CN112480086A - Ostinib refining method - Google Patents
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- CN112480086A CN112480086A CN202011543467.2A CN202011543467A CN112480086A CN 112480086 A CN112480086 A CN 112480086A CN 202011543467 A CN202011543467 A CN 202011543467A CN 112480086 A CN112480086 A CN 112480086A
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- 238000000034 method Methods 0.000 title claims abstract description 64
- 238000007670 refining Methods 0.000 title claims description 57
- 239000012043 crude product Substances 0.000 claims abstract description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000013078 crystal Substances 0.000 claims abstract description 34
- 239000003960 organic solvent Substances 0.000 claims abstract description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001816 cooling Methods 0.000 claims abstract description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 40
- 239000012535 impurity Substances 0.000 abstract description 27
- 239000006227 byproduct Substances 0.000 abstract description 5
- 239000000376 reactant Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 50
- 238000001514 detection method Methods 0.000 description 28
- 230000002194 synthesizing effect Effects 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 229940121647 egfr inhibitor Drugs 0.000 description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229960003278 osimertinib Drugs 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种奥斯替尼的精制方法。所述奥斯替尼的精制方法包括以下步骤：将有机溶剂和奥斯替尼粗品混合，使所述奥斯替尼粗品溶解，然后降温析出晶体，收集所述晶体；所述有机溶剂选自2‑丁酮、乙酸乙酯、甲苯和四氢呋喃中的一种或几种。区别于常规的纯化方法，本发明通过特定的有机溶剂对奥斯替尼粗品进行重结晶，有效提高了奥斯替尼的纯度，能够显著降低反应物的残留，并显著降低工艺副产物。HPLC检测奥斯替尼的纯度可达到98.5％以上，杂质限量均小于0.1％。The present invention relates to a purification method of ostinib. The method for purifying ostinib comprises the following steps: mixing an organic solvent and crude ostinib, dissolving the crude product of ostinib, then cooling down to separate out crystals, and collecting the crystals; the organic solvent is selected from the group consisting of: One or more of 2-butanone, ethyl acetate, toluene and tetrahydrofuran. Different from the conventional purification method, the present invention recrystallizes crude ostinib through a specific organic solvent, which effectively improves the purity of ostinib, can significantly reduce the residue of reactants, and significantly reduce process by-products. The purity of ostinib detected by HPLC can reach more than 98.5%, and the impurity limit is less than 0.1%.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a refining method of Ostinib.
Background
Austenitib (Osimertinib), also known as austenitib, original factory name: tagrisso, chinese commodity name: tagares, AZD9291 is its development code. The chemical name is N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide, the molecular weight is 499.61, the molecular formula is C28H33N7O2, and the chemical structural formula is shown as the formula (1):
it is a therapeutic drug for lung cancer, is mainly applied to the most difficult to effectively treat lung cancer type non-small cell lung cancer (NSCLC), and is an oral, irreversible, third-generation EGFR inhibitor (EGFR-TKI). The clinical model research has obvious effect, and the medicine has better treatment effect on NSCLC patients with EGFR-TKI resistance and T790M mutation.
In recent years, Ostinib has attracted more and more attention, and many routes or methods for synthesizing Ostinib have been developed, and one of the synthesis methods that is commonly used is as follows:
the compound a, the solvent A and the alkali are mixed and reacted to prepare the Ostinib, although the synthesis method has simple process and easily controlled reaction conditions. However, researches show that the residual quantity of the compound a reaches about 0.7%, process impurities such as process byproducts reach about 1%, the effect is not obvious after multiple purification, the quality requirement of a high-grade intermediate cannot be met, namely, less than 0.1% of single impurity remains, and after multiple purification, the yield of Ostinib is very low, so that the production efficiency is low and the cost is increased. However, since the purity and the drug effect of oseltamiib have a direct relationship, it is highly desirable to develop a purification method capable of improving the purity of oseltamiib.
Disclosure of Invention
Based on the method, the purity of the Ostinib obtained by the method reaches over 98.5%, and the impurity limit is less than 0.1%.
