新药Ruxolitinib(鲁索替尼)合成检索总结报告
新药Itacitinib(伊他替尼)合成检索总结报告
一、Itacitinib（伊他替尼）简介 Incyte 宣布一项重要的 3 期 GRAVITAS-301 研究结果，该研究评 估了 Itacitinib（伊他替尼）联合皮质类固醇在未接受过治疗的急性移 植物抗宿主病（GVHD）患者中的疗效。与安慰剂联合皮质类固醇相 比，Itacitinib（伊他替尼）联合皮质类固醇在第 28 天未达到改善总缓 解率（ORR）的主要终点（分别为 74.0％和 66.4％，p = 0.08）。在未 接受过治疗的急性 GVHD 患者中，将 Itacitinib（伊他替尼）联合皮 质类固醇中可改善总体缓解率。 Itacitinib（伊他替尼）分子结构式如下:
五、Itacitinib（伊他替尼）合成路线一检索总结报告 (一) Itacitinib（伊他替尼）中间体 2 的合成（路线一）
2
合成方法 操作方法
一
操作方法 二
操作方法 三
操作方法 olution of 3-hydroxyazetidine hydrochloride 1 (2.20 g) and triethylamine (4.0 mL) in MeOH (20 mL) at 0°C, di-tert-butyl dicarbonate (3.12 g) was added. After stirring at room temperature for 6 h, the solvent was evaporated. The residue was diluted with CH2Cl2, washed with water and the organic phase was evaporated to dryness to give tert-butyl 3-hydroxy-l-azetidinecarboxylate 2 (3.22 g, 93%) which was used without purification in the next step. To a solution of azetidin-3-ol hydrochloride 1 (45 g, 410.75 mmol, 1 eq) in MeOH (1.2 L) was added TEA (83.13 g, 821.51 mmol, 2 eq) and di-tert-butyl dicarbonate (89.65 g, 410.75 mmol, 1 eq). The mixture was stirred at 25°C for 16 hours. Then the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (1 L). The mixture was washed with H2O (3 ×500 mL) and brine (3× 500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound 2 (65 g, 91 %) as a yellow oil, which was used directly in the next step. To a solution of azetidin-3-ol hydrochloride 1 (2.00 g, 18.3 mmcl) in CH2Cl2 (20 mL) was added TEA (5 mL) and (Boc)2O (4.80 g, 22.0 mmcl). The mixture was stirred at rt overnight. The reaction mixture was concentrated. The residue was dissolved in EtOAc (20 mL). The mixture was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4 and concentrated to give the title compound 2 (2.80 g, yield 88%) as yellow oil. To a stirred cold (0°C) solution of 3-hydroxyazetidine hydrochloride 1 (75 g, 0.68 mol) in ethanol (1300 mL) was added triethylamine (208g/280mL, 2.05mol) followed by Boc2O (164 g, 0.75 mol). The resultant solution was stirred at ambient temperature for 16 hours. GC/MS analysis of the reaction mixture revealed complete reaction. Volatiles were removed in vacuo and the residue was diluted with EtOAc (1300 mL) and washed with 10% citric acid (700 mL), water (700 mL) and brine (700 mL). The organics were dried over sodium sulfate filtered, and concentrated to give the desired product 2 (100.8 g, 85% yield). A mixture of 3-azetidinol hydrochloride 1 (10 g, 91 mmol), di-tert-butyl dicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182 mmol) in dioxane:water (400 mL, 1:1) was stirre'd at room temperature for 15 hours. The organic portion was removed in vacuo and the aqueous portion was extracted with ethyl acetate three times. The
鲁索利替尼
安全性
安全性
