CN112028880A - Oxitinib dimer, preparation method and application thereof - Google Patents
Oxitinib dimer, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicines, and particularly relates to an oxitinib dimer, a preparation method and application thereof, wherein the oxitinib dimer has a chemical structure as follows:
. The synthesis of the Oxitinib dimer takes the compound 1 as a starting material, gradually adds acrylic anhydride and acrylic acid according to a synthesis route in an intermediate reaction process, and prepares the Oxitinib dimer through reduction, acylation, addition and condensation.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an oxitinib dimer, and a preparation method and application thereof.
Background
Oxitinib (Osimertinib), having the trade name TAGRISSO, was developed by asikang ltd, usa, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have been treated with an Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) or have developed disease progression before or after treatment, and were confirmed to have positive EGFR T790M mutation by examination. About 30% -40% of patients with non-small cell lung cancer develop EGFR mutation, while about two thirds of patients develop drug resistance due to T790M mutation and the disease progresses again in EGFR mutation patients treated by traditional EGFR-TKI drugs (such as gefitinib, erlotinib and erlotinib), and the concentration of irreversible binding of Oxitinib to EGFR mutants (T790M, L858R and exon 19 deletion) is about 9 times lower than that of wild type, so that the new drug will become the cause of doctors for treating patients of this type.
Oxitinib has CAS number [1421373-65-0] and chemical name N- [2- (2-dimethylaminoethylmethylamino) -4-methoxy-5- [ (4- (1-methyl-1H-indol-3-yl) -2-pyrimidine) aminophenyl ] acrylamide, or 2- (2-methoxy-4- (2-dimethylaminoethylmethyl) amino-5-acrylamido) anilino-4- (N-methylindol-3-yl) pyrimidine, and has the following structural formula:
in the preparation process of the oxitinib, oxitinib dimer may be generated, and the existence of the oxitinib dimer not only affects the purity of the oxitinib, but also affects the safety, effectiveness and quality controllability of the medicine, and may bring non-therapeutic toxic and side effects, so that the determination of the preparation method of the oxitinib dimer and the impurity control by using the clear oxitinib dimer have important significance for effectively controlling the quality of the oxitinib.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide an oxitinib dimer, a preparation method and application thereof, provides an impurity reference substance for the quality research of oxitinib, and has important guiding significance for improving the quality standard of oxitinib and the safe medication of oxitinib.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides an oxitinib dimer, wherein the oxitinib dimer has a chemical structural formula:
wherein Me represents methyl, the chemical name of the oxitinib dimer is N- (2- ((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) ethyl) -3- ((2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) amino) -N, N-dimethyl-3-oxopropan-1-amino, and the molecular formula is C.56H67N14O4And the molecular weight is 1000.2. The oxitinib dimer can be used as an impurity reference substance, is applied to qualitative and quantitative research and detection of oxitinib impurities, has important significance for effectively controlling the quality of oxitinib, and provides guarantee for safe medication of oxitinib.
In a second aspect, the present invention provides a method for preparing an oxitinib dimer according to the first aspect, comprising the following steps:
synthesis of intermediate 2:
carrying out reduction reaction on the compound 1 in a first reaction solvent under the action of a catalyst and hydrogen to obtain an intermediate 2;
synthesis of intermediate 3:
carrying out acylation reaction on the intermediate 2 and acrylic anhydride in a second reaction solvent under the action of an acid-binding agent to obtain an intermediate 3;
synthesis of intermediate 4:
heating the intermediate 3 and acrylic acid in a third reaction solvent for addition reaction to obtain an intermediate 4;
synthesis of oxitinib dimer:
and heating the intermediate 4 and the intermediate 2 in a fourth reaction solvent under the action of a condensing agent to perform condensation reaction to obtain the oxitinib dimer.
Preferably, in the step of synthesizing the intermediate 2, the catalyst comprises at least one of palladium carbon and raney nickel, the first reaction solvent comprises at least one of methanol, ethanol, isopropanol, toluene and tetrahydrofuran, the mass ratio of the catalyst to the compound 1 is 0.05-0.25, the reaction temperature is 20-50 ℃, and the reaction time is 3-6 h.
