合成化學(xué) Chinese Joumal of Synthetic Chemistry481對(duì)羥基苯乙醇的合成繆震元,孫長(zhǎng)恩,華萬(wàn)森,陸路德(南京理工大學(xué)江蘇南京210094)摘要:綜述了對(duì)羥基苯乙醇的重要合成方法及其最新進(jìn)展。參考文獻(xiàn)33篇關(guān)鍵詞:對(duì)羥基苯乙醇;合成進(jìn)展;綜述中圍分類號(hào):TQ460.31文獻(xiàn)標(biāo)識(shí)碼:A文章編號(hào):105-1512002)06-481-04 The Synthesis of p-Hydroxyphenylethyl Alcohol MIAO Zhen-yuan, SUN Chang-en, HUA Wan-shen, LU Lu-de (Nanjing Uhiversity of Science and Technology, Nanjing 210094, China) Abstract: The main preparation methods of p-hydroxypheny alcohol have been described and the new development of the methods is also introduced with 33 references. Keywords: p-hydroxyphenylethy] alcohol; synthesis; development; review1引言3酯還原法對(duì)羥基苯乙醇(phydroxyphenylethyl alcohol;羧酸一般不易還原,但其酯相對(duì)而言較為容 phydroxybenzencethanol; tyrosol),分子式CaH1易還原,1996年李國(guó)青提出了一種用四氫鋁鋰O2,分子量138.1658,m.p.88℃~92,b..作還原劑的方法。反應(yīng)式如下:310C,極易溶于水、乙醇、乙醚、丙酮和醋酸從氯仿中得到針狀晶體。天然存在于橄欖油、醬油、果 OEt OEt酒和覆盆子中,是一種重要的醫(yī)藥和香料中間體。HO B2O它能合成許多有用的藥物如:美多洛爾、倍他洛爾、紅景天甙等?，F(xiàn)對(duì)其主要合成方法及其研究進(jìn) OH OH展作一簡(jiǎn)要綜述。 HO2發(fā)酵法=Ph-CH-早期的對(duì)羥基苯乙醇是通過(guò)細(xì)菌、酶、真菌等在發(fā)酵過(guò)程中產(chǎn)生的。例如精制甘蔗糖1200g,水將對(duì)羥基苯乙酸乙酯溶丙酮中,加入無(wú)水碳酸10L和L酪氨酸15g混合后加入酵母發(fā)酵,三四鉀和氯化芐,加熱回流20h蒸去丙酮,用乙酸乙天發(fā)酵完成后,除去酵母,濾液蒸發(fā)到糖漿狀時(shí),酯提取,然后用水洗,無(wú)水氯化鈣干燥減壓濃縮先用醇提取羥苯基衍生物,然后用乙醚提取,再用得4苯甲氧基苯乙酸乙酯,然后在乙醚中用四氫氯仿提取得具有光澤的菱形針狀晶體,產(chǎn)率60%鋁鋰還原接著催化氫化脫去苯甲基得對(duì)羥基苯~80%乙醇。每步產(chǎn)率均在90%左右。收稿日期:2001-12-18作者簡(jiǎn)介:綠展元(1974一),男,漢族,南京理工大學(xué)碩士主嬰從事醫(yī)藥中間體的合成研究482-合成化學(xué)Vol.10,2002文獻(xiàn)3-5也分別提出了用四氫鋁鋰或硼氫化通過(guò)氧化酶或還原酶催化可以得到醛,但產(chǎn)鈉還原酯得到相應(yīng)的醇。 Roesky則提出了用固率不高,酶的活性不好控制,不易工業(yè)化生產(chǎn)101體氧化物CuO/ZO2作為催化劑催化氫化酯得到(3)臭氧氧化(r=ch2ch=ch2,r2OMe)相應(yīng)的醇3-(4-甲氧基苯基)丙烯溶于氯仿和甲醇的混合溶劑中,降溫至0C,通入含有5.6%臭氧的氧以醛為中間體的合成法氣并攪拌至臭氧完全吸收,混合物立即蒸餾得產(chǎn)起始原料RCHR生成醛后用還原劑(如物,產(chǎn)率約為37%。ic26h2(/dmf-h2oCo-6h2n-TH)5苯乙胺合成法還原為醇7,然后轉(zhuǎn)化成對(duì)羥基苯乙醇。按生成醛的途徑可分為三類:苯乙胺硝化后還原變成對(duì)氨基苯乙胺,然后(1)重排反應(yīng)制備醛(R2=OMe,Cl)進(jìn)行重氮化、水解得到對(duì)羥基苯乙醇,但產(chǎn)率很對(duì)位上帶有R2基團(tuán)的氧化苯乙烯在HZSM低。