在Ⅰ/Ⅱ期临床试验中，非血液不良反应如瘀斑、眩晕和头痛的发生率较低( 10% )，主要血液学毒性是贫 血和血小板减少( > 20% )。
治疗期间应评估和监测患者发生严重的细菌、结核分枝杆菌、真菌和病毒感染的风险。开始用鲁索利替尼治 疗前应解决活动性严重感染。中断或终止鲁索利替尼治疗后，一般约 1周左右骨髓纤维化症状恢复至治疗前水平。 某些病例在终止鲁索利替尼治疗后其临床病程继续恶化，但不能确定终止治疗是否影响疾病进展。一般认为，除 了血小板计数减低需要终止治疗，一般考虑减少鲁索利替尼的剂量。
临床评价
临床评价
本品适应证包括中度或高危 MF、原发性 MF、红细胞增加症后 MF和原发性血小板增加症后 MF。
在一项来自安德森癌症中心( MDACC)和 Mayo Clinic-Rochester纳入 153例 MF患者的Ⅰ/Ⅱ期临床试验 中，鲁索利替尼的疗效得到肯定，支持了其在临床上的应用。经过 3个月的治疗，客观指标得到改善(脾脏体积 减少≥50% )的患者有 44%。Mayo Clinic-Rochester分析表明，脾脏体积、贫血和临床症状长期改善的比例分 别为 29%，21%和 63%。由MADCC发布的长期数据表明， 97例脾肿大的患者在持续 166周治疗后，有 61例脾脏 体积减小超过50%。与鲁索利替尼治疗相关的症状改善超过 2年者约 60%。
在体外，鲁索利替尼的浓度在低于 1 nmol·L时即可对 JAK2产生抑制作用，且其对 JAK2的选择性是对其 他激酶的 500倍。本品抑制 JAK2V617F突变型 FDCP和 BaF/3细胞增生的 IC50为 100 ～ 130 nmol·L，但对 活化突变型 BCR/ABL和 c-Kit细胞的增生无抑制作用。本品对细胞增生的抑制作用与降低 BaF/3细胞模型中的 JAK2和 STAT5磷酸化水平有良好的相关性，表明此抑制作用由阻断 JAKSTAT通路而介导。
骨髓纤维化新药卢索替尼药理及临床评价
骨髓纤维化新药卢索替尼药理及临床评价桑妍蕾;羊红玉;张幸国【期刊名称】《药品评价》【年(卷),期】2014(000)002【摘要】Myelofibrosis is a commonly refractory disease. The new medication Ruxolitinib produced by Incyte Corporation is the first U.S.FDA approved oral MF therapeutic drug. Here its mechanism of action, pharmacokinetic and pharmacodynamic properties, clinical efficacy evaluation and adverse drug reactions were reviewed. Ruxolitinib will play an important role in treatment of serious MF.%骨髓纤维化(MF)是临床常见的复杂难治性疾病，Incyte公司研发的新药卢索替尼(Ruxolitinib)是首个获得美国FDA批准的口服治疗MF的药物。
本文对其作用机制，药动学和药代学特性，临床药效学评价及药物不良反应等方面进行了综述。
卢索替尼对重症MF患者具有重要的临床治疗作用，其批准上市将为骨髓纤维化的治疗带来希望。
【总页数】4页(P25-27,32)【作者】桑妍蕾;羊红玉;张幸国【作者单位】浙江大学附属第一医院药学部，浙江杭州310003;浙江大学附属第一医院药学部，浙江杭州310003;浙江大学附属第一医院药学部，浙江杭州310003【正文语种】中文【中图分类】R979.9【相关文献】1.新药Cobimetinib的药理作用与临床评价 [J], 晁颖颖;艾斌;柯会星2.抗慢性淋巴细胞白血病新药venetoclax药理作用及临床评价 [J], 张亚安;任莉萍;钮娴;张晴晴;周新月;潘喆3.新药临床前药理研究与临床评价应注意的问题 [J], 刘振华4.偏头痛治疗新药ubrogepant的药理作用与临床评价 [J], 李春杏;刘丽艳;高丽君;赵敬贤;刘桦5.鲁索利替尼治疗骨髓纤维化的药物经济学研究 [J], 严方方;刘春军因版权原因，仅展示原文概要，查看原文内容请购买。
新药Tepotinib(特泊替尼)合成检索总结报告
新药Tepotinib（特泊替尼）合成检索总结报告一、Tepotinib（特泊替尼）简介2019年09月12日，美国食品和药物管理局已授予其靶向抗癌药MET抑制剂Tepotinib（特泊替尼）突破性药物资格，用于治疗接受含铂化疗后病情进展、携带MET基因第14号外显子跳跃突变的转移性非小细胞肺癌患者。
2018年3月，Tepotinib（特泊替尼）被日本卫生劳动福利部授予了治疗携带MET基因第14号外显子跳跃突变的晚期NSCLC患者的SAKIGAKE资格（创新药物）。
Tepotinib（特泊替尼）分子结构式如下:英文名称：Tepotinib中文名称：特泊替尼本文主要对Tepotinib（特泊替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。
二、Tepotinib（特泊替尼）合成路线三、Tepotinib （特泊替尼）合成检索总结报告(一)Tepotinib （特泊替尼）中间体3的合成合成方法实验步骤参考文献操作方法一2.2L of a freshly prepared 1.5M sodium methoxide solution are added dropwise with stirring to a suspension of 259g (1.09mol)of 3-methoxycarbonylbenzamidinium acetate 1and 528g (1.08mol)of ({2-dimethylamino-1-[dimethyli-mmoniomethyl]vinylamino}methylene)dimethyl-ammonium dihexafluorophosphate 2(“a minoreductone precursor”,prepared in accordance with C.B.Dousson et al.,Synthesis 2005,1817)in 1L of methanol.The reaction mixture is then warmed to 60°C.over the course of 40min and held at this