CN117402163A - Preparation method of reed-keatinib phosphate impurity - Google Patents
Preparation method of reed-keatinib phosphate impurity Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 93
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 44
- 239000010452 phosphate Substances 0.000 title claims abstract description 44
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229940125898 compound 5 Drugs 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- 229940126214 compound 3 Drugs 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 230000009471 action Effects 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims description 10
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims description 10
- 229960005061 crizotinib Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000013558 reference substance Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract description 6
- 238000012827 research and development Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 206010028537 myelofibrosis Diseases 0.000 description 4
- 238000011946 reduction process Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 208000003476 primary myelofibrosis Diseases 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- -1 phosphate compound Chemical class 0.000 description 2
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 2
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- BOGSOFADOWIECK-UHFFFAOYSA-N [N].C=1C=NNC=1 Chemical group [N].C=1C=NNC=1 BOGSOFADOWIECK-UHFFFAOYSA-N 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960002539 ruxolitinib phosphate Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to the field of organic chemistry, and discloses a preparation method of a reed-solomonseal rhizome impurity, which synthesizes a reed-solomonseal rhizome impurity 9 and an impurity 11 by taking a compound 3 and a compound 7 as starting materials, provides necessary impurity reference substances for medicine research and development, greatly reduces research and development cost for preparing the reed-solomonseal rhizome impurity, has higher yield, and specifically comprises the following steps: reacting the compound 3 with the compound 5 in an organic solvent I under the action of an alkaline reagent to generate an impurity 9; compound 7 reacts with compound 5 in an organic solvent one under the action of an alkaline reagent to form impurity 11. The innovation point of the invention is that: the method for directionally synthesizing the impurity 9 and the impurity 11 of the poncirinib phosphate is disclosed for the first time, and provides a low-cost preparation method of an impurity reference substance for the quality research of the poncirinib phosphate.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a preparation method of a reed-ketinib phosphate impurity.
Background
Poncotinib phosphate (Ruxolitinib Phosphate), chemical name: (R) -3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropionitrile phosphate was developed by North America, inc., approved for sale by the FDA in the United states in 2011, marketed in the European Union and Japan in the 2012 and 2014, and marketed in China in 2017. Pontine is a selective tyrosine kinase-Janus kinase (JAK 1/JAK 2) inhibitor. Clinically used for treating spleen enlargement or symptoms related to diseases related to the related diseases in adult patients with medium-or high-risk Primary Myelofibrosis (PMF) (also called chronic idiopathic myelofibrosis), myelofibrosis (PPV-MF) secondary to polycythemia vera or myelofibrosis (PET-MF) secondary to essential thrombocythemia. The structural formula is as follows:
in the process of drug development, the research of impurities is an important link, a certain amount of impurity standard substances are needed for establishing quality standards, and in order to obtain enough impurity standard substances, the development of an impurity directional synthesis method is an important task of drug development. The targeted impurity is directionally synthesized, and the impurity is used as a reference substance of the raw material drug of the lacteib phosphate, so that the method has important significance for establishing the quality standard of the lacteib phosphate.
More impurities are generated in the synthesis route of the poncirtinib phosphate, are difficult to remove in subsequent reactions and can be transferred to the poncirtinib phosphate bulk drug, so the impurities are process impurities which must be researched in the process of establishing the quality standard of the poncirtinib phosphate bulk drug. The impurity reference substance needed at present needs to be enriched and purified from the compound reaction liquid mother liquor, and the method has low efficiency and high cost.
Disclosure of Invention
In order to meet the requirement of the impurity reference substance in the quality research of the poncirtinib phosphate, the invention provides a method for directionally synthesizing the poncirtinib phosphate impurity 9 and the poncirtinib phosphate impurity 11, provides a necessary reference substance for the research and the development of medicines, and simultaneously greatly reduces the research and development cost for preparing the impurity.
In one aspect, the invention provides a method for preparing the impurity 9 of the crizotinib phosphate, which comprises the following steps:
the compound 3 reacts with the compound 5 in the first organic solvent under the action of an alkaline reagent to generate the impurity 9, and the specific synthetic route is as follows:
。
adding the compound 3 and the compound 5 into a reaction bottle at room temperature, adding an organic solvent I, stirring uniformly, adding an alkaline reagent, reacting at 10-60 ℃ for 4-18 hours, adding water after the reaction is finished, extracting with ethyl acetate, drying an organic phase, concentrating a filtrate after suction filtration, adding ethyl acetate, heating to 60-70 ℃ for dissolution, adding n-heptane, cooling to 0-10 ℃ for crystallization, suction filtration, and drying to obtain the impurity 9.
