高 玲
(赤峰學(xué)院 化學(xué)化工學(xué)院,內(nèi)蒙古 赤峰 024000)
伊羅夫文合成路線圖解
高 玲
(赤峰學(xué)院 化學(xué)化工學(xué)院,內(nèi)蒙古 赤峰 024000)
本文綜述了抗腫瘤藥伊羅夫文的合成路線,根據(jù)文獻(xiàn)報(bào)道分別以乙酰乙酸乙酯、2,4-乙酰丙酮、丙酮酸甲酯為原料共有三種路線,這三種方法各有優(yōu)勢,在生產(chǎn)中可選擇適當(dāng)?shù)姆椒ê铣?
伊羅夫文;合成路線;圖解
伊羅夫文(Irofulven,1),化學(xué)名為 2,7- 二甲基-6-螺環(huán)丙烷-1-羥甲基-(5R)-羥基-4(5H)-茚酮,1在Ⅰ、Ⅱ期臨床試驗(yàn)中對(duì)卵巢癌、前列腺癌、胃腸道腫瘤及胰腺癌等的治療及與其它抗癌藥物的聯(lián)合治療上均取得了令人滿意的結(jié)果,目前正在進(jìn)行Ш期臨床試驗(yàn).根據(jù)目前文獻(xiàn)報(bào)道,1的合成路線有三種,總結(jié)如下(見圖1):
乙酰乙酸乙酯(4)在1,2-二溴乙烷和K2CO3作用下烷基化[1],在KOH堿性下水解后得6,再在氯甲酸甲酯作用下與重氮甲烷脫水縮合得7[2].
甲基丙烯酰氯(8)在無水AlCl3催化下與乙炔環(huán)合加成得9[3],采用(S)-2-甲基-CBS-惡唑硼烷與甲硼烷-四氫呋喃進(jìn)行手性拆分,得到旋光異構(gòu)體10,再經(jīng)PCC還原得11[4].
7和11在Rh(OAc)4的催化下經(jīng)環(huán)加成反應(yīng),羥基乙?;?,格式反應(yīng),制得15.15與2,2-二甲氧基丙烷反應(yīng)得16,再經(jīng)脫鹵化氫,脫保護(hù)基,酮基還原,伴隨著1,4-消除,得到3[5].3被氧化得2,2在多聚甲醛和稀硫酸作用下得終產(chǎn)物1[6].
2,4-乙酰丙酮(19)與1,2-二溴乙烷、K2CO3在DMF中烷基化得1,1-二乙酰基環(huán)丙烷(20)[4],20的酮基被還原后,采用3-三甲基硅基-3-丙炔醇保護(hù)醇羥基得21,21經(jīng)還原,脫鹵化氫加成,酯化后得 23,再在[CuH(PPh3)]6的作用下得丙二烯物24,24在碳酸鉀和甲醛作用下脫三甲基硅基得25.25經(jīng)丙二烯P-K環(huán)加成反應(yīng)得26,再經(jīng)還原,脫保護(hù)基得到3,3按“1”法制得終產(chǎn)物1.
丙酮酸甲酯(28)與直鏈的半硫縮醛烯酮(29)加成得30,30的硫醇酯與甲基碘化鋅交叉耦合后再經(jīng)甲基化,還原得33.33與34經(jīng)去硅烷基化,F(xiàn)elken-Ahn碳加成反應(yīng),得到35.35的3位醇羥基經(jīng)烯丙基氧基二乙基硅烷基化得到36,再經(jīng)Grubbs G2催化得37.對(duì)37的2,3位醇羥基進(jìn)行保護(hù)后脫去羥甲基后,再經(jīng)過環(huán)合,脫氫得3.3按“1”法制得終產(chǎn)物1.
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R962
A
1673-260X(2012)03-0009-02
內(nèi)蒙古教育廳高等學(xué)校自然科學(xué)基金(NJ10239)資助項(xiàng)目