temperature for 30min.The reaction mixture is then cooled to room temperature,diluted with 10L of dichloromethane and washed three times with 5L of water each time.The organic phase is dried over sodium sulfate and evaporated.The residue is recrystallised from ethyl acetate:methyl 3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]-benzo ate 3as beige crystals;m.p.146°2010/280030;(2010);(A1)English;US2010/273796;(2010);(A1)English;US2011/269765;(2011);(A1)English;US2011/269756;(2011);(A1)English 操作方法二100g of 3-hydroxymethylbenzamidinium acetate 1(419.75mmol)and 204.93g of a minoreductone precursor 2(419.74mmol)are suspended in 1000ml of dried MeOH in an N 2-flushed 2L three-necked flask,and a freshly prepared solution of 28.99g of sodium in 300ml of MeOH is added dropwise with stirring,and the mixture is subsequently stirred at 60°C.for 30min,giving a clear solution.For work-up,the reaction batch is cooled,diluted with dichloromethane,washed 2×with water,dried over sodium sulfate and evaporated to dryness in a rotary evaporator.The residue 3is crystallised from a little methanol and diethyl 2010/311733;(2010);(A1)English(二)Tepotinib （特泊替尼）中间体4的合成合成方法实验步骤参考文献操作方法一160ml(2.88mol)of concentrated sulfuric acid are added to a suspension of 103.5g (364mmol)of methyl 3-[5-(di-methylaminomethyleneamino)-pyrimidin-2-yl]benzoate 3in 1.3L of water,and the mixture is heated at the boil for 4hours.The reaction mixture is cooled to room temperature,diluted with water and filtered with suction.The residue is washed with water and dried in vacuo:3-(5-hydroxypyri-midin-2-yl)benzoic acid as brownish crystals;m.p.293-295°2010/280030;(2010);(A1)English;US2010/273796;(2010);(A1);US2011/269765;(2011);(A1);US2011/269756;(2011);(A1).操作方法二103.5g of methyl 3-[5-(dimethylaminomethylenamino)-pyrimidin-2-yl]benzoate 3(364.04mmol)are suspended in 1300ml of water in a 2l single-necked flask,and 160ml of conc.sulfuric acid (95-97%)(2.88mol)are subsequently added,and the reaction batch is warmed at 130°C.(oil-bath temperature)for 4h.For work-up,the reaction batch is cooled,and the precipitate formed is filtered off,washed with water and dried at 50°C.in a vacuum drying cabinet.Yield:78.9g (364.5mmol)of 3-(5-hydroxypyrimidin-2-yl)-benzoic acid 2010/311733;(2010);(A1)English(三)Tepotinib （特泊替尼）中间体5的合成合成方法实验步骤参考文献操作方法一32.7ml (445mmol)of thionyl chloride are added to a suspension of 88.0g (366mmol)of 3-(5-hydroxypyrimidin -2-yl)benzoic acid 4in 1.4l of methanol,and the mixture is heated at 80°C.for 2hours.20ml (276mmol)of thionyl chloride and,after 2hours,a further 10ml (138mmol)of thionyl chloride are then added.After each addition,the reaction mixture is stirred at 80°C.for 2hours.The reaction mixture is concentrated to a volume of about 300ml in vacuo.The resultant precipitate is filtered off and dried in vacuo:methyl 3-(5-hydroxypyrimidin-2-yl)benzoate 5as brownish crystals;m.p.219-223°C.US2010/280030;(2010);(A1)English;US2010/273796;(2010);(A1)English;US2011/269765;(2011);(A1)English;US2011/269756;(2011);(A1).78.8g of 3-(5-hydroxypyrimidin-2-yl)benzoic acid 4are suspended in 1.4l of absolute methanol,and 32.7ml of。