The technical scheme is as follows:
a refining method of Ostinib comprises the following steps:
mixing an organic solvent and the crude product of Ostinib, dissolving, cooling to separate out crystals, and collecting the crystals;
the organic solvent is selected from one or more of 2-butanone, ethyl acetate, toluene and tetrahydrofuran.
In one embodiment, the organic solvent is tetrahydrofuran.
In one embodiment, the mass-to-volume ratio of the crude austenib product to the organic solvent is 1g: (0.5-30) mL.
In one embodiment, the mass-to-volume ratio of the crude austenib product to the organic solvent is 1g: (1-2.5) mL.
In one embodiment, when the crude austenib is dissolved, the temperature of the system is 10-85 ℃.
In one embodiment, when the crude austenib is dissolved, the temperature of the system is 40-75 ℃.
In one embodiment, after the temperature reduction operation is performed, the temperature of the system is 0 ℃ to 10 ℃.
In one embodiment, the cooling rate is 2 ℃/min to 20 ℃/min.
In one embodiment, the preparation method of the crude austenib comprises the following steps:
mixing the compound a, a solvent A and a base, and reacting;
the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide and potassium tert-butoxide;
the solvent is selected from one or more of acetone, dimethyl sulfoxide and tetrahydrofuran;
the reaction temperature of the reaction is 60-100 ℃.
In one embodiment, the time for precipitating the crystals is 0.5h to 5 h.
In one embodiment, after the step of cooling to precipitate the crystals, the operation of filtering is further included.
In one embodiment, after the step of collecting the crystals, the step of drying the crystals is further included.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the Ostinib with the structure shown in the formula (1) is dissolved in a specific organic solvent, and then the temperature is reduced to precipitate crystals, so that the purity of the Ostinib is effectively improved, the residues of the compound a and the process by-products can be remarkably reduced, the residual quantity is less than 0.1%, the purity of the Ostinib can reach more than 98.5% by HPLC detection, and the impurity limit is less than 0.1%. In addition, the yield of Ostinib can reach more than 78%.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Ostinib is a lung cancer therapeutic drug, is mainly applied to the lung cancer type non-small cell lung cancer (NSCLC) which is the most difficult to effectively treat, and is an oral, irreversible, third-generation EGFR inhibitor (EGFR-TKI). The clinical model research has obvious effect, and the medicine has better treatment effect on NSCLC patients with EGFR-TKI resistance and T790M mutation.
A more common method for synthesizing austenib is as follows:
the compound a, the solvent A and the alkali are mixed and reacted to prepare the Ostinib, although the synthesis method has simple process and easily controlled reaction conditions. However, researches show that the residual quantity of the compound a reaches about 0.7%, process impurities such as process byproducts reach about 1%, the effect is not obvious after multiple purification, the quality requirement of a high-grade intermediate cannot be met, namely, less than 0.1% of single impurity remains, and after multiple purification, the yield of Ostinib is very low, so that the production efficiency is low and the cost is increased. However, since the purity and the drug effect of oseltamiib have a direct relationship, it is highly desirable to develop a purification method capable of improving the purity of oseltamiib.
Aiming at the problems, the invention provides a refining method which can ensure that the purity of Ostinib reaches more than 98.5 percent and the impurity limit is less than 0.1 percent.
The specific technical scheme is as follows:
a refining method of Ostinib comprises the following steps:
a refining method of Ostinib comprises the following steps:
mixing an organic solvent and the crude product of Ostinib, dissolving, cooling to separate out crystals, and collecting the crystals;
the organic solvent is selected from one or more of 2-butanone, ethyl acetate, toluene and tetrahydrofuran.
According to the invention, the Ostinib with the structure shown in the formula (1) is dissolved in a specific organic solvent, and then the temperature is reduced to precipitate crystals, so that the purity of the Ostinib is effectively improved, the residues of the compound a and the process by-products can be remarkably reduced, the residual quantity is less than 0.1%, the purity of the Ostinib can reach more than 98.5% by HPLC detection, and the impurity limit is less than 0.1%. In addition, the yield of Ostinib can reach more than 78%.
In one preferred embodiment, the organic solvent is tetrahydrofuran.