In another aspect, the invention provides a method for preparing the crizotinib phosphate impurity 11, comprising the following steps:
the compound 7 reacts with the compound 5 in the first organic solvent under the action of an alkaline reagent to generate the impurity 11, and the specific synthetic route is as follows:
adding the compound 7 and the compound 5 into a reaction bottle at room temperature, adding an organic solvent I, stirring uniformly, adding an alkaline reagent, reacting at 10-60 ℃ for 4-18 hours, adding water after the reaction is finished, extracting with ethyl acetate, drying an organic phase, concentrating a filtrate after suction filtration, adding ethyl acetate, heating to 60-70 ℃ for dissolution, adding n-heptane, cooling to 0-10 ℃ for crystallization, suction filtration, and drying to obtain the impurity 11.
Preferably, in the preparation method of the impurity of the crizotinib phosphate, the organic solvent I is one or a mixture of several of chloroform, methanol, ethanol, methylene dichloride, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, tetrahydrofuran and N-methylpyrrolidone.
Preferably, in the preparation method of the impurity of the rucortinib phosphate, the alkaline reagent is any one of sodium carbonate, potassium carbonate, lithium carbonate, potassium tert-butoxide, sodium methoxide, sodium hydroxide and potassium hydroxide.
Preferably, in the above preparation method of the impurity of the phosphoric acid ruketinib, the molar ratio of the compound 3 to the alkaline reagent is 1:0.1-5, preferably 1:0.1-1, more preferably 1:0.2; the molar ratio of compound 3 to compound 5 is 1:1-5, preferably 1:1-2, more preferably 1:1.5.
Preferably, in the above preparation method of the impurity of the phosphoric acid ruketinib, the molar ratio of the compound 7 to the alkaline reagent is 1:0.1-5, preferably 1:0.5-1, more preferably 1:0.6; the molar ratio of compound 7 to compound 5 is 1:1-5, preferably 1:1-1.5, more preferably 1:1.2.
Preferably, in the above method for preparing the impurity of the poncirtinib phosphate, the impurity 9 and the impurity 11 of the poncirtinib phosphate are used as reference substances of the poncirtinib phosphate.
The invention has the advantages that: the first time discloses a directional synthesis method of the reed-solomonseal rhizome impurity 9 and the reed-solomonseal rhizome impurity 11, which provides a low-cost preparation method of an impurity reference substance for the quality research of the reed-solomonseal rhizome impurity, and the synthesis method has mild reaction conditions, environment friendliness and high yield which are all over 90 percent.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the impurity 9 of the pontinib phosphate;
FIG. 2 is a nuclear magnetic carbon spectrum of the impurity 9 of the pontinib phosphate;
FIG. 3 is a nuclear magnetic resonance spectrum of the impurity 11 of the pontinib phosphate;
fig. 4 is a nuclear magnetic carbon spectrum of the pontinib phosphate impurity 11.
Detailed Description
In the synthesis route of the phosphoric acid rucotinib, the compound 3 possibly generates impurities 10 which are removed from pyrrole and pyrazole ring protecting groups completely and only impurities 8 which are generated from pyrrole rings when the pyrazole nitrogen protecting groups are removed from the hydrochloric acid; the synthesis route of the poncirtinib phosphate is as follows:
the impurity 8 and the impurity 10 can react with the compound 5 to generate the impurity 9 and the impurity 11, the impurity 9 and the impurity 11 are difficult to remove in the subsequent reaction and can be transferred to the raw material drug of the poncirtinib phosphate, so that the impurity 9 and the impurity 11 are process impurities which are necessary to be researched in the quality standard establishment process of the raw material drug of the poncirtinib phosphate, the directional synthesis method of the impurity 9 and the impurity 11 is not reported at present, and the required impurity reference substance needs to be enriched and purified from the mother solution of the intermediate reaction liquid, so that the efficiency is low and the cost is high. The structural formulas of the impurity 9 and the impurity 11 are shown below.
Therefore, aiming at the problems that the impurity 9 and the impurity 11 generated in the process of preparing the pontinib phosphate need to be enriched and purified from an intermediate reaction liquid mother liquor, the efficiency is low and the cost is high, the invention provides a preparation method of the pontinib phosphate impurity, which comprises the following steps:
compound 3 reacts with compound 5 in an organic solvent one under the action of an alkaline reagent to produce impurity 9.