依鲁替尼的合成
依鲁替尼(Ibrutinib)是一种口服的名为BTK抑 制剂的首创新药, 该药通过与靶蛋白BTK活性位点 半胱氨酸残基（Cys-481）选择性地共价结合, 不 可逆性地抑制BTK, 从而有效地阻止肿瘤从B细胞 迁移到适应于肿瘤生长环境的淋巴组织。之前用 于治疗套细胞淋巴瘤的药物有硼替佐米和来那度 胺, 而依鲁替尼是获准用于治疗MCL的第三个药 品。
Mitsunobu反应是一个脱水缩合过程反应应在无水条 件下进行，另外用DEAD,DIAD做试剂时，前亲核试剂 NuH必须具有足够强的酸性(pKa<13)，若pKa大于13则反 应不容易进行，并且反应产物往往需要通过仔细的色谱分 离操作才能与未反应的试剂、副产物等杂质完全分离。
mitsunobu反应是一个脱水缩合过程反应应在无水条件下进行另外用deaddiad做试剂时前亲核试剂nuh必须具有足够强的酸性pka13若pka大于13则反应不容易进行并且反应产物往往需要通过仔细的色谱分离操作才能与未反应的试剂副产物等杂质完全分离
抗肿瘤新药依鲁替尼(Imbruvica,Ibrutinib)的合成
反应机理：
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nucelophilic backside attack
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新药Ripretinib(瑞普替尼)合成检索总结报告
新药Ripretinib（瑞普替尼）合成检索总结报告
一、Ripretinib（瑞普替尼）简介
2019年8月13日，Deciphera宣布，其用于治疗四线及四线以上的胃肠间质瘤（GIST）的基因突变激酶抑制剂Ripretinib，在关键性的3期临床研究中获得了阳性结果。
这项名为INVICTUS的3期临床研究是一项随机、双盲和安慰剂对照的国际多中心研究，旨在评估ripretinib在晚期GIST患者中的安全性，耐受性和疗效。
对于药物的不良事件，Ripretinib的总体耐受性表现良好，发生贫血、腹痛和高血压事件的概率和安慰剂类似，分别为49%和44%。
Ripretinib（瑞普替尼）分子结构式如下:
英文名称：Ripretinib
中文名称：瑞普替尼
本文主要对Ripretinib（瑞普替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。
二、Ripretinib（瑞普替尼）合成路线
三、Ripretinib（瑞普替尼）合成检索总结报告(一) Ripretinib（瑞普替尼）中间体2的合成
(二) Ripretinib（瑞普替尼）中间体3的合成
(三) Ripretinib（瑞普替尼）中间体4的合成
(四) Ripretinib（瑞普替尼）中间体7的合成方法一
(五) Ripretinib（瑞普替尼）中间体7的合成方法二。
新药Abrocitinib(阿布罗替尼)合成检索总结报告
一、Abrocitinib（阿布罗替尼）简介2020年3月19日宣布评估口服JAK1抑制剂Abrocitinib（阿布罗替尼）治疗中度至重度特应性皮炎（AD）成人患者的III期JADE COMPARE研究达到了共同主要疗效终点，显示在皮损清除、疾病程度和严重程度、瘙痒等方面表现出改善。
Abrocitinib（阿布罗替尼）分子结构式如下:英文名称：Abrocitinib中文名称：阿布罗替尼本文主要对Abrocitinib（阿布罗替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。
二、Abrocitinib（阿布罗替尼）合成路线一三、Abrocitinib（阿布罗替尼）合成路线二(一)Abrocitinib （阿布罗替尼）中间体3的合成（路线一）合成方法实验步骤参考文献操作方法一To a solution of 3-oxocyclobutanecarboxylic acid 1(1.0g,8.77mmol)and DIEA (1.92g,14.92mmol)in toluene (8mL)was added DPPA (2.89g,10.52mmol)at rt.The mixture was heated to 60°C under Argon for 3h,then benzyl alcohol 2(1.14g,10.52mmol)was added.The mixture was stirred at 60°C overnight.The reaction was concentrated,the residue was purified by SGC (PE :EA =8:1)to afford the desired compound 3(240mg,yield 50%).WO2012/75381;(2012);(A1)English 操作方法二A solution of 3-Oxo-cyclobutanecarboxylic acid 1(1.01g,8.8mmol)and Et 3N (1.5ml,10.5mmol)in THF/Toluene (1:1,30ml)was treated with DPPA (1.9ml,8.8mmol).The mixture was stirred for 3hours at 60°C and then BnOH 2(1ml,9.7mmol)added.The reaction mixture was stirred for another 3hours at the same temperature.The resulting mixture was concentrated