methoxymalonate used is 1 to 4 equivalents of the structural compound represented by formula I.
Preferably, in the first step, the usage amount of the dimethyl methoxymalonate is 1 to 3 equivalents of the compound having the structure shown in the formula I.
In some embodiments of the present invention, in the step one, the base added in the reaction is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, triethylamine and diisopropylethylamine.
Preferably, in the step one, the base added in the reaction is any one of sodium carbonate, potassium carbonate and cesium carbonate.
In some embodiments of the present invention, in the first step, the amount of the base is 1 to 4 equivalents of the compound having the structure shown in formula I.
Preferably, in the step one, the amount of the base used is 1 to 3 equivalents of the compound having the structure shown in formula I.
In some embodiments of the present invention, in the first step, the reaction temperature of the compound of formula I and dimethyl methoxymalonate is 110 ℃ to 160 ℃.
Preferably, in the first step, the reaction temperature of the compound with the structure shown in the formula I and dimethyl methoxymalonate is 110-140 ℃.
In some embodiments of the present invention, in the step one, after the reaction is completed, water is added in an amount of 3 to 10 times by volume of the mass of the structural compound represented by formula I.
Preferably, in the step one, after the reaction is completed, the amount of water added is 5-10 times of the mass of the structural compound shown in the formula I.
In some embodiments of the present invention, in the second step, the organic solvent used for dissolving the compound having a structure represented by formula II comprises any one of acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide, or a mixture of two or more thereof, or is solvent-free.
Preferably, in the second step, the organic solvent used for dissolving the structural compound represented by formula II includes any one of acetonitrile, N-dimethylformamide, and dimethylsulfoxide, or a mixture of two or more thereof, or no solvent.
In some embodiments of the present invention, in the second step, the amount of the organic solvent used for dissolving the compound having the structure represented by formula II is 0 to 10 times by volume of the mass of the compound having the structure represented by formula II.
Preferably, in the second step, the amount of the organic solvent used for dissolving the compound having the structure represented by formula II is 0 to 8 times by volume of the mass of the compound having the structure represented by formula II.
In some embodiments of the present invention, in the second step, the halogen donor is any one of phosphorus pentachloride, phosphorus trichloride, thionyl chloride and phosphorus oxychloride.
Preferably, in the second step, the halogen donor is any one of thionyl chloride and phosphorus oxychloride.
In some embodiments of the present invention, in the second step, the amount of the halogen donor is 2 to 20 equivalents of the structural compound represented by formula II.
Preferably, in the second step, the amount of the halogen donor used is 2 to 15 equivalents of the compound having the structure represented by formula II.
In some embodiments of the present invention, in the second step, the reaction temperature of the halogen donor and the compound having the structure represented by formula II is 80 ℃ to 140 ℃.
Preferably, in the second step, the reaction temperature of the halogen donor and the structural compound represented by the formula II is 80-120 ℃.
In some embodiments of the present invention, in step three, the organic solvent used for dissolving the compound having the structure represented by formula III comprises any one of acetonitrile, dichloromethane, dichloroethane and tetrahydrofuran.
Preferably, in the third step, the organic solvent used for dissolving the structural compound represented by formula III is any one of acetonitrile and dichloromethane.
In some embodiments of the present invention, in step three, the amount of the organic solvent used for dissolving the compound having the structure represented by formula III is 1 to 10 times by volume of the mass of the compound having the structure represented by formula III.
Preferably, in the third step, the amount of the organic solvent used for dissolving the compound having the structure shown in the formula III is 2-8 times of the mass of the compound having the structure shown in the formula III.
In some embodiments of the present invention, in step three, the demethylating agent is any one of aluminum trichloride and iodotrimethylsilane.
In some embodiments of the present invention, in step three, the amount of the demethylating agent is 3 to 10 equivalents of the compound having a structure represented by formula III;
preferably, in the third step, the amount of the demethylating reagent is 3-8 equivalents of the structural compound shown in the formula III;
in a second aspect, the present invention also provides 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol prepared according to the above synthetic process.
