技术领域technical field
本发明属于药物化学领域，具体涉及到一种利匹韦林的制备方法。The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of rilpivirine.
背景技术Background technique
利匹韦林(Rilpivirine,R278474,TMC-278)，商品名化学名为4-[[4-[[4-[(1E)-2-氰基乙烯基]-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苯腈。原研公司是美国Tibotec Therapeutics公司，2011年5月20日由美国FDA批准上市，是继奈韦拉平、地拉韦啶、依法韦仑、依曲韦林之后又一上市非核苷类抗艾滋病药物。Rilpivirine (R278474, TMC-278), trade name The chemical name is 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. The original research company is Tibotec Therapeutics of the United States, which was approved by the FDA on May 20, 2011. It is another non-nucleoside anti-AIDS drug on the market after nevirapine, delavirdine, efavirenz, and etravirine.
利匹韦林是通过非竞争性地结合距离艾滋病毒逆转录酶活性位点的变构疏水性结合口袋内，结合后的复合体干扰逆转录酶的活性，从而达到抑制病毒复制的目的。大量的临床研究显示，利匹韦林对野生型和突变型的病毒株都有很高的活性，使用利匹韦林治疗导致的不良反应的发生率低于依法韦仑。在尚未接受过抗逆转录病毒治疗的艾滋病成年患者的治疗中，利匹韦林具有剂量小、抗病毒活性及抗耐药性高、耐受性和安全性好以及药物相互作用少等优势，在临床应用中，利匹韦林和其他抗逆转录病毒药物联合用于对从未进行过抗逆转录病毒治疗的艾滋病毒感染成年患者的首次治疗，效果显著，为艾滋病患者尤其是艾滋病耐药患者提供了新的选择。Rilpivirine binds noncompetitively to the active site of HIV reverse transcriptase In the allosteric hydrophobic binding pocket, the combined complex interferes with the activity of reverse transcriptase, thereby achieving the purpose of inhibiting virus replication. A large number of clinical studies have shown that rilpivirine has high activity against wild-type and mutant virus strains, and the incidence of adverse reactions caused by rilpivirine treatment is lower than that of efavirenz. In the treatment of adult AIDS patients who have not received antiretroviral therapy, rilpivirine has the advantages of small dose, high antiviral activity and anti-drug resistance, good tolerance and safety, and few drug interactions. In clinical application, rilpivirine and other antiretroviral drugs are used in combination for the first treatment of HIV-infected adult patients who have never received antiretroviral treatment. Patients are offered new options.
目前关于利匹韦林的合成方法主要分为三部分：中间体1的合成、中间体2的合成、利匹韦林的合成。At present, the synthesis method of rilpivirine is mainly divided into three parts: the synthesis of intermediate 1, the synthesis of intermediate 2, and the synthesis of rilpivirine.
一、中间体1的合成主要有两条：1. There are two main steps in the synthesis of intermediate 1:
该化合物首次公开于国际专利WO2003016306，以4-卤代-2,6-二甲基苯胺为起始原料制备得到。另外在国际公开专利WO2004016581中同时公开了以4-卤代-2,6-二甲基苯胺为起始原料的两条合成路线：The compound was first disclosed in the international patent WO2003016306, and was prepared from 4-halogenated-2,6-dimethylaniline as a starting material. In addition, two synthetic routes using 4-halo-2,6-dimethylaniline as starting materials are simultaneously disclosed in the international published patent WO2004016581:
路线1用到醋酸钯及三(邻甲基苯基)膦配体(P(o-Tol)3)，价格昂贵，成本较高且对环境有污染，但文献报导显示醋酸钯和三(邻甲基苯基)膦配体的使用可以显著提高反式异构体的产率。路线2虽然较路线1短，钯/碳相对醋酸钯便宜,且可以回收利用。但所用溶剂二甲基乙酰胺沸点较高，耗能大；所用的丙烯腈为B级有机剧毒品，毒性大，受公安部门管制，使工业上规模化生产受限。Route 1 uses palladium acetate and tri(o-methylphenyl)phosphine ligand (P(o-Tol)3 ), which is expensive, expensive and pollutes the environment, but literature reports show that palladium acetate and tri(o-Tol) The use of methylphenyl)phosphine ligands can significantly increase the yield of the trans isomer. Although route 2 is shorter than route 1, palladium/carbon is cheaper than palladium acetate, and can be recycled. However, the solvent dimethylacetamide used has a high boiling point and consumes a lot of energy; the acrylonitrile used is a Class B organic poison with high toxicity and is controlled by the public security department, which limits industrial scale production.
