CN1044810C - Synthesis of dosotheophylline - Google Patents

Synthesis of dosotheophylline Download PDF

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CN1044810C
CN1044810C CN94113971A CN94113971A CN1044810C CN 1044810 C CN1044810 C CN 1044810C CN 94113971 A CN94113971 A CN 94113971A CN 94113971 A CN94113971 A CN 94113971A CN 1044810 C CN1044810 C CN 1044810C
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theophylline
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synthesis
dioxolane
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CN1106404A (en
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郭彩云
舒敬值
陈庆云
张准祥
李文杰
王雄
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中国科学院上海有机化学研究所
广东新会市制药厂
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Abstract

一种多索茶碱的合成方法,是由茶碱与2-卤甲基-1,3-二甲氧杂环戊烷在极性溶剂中,用碱作酸吸收剂,一步反应生成多索茶碱,产率可达75-85%。 A method of synthesis of doxofylline, theophylline is reacted with 2-halo-1,3-dimethoxy-dioxolane in a polar solvent, with a base as an acid absorber, a multi-step reaction cable theophylline, a yield of up to 75-85%. 反应原料易得,反应条件易控制,分离纯化简便,适宜于工业生产。 The reaction raw materials, the reaction conditions are easily controlled, simple separation and purification, is suitable for industrial production. 一步合成法反应新颖,为嘌呤药物结构改造开拓新方法。 Step synthesis reaction novel purine develop new drugs structure modification method.

Description

新药多索茶碱的合成方法 The method of synthesis of new drugs Doxofylline

本发明涉及黄嘌呤化合物的合成方法,具体地说是一种多索茶碱的合成方法。 The present invention relates to a method for the synthesis of a xanthine compound, in particular a method for synthesis of Doxofylline.

多索茶碱(Doxofylline)是苯碱类新药物,是黄嘌呤的衍生物。 Doxofylline (Doxofylline) benzene bases of new drugs, xanthine derivatives. 学名为2-(7'茶碱甲基)-1,3-二氧杂环戊烷[2-(7'-theophyllinemethyl)-1,3-dioxolane]或7-(1,3-二氧杂环戊甲基)-苯碱[7-(1,3-dioxolan 2yl methyl)theophylline]。 Scientific name 2- (7 'theophylline) -1,3-dioxolane [2- (7'-theophyllinemethyl) -1,3-dioxolane] or 7- (1,3-dioxo heterocyclic amyl methyl) - benzene base [7- (1,3-dioxolan 2yl methyl) theophylline]. 它是镇咳止喘,扩张支气管的新药,商品名为Anismar。 It is Zhichuan antitussive, bronchodilating drug under the trade name Anismar. 它的药效是同类药物氨茶碱的10-15倍,无成瘾性,对中枢神经系统和心血管无付作用。 Its efficacy is 10-15 times faster than competing drugs theophylline, non-addictive, no side effects on the central nervous system and cardiovascular. 美国专利(US4187308,1980年)报道了多索茶碱的合成方法,是用无水茶碱乙醛和乙二醇在对甲苯磺酸催化下,于苯中回流生成,产率平均约70%,仅报道熔点144-145.5℃,未提及光谱数据。 U.S. Patent No. (US4187308, 1980) reported the synthesis of doxofylline, theophylline anhydrous acetaldehyde with ethylene glycol and p-toluenesulfonic acid catalyst, at reflux in benzene generated, the average yield of about 70% , it reported only m.p. 144-145.5 ℃, not mentioned spectral data. 该法所用原料无水茶碱乙醛不易制得,合成步骤多,产率低,在反应中还需加入对甲苯磺酸,分离纯化麻烦,此外,溶剂苯的毒性大,属致癌物质,不适宜于工业生产。 This method is easy to dry materials used to prepare theophylline acetaldehyde, multi-step synthesis, low yields, the reaction was added p-toluenesulfonic acid needed, separation and purification problems, in addition, toxic solvent benzene, is a carcinogen, not suitable for industrial production. 因此,为多索茶碱寻找一个简易合成方法,仍是可研究的重要课题。 Therefore, doxofylline looking for a simple synthesis method, is still an important issue be studied.

上述美国专利法是将多索茶碱当做茶碱乙醛乙二醇缩醛来考虑,而本发明是将多索茶碱看做茶碱7-位氢被甲基环戊基团 The aforementioned U.S. patent law is as doxophylline theophylline acetaldehyde ethylene acetal considered, but the present invention is seen as theophylline, doxofylline 7-position is hydrogen methylcyclopentyl group

的取代物,在这一新构思基础上设计和探索了本发明的合成方法。 Substituents, and designed to explore synthetic methods of the present invention is based on this new concept.

