CN104177300A - 一种安立生坦降解产物及其制备方法 - Google Patents
一种安立生坦降解产物及其制备方法 Download PDFInfo
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- CN104177300A CN104177300A CN201410097805.2A CN201410097805A CN104177300A CN 104177300 A CN104177300 A CN 104177300A CN 201410097805 A CN201410097805 A CN 201410097805A CN 104177300 A CN104177300 A CN 104177300A
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- ambrisentan
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- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 title claims abstract description 32
- 229960002414 ambrisentan Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000007857 degradation product Substances 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012312 sodium hydride Substances 0.000 claims abstract description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 6
- HLLGFGBLKOIZOM-UHFFFAOYSA-N 2,2-diphenylacetaldehyde Chemical compound C=1C=CC=CC=1C(C=O)C1=CC=CC=C1 HLLGFGBLKOIZOM-UHFFFAOYSA-N 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 2
- 239000000047 product Substances 0.000 abstract description 13
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- -1 4,6-dimethyl pyrimidine-2-yl Chemical group 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000002308 endothelin receptor antagonist Substances 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZHPSNGCLCHWTRG-UHFFFAOYSA-N 4,6-dimethyl-2-methylsulfonylpyrimidine Chemical compound CC1=CC(C)=NC(S(C)(=O)=O)=N1 ZHPSNGCLCHWTRG-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940090243 letairis Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Abstract
本发明公开了一种安立生坦降解产物及其制备方法，安立生坦降解产物如I所示，是安立生坦原料或其制剂的主要杂质之一，I可用于分析检测安立生坦的纯度，可用于控制安立生坦的质量。本发明公开了一种制备I的方法，通过2,2-二苯基乙醛与式II所示的化合物在氢化钠等碱性化合物作用下，通过取代反应获得。
Description
技术领域
本发明属于生物医药领域，具体涉及一种安立生坦降解产物及其制备方法。
背景技术
安立生坦是最初由美国雅培公司（Abbott）研制开发的一种内皮素受体拮抗剂(ERA)，美国Myogen公司受让得到了其在全球的开发和市场权利。随后，美国葛兰素史克公司(Glaxosmithkline)与Myogen签定协议，获得了本品在美国以外的生产权利。2006年11月17日美国Gilead Science公司收购Myogen作为子公司，并获得安立生坦的所有权。该药物于2007年6月15日获得美国FDA批准，商品名为Letairis，口服用于治疗肺动脉高血压（PAH），化学名称为(+)-(2S)-2-[(4,6-二甲基嘧啶-2-基)氧基]-3-甲氧基-3,3-二苯基丙酸。安立生坦拥有良好的治疗效果、安全性数据、无重大的药物相互作用，已成为动脉高压市场上的领头羊。
研究发现，安立生坦会发生少量降解，生成一种降解产物，然而目前文献未公开该降解产物为何种化合物，也不知其具体结构。
发明内容
本发明通过研究，首次披露了一种安立生坦降解产物I，I如下式所示：
上述I为安立生坦降解产物，经过结构确认和质量分析验证I为安立生坦药品中的一种杂质。上述安立生坦杂质I可用于监测或控制安立生坦及其药剂的质量。
本发明还提供了一种安立生坦降解产物I的制备方法，通过2,2-二苯基乙醛与式II所示的化合物在碱性化合物作用下，通过取代反应获得。
其中，R为卤素、硝基、磺酰基，优选为甲磺酰基；所述的碱性化合物选自氢化钠、氨基钠、氨基锂、氢氧化钾、碳酸钾或叔丁醇钾，优选为氢化钠；所述的反应是在有机溶剂存在下进行，所述有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-乙基吡咯烷酮、二甲亚砜的一种或多种，优选为N，N-二甲基甲酰胺。
附图说明
图1为实施例2安立生坦降解产物 I的HPLC图。
图2为实施例2安立生坦的HPLC图。
具体实施方式
实施例1 安立生坦降解产物I的制备