In any of the above embodiments, in the step of synthesizing the intermediate 2, the mass ratio of the catalyst to the compound 1 is preferably 0.1 to 0.2.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 2, the reaction time is 4-5 h.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 2, the reaction temperature is 35 ℃ to 45 ℃.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 3, the acid-binding agent includes at least one of N, N-Diisopropylethylamine (DIEA), triethylamine, and pyridine, the second reaction solvent includes at least one of dichloromethane, acetone, tetrahydrofuran, acetonitrile, and toluene, the molar ratio of the acid-binding agent to the intermediate 2 is 1-3, the reaction temperature is 0-15 ℃, and the reaction time is 1-5 h.
In any of the above schemes, it is preferred that in the step of synthesis of said intermediate 3, the reaction temperature is 0 ℃ to 10 ℃.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 3, the reaction time is 2-3 h.
In any of the above embodiments, in the step of synthesizing the intermediate 3, the molar ratio of the acid scavenger to the intermediate 2 is preferably 1 to 1.5.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 4, the third reaction solvent is water, the molar ratio of the acrylic acid to the intermediate 3 is 2-10, the reaction temperature is 30-80 ℃, and the reaction time is 1-4 h.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 4, the reaction temperature is 40 ℃ to 60 ℃.
In any of the above schemes, preferably, in the step of synthesizing the intermediate 4, the reaction time is 1-2 h.
In any of the above embodiments, preferably, in the step of synthesizing the oxitinib dimer, the condensing agent includes at least one of N, N '-Diisopropylcarbodiimide (DIC) and N, N' -Carbonyldiimidazole (CDI), the fourth reaction solvent includes at least one of N, N-Dimethylformamide (DMF) and N, N-dimethylacetamide, a molar ratio of the condensing agent to the intermediate 4 is 1 to 3, a reaction temperature is 40 to 70 ℃, and a reaction time is 3 to 8 hours.
In any of the above embodiments, in the step of synthesizing the oxicetinib dimer, the molar ratio of the condensing agent to the intermediate 4 is preferably 1.5 to 2.5.
In any of the above schemes, preferably, in the step of synthesizing the oxitinib dimer, the reaction temperature is 50 ℃ to 60 ℃.
In any of the above schemes, preferably, in the step of synthesizing the oxitinib dimer, the reaction time is 4-6 h.
The invention provides a preparation method of an oxitinib dimer, which comprises the steps of taking a compound 1 (the chemical name is N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methyl-1H-indol-3-yl) pyrimidine-2-yl) -2-nitrobenzene-1, 4-diamine) as a starting material, gradually adding acrylic anhydride and acrylic acid according to a synthetic route, and carrying out reduction, acylation, addition and condensation to obtain the oxitinib dimer. In the synthesis of the intermediate 2, the compound 1 is subjected to a reduction reaction in a first reaction solvent under the action of a catalyst and hydrogen; during the synthesis of the intermediate 3, the intermediate 2 and acrylic anhydride are subjected to acylation reaction in a second reaction solvent under the action of an acid-binding agent; heating the intermediate 3 and acrylic acid in a third reaction solvent for addition reaction during the synthesis of the intermediate 4; in the synthesis of the oxitinib dimer, the intermediate 4 and the intermediate 2 are heated in a fourth reaction solvent under the action of a condensing agent to carry out a condensation reaction. The preparation method is simple, convenient to operate, low in requirement on equipment conditions, easy to realize and simple in post-treatment, and the oxitinib dimer prepared by the preparation method is high in purity, can be used as an impurity reference substance to be applied to qualitative and quantitative research and detection of oxitinib impurities, has important significance for effectively controlling the quality of oxitinib, and provides guarantee for safe medication of oxitinib.