二、中间体2的合成主要有三条：2. There are three main steps in the synthesis of intermediate 2:
文献(Synthetic Communacations,27(11),1943-1949(1997))中首次公开了以硫脲嘧啶为起始原料的合成路线：In the literature (Synthetic Communacations, 27(11), 1943-1949(1997)), a synthetic route using thiouracil as a starting material was disclosed for the first time:
此路线经硫脲嘧啶的烃化、亲核取代、氯化后得到关键中间体2。此路线的反应步骤较简单，总收率为47％，但反应过程中产生有毒且极其难闻的甲基硫醇，难以完全袪除气味，达到环评要求会增加了工业大规模生产的成本；另外，用二乙二醇二甲醚(DME)做溶剂回流温度较高、能耗较大，需进一步改进。This route obtains the key intermediate 2 after alkylation of thiouracil, nucleophilic substitution, and chlorination. The reaction steps of this route are relatively simple, and the total yield is 47%. However, toxic and extremely unpleasant methyl mercaptan is produced during the reaction, and it is difficult to completely eliminate the odor. Meeting the requirements of environmental impact assessment will increase the cost of large-scale industrial production; In addition, using diethylene glycol dimethyl ether (DME) as a solvent has higher reflux temperature and higher energy consumption, which needs further improvement.
在专利文献WO2003016306中公开了以对氰基苯胍为起始原料的合成路线：In the patent document WO2003016306, a synthetic route using p-cyanobenzoguanidine as a starting material is disclosed:
此路线中，氰基苯胍与取代的丙二酸二乙酯进行环合，然后经氯化得到中间体2。此路线第一步可以不经纯化经“一锅法”直接进行第二步，反应步骤简单，总产率为58.5％。但是对氰基苯胍的价格昂贵且不易得到，限制了这条路线的工业化使用。In this route, cyanobenzoguanidine is cyclized with substituted diethyl malonate followed by chlorination to give intermediate 2. The first step of this route can be directly carried out to the second step by "one-pot method" without purification, the reaction steps are simple, and the total yield is 58.5%. However, p-cyanobenzoguanidine is expensive and difficult to obtain, which limits the industrial use of this route.
在专利文献WO2012147091中公开了以尿嘧啶为起始原料的合成路线：In the patent document WO2012147091, a synthetic route using uracil as a starting material is disclosed:
此路线经尿嘧啶氯化、亲核取代、甲氧基的还原、氯化得到中间体2，但反应步骤冗长繁琐，产率较低，总产率仅为7％，且两次用到毒性较大的试剂三氯氧磷，工业化扩大生产对环境污染严重。整条路线反应时间较长，耗能大，不适合工业化生产。This route obtains intermediate 2 through uracil chlorination, nucleophilic substitution, reduction of methoxy, and chlorination, but the reaction steps are tedious and cumbersome, and the yield is low. The total yield is only 7%, and the toxicity is used twice. Larger reagent phosphorus oxychloride, industrial expansion of production will cause serious environmental pollution. The reaction time of the whole route is long, the energy consumption is large, and it is not suitable for industrialized production.