将氢化钠 (3.5 g, 0.08 mol) 加入到50 mL的DMF溶液中，氮气保护，冷却至0~5度，再滴加2,2-二苯基乙醛 (5 g, 0.026 mol ) 的DMF (50 mL) 溶液，维持温度0~5度，滴完后继续搅拌反应0.5 h，然后滴加4,6-二甲基-2-甲磺酰基嘧啶 (5.2 g, 0.028 mol ) 的 DMF (50 mL) 溶液，滴完后继续搅拌2 h，TLC检测反应完毕，将反应液倒入200 mL冰水混合物中，过滤，滤饼用水 (30 ml x 3) 洗涤3次，然后真空干燥，得类白色固体8 g，即为安立生坦的降解产物I。
质谱(ESI)：m/z 303.1(M+H)+。
1H NMR (400 MHz, CDCl3) δ: 7.91 (s, 1H), 7.43 (d, J = 8 Hz, 2H), 7.35 ~ 7.25 (m, 8H), 6.78 (s, 1H), 2.44 (s, 6H)。
13C NMR (101 MHz, CDCl3) δ: 169.16, 162.75, 139.49, 136.49, 135.37, 129.69, 128.02, 127.77, 126.60, 125.15, 115.05, 23.33。
实施例2 安立生坦降解产物I的分离检测
HPLC条件：
用十八烷基硅烷键合硅胶为填充剂，流动相A 为0.01 mol/L的磷酸氢二钾缓冲液（磷酸调节pH值至4.5），流动相B为乙腈，按如下梯度洗脱表1进行洗脱，检测波长为210 nm，柱温30 ℃。理论塔板数按安立生坦峰计算应不低于5000。
梯度洗脱表1
| 时间(min) | 流动相A（%） | 流动相B（%） |
| 0 | 90 | 10 |
| 3 | 90 | 10 |
| 13 | 35 | 65 |
| 40 | 35 | 65 |
分别取杂质I和安立生坦适量，用乙腈稀释，配制成0.5 mg/mL，各取20 μL注入进样，在以上HPLC条件下分离检测。
分析结果：安立生坦杂质I的HPLC图如附图1所示，保留时间35.032 min的峰为安立生坦杂质I。安立生坦的HPLC图如附图2所示，保留时间为17.588 min的峰为安立生坦，保留时间36.232 min的峰为安立生坦杂质I。
Claims (8)
1.一种安立生坦降解产物I，如下式I所示：
。
2.如权利要求1所述的如式I所示化合物的制备方法，其特征在于包括如下步骤：式II所示的化合物与2，2-二苯基乙醛在碱性化合物的作用下反应即可；
其中，R为卤素、硝基、磺酰基。
3.根据权利要求2所述的方法，其特征在于，所述的碱性化合物选自氢化钠、氨基钠、氨基锂、氢氧化钾、碳酸钾或叔丁醇钾。
4.根据权利要求2所述的方法，其特征在于，所述的R选自甲磺酰基。
5.根据权利要求2所述的方法，其特征在于，所述反应是在有机溶剂存在下进行，所述有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-乙基吡咯烷酮、二甲亚砜的一种或多种。
6.根据权利要求3所述的方法，其特征在于，所述的碱性化合物选自氢化钠。
7.根据权利要求5所述的方法，其特征在于，所述反应的有机溶剂选自N，N-二甲基甲酰胺。
8.如权利要求1所述的如式I所示化合物在监测或控制安立生坦及其药剂的质量中的应用。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104359993A (zh) * | 2014-12-09 | 2015-02-18 | 江苏康缘药业股份有限公司 | 一种安立生坦有关物质的检测方法 |
| CN106146405A (zh) * | 2016-06-22 | 2016-11-23 | 湖北生物医药产业技术研究院有限公司 | 药物中间体及其制备方法和用途 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010091877A2 (en) * | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
| CN104515816A (zh) * | 2013-09-29 | 2015-04-15 | 天津药物研究院 | 一种安立生坦原料及制剂有关物质的检测方法 |
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2014
- 2014-03-18 CN CN201410097805.2A patent/CN104177300B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010091877A2 (en) * | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
| CN104515816A (zh) * | 2013-09-29 | 2015-04-15 | 天津药物研究院 | 一种安立生坦原料及制剂有关物质的检测方法 |
Non-Patent Citations (1)
| Title |
|---|
| RAMAKRISHNA NIROGI等: "LC-ESI-MS/MS method for quantification of ambrisentan in plasma and application to rat pharmacokinetic study", 《BIOMEDICAL CHROMATOGRAPHY》, vol. 26, no. 10, 4 January 2012 (2012-01-04), pages 1150 - 1156 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104359993A (zh) * | 2014-12-09 | 2015-02-18 | 江苏康缘药业股份有限公司 | 一种安立生坦有关物质的检测方法 |
| CN104359993B (zh) * | 2014-12-09 | 2016-03-30 | 江苏康缘药业股份有限公司 | 一种安立生坦有关物质的检测方法 |
| CN106146405A (zh) * | 2016-06-22 | 2016-11-23 | 湖北生物医药产业技术研究院有限公司 | 药物中间体及其制备方法和用途 |
| CN106146405B (zh) * | 2016-06-22 | 2018-11-30 | 湖北生物医药产业技术研究院有限公司 | 药物杂质中间体及其制备方法和用途 |
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