本发明目的是提供一种多索茶碱新的合成方法,是用茶碱作原料,与2-卤甲基-1,3-二氧杂环戊烷一步反应合成,反应条件容易控制,产物分离纯化简便,适宜于工业生产。 Object of the present invention to provide a Doxofylline new synthesis, theophylline is used as a starting material, the synthesis reaction with 2-halo-1,3-dioxolane step, the reaction conditions are easily controlled, the product purification easy, suitable for industrial production.

本发明多索茶碱的合成方法,是茶碱与2-卤甲基-1,3-二氧杂环戊烷在极性溶剂中,用碱作酸吸收剂,一步反应即可生成。 The method of the present invention Ming Duosuo Synthesis of theophylline, theophylline and 2-halo-1,3-dioxolane in a polar solvent, with a base as acid acceptor, to generate a one-step reaction.

本发明反应以下列反应式表示: The reaction of the present invention is represented by the following reaction formula:

式中x是卤素,为氯、溴或碘。 Wherein x is halogen, chlorine, bromine or iodine. 反应中所用的碱是碱金属碳酸盐如碳酸钠、碳酸钾和碳酸锂等;碱土金属碳酸盐如碳酸镁、碳酸钙和碳酸钡等;碳酸铵或有机碱如三乙胺、三丙胺和吡啶等。 The base used in the reaction are alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate and the like; alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, barium carbonate and the like; ammonium carbonate or an organic base such as triethylamine, tripropylamine and pyridine. 反应中所用的极性溶剂是醇类如乙醇、异丙醇和环己醇等;醚类如四氢呋喃、二氧六环和乙二醇二甲醚等;脯类如乙腈、丁腈和苯腈等;酰胺类如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和N-甲基吡咯酮等或它们中任何二种的混合溶剂。 Polar solvent used in the reaction are alcohols such as ethanol, isopropanol, cyclohexanol and the like; ethers such as tetrahydrofuran, dioxane and ethylene glycol dimethyl ether and the like; preserved, such as acetonitrile, butyronitrile and benzonitrile, etc. ; amides such as N, N- dimethylformamide, N, N- dimethylacetamide and N- methylpyrrolidone and the like, or any two kinds of mixed solvents. 反应物克分子比为茶碱∶2-卤甲基-1,3-二氧杂环戊烷∶碱=1∶1-5∶1-3,茶碱与极性溶剂重量比为1∶6-12。 The reaction was :2- theophylline molar ratio of halomethyl-1,3-dioxolan: base = 1:1-5:1-3, theophylline with a polar solvent weight ratio 1:6 -12. 反应温度60-125℃,反应时间8-18小时,反应进程中用气相色谱跟踪检测,待原料几乎完全转化,即停止反应。 The reaction temperature is 60-125 deg.] C, the reaction time is 8-18 hours, the reaction progress by gas chromatographic trace detection, starting material to be almost complete conversion, the reaction is stopped. 反应溶剂可以回收,产物经重结晶纯化。 The reaction solvent can be recovered, the product was purified by recrystallization. 重结晶使用的溶剂是乙酸乙酯、乙醇、二氧六环、甲醇、氯仿、异丙醇、乙二醇单甲酯等或它们中任何二种的混合溶剂。 Recrystallization solvent used is ethyl acetate, ethanol, dioxane, methanol, chloroform, isopropanol, ethylene glycol monomethyl ester, or any other two kinds of mixed solvents. 产率可达75-85%。 Yield up to 75-85%. 产物结构用1HNMR,13CNMR,IR,UV,MS和元素分析证实。 Analysis of structure of the product was confirmed by 1HNMR, 13CNMR, IR, UV, MS and elemental.