三、利匹韦林的合成：Three, the synthesis of rilpivirine:
专利文献WO2003016306和专利文献WO2004016581中公开了以乙腈作为溶剂时，利匹韦林的合成路线：Patent document WO2003016306 and patent document WO2004016581 disclose the synthetic route of rilpivirine when acetonitrile is used as solvent:
此路线以乙腈作为反应溶剂，中间体1和中间体2经取代反应得到利匹韦林。此反应虽然比较简单，但是反应时间较长，延长工业化循环生产时间导致设备的磨损，并且降低产率及产物的质量。This route uses acetonitrile as the reaction solvent, and intermediates 1 and 2 undergo substitution reactions to obtain rilpivirine. Although this reaction is relatively simple, the reaction time is longer, prolonging the industrial cycle production time causes equipment wear, and reduces the yield and product quality.
在专利文献WO2013038425中公开了以N-甲基吡咯烷酮作为溶剂合成利匹韦林：The patent document WO2013038425 discloses the synthesis of rilpivirine using N-methylpyrrolidone as a solvent:
此路线以N-甲基吡咯烷酮作为溶剂，90℃反应16h得到终产物利匹韦林。整体反应时间仍然较长。另外所用溶剂N-甲基吡咯烷酮沸点较高，工业上回收较困难，增加了工业生产的成本。This route uses N-methylpyrrolidone as a solvent, and reacts at 90°C for 16 hours to obtain the final product rilpivirine. The overall reaction time is still longer. In addition, the used solvent N-methylpyrrolidone has a high boiling point, and industrial recovery is difficult, which increases the cost of industrial production.
综上所述，利匹韦林的合成路线中，存在反应温度高、起始原料昂贵不易得到、反应步骤冗长繁琐导致反应收率较低、反应时间过长等的问题。因此，开展对利匹韦林合成工艺研究，寻找一种更加高效并且具有工业化生产价值的方法来合成利匹韦林，加速实现其国内产业化，对于缓解我国艾滋病患者“用药难，用药贵”的现状，具有重要意义。In summary, in the synthetic route of rilpivirine, there are problems such as high reaction temperature, expensive and difficult to obtain starting materials, long and cumbersome reaction steps leading to low reaction yield and long reaction time. Therefore, carrying out research on the synthesis process of rilpivirine, looking for a more efficient and industrialized production value method to synthesize rilpivirine, and accelerating its domestic industrialization will help alleviate the "difficult and expensive medication" of AIDS patients in my country status quo is of great significance.
发明内容Contents of the invention
针对现有技术的不足，本发明提供一种操作简便、总收率高、具有工业化生产价值的利匹韦林的制备方法。Aiming at the deficiencies of the prior art, the invention provides a method for preparing rilpivirine with simple operation, high total yield and industrial production value.
本发明的技术方案如下：Technical scheme of the present invention is as follows:
一种式3所示利匹韦林的制备方法，A preparation method for rilpivirine shown in formula 3,
式I化合物和式II化合物在催化剂、配体和碱的作用下发生Heck反应，然后脱水、成盐酸盐得到关键中间体1；The compound of formula I and the compound of formula II undergo a Heck reaction under the action of a catalyst, a ligand and a base, and then dehydrate and form a hydrochloride to obtain the key intermediate 1;
式V化合物和式VI化合物经取代、氯化后得关键中间体2；The key intermediate 2 is obtained after the compound of formula V and the compound of formula VI are substituted and chlorinated;
中间体1和中间体2最终利用微波反应发生取代得到利匹韦林3。Intermediate 1 and Intermediate 2 were finally substituted by microwave reaction to obtain rilpivirine 3.
所述的制备中间体1的合成中所用到的催化剂、配体和碱分别是醋酸钯、三(邻甲基苯基)膦和醋酸钠；The catalyst, ligand and base used in the synthesis of the described preparation intermediate 1 are palladium acetate, three (o-methylphenyl) phosphine and sodium acetate respectively;
所述的制备中间体2的过程中取代反应选择熔融反应进行；氯化反应的氯化试剂为三氯氧磷。In the process of preparing intermediate 2, the substitution reaction is carried out by melting reaction; the chlorination reagent of the chlorination reaction is phosphorus oxychloride.