In one embodiment, the mass-to-volume ratio of the crude austenib product to the organic solvent is 1g: (0.1-3) mL. Controlling the addition amount of the crude product and the organic solvent within such a range is more favorable for improving the purity of the Ostinib and reducing the content of impurities. It is understood that, in the present invention, the ratio by mass/volume of the crude Ostinib product to the organic solvent may be, but not limited to, 1g:0.5mL, 1g:0.6mL, 1g:0.7mL, 1g:0.8mL, 1g:0.9mL, 1g:0.95mL, 1g:1.0mL, 1g:1.1mL, 1g:1.2mL, 1g:1.3mL, 1g:1.4mL, 1g:1.5mL, 1g:1.6mL, 1g:1.8mL, 1g:1.9mL, 1g:2mL, 1g:2.06mL, 1g:2.2mL, 1g:2.5mL, 1g:2.6mL, 1g:2.8mL, 1g:2.9mL, 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:2.5mL, 1g:2.6mL, 1g:2.8mL, 1g:2.9mL, 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:12mL, 1g: 1.14 mL, 1g: 1mL, 15.4mL of 1g, 16mL of 1g, 16.2mL of 1g, 16.5mL of 1g, 17mL of 1g, 18mL of 1g, 18.5mL of 1g, 19.0mL of 1g, 19.5mL of 1g, 20mL of 1g, 1g: 21mL, 1g:22mL, 1g:23mL, 1g:24mL, 1g:25mL, 1g: 26mL, 1g:27mL, 1g:28mL, 1g:29mL and 1g:30 mL. Particularly preferably, the mass-to-volume ratio of the crude austenib product to the organic solvent is 1g: (1-2.5) mL.
In one embodiment, when the crude austenib is dissolved, the temperature of the system is 10-85 ℃. The dissolution temperature is controlled, so that the purity of the Ostinib is improved, and the content of impurities is reduced. As will be understood, in the present invention, the dissolution temperature can be, but is not limited to, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 46 ℃, 47 ℃, 50 ℃, 51 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃, 62 ℃, 64 ℃, 66 ℃, 68 ℃, 70 ℃, 71 ℃, 72 ℃, 75 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃ and 85 ℃. Preferably, when the crude Ostinib is dissolved, the temperature of the system is 20-80 ℃. Particularly preferably, when the crude Ostinib is dissolved, the temperature of the system is 40-75 ℃.
In one embodiment, after the temperature reduction operation is performed, the temperature of the system is 0 ℃ to 10 ℃. The crystallization temperature is controlled, the growth of crystals is facilitated, the purity of Ostinib is improved, and the content of impurities is reduced. It is understood that, in the present invention, the crystallization temperature can be, but not limited to, 0 ℃, 0.1 ℃, 0.2 ℃, 0.3 ℃, 0.4 ℃, 0.5 ℃, 0.6 ℃, 0.7 ℃, 0.8 ℃, 0.9 ℃, 1 ℃, 1.1 ℃, 1.2 ℃, 1.3 ℃, 1.4 ℃, 1.5 ℃, 1.6 ℃, 1.7 ℃, 1.8 ℃, 1.9 ℃, 2 ℃, 2.5 ℃, 3 ℃, 3.1 ℃, 3.2 ℃, 3.3 ℃, 3.4 ℃, 3.5 ℃, 3.6 ℃, 3.7 ℃, 3.8 ℃, 3.9 ℃, 4.0 ℃, 4.1 ℃, 4.2 ℃, 4.6 ℃, 4.7 ℃, 5.0 ℃, 5.3 ℃, 5.4 ℃, 5.5 ℃, 5.6 ℃, 5.7 ℃, 5.8 ℃, 5.9 ℃, 6.0 ℃, 6.2 ℃, 6.4 ℃, 6.6.8 ℃, 6.8 ℃, 7.0.7 ℃, 7.0 ℃, 7.7 ℃, 5.5.4 ℃, 5.5.5.5 ℃, 5.5.5.9 ℃, 8 ℃, 9.9.9, 9.9 ℃, 10.6.6 ℃.
