CN104177300B - 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
- Publication number
- CN104177300B CN104177300B CN201410097805.2A CN201410097805A CN104177300B CN 104177300 B CN104177300 B CN 104177300B CN 201410097805 A CN201410097805 A CN 201410097805A CN 104177300 B CN104177300 B CN 104177300B
- Authority
- CN
- China
- Prior art keywords
- ambrisentan
- preparation
- degraded product
- basic cpd
- sodium hydride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 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 abstract description 31
- 229960002414 ambrisentan Drugs 0.000 title abstract description 30
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 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
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 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 3
- 230000000694 effects Effects 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims abstract 6
- 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 3
- 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
- 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
- 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
- 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
- 239000000047 product Substances 0.000 description 12
- 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
- 239000003814 drug Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 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
- -1 filter Substances 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
- 238000012544 monitoring process Methods 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
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 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
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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GileadScience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(3.5g,0.08mol)加入到50mL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(5g,0.026mol)的DMF(50mL)溶液,维持温度0~5度,滴完后继续搅拌反应0.5h,然后滴加4,6-二甲基-2-甲磺酰基嘧啶(5.2g,0.028mol)的DMF(50mL)溶液,滴完后继续搅拌2h,TLC检测反应完毕,将反应液倒入200mL冰水混合物中,过滤,滤饼用水(30mlx3)洗涤3次,然后真空干燥,得类白色固体8g,即为安立生坦的降解产物I。
质谱(ESI):m/z303.1(M+H)+。
1HNMR(400MHz,CDCl3)δ:7.91(s,1H),7.43(d,J=8Hz,2H),7.35~7.25(m,8H),6.78(s,1H),2.44(s,6H)。
13CNMR(101MHz,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0.01mol/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210nm,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0.5mg/mL,各取20μL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35.032min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17.588min的峰为安立生坦,保留时间36.232min的峰为安立生坦杂质I。
Claims (6)
1.一种如式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。
2.根据权利要求1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。
3.根据权利要求1所述的方法,其特征在于,所述的R选自甲磺酰基。
4.根据权利要求1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。
5.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。
6.根据权利要求4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。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410097805.2A CN104177300B (zh) | 2014-03-18 | 2014-03-18 | 一种安立生坦降解产物及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410097805.2A CN104177300B (zh) | 2014-03-18 | 2014-03-18 | 一种安立生坦降解产物及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104177300A CN104177300A (zh) | 2014-12-03 |
CN104177300B true CN104177300B (zh) | 2016-02-24 |
Family
ID=51958681
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410097805.2A Expired - Fee Related CN104177300B (zh) | 2014-03-18 | 2014-03-18 | 一种安立生坦降解产物及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104177300B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010091877A2 (en) * | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
-
2014
- 2014-03-18 CN CN201410097805.2A patent/CN104177300B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
---|
LC-ESI-MS/MS method for quantification of ambrisentan in plasma and application to rat pharmacokinetic study;Ramakrishna Nirogi等;《Biomedical Chromatography》;20120104;第26卷(第10期);第1150-1156页 * |
Also Published As
Publication number | Publication date |
---|---|
CN104177300A (zh) | 2014-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113906022B (zh) | 作为a2a/a2b抑制剂的吡唑并吡啶和三唑并吡啶 | |
CN105130955B (zh) | 富马酸沃诺拉赞的制备方法 | |
CN104177300B (zh) | 一种安立生坦降解产物及其制备方法 | |
CN106146560B (zh) | 一种高纯度磷酸特地唑胺的精制方法 | |
CN104292158A (zh) | 一种盐酸莫西沙星杂质的制备方法、检测方法和用途 | |
CN104020239A (zh) | 通过高效液相色谱法分离测定雷贝拉唑钠及其杂质的方法 | |
CN103755628B (zh) | 2-氨基-3-碘-5-溴吡啶的合成方法 | |
CN106188044B (zh) | 一种碘催化的3-芳硫基咪唑并[1,5-a]N-杂环化合物的合成方法 | |
CN108203437A (zh) | 两种替吡嘧啶杂质制备方法与应用 | |
CN105017218A (zh) | 一种右兰索拉唑晶型及其制备方法 | |
CN104311485B (zh) | 一种治疗白血病的药物博舒替尼的制备方法 | |
CN104945285A (zh) | 同位素标记丹磺酰氯-13c2的合成方法 | |
CN107941946B (zh) | 一种富马酸沃诺拉赞的检测方法 | |
CN107445894B (zh) | 一种手性环丙基氨基酸的制备方法 | |
CN104910080A (zh) | 一种新的厄洛替尼相关物质及其制备方法 | |
CN109796441B (zh) | 一种盐酸替比嘧啶的杂质a的制备方法 | |
CN109096332A (zh) | 一种氯化三苯基-4-(三氟甲基苯酰胺基)丁基鏻的合成方法及其在抗肿瘤药物中的应用 | |
CN105837573B (zh) | 一种9-[3a,6-二羟基六氢-1H-环戊二烯并[c]呋喃-4-基]鸟嘌呤的制备方法 | |
CN108218793A (zh) | 一种含氟嘧啶酮类化合物的合成方法 | |
CN103483320B (zh) | 雷贝拉唑砜(2-[[[4-(3-甲氧基丙氧基)-3-甲基-2-吡啶基]甲基]磺酰基]-1h-苯并咪唑)的合成方法 | |
CN103848848A (zh) | 一种他克莫司已知杂质双烯他克莫司的制备方法 | |
CN108732276B (zh) | 马昔腾坦有关物质的高效液相色谱分析方法 | |
CN103396370A (zh) | 一种安立生坦的纯化方法 | |
CN106928138B (zh) | 一种孟鲁司特钠杂质d的制备方法 | |
Liu et al. | Synthesis and characterization of two impurities in esomeprazole, an antiulcerative drug |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160224 |
|
CF01 | Termination of patent right due to non-payment of annual fee |