Compared with the prior art, the invention provides an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol and a synthesis method thereof, and the synthesis method has the following beneficial effects:
the invention provides a new synthetic approach, which is prepared by taking 3-amino-4-bromopyrazole as an initial raw material and performing three-step reactions of cyclization, chlorination and demethylation.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a one-dimensional nuclear magnetic hydrogen spectrum of a compound of formula IV synthesized in example 1 of the present invention;
FIG. 2 is a mass spectrum of a compound of formula IV synthesized in example 1;
FIG. 3 is a high performance liquid chromatogram of a compound of formula IV synthesized in example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The raw materials used in the invention are as follows: wherein, the chemical name of the compound with the structure shown in the formula I is 3-amino-4-bromopyrazole, and the material dimethyl 2-methoxy malonate reacted with the compound is a raw material which can be obtained by commercial means; other reagents such as halogen donors, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosphorus oxychloride, bases including sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, triethylamine, diisopropylethylamine, and the organic reagents of the present invention are commercially available.
In order to facilitate a clearer understanding of the present disclosure, the present disclosure will now be described in further detail with reference to specific examples.
The reagents used according to the invention are, unless otherwise specified, all customary reagents available on the market, the operating temperatures involved, unless otherwise stated, being carried out at room temperature.
Example 1
The embodiment provides a synthesis method of an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol, which specifically comprises the following steps:
(1) adding a compound with a structure shown in a formula I into a reaction kettle, adding N, N-dimethylacetamide with the volume being 8 times of the mass of the compound with the structure shown in the formula I, adding 2.5 equivalents of 2-methoxy dimethyl malonate and 3 equivalents of potassium carbonate into the compound with the structure shown in the formula I, heating to 125 ℃ under stirring, and carrying out heat preservation reaction for 5 hours. After the reaction is monitored by thin layer chromatography, ice water with the volume 10 times of that of the compound with the structure shown in the formula I is added for dilution, concentrated hydrochloric acid is used for adjusting the pH value to 2, a brown solid is separated out, and the compound with the structure shown in the formula II, namely 3-bromo-6-methoxy pyrazolo [1,5-a ] pyrimidine-5 (4H) -ketone, is obtained by filtration, wherein the yield is 91.56%.
(2) Adding phosphorus oxychloride with the volume 5 times of the mass of the compound with the structure shown in the formula II into a reaction kettle, adding the compound with the structure shown in the formula II into the reaction kettle while stirring, heating to reflux, and reacting overnight. After the reaction is finished, the solvent is removed to one fourth of the original volume to obtain a black viscous object. Slowly adding the black viscous substance into ice water, separating out a large amount of brown solid, and filtering to obtain the compound 3-bromo-5-chloro-6-methoxy pyrazolo [1,5-a ] pyrimidine with the structure shown in the formula III, wherein the yield is 92.33%.
(3) Adding dichloromethane with the mass of 8 times of that of the structural compound shown in the formula III into a reaction kettle, cooling to 0 ℃, slowly adding 3.5 equivalents of iodotrimethylsilane of the structural compound shown in the formula III, keeping the temperature and stirring, after the reaction is finished, evaporating the solvent by rotation, adding purified water with the mass of 5 times of that of the structural compound shown in the formula III for dilution, adjusting the pH value to be alkaline by using sodium hydroxide until the solid is completely dissolved, adding ethyl acetate with the mass of 5 times of that of the structural compound shown in the formula III for washing for 2 times, and discarding the organic phase. Adjusting the pH value of the water phase to 2 by using concentrated hydrochloric acid, precipitating a large amount of solid, and filtering to obtain a light yellow solid, namely a compound with a structure shown in formula IV, which is an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol, wherein the yield is 91.46%.
1 H NMR(DMSO-d 6 ,400MHz.):δ11.0562(s,1H),8.5836(s,1H),8.2199-8.2176(d,J＝0.92Hz 1H).LC-MS:(m/z)248.0[M+1] + .HPLC purity:95.322％。
Example 2
The embodiment provides a synthesis method of an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol, which specifically comprises the following steps:
(1) adding a compound with a structure shown in a formula I into a reaction kettle, adding N, N-dimethylformamide with the volume 10 times that of the compound with the structure shown in the formula I, adding 2 equivalents of dimethyl 2-methoxy malonate and 2.5 equivalents of sodium carbonate into the compound with the structure shown in the formula I, heating to 115 ℃ under stirring, and carrying out heat preservation reaction for 5 hours. After the reaction is monitored by thin layer chromatography, ice water with the volume 10 times of that of the compound with the structure shown in the formula I is added for dilution, concentrated hydrochloric acid is used for adjusting the pH value to 2, a brown solid is separated out, and the compound with the structure shown in the formula II, namely 3-bromo-6-methoxy pyrazolo [1,5-a ] pyrimidine-5 (4H) -ketone, is obtained by filtration, wherein the yield is 93.46%.
