CN113024550A - Impurity of apatinib mesylate and preparation method thereof - Google Patents
Impurity of apatinib mesylate and preparation method thereof Download PDFInfo
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- CN113024550A CN113024550A CN202110331631.1A CN202110331631A CN113024550A CN 113024550 A CN113024550 A CN 113024550A CN 202110331631 A CN202110331631 A CN 202110331631A CN 113024550 A CN113024550 A CN 113024550A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to an impurity 1- (4- (4-oxo-2- (pyridine-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidine-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile of apatinib mesylate. The invention also relates to a preparation method of the impurity, wherein the preparation method takes the apatinib free base N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridinecarboxamide as a raw material, and the apatinib free base solution is obtained by irradiating under the light with a certain wavelength. The impurities have important influence on the quality control of the apatinib, so that the impurities are directionally synthesized, and the method has important significance on the quality control of the apatinib bulk drug by establishing an analysis method of the impurities.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to an impurity of apatinib mesylate and a preparation method thereof.
Background
Apatinib mesylate (the english name apatinib mesylate), the chemical name of which is N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridinecarboxamide mesylate, has the following structural formula:
apatinib mesylate is a tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor (TKI). Developed by Jiangsu Henry pharmaceutical company, marketed in China in 10 months in 2014, with the trade name of Eitan, and is suitable for patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction who have progressed or recurred after receiving at least 2 kinds of systemic chemotherapy.
In the process of synthesizing apatinib mesylate, an analysis method of impurities is established, and the method has important significance on the quality control of apatinib bulk drugs.
Disclosure of Invention
In the process of synthesizing apatinib mesylate, the inventors found that an impurity of apatinib mesylate has a structure shown in formula I:
the impurities have an important influence on the quality control of apatinib. At present, no literature reports the structure and the preparation method of the impurity, so that the impurity is directionally synthesized, and the method has important significance on the quality control of the apatinib bulk drug by establishing an analysis method of the impurity.
An object of the present invention is to provide an impurity of formula 1, 1- (4- (4-oxo-2- (pyridin-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidin-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile of apatinib mesylate.
Another object of the invention is to provide a preparation method of the impurity 1- (4- (4-oxo-2- (pyridine-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidine-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile of formula 1 of apatinib mesylate. The method takes Apatinib free base N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridine carboxamide as a raw material, and the solution of the Apatinib free base is obtained by irradiation under light with certain wavelength, and the reaction formula is shown as follows:
wherein the solvent is selected from methanol, ethanol or isopropanol;
the light source is selected from a sodium lamp with the wavelength of 589 nm;
the concentration of the solution of the apatinib free alkali is 0.5-2g/100 mL;
the illumination temperature range is 25-35 ℃;
the illumination time is 48-60 hours.
Detailed Description
The present invention is further illustrated below with reference to examples, but the embodiments of the present invention are not limited thereto.
All instrument reagent information of the invention is as follows:
all reagents used in the invention are purchased from Aladdin reagent company, and all the reagents are analytically pure; high resolution mass spectrometry data were measured using a Waters Xevo G2-S QTof high resolution mass spectrometer; nuclear magnetic resonance spectroscopy data were measured using BrukerAVANCE III HD 400M; HPLC purity was measured using Agilent 1260 high Performance liquid chromatography.
Example 1:
synthesis of 1- (4- (4-oxo-2- (pyridin-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidin-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile:
to a 250mL flask, 0.5g of apatinib free base N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridinecarboxamide and 100mL of methanol were added in this order, dissolved with stirring, and the resulting solution was exposed to a sodium lamp with a wavelength of 589nm at 25 ℃ for 48 hours. The obtained synthetic liquid is concentrated, and a product is separated by column chromatography (the column chromatography condition is dichloromethane (V)): methanol (V) ═ 2:1), so that the apatinib mesylate impurity with the purity of 0.05g, the HPLC purity of 98 percent and the yield of 5 percent can be obtained.
ESI-HRMS(m/z):C24H22N5O[M+H+]Theoretical calculation value: 396.1819, found: 396.1825, respectively;1H NMR(CD3CN)δ:8.43(d,J＝1.7Hz，1H),8.42(d,J＝1.8Hz，1H),8.14(dd,J＝4.8,1.7Hz，1H),8.04(dd,J＝7.6,1.8Hz，1H),7.40(d,J＝8.6Hz，1H),7.26-7.22(m,4H),6.76(dd,J＝7.6,4.9Hz，1H),6.72(br,1H),6.22(s,1H),2.35(m,2H),2.00(m,2H),1.89-1.83(m,4H)；13C NMR(CD3CN)δ:162.86,157.18,154.59,151.27,149.56,140.69,139.66,137.87,127.92,127.75,125.07,122.18,116.32,111.52,72.40,48.32,40.76,40.73,24.61。
example 2:
synthesis of 1- (4- (4-oxo-2- (pyridin-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidin-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile:
to a 250mL flask, 2g of apatinib free base N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridinecarboxamide and 100mL of ethanol were added in this order, dissolved with stirring, and the resulting solution was exposed to a sodium lamp with a wavelength of 589nm at 35 ℃ for 60 hours. The obtained synthetic solution is concentrated, and a product (column chromatography condition: dichloromethane (V)): methanol (V) ═ 2:1) is separated by column chromatography, so that the apatinib mesylate impurity of formula 1 can be obtained, the white solid is 0.07g, the HPLC purity is 97%, and the yield is 7%.