如果硝化后先進(jìn)行重氮化和水解得到對(duì)硝基沸石存在下以HCCl3為溶劑,N2氣保護(hù),室溫條苯乙醇,接著還原成對(duì)胺基苯乙醇,再進(jìn)行重氮化件下反應(yīng)30min,可得到相應(yīng)的醛。此法產(chǎn)率高和水解得到對(duì)羥基苯乙醇,反應(yīng)分兩步進(jìn)行產(chǎn)率選擇性好、條件溫和可達(dá)到45%反應(yīng)式如下(2)生物酶催化(R=Ch2C2NH2,R2=OH) NH2 HNO, NH2)diazotisation 2) hydrolysis OH dia HN 2)hydr HO1963年 Yamada應(yīng) Whitel193方法合成了6苯乙醇合成法對(duì)羥基苯乙醇。他先使對(duì)羥基苯乙胺?；?接著亞硝化酰胺得到N-烷基亞硝酰胺,熱消除N2得6.1以對(duì)氨基苯乙醇為中間產(chǎn)物到相應(yīng)的酯,最后水解生成對(duì)羥基苯乙醇。以苯乙醇為原料的合成方法文獻(xiàn)報(bào)道較美國(guó)科學(xué)家5則于1992年提出了一種新穎多,大部分都用先酯化、硝化、水解及催化氫化的路線,他們以對(duì)甲氧基苯乙胺為原料,經(jīng)過(guò)三步得(4氨基苯基)乙醇,然后再經(jīng)過(guò)重氮化和水反應(yīng)生成對(duì)甲氧基苯乙醇,然后再通過(guò)官能團(tuán)轉(zhuǎn)解得到對(duì)羥基苯乙醇121化得到對(duì)羥基苯乙醇。反應(yīng)條件溫和,產(chǎn)率達(dá)到 Henryt還提出了在硝基還原為氨基時(shí)采用90%以上。并且在此路線中提出了用羥基取代伯不同的催化劑,得到的產(chǎn)率不一樣采用氯化亞錫胺中的氮原子的一種簡(jiǎn)便方法。和鹽酸作為催化劑,還原產(chǎn)率可達(dá)88%。 OH OAc OAc ON人HH HN HO第6期繆震元等:對(duì)羥基苯乙醇的合成4836.2以4-(2-甲氧基乙基)苯酚為中間產(chǎn)物及重氮化和水解得到4-(2-甲氧乙基)苯酚,然后黃嘉22-2采用苯乙醇經(jīng)過(guò)氫氧化鈉和經(jīng)過(guò)官能團(tuán)轉(zhuǎn)化生成對(duì)羥基苯乙醇反應(yīng)式如下:硫酸二甲酯生成苯乙甲醚,再經(jīng)過(guò)硝化、催化氫化 OH OMe ON OMe OH HoH7對(duì)羥基苯甲酮法存在下氧化對(duì)羥基苯甲酮,得到二烷基乙縮醛衍生物,接著水解可得相應(yīng)的乙二醛衍生物,然后同 Durrwachter[2在1993年提出了一種新時(shí)還原兩個(gè)羰基,得到對(duì)羥基苯乙醇反應(yīng)步驟簡(jiǎn)的合成方法,他們采用烷基亞硝酸鹽在酸和醇的單,具有一定的經(jīng)濟(jì)價(jià)值。0 LORH人HH HOOR HO HOY84溴苯酚合成法在碳酸鉀存在下4-溴苯酚與烯丙基溴在丙酮中回流,再經(jīng)過(guò)格氏反應(yīng)制備2-(4烯丙氧基)苯乙張三奇等28在合成紅景天甙的過(guò)程中提出醇然后在氯化鈀和氯化亞銅催化下通入氧氣,脫了以4溴苯酚為原料,選擇烯丙基保護(hù)酚羥基去烯丙基得到產(chǎn)物 OH BrCH:=CH: Mg PICI: OH Br Br HOH9對(duì)硝基氧化苯乙烯法種以苯酚為原料在 Lewis酸條件下合成對(duì)羥基苯乙醇的方法,也取得了很好的效果,產(chǎn)率都達(dá)到了此方法2采用對(duì)硝基氧化苯乙烯在甲醇中95%左右。于4×10Pa氫氣壓 Rancy力下用 Ni催化氫化得對(duì)羥基苯乙醇作為一種重要的醫(yī)藥中間體,到對(duì)氨基苯乙醇,產(chǎn)率達(dá)到40%,然后按上面的隨著醫(yī)藥工業(yè)的發(fā)展需求量會(huì)越來(lái)越大,并且出重氮化得到對(duì)羥基苯乙醇。還有采用鋅和氯化鈣口看好,但國(guó)內(nèi)還沒(méi)有工業(yè)化生產(chǎn)天津化工研究作為還原劑0的報(bào)道。設(shè)計(jì)院正在開發(fā)電解制備工藝,南京理工大學(xué)也準(zhǔn)備開發(fā)新的工藝,使之能在國(guó)內(nèi)早日實(shí)現(xiàn)工業(yè)10結(jié)束語(yǔ)化生產(chǎn)。