The method comprises the following steps: adding the compound 3, the compound 5 and the organic solvent I into a reaction bottle, stirring uniformly, adding an alkaline reagent, reacting at 10-60 ℃, preferably 20-30 ℃ for 4-18 hours, adding water after the reaction is finished, extracting with ethyl acetate, drying an organic phase, concentrating a filtrate after suction filtration, adding ethyl acetate, heating to 60-70 ℃ for dissolution, adding n-heptane, cooling to 0-10 ℃ for crystallization, suction filtration and drying to obtain an impurity 9;
the molar amount of the alkaline agent to be added is 0.1 to 5 times, preferably 0.1 to 1 time, more preferably 0.2 time that of the compound 3; the molar amount of compound 5 to be fed is 1 to 5 times, preferably 1 to 2 times, more preferably 1.5 times that of compound 3; the organic solvent I can be one or more of chloroform, methanol, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, tetrahydrofuran and N-methylpyrrolidone, preferably dimethyl sulfoxide and N, N-dimethylformamide, more preferably dimethyl sulfoxide; the alkaline reagent is any one of sodium carbonate, potassium carbonate, lithium carbonate, potassium tert-butoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, preferably potassium carbonate and sodium carbonate, more preferably potassium carbonate.
Compound 7 reacts with compound 5 in an organic solvent one under the action of an alkaline reagent to form impurity 11.
The method comprises the following steps: adding the compound 7, the compound 5 and the organic solvent I into a reaction bottle, stirring uniformly, adding an alkaline reagent, reacting at 10-60 ℃, preferably 20-30 ℃ for 4-18 hours, adding water after the reaction is finished, extracting with ethyl acetate, drying an organic phase, concentrating a filtrate after suction filtration, adding ethyl acetate, heating to 60-70 ℃ for dissolution, adding n-heptane, cooling to 0-10 ℃ for crystallization, suction filtration and drying to obtain an impurity 11;
the molar amount of the alkaline agent to be added is 0.1 to 5 times, preferably 0.5 to 1 time, more preferably 0.6 time that of the compound 7; the molar amount of compound 5 to be fed is 1 to 5 times, preferably 1 to 1.5 times, more preferably 1.2 times that of compound 7; the organic solvent I can be one or more of chloroform, methanol, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, tetrahydrofuran and N-methylpyrrolidone, preferably dimethyl sulfoxide and N, N-dimethylformamide, more preferably dimethyl sulfoxide; the alkaline reagent is any one of sodium carbonate, potassium carbonate, lithium carbonate, potassium tert-butoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, preferably potassium carbonate and sodium carbonate, more preferably potassium carbonate.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. The compound 3 and compound 7 used were prepared according to the method disclosed in patent CN105669676, the other reagents being obtained by purchase.
Example 1: synthesis of impurity 9
Dimethyl sulfoxide (50 mL), compound 3 (2.0 g,5.38 mmol) and compound 5 (1.0 g,8.08 mmol) were added sequentially to the reaction flask, potassium carbonate (150 mg,1.08 mmol) was added after stirring for 5min, the reaction was allowed to proceed at 25-30℃for 8h, and the reaction was essentially complete by TLC. To the reaction solution were added ethyl acetate (100 mL) and 5% sodium chloride solution (100 mL) in this order, and after sufficient shaking, the separated aqueous phases were separated in a separating funnel, extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed three times with saturated sodium chloride solution (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a yellow oil. Ethyl acetate (10 mL) is added, the temperature is raised to 65 ℃, the solution is stirred, n-heptane (100 mL) is slowly added dropwise, the mixture is stirred for 10min at 65 ℃ after the addition, the temperature is gradually reduced to 0-5 ℃ and is not lower than 2h in the temperature reduction process, and the mixture is stirred and crystallized for 3h at 0-5 ℃. The solid was suction filtered, rinsed with n-heptane and dried under vacuum at room temperature to give impurity 9 (1.9 g) in 95% yield.
Example 2: synthesis of impurity 9
DMF (50 mL), compound 3 (2.0 g,5.38 mmol) and compound 5 (1.0 g,8.08 mmol) were added sequentially to the flask, sodium carbonate (135 mg,1.62 mmol) was added after stirring for 5min, the reaction was allowed to proceed at 25-30deg.C for 12h, and the reaction was essentially complete as detected by TLC. To the reaction solution were added ethyl acetate (100 mL) and 5% sodium chloride solution (100 mL) in this order, and after sufficient shaking, the separated aqueous phases were separated in a separating funnel, extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed three times with saturated sodium chloride solution (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a yellow oil. Ethyl acetate (10 mL) is added, the temperature is raised to 65 ℃, the solution is stirred, n-heptane (100 mL) is slowly added dropwise, the mixture is stirred for 10min at 65 ℃ after the addition, the temperature is gradually reduced to 0-5 ℃ and is not lower than 2h in the temperature reduction process, and the mixture is stirred and crystallized for 3h at 0-5 ℃. The solid was suction filtered, rinsed with n-heptane and dried under vacuum at room temperature to give impurity 9 (1.87 g) in 92% yield.