本发明更为详细的，一种利匹韦林的制备方法，步骤如下：The present invention is more detailed, a kind of preparation method of rilpivirine, the steps are as follows:
(1)起始原料式I化合物和式II化合物溶解在非质子性溶剂中，在催化剂醋酸钯、配体三(邻甲基苯基)膦和碱醋酸钠的作用下发生Heck反应，然后在盐酸乙醇溶液中成盐酸盐生成中间体1；其中，化合物I：化合物II：醋酸钯：三(邻甲基苯基)膦：醋酸钠的摩尔比为1.0:1.0-1.1:0.1-0.3:0.1-0.3:1.5，反应溶剂为1,4-二氧六环、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，反应温度为80-130℃；(1) starting material formula I compound and formula II compound are dissolved in aprotic solvent, under the effect of catalyzer palladium acetate, ligand three (o-methylphenyl) phosphine and alkali sodium acetate, Heck reaction occurs, then in In the hydrochloric acid ethanol solution, the hydrochloride is formed to generate intermediate 1; wherein, compound I: compound II: palladium acetate: three (o-methylphenyl) phosphine: the mol ratio of sodium acetate is 1.0:1.0-1.1:0.1-0.3: 0.1-0.3:1.5, the reaction solvent is 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide, the reaction temperature is 80-130 ℃;
(2)中间体V和对氰基苯胺VI在熔融条件下发生中间体V的甲巯基的亲核取代反应，然后在三氯氧磷作为氯化试剂的条件下氯化生成中间体2；其中，化合物V：对氰基苯胺VI的摩尔比为1.0:1.0-1.1，反应温度为150-180℃；(2) Intermediate V and p-cyanoaniline VI undergo a nucleophilic substitution reaction of the methylmercapto of intermediate V under melting conditions, and then chlorination generates intermediate 2 under the condition that phosphorus oxychloride is used as a chlorination reagent; wherein , the molar ratio of compound V:p-cyanoaniline VI is 1.0:1.0-1.1, and the reaction temperature is 150-180°C;
(3)将中间体1与中间体2加入到极性反应溶剂中，反应得到利匹韦林；其中，中间体1和中间体2的摩尔比例为1.0:1.0-1.1；反应溶剂为N-甲基吡咯烷酮、二氧六环或者乙腈，反应温度100-150℃，反应时间为5-120min。(3) Intermediate 1 and Intermediate 2 are added to the polar reaction solvent to react to obtain rilpivirine; wherein, the molar ratio of Intermediate 1 and Intermediate 2 is 1.0:1.0-1.1; the reaction solvent is N- Methylpyrrolidone, dioxane or acetonitrile, the reaction temperature is 100-150°C, and the reaction time is 5-120min.
根据本发明，优选的，According to the present invention, preferably,
步骤(1)中所述的化合物I：化合物II：醋酸钯：三(邻甲基苯基)膦：醋酸钠的摩尔比为1.0:1.0:0.3:0.3:1.5；反应温度优选130℃；反应溶剂优选N,N-二甲基乙酰胺。Compound I described in step (1): compound II: palladium acetate: three (o-methylphenyl) phosphine: the mol ratio of sodium acetate is 1.0:1.0:0.3:0.3:1.5; The preferred 130 ℃ of reaction temperature; Reaction The solvent is preferably N,N-dimethylacetamide.
步骤(2)中，化合物V：对氰基苯胺VI的摩尔比为1.0:1.0，反应温度优选为160-180℃，160℃反应2h，然后升高温度至180℃反应2h。In step (2), the molar ratio of compound V:p-cyanoaniline VI is 1.0:1.0, and the reaction temperature is preferably 160-180°C, reacting at 160°C for 2h, and then increasing the temperature to 180°C for 2h.
