利奈唑胺注射液中主要降解产物的合成
收稿日期: 2013-12-25
修回日期: 2014-01-16
网络出版日期: 2014-02-10
基金资助
教育部博士点基金（No. 20110181110079）和国家科技重大专项（Nos. 2013ZX09301304-002，2013ZX09202002）资助项目.
Synthesis of Major Degradation Products of the Injection of Linezolid
Received date: 2013-12-25
Revised date: 2014-01-16
Online published: 2014-02-10
Supported by
Project supported by the Research Fund for the Doctoral Program of Higher Education (No. 20110181110079) and the National Science and Technology Major Project (Nos. 2013ZX09301304-002, 2013ZX09202002).
以利奈唑胺为起始原料，利用LiOH选择性水解利奈唑胺的酯键和酰胺键，得利奈唑胺注射液中的部分水解产物N-[（2R）-3-[[3-氟-4-（4-吗啉基）苯基]氨基]-2-羟基丙基]-乙酰胺（2）和完全水解杂质（2S）-1-氨基-3-[[3-氟-4-（4-吗啉基）苯基]氨基]-2-丙醇（4），收率分别为78.3%和86.6%；然后将化合物4的末端氨基用叔丁氧羰基保护，经N，O-双乙酰化后用氨水/甲醇脱除O-乙酰基，再利用饱和氯化氢乙醚溶液脱除叔丁氧羰基保护基，得N-[（2S）-3-氨基-2-羟基丙基]-N-[3-氟-4-（4-吗啉基）苯基]-乙酰胺（3）盐酸盐，五步总收率62.3%.
黄志雄 , 桑志培 , 曹海彦 , 晁若冰 , 邓勇 . 利奈唑胺注射液中主要降解产物的合成[J]. 有机化学, 2014 , 34(5) : 989 -993 . DOI: 10.6023/cjoc201312033
The ester bond and amide bond of linezolid were selectively hydrolyzed by using LiOH to afford N-[(2R)-3-[[3-fluoro-4-(4-morpholino)phenyl]amino]-2-hydroxypropyl] acetamide (2) and (2S)-1-amino-3-[[3-fluoro-4-(4-morpholino)- phenyl]-amino]-2-propanol (4) with 78.3% and 86.6% yields respectively, which were the partially hydrolyzed impurity and fully hydrolyzed impurity of the injection of linezolid. The terminal amino group of compound 4 was then protected with tert-butyloxycarbonyl and subjected to N,O-diacetylation. Subsequently, N-[(2S)-3-amino-2-hydroxypropyl]-N-[3-fluoro-4-(4-morpholino)phenyl]acetamide (3) hydrochloride was synthesized by removal of O-acetyl with ammonia/methanol and then deprotection tert-butoxycarbonyl using saturated solution of hydrogen chloride in ether with 62.3% overall yield.
Key words： oxazolidinone antibacterial; linezolid; injection; degradation product; impurity; synthesis
[1] Zhang, H.; Du, K.; Shang, Z. P.; Deng, Y. Chin. J. Pharm. 2011, 42, 245 (in Chinese).
(张慧, 杜鲲, 桑志培, 邓勇, 中国医药工业杂志, 2011, 42, 245.)
[2] Clemett, D.; Markham, A. Drugs 2000, 59, 815.
[3] Hadden, C. E.; Bowman, P. B.; Duholke, W. H.; Guido, J. E.; Kaluzny, B. D.; Robins, R. H.; Russell, S. M.; Sims, S. M.; Thamann, T. J.; Martin, G. E. J. Heterocycl. Chem. 2000, 37, 1623.
[4] Wang, G. Anti-Infect. Agents Med. Chem. 2008, 7, 32.
[5] Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed. 2003, 42, 2010.
[6] Wang, S. Q.; Deng, Y.; Chen, Z. X.; Zhang, H.; Sang, Z. P.; Mao, B. Y.; Xia, Z. J. WO 2012171248, 2012 [Chem. Abstr. 2012, 158, 77243].
[7] Babu, K. C.; Reddy, R. B.; Gangaiah, L.; Madhusudhan, G.; Mukkanti, K. Pharma Chem. 2011, 3, 219. Li, H. W.; Li, X. D.; Xie, W. B.; Zhang, L.; Wang, L. X. CN 102516191, 2012 [Chem. Abstr. 2012, 157, 165559].
/
| 〈 |
|
〉 |