Example 3: synthesis of impurity 11
Dimethyl sulfoxide (50 mL), compound 7 (pre-phosphate compound, 2.0g,6.53 mmol) and compound 5 (0.95 g,7.83 mmol) were added sequentially to the reaction flask, and potassium carbonate (150 mg,1.08 mmol) was added after stirring for 5min, and the reaction was allowed to proceed at 25-30℃for 6h, with TLC detection being essentially complete. To the reaction solution were added ethyl acetate (100 mL) and 5% sodium chloride solution (100 mL) in this order, and after sufficient shaking, the separated aqueous phases were separated in a separating funnel, extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed three times with saturated sodium chloride solution (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a yellow oil. Ethyl acetate (10 mL) is added, the temperature is raised to 65 ℃, the solution is stirred, n-heptane (100 mL) is slowly added dropwise, the mixture is stirred for 10min at 65 ℃ after the addition, the temperature is gradually reduced to 0-5 ℃ and is not lower than 2h in the temperature reduction process, and the mixture is stirred and crystallized for 3h at 0-5 ℃. The solid was suction filtered, rinsed with n-heptane and dried under vacuum at room temperature to give impurity 11 (2.57 g) in 92% yield.
Example 4: synthesis of impurity 11
DMF (50 mL), compound 7 (pre-phosphate compound, 2.0g,6.53 mmol) and compound 5 (0.95 g,7.83 mmol) were added sequentially to the flask, sodium carbonate (165 mg,1.96 mmol) was added after stirring for 5min, the reaction was allowed to proceed at 25-30deg.C for 10h, and TLC detection was essentially complete. To the reaction solution were added ethyl acetate (100 mL) and 5% sodium chloride solution (100 mL) in this order, and after sufficient shaking, the separated aqueous phases were separated in a separating funnel, extracted twice with ethyl acetate (100 mL), the organic phases were combined, washed three times with saturated sodium chloride solution (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a yellow oil. Ethyl acetate (10 mL) is added, the temperature is raised to 65 ℃, the solution is stirred, n-heptane (100 mL) is slowly added dropwise, the mixture is stirred for 10min at 65 ℃ after the addition, the temperature is gradually reduced to 0-5 ℃ and is not lower than 2h in the temperature reduction process, and the mixture is stirred and crystallized for 3h at 0-5 ℃. The solid was suction filtered, rinsed with n-heptane and dried under vacuum at room temperature to give impurity 11 (2.57 g) in 92% yield.
According to the embodiment, the invention provides the preparation method of the impurity of the poncirtinib phosphate, and provides a method for directionally synthesizing the impurity reference substance for the quality research of the poncirtinib phosphate.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (8)
1. A pontinib phosphate impurity 9 having the structural formula:
。
2. a pontinib phosphate impurity 11 having the structural formula:
。
3. the method for preparing the crizotinib phosphate impurity 9 according to claim 1, comprising the following steps:
the compound 3 reacts with the compound 5 in the first organic solvent under the action of an alkaline reagent to generate the impurity 9, and the specific synthetic route is as follows:
。
4. the method for preparing the crizotinib phosphate impurity 11 according to claim 2, comprising the following steps:
the compound 7 reacts with the compound 5 in the first organic solvent under the action of an alkaline reagent to generate the impurity 11, and the specific synthetic route is as follows:
。
5. the preparation method of the crizotinib phosphate impurity 9 and the crizotinib phosphate impurity 11 according to claims 3 to 4, wherein the organic solvent I is one or a mixture of several of chloroform, methanol, ethanol, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, tetrahydrofuran and N-methylpyrrolidone.
6. The preparation method of the crizotinib phosphate impurity 9 and the crizotinib phosphate impurity 11 according to claims 3 to 4, wherein the alkaline reagent is any one of sodium carbonate, potassium carbonate, lithium carbonate, potassium tert-butoxide, sodium methoxide, sodium hydroxide and potassium hydroxide.
7. A process for the preparation of the impurity 9 of ponyinib phosphate according to claim 3, characterized in that the molar ratio of compound 3 to alkaline agent is 1:0.1-5, preferably 1:0.1-1, more preferably 1:0.2;
the molar ratio of compound 3 to compound 5 is 1:1-5, preferably 1:1-2, more preferably 1:1.5.
8. The process for the preparation of the crizotinib phosphate impurity 9 according to claim 4, characterized in that the molar ratio of compound 7 to alkaline agent is 1:0.1-5, preferably 1:0.5-1, more preferably 1:0.6;
the molar ratio of compound 7 to compound 5 is 1:1-5, preferably 1:1-1.5, more preferably 1:1.2.
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