In a third aspect, the present invention provides a use of the aforementioned oxitinib dimer, wherein the oxitinib dimer is used as a standard control in an oxitinib-related substance examination.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an oxitinib dimer obtained in example 1 of the present invention;
FIG. 2 is a mass spectrum of an oxitinib dimer obtained in example 1 of the present invention;
FIG. 3 is a high performance liquid chromatography chromatogram of an oxitinib dimer obtained in example 1 of the present invention;
FIG. 4 is a peak table of HPLC chromatogram of the oxitinib dimer obtained in example 1 of the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In a first aspect, an embodiment of the present invention provides an oxitinib dimer, where a chemical structural formula of the oxitinib dimer is:
the oxitinib dimer has the chemical name of N- (2- ((2-acrylamide-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) ethyl) -3- ((2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) amino) -N, N-dimethyl-3-oxopropane-1-amino and the molecular formula of C56H67N14O4And the molecular weight is 1000.2. The oxitinib dimer can be used as an impurity reference substance, has important significance for effectively controlling the quality of oxitinib, can be applied to qualitative and quantitative research and detection of oxitinib impurities, and provides guarantee for safe medication of oxitinib.
In a second aspect, the embodiments of the present invention further provide a method for preparing an ocitinib dimer according to the first aspect, including the following steps:
(1) synthesis of intermediate 2:
carrying out reduction reaction on the compound 1 in a first reaction solvent under the action of a catalyst and hydrogen to obtain an intermediate 2;
(2) synthesis of intermediate 3:
carrying out acylation reaction on the intermediate 2 and acrylic anhydride in a second reaction solvent under the action of an acid-binding agent to obtain an intermediate 3;
(3) synthesis of intermediate 4:
heating the intermediate 3 and acrylic acid in a third reaction solvent for addition reaction to obtain an intermediate 4;
(4) synthesis of oxitinib dimer:
and heating the intermediate 4 and the intermediate 2 in a fourth reaction solvent under the action of a condensing agent to perform condensation reaction to obtain the oxitinib dimer.
The preparation method of the Oxitinib dimer provided by the invention comprises the steps of taking the compound 1 as a starting material, gradually adding acrylic anhydride and acrylic acid according to a synthetic route, and carrying out reduction, acylation, addition and condensation to obtain the Oxitinib dimer. In the synthesis of the intermediate 2, the compound 1 is subjected to a reduction reaction in a first reaction solvent under the action of a catalyst and hydrogen; during the synthesis of the intermediate 3, the intermediate 2 and acrylic anhydride are subjected to acylation reaction in a second reaction solvent under the action of an acid-binding agent; heating the intermediate 3 and acrylic acid in a third reaction solvent for addition reaction during the synthesis of the intermediate 4; in the synthesis of the oxitinib dimer, the intermediate 4 and the intermediate 2 are heated in a fourth reaction solvent under the action of a condensing agent to carry out a condensation reaction. The preparation method is simple, convenient to operate, low in requirement on equipment conditions, easy to realize and simple in post-treatment, and the oxitinib dimer prepared by the preparation method is high in purity, can be used as an impurity reference substance to be applied to qualitative and quantitative research and detection of oxitinib impurities, has important significance for effectively controlling the quality of oxitinib, and provides guarantee for safe medication of oxitinib.
Further, in the step (1), the catalyst includes at least one of palladium carbon and raney nickel, wherein the palladium carbon is 10% wet palladium carbon, and the moisture content is 62%.
Further, in the step (1), the mass ratio of the catalyst to the compound 1 is 0.05 to 0.25, for example, the mass ratio of the catalyst to the compound 1 is 0.05, 0.1, 0.15, 0.2, 0.25, or the like.
Further, in the step (1), the first reaction solvent includes at least one of methanol, ethanol, isopropanol, toluene, and tetrahydrofuran.
Further, in the step (1), the reaction temperature is 20 ℃ to 50 ℃, for example, the reaction temperature is 20 ℃, 30 ℃, 40 ℃ or 50 ℃, and the like. Preferably, the reaction temperature is 35 ℃ to 45 ℃, for example, the reaction temperature is 35 ℃, 38 ℃, 39 ℃, 41 ℃, 43 ℃ or 45 ℃ and the like.