(2) Adding thionyl chloride with the volume 5 times of the mass of the compound with the structure shown in the formula II into the reaction kettle, stirring, adding the compound with the structure shown in the formula II, heating to reflux, and reacting overnight. After the reaction is finished, the solvent is removed to one fourth of the original volume to obtain a black viscous object. Slowly adding the black viscous substance into ice water, separating out a large amount of brown solid, and filtering to obtain the compound 3-bromo-5-chloro-6-methoxypyrazolo [1,5-a ] pyrimidine with the structure shown in the formula III, wherein the yield is 89.26%.
(3) Adding acetonitrile with the volume 8 times of the mass of the structural compound shown in the formula III into a reaction kettle, cooling to 0 ℃, slowly adding 3 equivalents of aluminum trichloride of the structural compound shown in the formula III, keeping the temperature and stirring, evaporating the solvent after the reaction is finished, adding purified water with the volume 5 times of the mass of the structural compound shown in the formula III for dilution, adjusting the pH value to be alkaline by using sodium hydroxide until the solid is completely dissolved, adding dichloromethane with the volume 5 times of the mass of the structural compound shown in the formula III, washing for 2 times, and discarding the organic phase. Adjusting the pH value of the water phase to 2 by concentrated hydrochloric acid, precipitating a large amount of solid, and filtering to obtain a light yellow solid which is a compound with a structure shown in formula IV and is an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol, wherein the yield is 90.23%.
Example 3
The embodiment provides a synthesis method of an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol, which specifically comprises the following steps:
(1) adding a compound with a structure shown in a formula I into a round-bottom flask, adding dimethyl sulfoxide with the volume being 10 times that of the compound with the structure shown in the formula I, adding 3 equivalents of dimethyl 2-methoxy malonate and 3 equivalents of cesium carbonate into the compound with the structure shown in the formula I, heating to 130 ℃ under stirring, and carrying out heat preservation reaction for 4 hours. After the reaction is monitored by thin layer chromatography, ice water with the volume 10 times of that of the compound with the structure shown in the formula I is added for dilution, concentrated hydrochloric acid is used for adjusting the pH value to 2, a brown solid is separated out, and the compound with the structure shown in the formula II, namely 3-bromo-6-methoxy pyrazolo [1,5-a ] pyrimidine-5 (4H) -ketone, is obtained by filtration, wherein the yield is 89.96%.
(2) Adding acetonitrile with the volume 5 times of the mass of the compound with the structure shown in the formula II into a reaction kettle, adding the compound with the structure shown in the formula II under stirring, slowly dropwise adding 3 equivalents of phosphorus oxychloride into the compound with the structure shown in the formula II, heating to reflux, and reacting overnight. After the reaction is finished, the solvent is removed to one fourth of the original volume to obtain a black viscous object. The black viscous substance was slowly added to ice water to precipitate a large amount of brown solid, which was then filtered to obtain 3-bromo-5-chloro-6-methoxypyrazolo [1,5-a ] pyrimidine, a structural compound represented by formula III, in 83.29% yield.