本发明多索茶碱合成方法的优点是反应选择性强,产物单一,重复性好,产率高,为合成多索茶碱提供了捷径。 Advantages of the invention Ming Duosuo synthesis method is the reaction selectivity of theophylline, a single product, good repeatability, high yield, provides a shortcut for the synthesis Doxofylline. 该反应原料易得,反应条件易控制,分离纯化简便,溶剂可回收再用,成本低,收益快,适宜于工业生产,为制药工业所欢迎。 The reaction raw materials, the reaction conditions are easily controlled, simple separation and purification, and then the solvent recovered, low cost, fast return, suitable for industrial production, for the pharmaceutical industry welcomed. 此外,这一新反应首次用环戊氧杂烷基取代茶碱7-位氢,把茶碱的反应扩展到氧杂环烷化,为嘌呤化学增添新内容,为嘌呤药物结构改造开拓新方法。 In addition, this new first reaction with cyclopentyl oxaalkyl substituted 7-position hydrogen theophylline, theophylline extended to oxacycloalkyloxy of reaction, adding new content to purine chemistry, to develop new methods for the structural modification of a pharmaceutical purine . 因此,本发明显示了理论和工业生产的双重意义,本发明通过以下实施例进一步阐述,但并不限止本发明的范围。 Accordingly, the present invention shows the dual meaning of theoretical and industrial production, the present invention is further illustrated by the following examples, but not limiting, of the scope of the invention.

实施例1苯碱(1,3二甲基黄嘌呤-水合物)24g(0.12mole),200ml乙二醇二甲醚和80ml N-甲基呲咯酮,Na2CO313g(0.12mole)置于三口反应瓶中,搅拌加热至50℃,2-氯甲基-1,3-二氧杂环戊烷15.5g(0.13mole)由分液漏斗逐滴加入,滴加完毕后,加热至120-125℃,维持在此温度下反应,用气体色谱跟踪,原料几乎完全转化时,停止反应。 Example 1 base benzene (1,3-dimethyl xanthine - monohydrate) 24g (0.12mole), 200ml of ethylene glycol dimethyl ether and 80ml N- methyl ketone polypyrrole, Na2CO313g (0.12mole) was placed three reactions flask, stirred and heated to 50 ℃, 2- chloromethyl-1,3-dioxolane 15.5g (0.13mole) of a separatory funnel is added dropwise. after completion of the dropwise addition, heating to 120-125 deg.] C , while maintaining the reaction at this temperature, trace gas chromatography, almost complete conversion of raw materials, the reaction was stopped. 回收溶剂后得粗产物,经乙酸乙酯∶乙醇(1∶3体积比)重结晶,得白色针状结晶多索茶碱27g,产率85%。 After recovering the solvent to give the crude product from ethyl acetate: ethanol (3 by volume ratio) was recrystallized to give white needles Doxofylline 27g, yield 85%. 产物的物理常数如下:熔点145-145.5℃元素分析计算值(%)C 49,62;H 5.27;N 21.05;O 24.06实测值(%)C 49.51;H 5.30;N 21.16;O 24.031HNMR[CDCl3,δ(ppm)]3.42(s,3H,N-CH3);3.62(s,3H,NCH3)3.96(s,4H,OCH2×2);4.62(d,2H,CH2);5.23(t,1H,CH);7.63(s,lH,CH=N)13CNMR[CDCl3,δ(ppm)]27.786(CH3);29.605(CH3);47.857(CH2);65.294(OCH2);100.757(CH);107.056(C=C);148.215(C=C);142.143(CH=N);151.053(C=O);155.146(C=O)IR(KBr,cm-1)1012-1032(COC);1654(C=C);1696(C=O);2950(CH)UV(CHCl3,nm)276(ε=8900);232(ε=2100)Ms 267(M++1)5.5%;266(M+)12.5%;73 Physical constants of the product are as follows: m.p. 145-145.5 ℃ Elemental analysis Calcd. (%) C 49,62; H 5.27; N 21.05; O 24.06 Found (%) C 49.51; H 5.30; N 21.16; O 24.031HNMR [CDCl3 , δ (ppm)] 3.42 (s, 3H, NCH3); 3.62 (s, 3H, NCH3) 3.96 (s, 4H, OCH2 × 2); 4.62 (d, 2H, CH2); 5.23 (t, 1H , CH); 7.63 (s, lH, CH = N) 13CNMR [CDCl3, δ (ppm)] 27.786 (CH3); 29.605 (CH3); 47.857 (CH2); 65.294 (OCH2); 100.757 (CH); 107.056 ( C = C); 148.215 (C = C); 142.143 (CH = N); 151.053 (C = O); 155.146 (C = O) IR (KBr, cm-1) 1012-1032 (COC); 1654 (C = C); 1696 (C = O); 2950 (CH) UV (CHCl3, nm) 276 (ε = 8900); 232 (ε = 2100) Ms 267 (M ++ 1) 5.5%; 266 (M +) 12.5 %; 73