ESI-HRMS(m/z):C24H22N5O[M+H+]Theoretical calculation value: 396.1819, found: 396.1821, respectively;1H NMR(CD3CN)δ:8.43(d,J＝1.7Hz，1H),8.42(d,J＝1.8Hz，1H),8.14(dd,J＝4.8,1.7Hz，1H),8.04(dd,J＝7.6,1.8Hz，1H),7.40(d,J＝8.6Hz，1H),7.26-7.22(m,4H),6.76(dd,J＝7.6,4.9Hz，1H),6.72(br,1H),6.22(s,1H),2.35(m,2H),2.00(m,2H),1.89-1.83(m,4H)；13C NMR(CD3CN)δ:162.86,157.18,154.59,151.27,149.56,140.69,139.66,137.87,127.92,127.75,125.07,122.18,116.32,111.52,72.40,48.32,40.76,40.73,24.61。
example 3:
synthesis of 1- (4- (4-oxo-2- (pyridin-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidin-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile:
to a 250mL flask, 1g of apatinib free base N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridinecarboxamide and 100mL of isopropanol were added in this order, dissolved with stirring, and the resulting solution was exposed to a sodium lamp with a wavelength of 589nm for 56 hours at 25 ℃. The obtained synthetic solution is concentrated, and a product is separated by column chromatography (the column chromatography condition is dichloromethane (V)): methanol (V) ═ 2:1), so that the apatinib mesylate impurity of formula 1 can be obtained, the white solid is 0.04g, the HPLC purity is 97%, and the yield is 4%.
ESI-HRMS(m/z):C24H22N5O[M+H+]Theoretical calculation value: 396.1819, found: 396.1815, respectively;1H NMR(CD3CN)δ:8.43(d,J＝1.7Hz，1H),8.42(d,J＝1.8Hz，1H),8.14(dd,J＝4.8,1.7Hz，1H),8.04(dd,J＝7.6,1.8Hz，1H),7.40(d,J＝8.6Hz，1H),7.26-7.22(m,4H),6.76(dd,J＝7.6,4.9Hz，1H),6.72(br,1H),6.22(s,1H),2.35(m,2H),2.00(m,2H),1.89-1.83(m,4H)；13C NMR(CD3CN)δ:162.86,157.18,154.59,151.27,149.56,140.69,139.66,137.87,127.92,127.75,125.07,122.18,116.32,111.52,72.40,48.32,40.76,40.73,24.61。
Claims (7)
1. an impurity 1- (4- (4-oxo-2- (pyridine-3-yl) -1, 4-dihydropyridine [2,3-d ] pyrimidin-3 (2H) -yl) phenyl) cyclopentane-1-carbonitrile of apatinib mesylate, which has a structure shown in formula 1:
2. a process for the preparation of an impurity apatinib mesylate according to claim 1,
the preparation method takes Apatinib free base N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-picolyl) amino ] -3-pyridinecarboxamide as a raw material, and the solution of the Apatinib free base is obtained by irradiation under light with certain wavelength, and the reaction formula is shown as follows:
3. the method of claim 2, wherein the solvent is selected from methanol, ethanol or isopropanol.
4. The method of claim 2, wherein the light source is selected from a sodium lamp having a wavelength of 589 nm.
5. The method of claim 2, wherein the solution of apatinib free base has a concentration of 0.5-2g/100 mL.
6. The method according to claim 2, wherein the light irradiation temperature is in the range of 25 to 35 ℃.
7. The method according to claim 2, wherein the light irradiation time is 48 to 60 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108467360A (en) * | 2018-06-22 | 2018-08-31 | 江苏美迪克化学品有限公司 | A kind of Ah pa replaces the Preparation Method And Their Intermediate of Buddhist nun |
| CN109020881A (en) * | 2018-06-28 | 2018-12-18 | 新发药业有限公司 | A kind of Ah pa replaces the preparation method of Buddhist nun |
| CN109810052A (en) * | 2017-11-20 | 2019-05-28 | 新发药业有限公司 | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109810052A (en) * | 2017-11-20 | 2019-05-28 | 新发药业有限公司 | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun |
| CN108467360A (en) * | 2018-06-22 | 2018-08-31 | 江苏美迪克化学品有限公司 | A kind of Ah pa replaces the Preparation Method And Their Intermediate of Buddhist nun |
| CN109020881A (en) * | 2018-06-28 | 2018-12-18 | 新发药业有限公司 | A kind of Ah pa replaces the preparation method of Buddhist nun |
Non-Patent Citations (1)
| Title |
|---|
| 贾雪冬等: "基于UHPLC-Q-Orbitrap HRMS 的甲磺酸阿帕替尼有关物质结构鉴定", 《药物分析杂志》 * |
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Effective date of registration: 20220928 Address after: 318020 Jiangkou Chemical Development Zone, Taizhou, Zhejiang, Huangyan Patentee after: Zhejiang Tianyu Pharmaceutical Co.,Ltd. Patentee after: Zhejiang Jingsheng Pharmaceutical Co.,Ltd. Address before: 318020 Jiangkou Chemical Development Zone, Taizhou, Zhejiang, Huangyan Patentee before: Zhejiang Tianyu Pharmaceutical Co.,Ltd. |