under vacuum to remove most THF and then diluted with EtOAc (20ml).This so-obtained mixture was washed with saturated NaHCO 3solution,brine,dried over Na 2SO 4and filtered.The solvent was evaporated and the residue was purified via chromatography eluted with PE/EtOAc (4:1)to give the desired product as a white solid 3(yield:0.48g,25%yield).WO2012/9678(2012);(A1)English 操作方法三A solution of (3-oxo-cyclobutyl)-carboxylic acid 1(20g,175mmol)and triethylamine (30mL,215mmol)in 1:1THF -toluene (150mL)was treated with diphenyl phosphoryl azide (38mL,175mmol).The solution was warmed to 60°C over 45minutes,at which point nitrogen evolution was noted.After 3hours,benzyl alcohol 2(18mL,175mmol)was added and the solution was kept at 60°C for 4hours.After cooling to room temperature,the solution was diluted with ethyl acetate,washed with saturated aqueous sodium bicarbonate,0.5M HCl (2×),saturated aqueous sodium bicarbonate,dried over anhydrous magnesium sulfate,filtered,and concentrated under reduced pressure.The crude product was recrystalized from ethyl acetate and petroleum ether to afford benzyl (3-oxocyclobutyl)carbamateWO2014/74421;(2014);(A1)English3.操作方法四A solution of (3-oxo-cyclobutyl)-carboxylicacid 1(506mg,4.4mmol)and Et 3N(734μl)in 1:1THF-Toluene (15mL)was treated with diphenyl phosphoryl azide (956μL,4.4mmol).The solutions warmed to 60°C.over ca.45minutes,at which point nitrogen evolution was noted.After 3hours,benzyl alcohol 2(500μL,4.8mmol)was added and the solution was kept at 60°C.for 4hours.After cooling to room temperature,the solution was diluted with ethylacetate,was washed with saturated aqueous sodium bicarbonate (1time),0.5NHCl (2times)NaHCO 3(1time),was dried (MgSO 4),filtered,and was purified by silica gel chromatography (4:1Hexanes-Ethylacetate)to afford 405mg of the title compound 2003/78252;(2003);(A1)English(二)Abrocitinib （阿布罗替尼）中间体4的合成（路线一）合成方法实验步骤参考文献操作方法一A 33%solution of methylamine (1000mL,9.13mol)in absolute ethanol was added to a mixture of benzyl (3-oxocyclobutyl)carbamate 3(200g,0.913mol)and acetic acid (88mL)stirring in ethanol (1000mL)at 0°C.The reaction mixture stirred for at 0°C for 1.5hours and then stirred at room temperature for 2hours.Lithium borohydride (41g,2.05mol)was added in portions to the reaction mixture at -70°C.After addition was complete,the reaction mixture was stirred at -70°C for 1hour and then allowed to warm to room temperature over 12hours.The reaction mixture was quenched with water (400mL),and concentrated under vacuum to remove ethanol.The aqueous layer was acidified with concentrated hydrochloric acid to pH 2,washed with ethyl acetate (2×1000mL),basified with 10%sodium hydroxide to pH 9-10and then extracted with dichloromethane (3×1000mL).The combined organic layers were washed with