Further, in the step (1), the reaction time is 3 h-6 h, for example, the reaction time is 3h, 4h, 5h or 6 h.
Further, in the step (2), the acid scavenger comprises at least one of N, N-Diisopropylethylamine (DIEA), triethylamine, and pyridine.
Further, in the step (2), the second reaction solvent includes at least one of dichloromethane, acetone, tetrahydrofuran, acetonitrile, and toluene.
Further, in the step (2), the molar ratio of the acid-binding agent to the intermediate 2 is 1 to 3, for example, the molar ratio of the acid-binding agent to the intermediate 2 is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, or 3.
Further, in the step (2), the reaction temperature is 0 ℃ to 15 ℃, for example, the reaction temperature is 0 ℃, 3 ℃, 6 ℃, 9 ℃, 12 ℃ or 15 ℃.
Further, in the step (2), the reaction time is 1 h-5 h, for example, the reaction time is 1h, 2h, 3h, 4h or 5 h. Preferably, the reaction time is 2h to 3h, for example, the reaction time is 2.2h, 2.4h, 2.6h or 2.8 h.
Further, in the step (3), the third reaction solvent is water.
Further, in the step (3), the molar ratio of the acrylic acid to the intermediate 3 is 2 to 10, for example, the molar ratio of the acrylic acid to the intermediate 3 is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
Further, in the step (3), the reaction temperature is 30 ℃ to 80 ℃, for example, the reaction temperature is 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.
Further, in the step (3), the reaction time is 1h to 4h, for example, the reaction time is 1h, 2h, 3h or 4 h.
Further, in the step (4), the condensing agent includes at least one of N, N '-diisopropylcarbodiimide and N, N' -carbonyldiimidazole.
Further, in the step (4), the fourth reaction solvent includes at least one of N, N-dimethylformamide and N, N-dimethylacetamide.
Further, in the step (4), the molar ratio of the condensing agent to the intermediate 4 is 1 to 3, for example, the molar ratio of the condensing agent to the intermediate 4 is 1, 1.5, 2, 2.5, 3, or the like.
Further, in the step (4), the reaction temperature is 40 ℃ to 70 ℃, for example, the reaction temperature is 40 ℃, 50 ℃, 60 ℃ or 70 ℃, and the like. When the reaction temperature is too low, the reaction time becomes long; when the reaction temperature is too high, side reactions occur, so that the yield of the oxitinib dimer is influenced, and the purity of the oxitinib dimer is also influenced. In the embodiment, the reaction temperature is controlled to be between 40 ℃ and 70 ℃, so that the reaction time can be ensured to be short, and side reactions can be avoided. Preferably, the reaction temperature is 50 ℃ to 60 ℃, for example, the reaction temperature is 52 ℃, 54 ℃, 56 ℃ or 58 ℃, and the like, and the yield of the oxitinib dimer is high in the temperature range.
Further, in the step (4), the reaction time is 3h to 8h, for example, the reaction time is 3h, 4h, 5h, 6h, 7h or 8h, and the like, and when the reaction time is too short, a phenomenon that the raw materials remain after the reaction, that is, the reaction is incomplete, may occur, so as to reduce the yield of the oxitinib dimer, and in this embodiment, the reaction time is controlled to be 3h to 8h, which may ensure that the yield of the oxitinib dimer is higher while the reaction is complete.
And (3) concentrating the reaction solution after the reaction in the step (4) at 50 ℃ under reduced pressure until the reaction solution is dried, purifying the obtained residue by a silica gel column chromatography separation and purification method, wherein an eluent is dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 20:1, collecting eluent, and concentrating the eluent at 40 ℃ under reduced pressure until the eluent is dried to obtain a yellow solid.