In one embodiment, the cooling rate is 2 ℃/min to 20 ℃/min. The temperature reduction rate is controlled, the growth of crystals is facilitated, the purity of Ostinib is improved, and the content of impurities is reduced. It is understood that, in the present invention, the cooling rate can be set to, but not limited to, 2 ℃/min, 2.5 ℃/min, 3 ℃/min, 3.1 ℃/min, 3.2 ℃/min, 3.3 ℃/min, 3.4 ℃/min, 3.5 ℃/min, 3.6 ℃/min, 3.7 ℃/min, 3.8 ℃/min, 3.9 ℃/min, 4.0 ℃/min, 4.1 ℃/min, 4.2 ℃/min, 4.6 ℃/min, 4.7 ℃/min, 5 ℃/min, 6 ℃/min, 6.2 ℃/min, 6.3 ℃/min, 6.4 ℃/min, 7 ℃/min, 7.6 ℃/min, 8 ℃/min, 8.8 ℃/min, 9 ℃/min, 10 ℃/min, 10.5 ℃/min, 11 ℃/min, 11.3 ℃/min, 12 ℃/min, 12.5 ℃/min, 13 ℃/min, 2 ℃/min, 3 ℃/min, 12.5 ℃/min, 3 ℃/min, or more, 13.7 deg.C/min, 14 deg.C/min, 15 deg.C/min, 15.3 deg.C/min, 16 deg.C/min, 17 deg.C/min, 17.5 deg.C/min, 18 deg.C/min, 19 deg.C/min and 20 deg.C/min. Preferably, the cooling rate is 2 ℃/min to 10 ℃/min when the cooling operation is carried out.
In one embodiment, the time for precipitating the crystals is 0.5h to 5 h. Controlling the time for precipitating crystals within such a range is advantageous for synergistically controlling the purity and yield of Ostinib.
In one embodiment, the preparation method of the crude austenib comprises the following steps:
mixing the compound a, a solvent A and a base, and reacting;
the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide and potassium tert-butoxide;
the solvent is selected from one or more of acetone, dimethyl sulfoxide and tetrahydrofuran;
the reaction temperature of the reaction is 60-100 ℃.
In one embodiment, after the step of cooling to precipitate the crystals, the operation of filtering is further included. Preferably, solid-liquid separation is carried out by adopting a suction filtration mode, and a filter cake and filtrate are separately collected. In order to further improve the purity of Ostinib, the refining method of the invention can be repeated for 2-3 times on the obtained product after the same batch of crude products are refined for 1 time. In order to improve the yield, the solvent of the filtrate obtained after single refining can be removed by adopting a rotary evaporation mode to obtain a solid, and the refining method of the invention is repeated for 2-3 times.
In one embodiment, after the step of collecting the crystals, the step of drying the crystals is further included. Preferably, the crystal is dried by adopting a vacuum drying mode, and the drying temperature is 20-80 ℃. More preferably, the drying temperature is 40 ℃ to 60 ℃.
The following examples and comparative examples are further described below, and the starting materials used in the following examples can be commercially available, unless otherwise specified, and the equipment used therein can be commercially available, unless otherwise specified.
Example 1
The embodiment provides Ostinib and a refining method thereof, and the steps are as follows:
step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the crude product of Ostinib prepared in the step 1) into 200mL of tetrahydrofuran, heating to 60 ℃ to dissolve the crude product of Ostinib, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 190g of white crystallized refined product, namely Ostinib refined product, wherein the yield is 95%, the purity of the Ostinib refined product is 99.9% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.01%.
Example 2
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the organic solvent adopted in the refining process is 2-butanone.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the Ostinib crude product prepared in the step 1) into 200mL of 2-butanone, heating to 60 ℃ to dissolve the Ostinib crude product, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 185g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 92.5%, and the purity of the Ostinib refined product is 99.7% and the maximum single impurity is 0.03% by HPLC (high performance liquid chromatography).
Example 3
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the organic solvent adopted in the refining process is ethyl acetate.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the Ostinib crude product prepared in the step 1) into 200mL of ethyl acetate, heating to 60 ℃ to dissolve the Ostinib crude product, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 176g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 88%, and the purity of the Ostinib refined product is 99% and the maximum single impurity is 0.06% by HPLC (high performance liquid chromatography).
