第41卷,第5期安徽化工Vol 41. No 52015年10月ANHUI CHEMICAL INDUSTRYOct.2015來(lái)曲唑的合成工藝研究徐志成1,李立標(biāo)2,施務(wù)務(wù)(1.福建中醫(yī)大學(xué)藥學(xué)院,福建福州350122;2.蚌埠豐原醫(yī)藥科技開(kāi)發(fā)有限責(zé)任公司,安徽蚌埠2330003.蚌埠市第一人民醫(yī)院,安徽蚌埠2330摘要:以對(duì)甲苯腈、對(duì)氟苯腈為原料,在甲醇鈉的催化下發(fā)生取代反應(yīng),制得中間體(I)4,4-腈基二苯基甲烷。在溴代試劑NBS的作用下,中間體(1)發(fā)生取代反應(yīng),生成中間體(Ⅱ)4-(a-溴代-4-氰基)苯甲腈。最后使中間體(Ⅱ)與1,2,4-三氮唑進(jìn)行縮合生成來(lái)曲唑。關(guān)鍵詞:來(lái)曲唑;抗癌藥;芳香酶抑制劑;合成doi:10.3969/isn.1008-553X201505017中圖分類號(hào):062626文獻(xiàn)標(biāo)識(shí)碼:A文章編號(hào):1008-553X(2015)05-0056-02來(lái)曲唑( Letrozole)是瑞士諾華有限公司開(kāi)發(fā)的一種12合成步驟非甾體高效選擇性芳香化酶抑制劑,1996年首次在英1.21中間體(I)的合成國(guó)上市,1997年獲得FDA批準(zhǔn),臨床上用于洽療婦女晚2000mL反應(yīng)瓶中加入500mL經(jīng)無(wú)水硫酸鎂干燥期乳腺癌。由于其選擇性較高,具有較高的治療指數(shù),與過(guò)的四氫呋喃,攪拌下加入36g甲醇鈉并用氮?dú)獗Ｗo(hù)其它芳香酶抑制劑和抗雌激素藥物相比,來(lái)曲唑的抗腫冰鹽浴降溫至0℃以下,緩慢滴加117g對(duì)甲苯腈和瘤作用更強(qiáng)6。125g對(duì)氟苯腈的四氫呋喃混合溶液,滴完后保持0℃以文獻(xiàn)報(bào)道本品的合成方法主要是以4-甲基苯甲腈下反應(yīng)2h。300mL飽和食鹽水洗滌3次,無(wú)水硫酸鈉干為原料習(xí),經(jīng)溴代得4-溴甲基苯甲腈,再和1,2,4-三燥,蒸去四氫呋喃,殘余物用甲基叔丁基醚結(jié)晶即得中氮唑縮合得4-[1-(1,2,4-三氮唑基)甲基}-苯,最后與間體I)1g,mp:167℃-169℃,HPC純度997%。對(duì)氟苯腈縮合制得來(lái)曲唑。該方法第一步產(chǎn)物4-溴甲122中間體(Ⅱ)的合成基苯甲腈對(duì)人皮膚具有非常強(qiáng)烈的刺激性,不利于人工將上述得到的113g中間體(1)溶解在600mL氯仿操作,最后一步反應(yīng)條件苛刻且收率較低,所用催化劑中,依次加入92gN-溴代丁二酰亞胺和4g過(guò)氧化苯甲叔丁醇鉀價(jià)格較高且不易得。本文按下面路線,經(jīng)三步酰,混合物加熱至回流溫度并保持此溫度下反應(yīng)9-10反應(yīng)合成來(lái)曲唑,克服了上述路線的缺點(diǎn)。h。反應(yīng)液冷卻至室溫,300mL飽和食鹽水洗滌氯仿層3次,無(wú)水硫酸鈉干燥,蒸去氯仿,殘余物加入240mL乙酸乙酯和100mL正己烷,室溫下攪拌Ih后過(guò)濾得中間中間體I體(Ⅱ)128g,mp:119℃-122℃,HPLC純度97%。1.23來(lái)曲唑的合成上述中間體(I)溶解在600mL異丙醇中,加入120g1,2,4-三氮唑、50g碳酸鉀、136g四丁基溴化銨,反應(yīng)中間體Ⅱ來(lái)曲唑混合物加熱到回流并在此溫度下反應(yīng)8~9h,蒸餾至1201實(shí)驗(yàn)部分mL,冷卻到室溫,過(guò)濾并水洗得來(lái)曲唑粗品,甲醇重結(jié)1.1儀器與試劑晶兩次得到73.2g較純的來(lái)曲唑。mp:180-183℃,熔點(diǎn)儀YRT-3、安捷倫LC1200液相色譜儀、HPLC純度9994%JNM-ECS400核磁共振譜儀、DF-101S集熱式恒溫加熱2結(jié)果與討論磁力攪拌器。對(duì)甲苯腈、對(duì)氟苯腈、三氮唑、甲醇鈉最終產(chǎn)品經(jīng)核磁共振氫譜、熔點(diǎn)進(jìn)行結(jié)構(gòu)確證,符NBS、過(guò)氧化苯甲酰,以上試劑均為工業(yè)級(jí),含量>98%,合結(jié)構(gòu)特征,mp:180-183℃,HNMR(CDC3)8626其余試劑為化學(xué)純(s,H,CH),744ArH)73d,4H,4ArH),8.15中國(guó)煤化工CNMHG收稿日期:201506-08作者簡(jiǎn)介:徐志成(1982-),男,福建中醫(yī)藥大學(xué)藥學(xué)院在職研究生,0552-4017840,13905524144,61727741@qom。徐志成,等:來(lái)曲唑的合成工藝研究(s,H,ao-H),8.23(s,H,a20-H)。該方法易于得到高純38-40度產(chǎn)品,反應(yīng)條件溫和,易于操作,適合工業(yè)化生產(chǎn)「3]夏凡.來(lái)曲唑的合成工藝研究[四川化工,2005,8(6):8-9參考文獻(xiàn)14]王軍.來(lái)曲唑的合成、表征及晶型研究有機(jī)化學(xué),2004,24[]周金培,朱鳳軍,黃文龍抗癌藥來(lái)曲唑的合成研究J中國(guó)藥科(5):550-553.大學(xué)學(xué)報(bào),2003,34(4):375-376[5]Peter L M. Process for the preparation of letrozole[P]. US770515 B212和國(guó)棟周志明來(lái)曲唑的合成研究廣東化工,20034(1):(西科爾公司制備來(lái)曲唑的改進(jìn)方法PCN0125160AStudy on the synthesis of letrozoleXU Zhi-cheng, LI Li-biao2, SHI Wu-wu'(1. Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; 2. Bengbu BBCAPharmaceutical Technology Development Co, Ltd, Bengbu 233000, China3. First Peoples Hospital of Bengbu City, Bengbu 233000, China)Abstract: With p-tolunitrile and 4-fluorobenzonitrile as starting materials, the intermediates(I)4, 4 -nitrile diphenylmethane were obtained from substitution reaction under the catalysis of sodium methoxide. Under the action of NBS, Theintermediates( )4-(a-bromine-4-cyano)cyanobenzene were obtained from intermediates( I) by substitution reactionFinally, the intermediates(ll)and 1, 2,4-lH-triazole generated the Letrozole by condensation reactionKey words: Letrozole; anticancer drug; aromatase inhibitors; synthesis(上接第55頁(yè))成硫酸鈣晶須的適宜工藝條件為:經(jīng)水洗除雜后未經(jīng)篩門]謝占金,石文建,金翠霞,等.晶種及晶型助長(zhǎng)劑對(duì)磷石膏制備分的磷石膏在反應(yīng)溫度為140℃,反應(yīng)時(shí)間為3h,陳化硫酸鈣晶須的影響環(huán)境工程學(xué)報(bào),2012,64):1348-1352時(shí)間Ih后趁熱過(guò)濾,在此條件下制得的硫酸鈣晶須的陳先勇,唐琴,胡衛(wèi)兵以廢棄磷石膏為原料水熱合成碳酸鈣晶須的研究即環(huán)境工程學(xué)報(bào),2008,2(12):1677-1680長(zhǎng)徑比較大(平均長(zhǎng)度為1595μm,平均直徑為45m,仵亞妮化全縣,湯建偉等磷石膏制備碳酸鈣晶須的工藝研長(zhǎng)徑比平均為354),形貌規(guī)整。參考文獻(xiàn)究化工礦物與加工,2011(12):18-22余瓊粉,寧平,楊月紅磷石膏的預(yù)處理及其資源化途徑!江⑧8劉百臣利用轉(zhuǎn)爐渣制備硫酸鈣晶須的試驗(yàn)研究[!粉煤灰,2012(3):30-32.西農(nóng)業(yè)學(xué)報(bào),2008,20(2):109-111凹9張華偉,陳繼濤,梁鵬,等.硫酸鈣晶須制備機(jī)理及技術(shù)研究進(jìn)[2饒箭星磷石膏的處理與綜合利用J化學(xué)與生物工程,2010,展U材料導(dǎo)報(bào),2011,25(6):46-5027(6):78-793]刑華,陸樹(shù)立周奇,等中國(guó)磷石膏資源化管理分析J環(huán)境污0黃哲元工業(yè)磷石膏渣制備硫酸鈣晶須條件及機(jī)理研究D」四川:西南科技大學(xué),2007染與防治,2008,30(4):90-93l)秦軍,謝占軍,于杰,等磷石膏制備硫酸鈣晶須的初步研究即4]楊榮華,宋錫高磷石膏的凈化處理及制備硫酸鈣晶須的研究無(wú)機(jī)鹽工業(yè).2010,40(10):50-53□無(wú)機(jī)鹽工業(yè),2012,44(4):31-34Preparation of Calcium Sulfate Whiskers from WastePhosphogypsum by Hydrothermal MethodZHENG Liang-chuan, LU Tian-yu, YANG Ben-hong, JIA NG Yong-xiang(1. Department of Biological and Environmental Engineering, Hefei University, Hefei 230601, China2. Department of Chemical and Material Engineering, Hefei University, Hefei 230601,China3. Anhui Research Institute of Chemical Industry, Hefei 230041, China)Abstract: Phosphogypsum, the solid wastes arising from the wet-process phosphoric acid industry. In this paper, preparationof calcium sulfate whiskers by hydrothermal method from waste phosphogypsum, and studied the phosphogypsum diameteraging time, reaction temperature, and reaction time effect of calcium sulfate whisker morphology. The products werecharacterized through XRD, SEM and TGA. The experimental results show ththe whisker are 35.4 when the reaction temperature is 140C, the reactiHa中國(guó)煤化工 average diameter of-ng time is lh. Thecharacterization results by sEm show that the whisker of diameter is neat andCNMHGKey words: Phosphogypsum; Calcium sulfate whisker; hydrothermal synthesis