The method is detected according to a high performance liquid chromatography method in a Chinese pharmacopoeia method of 2015 edition, the purity of the Oxitinib dimer is determined according to an HPLC (high performance liquid chromatography) area normalization method, and the purity of the Oxitinib dimer obtained according to a detection result is 99.32%, and the purity is very high, so that the Oxitinib dimer obtained by the preparation method can be used as a standard substance, can be applied to qualitative and quantitative research and detection of Oxitinib impurities, and has important significance for effectively controlling the quality of Oxitinib.
The preferable steps of the preparation method of the oxitinib dimer provided by the embodiment of the invention are as follows:
(1) synthesis of intermediate 2:
the compound 1 is subjected to reduction reaction in ethanol under the action of a catalyst and hydrogen, the mass ratio of the catalyst to the compound 1 is 0.1-0.2, the reaction temperature is controlled to be 20-50 ℃, the reaction time is 4-5 h, and an intermediate 2 is finally obtained;
(2) synthesis of intermediate 3:
carrying out acylation reaction on the intermediate 2 and acrylic anhydride in dichloromethane under the action of N, N-Diisopropylethylamine (DIEA), wherein the molar ratio of the N, N-Diisopropylethylamine (DIEA) to the intermediate 2 is 1-1.5, the reaction temperature is controlled to be 0-10 ℃, the reaction time is 2-3 h, and the intermediate 3 is finally obtained;
(3) synthesis of intermediate 4:
heating the intermediate 3 and acrylic acid in water to perform addition reaction, wherein the molar ratio of the acrylic acid to the intermediate 3 is 2-10, the reaction temperature is controlled to be 40-60 ℃, and the reaction time is 1-2 h, so that an intermediate 4 is finally obtained;
(4) synthesis of oxitinib dimer:
and heating the intermediate 4 and the intermediate 2 in N, N-Dimethylformamide (DMF) under the action of N, N '-Diisopropylcarbodiimide (DIC) to perform condensation reaction, wherein the molar ratio of the N, N' -Diisopropylcarbodiimide (DIC) to the intermediate 4 is 2, the reaction temperature is controlled to be 50 ℃, and the reaction time is 4-6 hours, so that the Oxichtinib dimer is finally obtained.
In a third aspect, the present embodiment provides a use of the aforementioned oxitinib dimer, which is used as a standard control in an oxitinib-related substance test.
The invention is described in further detail with reference to a number of tests performed in sequence, and a part of the test results are used as reference, and the following detailed description is given with reference to specific examples.
The synthetic routes of the examples described below are all shown in the following figures:
example 1
Step (1) synthesis of intermediate 2:
adding 10g of compound 1 (N1- [2- (dimethylamino) ethyl ] -5-methoxy-N1-methyl-N4- [4- (1-methyl-3-indolyl) -2-pyrimidinyl ] -2-nitro-1, 4-phenylenediamine, 21.05 mmol), 1.0g of 10% wet palladium-carbon (moisture content of 62%) and 100mL of ethanol into a reaction flask, stirring and heating to 40 ℃, introducing hydrogen into the reaction flask, reacting for 4 hours, detecting the reaction progress by TLC (thin layer chromatography), using dichloromethane and methanol as developing agents, wherein the volume ratio of the dichloromethane to the methanol is 10:1, filtering while hot after the reaction is finished, cooling the filtrate to 5 ℃, stirring, slowly adding 20mL of water, then maintaining the same temperature and stirring for 2 hours, and (3) separating out crystals, performing suction filtration, leaching a filter cake with 5mL of water, and then performing vacuum drying treatment on the filter cake at the drying temperature of 45 ℃ for 8 hours to obtain 8.2g of yellow solid with the yield of 87.5%. .