步骤(3)中，将中间体1与中间体2加入到微波反应器中进行微波反应；其中所述的微波反应优选反应溶剂为乙腈；温度优选140-150℃；反应时间优选90-120min。In step (3), intermediate 1 and intermediate 2 are added into a microwave reactor for microwave reaction; the preferred reaction solvent of the microwave reaction is acetonitrile; the temperature is preferably 140-150° C.; the reaction time is preferably 90-120 min.
步骤(3)中，中间体1和中间体2的摩尔比例为1.0:1.0。In step (3), the molar ratio of intermediate 1 and intermediate 2 is 1.0:1.0.
本发明以化合物I和化合物II以及化合物V和化合物VI为初始原料制备利匹韦林。包括如下步骤：化合物I和化合物II在催化剂及其配体和碱的作用下发生Heck反应，然后脱水、成盐酸盐得到关键中间体1；化合物V和化合物VI经取代、氯化后得关键中间体2；中间体1和中间体2最终利用微波反应发生取代后得到产物利匹韦林3。The present invention prepares rilpivirine by taking compound I and compound II and compound V and compound VI as initial raw materials. The method comprises the following steps: compound I and compound II undergo a Heck reaction under the action of a catalyst and its ligand and a base, then dehydrate and form a hydrochloride to obtain the key intermediate 1; compound V and compound VI are substituted and chlorinated to obtain the key intermediate Intermediate 2; Intermediate 1 and Intermediate 2 were finally substituted by microwave reaction to obtain the product rilpivirine 3.
本发明合成路线如下：The synthetic route of the present invention is as follows:
试剂和条件：(i)醋酸钯，三(邻甲基苯基)膦，醋酸钠，N,N-二甲基乙酰胺，N2，130℃，24h；(ii)三氯氧磷，40℃，1h；(iii)乙醇，盐酸乙醇，30min；(iv)熔融，160℃，2h；180℃，2h；(v)三氯氧磷，回流，1h；(vi)微波，乙腈，140℃，90min。Reagents and conditions: (i) palladium acetate, tris(o-methylphenyl)phosphine, sodium acetate, N,N-dimethylacetamide, N2 , 130°C, 24h; (ii) phosphorus oxychloride, 40 ℃, 1h; (iii) ethanol, ethanol hydrochloride, 30min; (iv) melting, 160℃, 2h; 180℃, 2h; (v) phosphorus oxychloride, reflux, 1h; (vi) microwave, acetonitrile, 140℃ , 90min.
本发明提供了一种合成利匹韦林及用微波反应器合成利匹韦林的新方法，本方法反应选择性高，操作简单，且相比于原来的合成方法大大地缩短了反应时间，其中，中间体1和中间体2发生取代反应生成利匹韦林的步骤中，由原来专利文献WO2004016581中的反应69h缩短为90min，减小了能源消耗，反应总收率由原来的18.5％提高到了21.4％，适合工业化生产。The invention provides a new method for synthesizing rilpivirine and using a microwave reactor to synthesize rilpivirine. The method has high reaction selectivity, simple operation, and greatly shortens the reaction time compared with the original synthesis method. Among them, in the step of generating rilpivirine by substitution reaction between intermediate 1 and intermediate 2, the reaction 69h in the original patent document WO2004016581 was shortened to 90min, which reduced energy consumption and increased the total reaction yield from the original 18.5%. To 21.4%, suitable for industrial production.
下面结合具体实施方式的实施案例对本发明做进一步说明。The present invention will be further described below in combination with examples of specific implementation modes.