Example 4
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the organic solvent adopted in the refining process is toluene.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the crude Ostinib prepared in the step 1) into 200mL of toluene, heating to 60 ℃ to dissolve the crude Ostinib, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 160g of white crystallized refined product, namely Ostinib refined product, wherein the yield is 80%, the purity of the Ostinib refined product is 98.6% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity is 0.05%.
Example 5
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the addition proportion of the organic solvent and the crude product is different in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the crude Ostinib prepared in the step 1) into 600mL of tetrahydrofuran, heating to 50 ℃ to dissolve the crude Ostinib, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 186g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 93%, and the purity of the Ostinib refined product is 99.9% and the maximum single impurity is 0.01% by HPLC detection.
Example 6
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the addition proportion of the organic solvent and the crude product is different in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the crude Ostinib prepared in the step 1) into 100mL of tetrahydrofuran, heating to 75 ℃ to dissolve the crude Ostinib, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 194g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 97%, the purity of the Ostinib refined product is 98.5% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity is 0.08%.
Example 7
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the organic solvent is compounded by toluene and ethyl acetate in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the Ostinib crude product prepared in the step 1) into a mixed solvent consisting of 100mL of toluene and 100mL of ethyl acetate, heating to 60 ℃ to dissolve the Ostinib crude product, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 175g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 88.5%, the purity of the Ostinib refined product is 99.9% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity is 0.05%.
Example 8
This example provides austenib and a refining method thereof, which are substantially the same as the steps in example 7, and mainly differ from the following steps: the organic solvent has different compound types in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
200g of the Ostinib crude product prepared in the step 1) is added into a mixed solvent consisting of 100mL of toluene and 100mL of 2-butanone, heated to 60 ℃ to dissolve the Ostinib crude product, then cooled to 5 ℃ at the speed of 3 ℃/min, crystallized for 1.5h, filtered, and dried under reduced pressure at 50 ℃ to obtain 179g of white crystallized refined product, namely Ostinib refined product, wherein the yield is 89.5%, the purity of the Ostinib refined product is 99.9% by HPLC detection, and the maximum single impurity is 0.05%.
Example 9
This example provides austenib and a refining method thereof, which are substantially the same as the steps in example 7, and mainly differ from the following steps: the organic solvent has different compound types in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the crude Ostinib product prepared in the step 1) into a mixed solvent consisting of 100mL of toluene and 100mL of tetrahydrofuran, heating to 60 ℃ to dissolve the crude Ostinib product, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 159g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 79.5%, the purity of the Ostinib refined product is 99.9% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity is 0.02%.
Example 10
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the crystallization temperature is different in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
200g of the Ostinib crude product prepared in the step 1) is added into a mixed solvent consisting of 833mL of toluene and 167mL of chlorobenzene, the mixed solvent is heated to 60 ℃ to dissolve the Ostinib crude product, then the mixed solvent is cooled to 0 ℃ at the speed of 3 ℃/min, crystallization is carried out for 1h, suction filtration is carried out, and reduced pressure drying is carried out at 50 ℃ to obtain 192g of white crystallized refined product, namely the Ostinib refined product, the yield is 96%, the purity of the Ostinib refined product is 99.4% by HPLC detection, and the maximum single impurity is 0.06%.
Example 11
This example provides austenib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ from the following steps: the cooling rate is different in the refining process.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
200g of the Ostinib crude product prepared in the step 1) is added into a mixed solvent consisting of 833mL of toluene and 167mL of chlorobenzene, the mixture is heated to 60 ℃ to dissolve the Ostinib crude product, then the mixture is cooled to 5 ℃ at the speed of 12 ℃/min, crystallization is carried out for 1h, suction filtration is carried out, and reduced pressure drying is carried out at 50 ℃ to obtain 156g of white crystal refined product, namely Ostinib refined product, the yield is 78%, the purity of the Ostinib refined product is 98.5% by HPLC detection, and the maximum single impurity is 0.09%.