最近,日本和俄羅斯的科學(xué)家[31-33提出了一484合成化學(xué)vol.10,2002參考文獻(xiàn) (3-amino-4-hydroxy Phenyl)- ethanol; 3- amino ty- rosol [J]. J. Amer. Chem. Soc. 1950, 72: 136]- [1] Pishchimuka P. S.. Fiological Syntheses p Hydrox-1364. yphenethyl Alcohol [].. Russ. Phys, Chern, Soc. [18] Erwin Ferber.. Existence Dihydro- and Oetahydro-p-in-1916,48:1-54. dole[]. Ber. Germany. 1929,62B: 183-195.2]李國(guó)青,李展紅景天甙合成方法的改進(jìn)[]中國(guó)藥[9] Rashevakaya.. Kashcheeva Mostoslavskaya物化學(xué)雜志,1996,6(2):136-137. T.. Origination of Dinitro Derivatives in Nitration 3: James H. Huuter John A. Hogg. Synthetic Sterols[J]. of-phenyl Alcohol []. Zh. Obshch, Khim.. S. S.j.an.chem.soc.,1949,71:1922-1925.R..1963,33(12)3998-4002. [4] Ekram 2. Khafagy. J. P. Lambooy. J. Med. Chem. [J], [20] Uhlmann, Fugen; Pfleiderer, Wolfgang.. Nucleotides.1966,9(6):936-951.. Substituted phenylethyl Groups [J j. Helv. [5] Rohman C. Meisel D.. Arch. Pharm. [].1961,294:Chim,acta Germany,1981.64(5):1688-1703.538-549 [21] Finn L. Greekoya B. Romankevich M. Ya.. [6] Roeskey, Rainer; Borchert, Holger Dingerdissen, Uwe.. (4-Aminophenyl)ethanol [J]. Khim. Reaktivov I Pre- Preparation of Phenylethanols Catalytic Hydro-genation paratov Russia. 1965,3:7-9. of Phenylacetate Esters[]. WO 98 41,492.22]魏運(yùn)洋,孫榮康.4-(2-甲氧基乙基)苯酚的合成 [7] Robindra N.. Baruah.. An Efficient System Ni-6H,]中國(guó)醫(yī)藥工業(yè)雜志,1993,24(10):470-471.n/dm-h for Conversion of Aldehydes to Alcohol23]黃嘉梓徐鐮胡鳴選擇性受體阻滿劑美多心].terett, India.1992,33(37):5417-5418安的合成[]醫(yī)藥工業(yè),1983,(1):5-6 [8] Goswanu. Aunrit; Borthakur. Naleen.. Selective Reduc- [24] Katayama, Tatsuo; Takita, Satosi.. Preparation of p tion of Aldehydes to Alcohols by CoCl-6H2O-Zn-THF and m-(2-methoxyethyl)phenols from Their tert-buty] System[j.j.chem.sect.b:org.chem.incl.med Ethers[p.j025663625199Che, India194,33B(5):495-496. [25] Katayama, Tatsuo; Takita. Satosi. Preparantion of 2- [9 Smith. Keithi: Al-Shamali. Mahrnoud. Rearrangement (p-tert and m-tert-butoxy-phenyl )ethyl Methyl Ether of Styrene Oxides under Zeolite Catclysis[J]. Proc. Int.