具体实施方式detailed description
实施例1：Example 1:
(1)中间体1的合成(1) Synthesis of Intermediate 1
将4-溴-2,6二甲基苯胺I(50mmol,10g)、丙烯酰胺II(50mmol,3.7g)、醋酸钠(75mmol,6.15g)、醋酸钯(15mmol,3.4g)和三(邻甲基苯基)膦(15mmol,4.6g)置于圆底烧瓶中，氮气保护下将N,N-二甲基乙酰胺缓慢加入上述圆底烧瓶中，油浴加热至130℃反应24h。反应结束后冷却至室温，硅藻土过滤，减压蒸干溶剂，然后加入水，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压蒸除多余的有机溶剂，乙酸乙酯、石油醚重结晶得产物(E)-3-(4-氨基-3,5-二甲基苯基)丙基-2-烯酰胺III粗品4.8g，产率51％。4-bromo-2,6-dimethylaniline I (50mmol, 10g), acrylamide II (50mmol, 3.7g), sodium acetate (75mmol, 6.15g), palladium acetate (15mmol, 3.4g) and three (ortho Methylphenyl)phosphine (15mmol, 4.6g) was placed in a round-bottomed flask, and N,N-dimethylacetamide was slowly added into the above-mentioned round-bottomed flask under nitrogen protection, and heated to 130°C in an oil bath to react for 24h. After the reaction, cool to room temperature, filter with diatomaceous earth, evaporate the solvent under reduced pressure, then add water, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, evaporate excess organic solvent under reduced pressure, acetic acid Ethyl ester and petroleum ether were recrystallized to obtain 4.8 g of crude product (E)-3-(4-amino-3,5-dimethylphenyl)propyl-2-enamide III, with a yield of 51%.
将上述反应生成的产物III加入圆底烧瓶中，加入10mL三氯氧磷40℃反应1h。反应结束后将反应液缓慢倒入50g碎冰中搅拌1h后过滤得粗产物(E)-3-(4-氨基-3,5-二甲基苯基)丙基-2-烯睛IV。将所得粗品溶于无水乙醇中，加入盐酸乙醇溶液后搅拌半小时，过滤得(E)-3-(4-氨基-3,5-二甲基苯基)丙基-2-烯氰盐酸盐1，5.0g，产率95％。The product III generated by the above reaction was added into a round bottom flask, and 10 mL of phosphorus oxychloride was added to react at 40° C. for 1 h. After the reaction was completed, the reaction solution was slowly poured into 50 g of crushed ice and stirred for 1 h, and then filtered to obtain the crude product (E)-3-(4-amino-3,5-dimethylphenyl)propyl-2-enenitrile IV. Dissolve the obtained crude product in absolute ethanol, add hydrochloric acid ethanol solution, stir for half an hour, and filter to obtain (E)-3-(4-amino-3,5-dimethylphenyl)propyl-2-encyanide Salt 1, 5.0 g, yield 95%.
中间体IV:白色羽毛状晶体，熔点：78-80℃。Intermediate IV: white feathery crystals, melting point: 78-80°C.
1H NMR(400MHz,CDCl3)δ7.22(d,J＝16.5Hz,1H，CH＝),7.05(s,2H,PhH),5.59(d,J＝16.5Hz,1H,＝CH),3.95(s,2H,NH),2.18(s,6H,CH3).13C NMR(100MHz,CDCl3)δ150.94,146.21,129.86,128.02,123.28,121.50,119.60,90.28,77.38,77.06,76.74,17.50.1 H NMR (400MHz, CDCl3 ) δ7.22(d, J=16.5Hz, 1H, CH=), 7.05(s, 2H, PhH), 5.59(d, J=16.5Hz, 1H,=CH), 3.95(s,2H,NH),2.18(s,6H,CH3 ).13 C NMR(100MHz,CDCl3 )δ150.94,146.21,129.86,128.02,123.28,121.50,119.60,90.28,77.38,77.06,76.74, 17.50.