Comparative example 1
This comparative example provides oseltamiib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ in that: the type of solvent used in the refining process is different.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the crude Ostinib prepared in the step 1) into 200mL of ethanol, heating to 70 ℃ to dissolve the crude Ostinib, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 160g of white crystallized refined product, namely Ostinib refined product, wherein the yield is 80%, the purity of the Ostinib refined product is 98.5% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.9%.
Comparative example 2
This comparative example provides oseltamiib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ in that: the type of solvent used in the refining process is different.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining
Adding 200g of the crude Ostinib prepared in the step 1) into 200mL of acetone, heating to 70 ℃ to dissolve the crude Ostinib, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 160g of white crystallized refined product, namely Ostinib refined product, wherein the yield is 80%, the purity of the Ostinib refined product is 98.6% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is 0.8%.
Comparative example 3
This comparative example provides oseltamiib and a refining method thereof, which are substantially the same as the steps of example 1, and mainly differ in that: the type of solvent used in the refining process is different.
Step 1) synthesizing crude Ostinib:
and adding 200g of the compound a, 23g of sodium hydroxide and 600mL of acetonitrile into a three-necked bottle, reacting for 10h at 80 ℃ to obtain crude Ostinib, wherein the purity of the crude Ostinib is 98.1% by HPLC detection.
Step 2) crude product refining:
adding 200g of the Ostinib crude product prepared in the step 1) into 200mL of dioxane, heating to 70 ℃ to dissolve the Ostinib crude product, cooling to 5 ℃ at the speed of 3 ℃/min, crystallizing for 1h, performing suction filtration, and drying at 50 ℃ under reduced pressure to obtain 162g of a white crystal refined product, namely the Ostinib refined product, wherein the yield is 81%, and the purity of the Ostinib refined product is 98.4% and the maximum single impurity is 0.8% by HPLC detection.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The purification method of Ostinib is characterized by comprising the following steps:
mixing an organic solvent and the crude product of Ostinib, dissolving, cooling to separate out crystals, and collecting the crystals;
the organic solvent is selected from one or more of 2-butanone, ethyl acetate, toluene and tetrahydrofuran.
2. The purification method of Ostinib, according to claim 1, wherein said organic solvent is tetrahydrofuran.
3. The purification method of Ostinib, according to claim 1, characterized in that the mass-to-volume ratio of crude Ostinib and organic solvent is 1g: (0.5-30) mL.
4. The purification method of Ostinib, according to claim 3, wherein the mass-to-volume ratio of crude Ostinib and organic solvent is 1g: (1-2.5) mL.
5. The method for refining Ostinib according to claim 1, wherein the temperature of the system is 10-85 ℃ when the Ostinib crude product is dissolved.
6. The Ostinib refining method according to claim 5, wherein the temperature of the system is 40-75 ℃ when the Ostinib crude product is dissolved.
7. The Ostinib refining method according to claim 5, wherein the temperature of the system is 0-10 ℃ after the temperature reduction operation.
8. The Ostinib refining method according to claim 7, wherein the cooling rate is 2-20 ℃/min; and/or the time for precipitating the crystal is 0.5-5 h.
9. The Ostinib refining method according to any one of claims 1 to 8, wherein the preparation method of the Ostinib crude product comprises the following steps:
mixing the compound a, a solvent A and a base, and reacting;
the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide and potassium tert-butoxide;
the solvent is selected from one or more of acetonitrile, dimethyl sulfoxide and tetrahydrofuran;
the reaction temperature of the reaction is 60-100 ℃.
10. The Ostinib refining method according to any one of claims 1 to 8, further comprising a filtration operation after the step of cooling to precipitate crystals; and/or the presence of a gas in the gas,
after the step of collecting the crystals, the operation of drying the crystals is also included.
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| CN115433169A (en) * | 2022-11-07 | 2022-12-06 | 北京鑫开元医药科技有限公司 | Preparation method of oxitinib mesylate dimer |
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| CN108623567A (en) * | 2017-03-15 | 2018-10-09 | 上海赛诺克医药科技有限公司 | Ao Si replaces the preparation method of Buddhist nun |
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