[.JP22566371990. Zeolite Conf. UK. ,1988, 12th, 2: 1129-1132. [26] Durrwachter, John. R.. Production of Exhanol [P]. [10] Nison, Goeran E Tottmar, Olof. J. Neurochem.wO9316975,1993wed.j,19785)1566572 [27] David T. Manning; Harry A. Stansbury.. A New Syn- [11] BrinerE., Fliszar S.. Ricca. Infrared Absorption thesis of Phenylglyoxai Acetals [J]. J. Org. Chem,, Spectra of Cronides []. Helv. Chim. Acta. France,1961,26:3755-37571959,42:749-754.[28]張三奇,李中軍合成紅景天的新途徑[]中國(guó) [12 Bianco A. Passacantilli P. Righi G.. Improved Proce-藥物化學(xué)雜志1997.7(4):256-257273 dure for Reduction of Esters to Alcohols by Sodium [29] Zuberovski V. M. Verlovskaya T... Synthesis of Borohydride]. Synth. Commun. Italy, 1988,18 Thiazole Derivatives[]. Zh. Obshch. Khim. U. S. S.(15):1765-1771R.196131:3056-3062 [13] White E. H.. J. Am. Chem. Soc. [J],1945476 4498. [30] Singavski V. G.. p-Aminophenylethanol [P7. U. S.. [14] Shun-ichi Yamada, Tozo Fuji.. Preparation of TyrosolR.147190,1962 and 4-Methoxyphenyl Alcohol)]. Chem. Pharm. Bult. E31] Kozhevnikov. V. Catalyst and Commercial Process for Japan,1963,11:258-260. Manufacture of Parp- substiruted Phenols[]. Aktual.[15] Frank. Guziec Jr; Dong chu Wei.base -promoted- Probl. Proizyod. Katal. Prom. Katal. Tr. Semin, Russi- Oxygenation of N-substituted-N. tosylhdrazines a Con-a,1994,2nd2:186-187 venient Route to Hydroxydeamination of Primary [32] Daimon, Fmiko: Waula, Isao; Akada, Mitsuo.. Prepara- AminesU]. Tetra. Lett.. S. A.,1992,33(49),7465 tion of 4-Hydroxyphenethyl Alcohol[P]. JP, 327 610,74682000.16]紀(jì)淑芳,周亞青,紅景天的合成],沈陽(yáng)藥學(xué)院[33]aimon,6..,《DimEnkWdA,MoPrr-,saoada,mtu.rpr學(xué)報(bào),1987.4(3):192-193. tion of 4-Hydroxyphenethy! Alcohol[] JP 319 213.] Henry M Woodlbuen; Calvin. Stunt. The synthesis 9.2000