brine (1000mL),dried over sodium sulfate,and concentrated to obtain the crude product as a pale brown liquid.This was dissolved in di-chloromethane (400mL)and cooled to 0°C.To the resulting solution was added a solution of 4M HCl in dioxane (300mL).The mixture was stirred at 0°C for 30minutes,and then at room temperature for 12hours.The reaction mixture was filtered and the remaining solid was recrystallized from a mixture ofWO2016/24185;(2016);(A1)English.methanol and methyl tert-butyl ether to afford the cis-isomer4as a white solid (111.09g,52%).(三)Abrocitinib （阿布罗替尼）中间体6的合成方法一（路线一）合成方法实验步骤参考文献操作方法一We have found that themicrowave assisted of reaction urea (1mmol)with cyano acetic acid 5(1mmol)under solvent free conditions results in rapid formation of the corresponding Amino uracil.The products 6were easily obtained by addition of water to the reaction mixture and recrystalization of crude products from ethanol.Oriental Journal of Chemistry ;vol.30;nb.3;(2014);p.1379–1383.操作方法二To the reaction flask,42.5g of cyanoacetic acid 5(0.5mol),76.5g of acetic anhydride (0.75mol)and 36.0g of urea (0.6mol)were charged.Heated to heat,dissolved at 100incubated 2h.The end of the incubation with negative pressure distillation,distillation of acetic acid generated reaction and no reaction of acetic anhydride.The reaction was cooled to room temperature after the addition of 280g mass percentage concentration of 50%NaOH (3.5mol),heated to 60°C and incubated for 2h.At the end of the incubation,hydrochloric acid is added and acidified to a pH of 7,at which point 4-aminouracil is precipitated.The temperature was lowered to 20°C to which 500g of acetone was added and stirred for 30min.63.7g of 4-aminouracil was obtained by centrifugation,the content was 99.2%,and the yield was 98.5%.The filtrate 6was recovered after acetone for the next 104447575;(2017);(B)Chinese(四)Abrocitinib （阿布罗替尼）中间体6的合成方法二（路线一）合成方法实验步骤参考文献55g of dry powder sodium methoxide and 37g of urea were put into a 500ml reaction flask and stirred to fully mix the above materials.Under water cooling,50g of methyl cyanoacetate was added dropwise at an internal temperature of about 50°C.After the addition,the mixture was stirred and incubated at 50°C for 5min.The methanol produced byCN107721938;。
鲁索替尼(Ruxolitinib, Jakafi)的合成
鲁索替尼(Ruxolitinib, Jakafi)的合成2014年12月4日，美国FDA批准鲁索替尼(Ruxolitinib；商品名Jakafi)用于治疗真性红细胞增多症患者，这是一种慢性骨髓疾病。
在美国鲁索替尼是获批用于这一疾病的首款药物。
2011年，FDA批准鲁索替尼用于患有另一种骨髓疾病-中或高风险骨髓纤维化患者的治疗，包括原发性骨髓纤维化、真性红细胞增多性骨髓纤维化及原发性血小板增多性骨髓纤维化。
鲁索替尼由特拉华州威尔明顿的Incyte公司上市销售。
合成路线：化合物吡唑S-1经过NBS溴代得到4-溴吡唑S-2,随后用乙基乙烯基醚保护得到S-3，S-3和iPrMgCl·LiCl(TurboGrignards,德国慕尼黑大学Paul Knochel等发展的一类较为温和的金属试剂)通过卤-镁交换后用甲基频哪醇硼酸酯S-4淬灭得到S-5，随后在酸性条件下脱保护得到频哪醇硼酸酯S-6。
Ruxolitinib的另一个片段合成如下，4,6-二羟基嘧啶在POCl3作用下将羟基氯代以及甲酰化得到化合物S-8，经过芳香亲核取代反应得到氨基嘧啶化合物S-9，接下来通过wittig反应引入烯基醚，酸性条件下水解/关环得到化合物S-11,NaH拔掉质子，SEM保护，得到S-12。