Step (2) synthesis of intermediate 3:
adding 5.9g of intermediate 2 (13.3 mmol), 90mL of dichloromethane and 2.0g of N, N-diisopropylethylamine (DIEA, 15.5 mmol) into a reaction bottle, stirring and cooling to 5 ℃, slowly dropwise adding 1.95g of acrylic anhydride (15.5 mmol), then continuing stirring at 5 ℃ for reaction for 2 hours, detecting the reaction progress by TLC (thin layer chromatography), using dichloromethane and methanol as developing agents, wherein the volume ratio of dichloromethane to methanol is 10:1, after the reaction is finished, adding 60mL of saturated sodium bicarbonate aqueous solution into the system, neutralizing the unreacted acrylic anhydride and acrylic acid in the system, stirring and standing for layering to obtain an organic layer 1 and an aqueous layer, extracting the aqueous layer once with 50mL of dichloromethane to obtain an organic layer 2, combining the organic layer 1 and the organic layer 2, concentrating the combined organic layer under reduced pressure at 40 ℃ until the organic layer is dried, adding 50mL of ethanol into the obtained residue, stirring at room temperature until the solution is clear, adding 10mL of water, continuing stirring at room temperature for 2 hours, precipitating crystals, performing suction filtration, and then performing vacuum drying treatment on the obtained solid at the drying temperature of 45 ℃ for 8 hours to obtain 4.1g of yellow solid with the yield of 62%.
And (3) synthesizing an intermediate 4:
adding 2.0g of intermediate 3 (4 mmol), 20mL of water and 1.7g of acrylic acid (23.6 mmol) into a reaction bottle, stirring and heating to 40 ℃, stirring and reacting for 2 hours, detecting the reaction progress by adopting TLC (thin layer chromatography), using dichloromethane and methanol as developing agents, wherein the volume ratio of dichloromethane to methanol is 10:1, concentrating the reaction liquid at 40 ℃ under reduced pressure until the reaction liquid is dry after the reaction is finished, purifying the obtained residue by column chromatography (silica gel 200 meshes and 300 meshes, using dichloromethane and methanol as eluent, wherein the volume ratio of dichloromethane to methanol is 30: 1), collecting eluent, and concentrating under reduced pressure at 40 ℃ until the obtained product is dry to obtain 520mg of yellow powder solid with the yield of 23%.
Step (4) synthesis of an oxitinib dimer:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 50 ℃, stirring for reaction for 5 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 50 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting, concentrating the obtained residue to dryness under reduced pressure at 40 ℃ to obtain 180mg of yellow solid, the yield thereof was found to be 21%.
The resulting yellow solid product was identified:
the nuclear magnetic resonance hydrogen spectrum of the yellow solid product is shown in figure 1,
1HNMR (400 MHz, DMSO-d 6) 9.65 (S, 1H), 9.49 (S, 1H), 9.22 (S, 1H), 8.80 (S, 1H), 8.61 (S, 1H), 8.49 (S, 1H), 8.32 (d, 1H), 8.27-8.31 (m, 3H), 7.52 (t, 2H), 7.23-7.28 (m, 4H), 7.14-7.20 (m, 2H), 7.04 (d, 2H), 6.66-6.71 (q, 1H), 6.23-6.26 (dd, 1H), 6.72-6.74 (d, 1H), 3.89 (d, 6H), 3.87 (d, 6H), 3.67 (m, 2H), 3.52 (m, 2H), 3.43(m, 2H), 3.30(m, 2H), 3.70 (m, 2H), 6H), 13.70 (m, 2H), S, 3.70H), S.
The Mass spectrum of the yellow solid product is shown in FIG. 2, the detection instrument is a Waters 3100 Mass Detector, the detection solvent is methanol and water solution with the volume ratio of 1:1, and the measured data is [ M + H ]]+= 1000.76, data corresponding to the compound having a molecular weight of 1000.2, indicating that the compound is oxitinib dimer, chemical name N- (2- ((2-acrylamido-5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) (methyl) amino) ethyl) -3- ((2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) amino) -N, N-dimethyl-3-oxopropan-1-amino, the chemical structural formula is as follows:
purity test of yellow solid product:
dissolving 4mg of a yellow solid product namely the oxitinib dimer in 10mL of acetonitrile-water (the volume ratio of acetonitrile to water is 6: 4) mixed solvent containing 0.04% by volume of trifluoroacetic acid to serve as a sample solution, wherein the sample concentration is 0.4mg/mL, the sample injection volume is 10uL, and the sample solution is measured according to a high performance liquid chromatography method in 2015 version Chinese pharmacopoeia method, the high performance liquid chromatography spectrogram and the peak table of the oxitinib dimer are shown in figures 3 and 4, and the purity of the yellow solid product is 99.32% according to the 2015 version Chinese pharmacopoeia method and the HPLC area normalization method according to the detection result.
