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.284· 当代新药合成工艺 参考文献 [1]Reynolds N A，Scott LJ. Ciclesonide[J].Drugs，2004，64(5):511-519.[2]姚鹏.环索奈德(ciclesonide)[J].中国药物化学杂志，2007，17(5):337-337. [3]姚远兵，王玲，夏悦，等.治疗哮喘新药-环索奈德[J].中国药房，2010，21(17): 1616-1618. [4]陈颖江，丁雁，王尔华，新型抗哮喘药物环索奈德的合成[J].化工时刊，2006，20(5): 30-32. [5]Kamijo T，Yamamoto R，Harada H，et al. 1 - Substituted imidazoles as useful catalysts for acylation of alcohols [J].Chemical &. Pharmacetical Bulletin，1983，31(10):3724-3727.[6]Shapiro E L, Gentles M J，Tiberi R L，et al.17-Heteroaroyl esters of corticosteroids. 2.11β- Hydroxy series [J]. Journal of Medicinal Chemistry，1987，30(9):1581-1588.[7]Calatayud J，Conde J R， Luna M. Pregna-1,4-diene -3,20-dionne-16,17-acetal - 21 - esters, process for their preparation，acompositon and methods for the treatments of inflammatory conditions:US，5482934[P].1996-01-09. [8]应明华，关定伟，陈鸿鹏.一锅法制备泼尼松龙衍生物:中国，1699395A[P].2005- 11-23. [9]李静，李金禄，卢彦昌，等，一种制备环索奈德的新的16,17-缩酮中间体:中国， 102477064 A[P].2012-05-30. [10] Reynolds N A. Ciclesonide: treatment of allergic rhinitis antiallergy/antiasthmatic, [J]. Drugs of the Future,2001，26(11):1033-1039. 8.2福莫特罗(Formoterol) 8.2.1福莫特罗概述 【中文化学名称]N-[5-[(R)-2-[(R)-1-(4-甲氧苯基)-2-丙烷基胺基]-1-羟基乙基-2-羟基苯]甲酰胺 [英文化学名称]N-[5-[(R)-2-[(R)-1-(4-methoxyphenyl)-propan-2-ylamino]-1-hydroxyethyl]-2-hydroxyphenyl]- formamide 【异名](R,R)- formoterol,Brovana，Arformoterol tartrate，(R,R)- Formoterol tar- trate，(-)-Formoterol，Arformotero。 【性状]从乙醇结晶，m.p.128~129℃,药用形式为其酒石酸盐,或富马酸盐[1]①。 【药理作用]该药是一个新的、长效的β肾上腺受体激动剂。它对β2肾上腺素有很高的选择性[2]。其外消旋化合物已被当做商业产品。但是它的两种立体结构具有不同的药理作用。作用强度如下R,R>R,S>S,R>S,S。最新研究表明Formoterol可以作为选择性受体拮 ①编者注:该药已被国家执业药师资格考试新版大纲新增收录。   第8章抗哮喘药(Antiasthmatic Drugs) .287. 5.29(s，2H，PhCH:O)，7.19(d,J=8.6Hz,1H,Ar-H)，7.42-7.32(m,5H，Ar-H)， 8.10(d,J=10.8Hz，1H，Ar-H)，8.40(s,1H，Ar- H).'C NMR(75MHz，CDCI) δ:26.6，71.6，114.8，126.2，127.1，128.7，129.0，129.9，134.0，134.9，139.8，155.2，194.8.LC/MS(ESD m/z:272.1(M+H+)，Cale mass: 271.171. (2) 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanone(8-2-5) To a suspension of 1-[4 -(benzyloxy)- 3-nitrophenyl]ethanone (8-2-4，11.42g，42mmol) in acetic acid (150mL) was slowly added bromine(8.75g，54.6mmol) at 20℃, The mixture was stirred until the color faded out. Ice water (75mL) was added to the mix- ture, the precipitate was filtered and washed with water. Crystallization of the crude solid in ethanol gave the pale yellow crystals (8-2-5,11.76g，85%)，m.p.137~138℃，'H NMR(300MHz,CDCl)♂:4.36(s，2H，COCH,Br)，5.31(s，2H，PhCH,O)，7.21(d，J= 8.7Hz,1H，Ar-H)，7.43-7.35(m，5H，Ar-H)，8.13(d,J=8.1Hz,1H，Ar-H)， 8.44(s，1H，Ar- H).'C NMR(75MHz，CDCl) 8:30.1，71.9，115.1，126.2，127.0，127.2，128.8，129.1，134.7，134.8，140.0，155.8，188.5.LC/MS(ESI) m/z:350.0，352.0(M+H+)，Calc mass: 348.9”. (3) (R)-1-[4 -(benzyloxy)-3-nitrophenyl]-2- bromoethanol(8-2-6) To a suspension of n5 - pentamethylcyclopentadienyl rhodium dimer ([RhCl (Cp* )]₂)(43.2mg，0.072mmol) and(S,S)-PEGBsDPEN(192mg，0.144mmol) in H:O (25mL) was added PEG 2000(25.0g，12.5mmol). The mixture was purged with argon and stirred at40℃ for 1h to afford the catalyst in situ.HCOONa(4.89g，72mmol) and 1-[4 -( benzy- loxy)-3-nitrophenyl]-2- bromoethanone (8-2-5，5.04g，14.4mmol) were added to the preformed catalyst solution. The mixture was stirred at r. t. for 1h until the reaction comple- ted. Diethyl ether was added to the reaction system, and the organic phase was extracted un- der argon, The aq. solution containing PEG 2000 and the catalyst remained for the next cy- cle. The combined organic phases were washed with brine (100mL) and dried over anhy- drous sodium sulfate. After the filtration, the organic solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to give 8-2-6 as white solid(4.76g，94%).The enantiomeric excess was determined by chiral HPLC on a Chiracel OJ- H column (Hex/IPA，V/V=65:35，254nm，0.8mL/min)，Retention time:27.01min(major)，31.81min.94%ee. m.p.69~70℃，[a]b-17.9°(c=1.07，EtOH)8.'H NMR(300MHz，CDCl,) 8: 3.52 (d,J=9.0Hz，1H,CH,Br)，3.63(d,J=10.5Hz,1H,CH:Br)，4.90(m，1H,Ar-CHOH)，5.23(s，2H，PhCH,O)，7.12(d,J=8.4Hz，1H，Ar-H)，7.42-7.31(m，5H，Ar-H)，7.52(d,J=8.7Hz,1H，Ar-H)，7.88(s，1H,Ar- H).'C NMR(75MHz，CDCls)8:39.8，71.6，72.5，123.6，127.2，128.5，128.9，131.8，133.3，135.5，140.1，151.9，115.5.LC/MS(ESI) m/z:352.2，354.2(M+H+)，Calc mass:351.07. (4) recycling of the catalyst Under an argon atmosphere, to the aq, solution containing PEG 2000 and the catalyst from the asymmetric hydrogenation above, was added HCO.H (0.29mL，14.4mmol) and 1 -          |
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