环戊基烯基腈也通过wittig 反应得到。
得到两个片段以后，通过钯催化的Suzuki反应将S-12和S-6拼接，得到化合物S-15，随后在碱性条件下，NH对烯基腈进行共轭加成，得到化合物S-16,经过拆分得到光学活性的化合物S-17，最后TFA脱出SEM保护基，即可得到鲁索替尼Ruxolitinib(Jakafi)。
合成路线参考：WO2013023119A1/US2014256941A1/US2010190981A1。
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新药Ruxolitinib（鲁索替尼）合成检索总结报告一、Ruxolitinib（鲁索替尼）简介Ruxolitinib（鲁索替尼）适应症于成人真性红细胞增多症。
2020年4月2日宣布，计划与INCEL合作启动三期临床试验，以评估Ruxolitinib用于治疗COVID-19患者的危及生命的呼吸道并发症。
Ruxolitinib（鲁索替尼）分子结构式如下:英文名称：Ruxolitinib中文名称：鲁索替尼本文主要对Ruxolitinib（鲁索替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。
二、Ruxolitinib（鲁索替尼）合成路线一三、Ruxolitinib（鲁索替尼）合成路线二四、Ruxolitinib （鲁索替尼）路线一合成检索总结报告(一)Ruxolitinib （鲁索替尼）中间体3的合成（路线一）合成方法实验步骤参考文献操作方法一With stirring in an ice bath,38.4g (250.4mmol,1.0eq.).4-chloro-7H-pyrrole [2,3-d]pyrimidine 1is dissolved in 200mL of dry DMF solution.13g (305mmol,1.2eq)of 57%NaH was added.The reaction was stirred at room temperature for 1hour,then 50.9g of SEMCl 2(305mmol,1.2eq.).After the addition,the reaction was stirred in an ice bath for 1hour.quenched with water,extracted with ethyl acetate.the title compound 3(71g,yield =100%)was obtained.CN109867676;(2019);(A)Chinese;CN109867675;(2019);(A)Chinese操作方法二Under cooling with an ice-salt bath,sodium hydride(340mg,60%)was added in two portions to a solution of4-chloropyrrolopyrimidine(1)(1.0g,6.5mmol)in DMF(15mL)while keeping the temperature of the reactants no higherthan10°C,and the reaction was stirred under nitrogenatmosphere protection for1h.SEMCl2(1.4g,8.5mmol)was slowly added via a syringe while keeping thetemperature no higher than10°C.The reaction was warmedto room temperature,and stirred overnight.The reaction wasquenched with water,extracted with EA,dried overanhydrous sodium sulfate,and the organic phase wasconcentrated,and purified by preparative flashchromatography(PE:EA=19:1),to afford4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(3)(1.834g,oil product),yield:97%.EP2018/3360878;(2018);(A1)English操作方法三Potassium t-butoxide(328.81g,2.93mol)andtetrahydrofuran were added to the reaction flask at-30°C to-20°C,a solution of4-chloro-7H-pyrrolo[2,3-d]pyrimidine1(300g,1.95mol)in tetrahydrofuran was added dropwiseto the reaction flask.after completion of the dropwiseaddition,the mixture was stirred at room temperature for4to6hours to control the reaction flask the temperature is nothigher than-15°C-5°C,2-(trimethylsilyl)ethoxymethylchloride2(390.80g,2.34mol)Is added to the reaction flask,and after completion of the dropwise addition,thetemperature is raised to room temperature and the reaction isstirred at that temperature for3to5hours.After completionof the reaction,the reaction was quenched to neutral withdilute hydrochloric acid,concentrated in tetrahydrofuran inthe