Example 2
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the amount of the condensing agent in the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 166 mg of N, N' -diisopropylcarbodiimide (DIC, 1.31 mmol) under the protection of nitrogen, stirring, heating to 50 ℃, stirring for reaction for 5 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 50 ℃, carrying out column chromatography separation on the obtained residue (silica gel 200-300 meshes, eluent of dichloromethane and methanol and volume ratio of dichloromethane and methanol of 20: 1), collecting, concentrating the eluate to dryness under reduced pressure at 40 ℃ to obtain 150mg of yellow solid eluent, the yield thereof was found to be 17%.
Example 3
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the amount of the condensing agent in the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 275mg of N, N' -diisopropylcarbodiimide (DIC, 2.18 mmol) under the protection of nitrogen, stirring, heating to 50 ℃, stirring for reaction for 5 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 50 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluting solvent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting the eluate, concentrating the eluate to dryness under reduced pressure at 40 ℃ to obtain 183mg of yellow solid, the yield thereof was found to be 21%.
Example 4
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the reaction temperature of the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 60 ℃, stirring for reaction for 5 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 60 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting, concentrating the obtained residue to dryness under reduced pressure at 40 ℃ to obtain 170mg of yellow solid, the yield thereof was found to be 20%.
Example 5
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the reaction temperature of the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 40 ℃, stirring for reaction for 5 hours, detecting the reaction progress by TLC (thin layer chromatography), detecting the reaction progress by using a developing agent of dichloromethane and methanol with the volume ratio of dichloromethane to methanol being 10:1, after the reaction is finished, adding 5mL of water into the reaction solution, quenching the reaction, concentrating to dryness under reduced pressure at 40 ℃, purifying the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, an eluent of dichloromethane and methanol with the volume ratio of dichloromethane to methanol being 20: 1), collecting, concentrating to dryness under reduced pressure at 40 ℃ to obtain 160mg of yellow solid, the yield thereof was found to be 18%.
Example 6
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the reaction temperature of the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 70 ℃, stirring for reaction for 5 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 70 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting, concentrating the obtained residue to dryness under reduced pressure at 40 ℃ to obtain 145mg of yellow solid, the yield thereof was found to be 16%.
Example 7
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the reaction time of the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 50 ℃, stirring for reaction for 3 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 50 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting the eluate, concentrating the eluate to dryness under reduced pressure at 40 ℃ to obtain 165mg of yellow solid, the yield thereof was found to be 19%.
Example 8
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the reaction time of the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 50 ℃, stirring for reaction for 6 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 50 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting the eluate, concentrating the eluate to dryness under reduced pressure at 40 ℃ to obtain 182mg of yellow solid, the yield thereof was found to be 21%.
Example 9
An intermediate 4 is prepared according to the steps (1), (2) and (3) in the example 1, and the reaction time of the step (4) in the example 1 is changed to synthesize the oxitinib dimer, which specifically comprises the following steps:
introducing nitrogen into a reaction bottle at room temperature, adding 500mg of intermediate 4 (0.87 mmol), 466mg of intermediate 2 (1.05 mmol), 3mL of N, N-Dimethylformamide (DMF) and 220 mg of N, N' -diisopropylcarbodiimide (DIC, 1.74 mmol) under the protection of nitrogen, stirring, heating to 50 ℃, stirring for reaction for 7 hours, detecting the reaction progress by TLC (thin layer chromatography), adding 5mL of water into the reaction solution after the reaction is finished, quenching the reaction, concentrating the reaction solution to dryness under reduced pressure at 50 ℃, separating the obtained residue by column chromatography (silica gel 200 meshes 300 meshes, eluent is dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 20: 1), collecting the eluate, concentrating the eluate to dryness under reduced pressure at 40 ℃ to obtain 178mg of yellow solid, the yield thereof was found to be 20%.