(2)化合物VII的合成(2) Synthesis of compound VII
将2-甲硫基-4-嘧啶酮V(70mmol,10g)与对氨基苯甲腈VI(77mmol,9.14g)置于圆底烧瓶，氮气保护下油浴加热至160℃反应2h，然后升高温度至180℃继续反应2h。反应结束冷却至室温，加入适量N,N-二甲基甲酰胺，超声击碎溶解搅拌半个小时后过滤，滤饼用乙腈和二氯甲烷洗涤后，真空干燥得化合物VII粗品10.3g，白色固体，产率为70％。Put 2-methylthio-4-pyrimidinone V (70mmol, 10g) and p-aminobenzonitrile VI (77mmol, 9.14g) in a round-bottomed flask, heat the oil bath to 160°C for 2h under the protection of nitrogen, and then rise to High temperature to 180 ° C to continue the reaction for 2h. After the reaction was completed, cool to room temperature, add an appropriate amount of N,N-dimethylformamide, ultrasonically disintegrate, dissolve and stir for half an hour, then filter, wash the filter cake with acetonitrile and dichloromethane, and dry in vacuo to obtain 10.3 g of crude compound VII, white Solid, 70% yield.
(3)中间体2的合成(3) Synthesis of Intermediate 2
将上述所得粗品加入圆底烧瓶中，加入20mL三氯氧磷，加热回流搅拌1h。反应结束后冷却至室温，将反应液缓慢倒入100g碎冰中，搅拌半小时。过滤，所得滤饼溶于50mL水，碳酸钾调节pH至7-8，过滤。滤饼用乙腈洗涤，真空干燥得中间体9.9g，白色固体，产率89％。Put the crude product obtained above into a round-bottomed flask, add 20 mL of phosphorus oxychloride, heat and reflux and stir for 1 h. After the reaction was completed, it was cooled to room temperature, and the reaction solution was slowly poured into 100 g of crushed ice, and stirred for half an hour. After filtering, the resulting filter cake was dissolved in 50 mL of water, adjusted to pH 7-8 with potassium carbonate, and filtered. The filter cake was washed with acetonitrile and dried in vacuo to obtain 9.9 g of the intermediate as a white solid with a yield of 89%.
(4)利匹韦林3的合成(4) Synthesis of Rilpivirine 3
将中间体1(1g,5mmol)和中间体2(1.2g,5mmol)加入到微波反应管中，向微波反应管中加入10mL乙腈后放入到微波反应器中，反应温度140℃，高速搅拌下反应90min。反应结束后向微波反应管中滴加10％的碳酸钾溶液调节pH为8-9。过滤，滤饼用乙腈洗涤后得到利匹韦林1.28g，白色固体，产率为71％，熔点为138-140℃。此合成路线的总收率为51％×95％×70％×89％×71％＝21.4％。Add Intermediate 1 (1g, 5mmol) and Intermediate 2 (1.2g, 5mmol) into a microwave reaction tube, add 10mL of acetonitrile into the microwave reaction tube and put it into a microwave reactor at a reaction temperature of 140°C with high-speed stirring Under reaction 90min. After the reaction, 10% potassium carbonate solution was added dropwise into the microwave reaction tube to adjust the pH to 8-9. After filtering and washing the filter cake with acetonitrile, 1.28 g of rilpivirine was obtained as a white solid with a yield of 71% and a melting point of 138-140°C. The total yield of this synthetic route is 51%×95%×70%×89%×71%=21.4%.
1H NMR(400MHz,DMSO)δ9.62(s,1H,NH),8.95(s,1H,NH),7.98(t,J＝27.2Hz,2H,PhH),7.69(m,3H,＝CH,PhH),7.49(s,2H,PhH),6.46(d,J＝16.7Hz,1H,＝CH),2.18(s,6H,CH3)。1 H NMR (400MHz, DMSO) δ9.62(s,1H,NH),8.95(s,1H,NH),7.98(t,J=27.2Hz,2H,PhH),7.69(m,3H,=CH , PhH), 7.49 (s, 2H, PhH), 6.46 (d, J = 16.7 Hz, 1H, = CH), 2.18 (s, 6H, CH3 ).
| Application Number | Priority Date | Filing Date | Title |
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| CN201610352775.4ACN106008366A (en) | 2016-05-25 | 2016-05-25 | Preparation method of rilpivirine |
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| CN201610352775.4ACN106008366A (en) | 2016-05-25 | 2016-05-25 | Preparation method of rilpivirine |
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