(3) Adding dichloromethane with the volume 8 times of the mass of the structural compound shown in the formula III into a reaction kettle, cooling to 0 ℃, slowly adding 5 equivalents of aluminum trichloride of the structural compound shown in the formula III, keeping the temperature and stirring, evaporating the solvent after the reaction is finished, adding purified water with the volume 5 times of the mass of the structural compound shown in the formula III for dilution, adjusting the pH value to be alkaline by using sodium hydroxide until the solid is completely dissolved, adding dichloromethane with the volume 5 times of the mass of the structural compound shown in the formula III, washing for 2 times, and discarding the organic phase. Adjusting the pH value of the water phase to 2 by concentrated hydrochloric acid, precipitating a large amount of solid, and filtering to obtain a light yellow solid which is a compound with a structure shown in formula IV and is an RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol, wherein the yield is 92.47%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (14)
1. A synthesis method of an RIP2 kinase inhibitor intermediate is characterized by comprising the following steps:
dissolving a compound with a structure shown in a formula I in a certain amount of organic solvent, adding dimethyl methoxymalonate and alkali, reacting at a certain temperature, adding water for dilution after the reaction is finished, adjusting the pH value to acidity, and filtering to obtain brown solid, namely the compound with the structure shown in a formula II;
dissolving the compound with the structure shown in the formula II in an organic solvent or reacting the compound with a halogen donor under a certain condition without the solvent, and after the reaction is completed, dropwise adding the reaction liquid into ice water to obtain brown solid, namely the compound with the structure shown in the formula III;
dissolving the structural compound shown in the formula III in an organic solvent, adding a demethylating reagent, after the reaction is finished, evaporating reaction liquid by rotary evaporation, adding water for dilution, adjusting the pH value to be alkaline, washing the organic solvent, adjusting the pH value of a water phase to be acidic, and obtaining a light yellow solid, namely the structural compound shown in the formula IV, namely the RIP2 kinase inhibitor intermediate 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol;
wherein the synthetic route of the 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidine-6-ol is as follows:
2. the method of synthesis according to claim 1, characterized in that: in the first step, the organic solvent used for dissolving the compound with the structure shown in the formula I comprises any one or a mixture of more than two of dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide, and the using amount of the organic solvent is 3-10 times of the mass of the compound with the structure shown in the formula I.
3. The method of synthesis according to claim 1, characterized in that: in the first step, the usage amount of the dimethyl methoxymalonate is 1-4 equivalents of the compound having the structure shown in the formula I.
4. The method of synthesis according to claim 1, characterized in that: in the first step, the alkali added in the reaction is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, triethylamine and diisopropylethylamine, and the usage amount is 1-4 equivalents of the structural compound shown in the formula I.
5. The method of synthesis according to claim 1, characterized in that: in the first step, the reaction temperature of the compound with the structure shown in the formula I and dimethyl methoxymalonate is 110-160 ℃.
6. The method of synthesis according to claim 1, characterized in that: in the first step, after the reaction is finished, the amount of added water is 3-10 times of the mass of the compound with the structure shown in the formula I.
7. The method of synthesis according to claim 1, characterized in that: in the second step, the organic solvent used for dissolving the structural compound shown in the formula II comprises one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide, and is mixed or solvent-free, and the using amount of the organic solvent is 0-10 times of the mass of the structural compound shown in the formula II.
8. The method of synthesis according to claim 1, characterized in that: in the second step, the halogen donor is any one of phosphorus pentachloride, phosphorus trichloride, thionyl chloride and phosphorus oxychloride.
9. The method of synthesis according to claim 1, characterized in that: in the second step, the usage amount of the halogen donor is 2-20 equivalents of the structural compound shown in the formula II.
10. The method of synthesis according to claim 1, characterized in that: in the second step, the reaction temperature of the halogen donor and the compound with the structure shown in the formula II is 80-140 ℃.
11. The method of synthesis according to claim 1, characterized in that: in the third step, the organic solvent used for dissolving the compound with the structure shown in the formula III comprises any one of acetonitrile, dichloromethane, dichloroethane and tetrahydrofuran, and the using amount of the organic solvent is 1-10 times of the mass of the compound with the structure shown in the formula III.
12. The method of synthesis according to claim 1, characterized in that: in the third step, the demethylating reagent is any one of aluminum trichloride and iodotrimethylsilane.
13. The method of synthesis according to claim 1, characterized in that: in the third step, the amount of the demethylating reagent is 3-10 equivalents of the structural compound shown in the formula III.
14. 3-bromo-5-chloropyrazolo [1,5-a ] pyrimidin-6-ol prepared according to the synthesis method of any one of claims 1 to 13.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102317291A (en) * | 2009-02-13 | 2012-01-11 | 拜耳医药股份有限公司 | Fused pyrimidines |
| WO2021152165A1 (en) * | 2020-01-31 | 2021-08-05 | Oncodesign S.A. | Macrocyclic rip2-kinase inhibitors |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102317291A (en) * | 2009-02-13 | 2012-01-11 | 拜耳医药股份有限公司 | Fused pyrimidines |
| WO2021152165A1 (en) * | 2020-01-31 | 2021-08-05 | Oncodesign S.A. | Macrocyclic rip2-kinase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| 刘举: "6-芳基取代吡唑并[1,5-a]嘧啶的合成" * |
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