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 and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. An oxitinib dimer, wherein the oxitinib dimer has a chemical formula:
2. a method for preparing an axitinib dimer according to claim 1, comprising the steps of:
synthesis of intermediate 2:
carrying out reduction reaction on the compound 1 in a first reaction solvent under the action of a catalyst and hydrogen to obtain an intermediate 2;
synthesis of intermediate 3:
carrying out acylation reaction on the intermediate 2 and acrylic anhydride in a second reaction solvent under the action of an acid-binding agent to obtain an intermediate 3;
synthesis of intermediate 4:
heating the intermediate 3 and acrylic acid in a third reaction solvent for addition reaction to obtain an intermediate 4;
synthesis of oxitinib dimer:
and heating the intermediate 4 and the intermediate 2 in a fourth reaction solvent under the action of a condensing agent to perform condensation reaction to obtain the oxitinib dimer.
3. The process for the preparation of oxitinib dimer according to claim 2, characterized in that, in the step of synthesis of intermediate 2:
the catalyst comprises at least one of palladium carbon and Raney nickel;
the first reaction solvent comprises at least one of methanol, ethanol, isopropanol, toluene and tetrahydrofuran;
the mass ratio of the catalyst to the compound 1 is 0.05-0.25;
the reaction temperature is 20-50 ℃;
the reaction time is 3-6 h.
4. The process for the preparation of oxitinib dimer according to claim 2, characterized in that, in the step of synthesis of intermediate 2:
the reaction temperature is 35-45 ℃.
5. The process for the preparation of oxitinib dimer according to claim 2, characterized in that, in the step of synthesis of intermediate 3:
the acid-binding agent comprises at least one of N, N-diisopropylethylamine, triethylamine and pyridine;
the second reaction solvent comprises at least one of dichloromethane, acetone, tetrahydrofuran, acetonitrile and toluene;
the molar ratio of the acid-binding agent to the intermediate 2 is 1-3;
the reaction temperature is 0-15 ℃;
the reaction time is 1-5 h.
6. The process for the preparation of oxitinib dimer according to claim 2, characterized in that, in the step of synthesis of intermediate 3:
the reaction time is 2-3 h.
7. The process for the preparation of oxitinib dimer according to claim 2, characterized in that, in the step of synthesis of intermediate 4:
the third reaction solvent is water;
the molar ratio of the acrylic acid to the intermediate 3 is 2-10;
the reaction temperature is 30-80 ℃;
the reaction time is 1-4 h.
8. The method for preparing an oxitinib dimer according to claim 2, wherein, in the step of synthesizing the oxitinib dimer:
the condensing agent comprises at least one of N, N '-diisopropyl carbodiimide and N, N' -carbonyl diimidazole;
the fourth reaction solvent comprises at least one of N, N-dimethylformamide and N, N-dimethylacetamide;
the molar ratio of the condensing agent to the intermediate 4 is 1-3;
the reaction temperature is 40-70 ℃;
the reaction time is 3-8 h.
9. The method for preparing an oxitinib dimer according to claim 2, wherein, in the step of synthesizing the oxitinib dimer:
the reaction temperature is 50-60 ℃.
10. Use of the ocitinib dimer according to claim 1, wherein the ocitinib dimer is used as a standard control in an ocitinib-related substance test.
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| WO2023006102A1 (en) * | 2021-07-30 | 2023-02-02 | 上海艾力斯医药科技股份有限公司 | Indole bipyrimidine compound, and intermediate thereof, preparation method therefor and use thereof |
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