100%;193 100%; 193

3.8%;87 3.8%; 87

9.5%实施例224g茶碱(0.12mole),250ml异丙醇和10gMgCO3(0.12mole)室温下置于三口反应瓶中。 Example 224g 9.5% theophylline embodiment (0.12mole), 250ml of isopropanol and 10gMgCO3 (0.12mole) placed in three reaction flask at room temperature. 搅拌加热至50℃,19.2g2-氯甲基-1,3-二氧杂环戊烷(0.16mole)由分液漏斗滴入反应瓶中,滴加完毕后,加热至80℃,反应约18小时后,回收溶剂,粗产物用二氧六环重结晶,得白色针状结晶多索茶碱23.5g,产率75%。 Was stirred and heated to 50 ℃, 19.2g2- chloromethyl-1,3-dioxolane (0.16mole) added dropwise to the reaction flask by a separatory funnel, After the addition, was heated to 80 ℃, for about 18 after hours, the solvent is recovered, the crude product was recrystallized from dioxane, to give white needles, 23.5 g of crystals Doxofylline, 75% yield.

实施例324g茶碱(0.12mole),200ml乙腈和51.4g三丙胺(0.36mole)在室温下置于三口反应瓶中,加热至50℃,20g 2-溴甲基-1,3-二氧杂环戊烷(0.12mole)滴入反应瓶中,加热至60-70℃反应约10小时结束,回收溶剂,粗产物经甲醇∶氯仿(5∶1体积比)重结晶,得白色针状结晶多索茶碱25.2g,产率80%。 Theophylline Example 324g (0.12 mole) embodiment, tripropylamine 200ml acetonitrile and 51.4g (0.36mole) was placed in three reaction flask at room temperature, heated to 50 ℃, 20g 2- bromomethyl-1,3-dioxa cyclopentane (0.12 mole) added dropwise to the reaction flask and heated to 60-70 deg.] C for about 10 hours to complete the reaction, recovery of the solvent, the crude product was methanol: chloroform (volume ratio 5:1) recrystallized as white needle crystals plurality doxophylline 25.2g, 80% yield.

实施例4茶碱19.8g(0.1mole),240ml乙二醇二甲醚和20g碳酸钙(0.2mole),置于三口反应瓶中,搅拌加热至50℃,21,4g 2-碘甲基-1,3-二氧杂环戊烷(0.1mole)由分液漏斗逐滴加入,滴完后加热至80-85℃,用气体色谱跟踪,当原料几乎完全转化时停止反应,回收溶剂后得粗产物,经异丙醇结晶得白色针状结晶多索茶碱20.7g,产率78%。 EXAMPLE 4 Theophylline 19.8g (0.1mole) embodiment, 240ml of ethylene glycol dimethyl ether and 20g of calcium carbonate (0.2 mole), was placed three reaction flask, stirred and heated to 50 ℃, 21,4g 2- iodomethyl - 1,3-dioxolane (0.1 mole) by dropwise added from the separatory funnel, and heated to 80-85 deg.] C dropwise addition, trace gas chromatography, the reaction was stopped when almost complete conversion of starting material, the solvent gave recovered The crude product was crystallized from isopropanol to give white needles 20.7 g of Doxofylline, yield 78%.

实施例5茶碱19.8g(0.1mole),150ml N,N二甲基乙酰胺和24g吡啶(0.3mole)置于三口瓶中,加热至50℃,42.7g 2-氯甲基-1,3-二氧杂环戊烷(0.35mole)滴入反应瓶中,加热至80-90℃,反应约8小时后,减压回收溶剂,粗产物经二乙醇单甲醚结晶得白色针状结晶多索茶碱22.5g,产率约85%。 Example 5 Theophylline 19.8g (0.1mole) embodiment, 150ml N, N-dimethylacetamide and pyridine 24g (0.3mole) placed in three-neck flask and heated to 50 ℃, 42.7g 2- chloro-1,3 - dioxolane (0.35mole) added dropwise to the reaction flask and heated to 80-90 deg.] C, about 8 hours after the reaction, recovery of the solvent under reduced pressure, the crude product was crystallized diethanol monomethyl ether to obtain a white needle crystal plurality doxophylline 22.5g, a yield of about 85%.

实施例6茶碱19.8g(0.1mole),100ml乙醇,50ml乙腈和124g碳酸铵(0.25mole),置于三口反应瓶中,加热至50℃,61g氯甲基-1,3-二氧杂环戊烷(0.50mole)滴入反应瓶中。 Example 6 Theophylline 19.8g (0.1mole) embodiment, 100ml of ethanol, 50ml of acetonitrile and 124g ammonium carbonate (0.25 mole), was placed three reaction flask, was heated to 50 ℃, 61g-chloro-1,3-dioxa cyclopentane (0.50 mole) added dropwise to the reaction flask. 维持反应温度在55-60℃ 18小时,停止反应回收溶剂后得粗产物,用乙酸乙酯∶甲醇(1∶体积比)重结晶,得白色针状结晶多索茶碱21g,产率80%。 Maintaining the reaction temperature at 55-60 ℃ 18 hours, the solvent was recovered to obtain a crude product of the reaction, ethyl acetate: methanol (1: by volume) was recrystallized to give white needles Doxofylline 21g, 80% yield .

Claims (6)

1. 1. 一种多索茶碱的合成方法,其特征在于由茶碱与2-卤甲基-1,3-二氧杂环戊烷在极性溶剂中,用碱作酸吸收剂,一步反应生成多索茶碱,反应物克分子比为茶碱∶2-卤甲基-1,3-二氧杂环戊烷∶碱=1∶1-5∶1-3,反应温度60-125℃,反应时间8-18小时。 A multi-cable synthesis theophylline, theophylline wherein the 2-halo-1,3-dioxolane in a polar solvent, with a base as an acid absorber, a multi-step reaction Doxofylline, theophylline molar ratio of reactants :2- halo-1,3-dioxolane: = 1:1-5:1-3 base, the reaction temperature is 60-125 deg.] C, the reaction time is 8-18 hours.
2. 2. 如权利要求1所述的合成方法,其特征在于2-卤甲基-1,3-二氧杂环戊烷中的卤索是氯、溴或碘。 The method of synthesis according to claim 1, characterized in that the 2-halo-1,3-dioxolane cable halogen is chloro, bromo or iodo.
3. 3. 如权利要求1所述的合成方法,其特征在于所述碱是金属碳酸盐、碱土金属碳酸盐、碳酸铵或有机碱。 The method of synthesis according to claim 1, wherein said base is a metal carbonate, alkaline earth metal carbonates, ammonium carbonate or an organic base.
4. 4. 如权利要求1所述的合成方法,其特征在于所述极性溶剂是醇类、醚类、腈类、酰胺类或它们中任何二种的混合溶剂。 The method of synthesis according to claim 1, wherein said polar solvent is an alcohol, ethers, nitriles, amides, or any two kinds of mixed solvents.
5. 5. 如权利要求1所述的合成方法,其特征在于反应物茶碱与溶剂重量比为1∶6-12。 The method of synthesis according to claim 1, characterized in that the reaction solvent weight ratio of theophylline 1:6-12.
6. 6. 如权利要求1所述的合成方法,其特征在于粗产物重结晶使用的溶剂是乙酸乙酯、乙醇、甲醇、氯伤、二氧六环、异丙醇、乙二醇单甲酯或它们中任何二种的混合溶剂。 The method of synthesis according to claim 1, characterized in that the solvent crude product was recrystallized using ethyl acetate, ethanol, methanol, chloro injury, dioxane, isopropanol, ethylene glycol, or the monomethyl ester any two kinds of mixed solvents.
CN94113971A 1994-11-03 1994-11-03 Synthesis of dosotheophylline CN1044810C (en)

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CN1044810C (en) * 1994-11-03 1999-08-25 中国科学院上海有机化学研究所 Synthesis of dosotheophylline
CN1041728C (en) * 1997-03-03 1999-01-20 黑龙江华星制药股份有限公司 Synthesis of doxofylline
CN102367254B (en) * 2011-08-26 2012-11-28 贺金凤 More stable doxofylline compound and pharmaceutical composite thereof
CN102775405B (en) * 2012-08-23 2014-03-12 天津梅花医药有限公司 High-solubility doxofylline compound
CN102936248A (en) * 2012-10-30 2013-02-20 开封明仁药业有限公司 Method for preparing doxofylline
CN103145713A (en) * 2013-03-26 2013-06-12 山西普德药业股份有限公司 Doxofylline crystalline compound and lyophilized powder thereof
CN103159769B (en) * 2013-04-01 2015-03-11 湖北美林药业有限公司 Doxofylline compound and medicine composition thereof
CN106916156B (en) * 2015-12-23 2019-03-26 北京颐方生物科技有限公司 A kind of preparation method of doxofylline
CN108840872A (en) * 2018-08-22 2018-11-20 湖北泓肽生物科技有限公司 The synthetic method of doxofylline

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