reverse solution,stirred with ethyl acetate and theaqueous phase was separated.The aqueous phase wasextracted with ethyl acetate once,and the reaction solutionwas cooled and filtered to obtain a wet product.The wetproduct was crystallized from n-hexane and dried to obtain534.50g of product3,purity:99.70%,and the residue waspurified.Yield:96.40%.CN107226814;(2017);(A)Chinese操作方法四A solution of4-chloropyrrolo[2,3-d]pyrimidine1(200g,1.3mol,1.0eq.)in N,N-dimethylformamide was added to60%NaH(62.4g,1.56mol,1.2eq.)in an ice bath.After thecompletion of the addition,the resulting mixture was stirredto react at room temperature for1hour.2-(Trimethylsilyl)-ethoxymethyl chloride2(SEMCl,260g,1.56mol,1.2eq.)was slowly added dropwise under cooling in an ice bath.After the completion of the addition,the resulting mixtureEP2019/3473626;(2019);(A1)English;was stirred to react in an ice bath for1hour,and the reaction was quenched with water.The resulting mixture was extracted with ethyl acetate.The organic phases were combined,washed with saturated salt solution,dried with anhydrous sodium sulfate,and filtered.The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine3(312.2g,91.8%yield).US2019/211021; (2019);(A1) English操作方法五To a solution of4-chloro-7H-pyrrolo[2,3-d]pyrimidine1(20.0g,130.4mmol,1.0eq.)in dry DMF was added NaH(6.6g,57%content,156.8mmol,1.2eq.),under stirring inan ice bath.After the reactants were stirred for1hr at room temperature,SEMCl2(26.1g,156.5mmol,1.2eq.)wasadded dropwise under the cooling of an ice bath.After theaddition was completed,the reactants were stirred for1hr inan ice bath,then the reaction was quenched by adding water,and the resulting mixture was extracted with ethyl acetate.The combined organic phase was washed with brine,driedover sodium sulfate,filtered and concentrated in vacuo.Theresulting residue was separated by column chromatographyon silica gel column to give4-chloro-7-{[2-(trimethylsilyl)-ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine3(33.43g,90.4%yield).EP2017/3235819;(2017);(A1)English操作方法六To a flask equipped with a nitrogen inlet,an addition funnel,a thermowell,and the mechanical stirrer was added4-chloro-7H-pyrrolo[2,3-d]pyrimidine1(600g,3.91mol)andN,N-dimethylacetimide(DMAC,9.6L)at roomtemperature.The mixture was cooled to0-5°C.in anice/brine bath before solid sodium hydride(NaH,60wt%,174g,4.35mol,1.1equiv)was added in portions at0-5°C.The reaction mixture went to a dark solution during15minutes.Trimethylsilylethoxymethyl chloride2(SEM-Cl,763mL,4.31mol,1.1equiv)was then added slowly via anaddition funnel at a rate that the internal reaction temperaturedid not exceed5°C.The reaction mixture was then stirred at0-5°C.for30minutes.When the reaction was deemedcomplete determined by TLC and HPLC,the reactionmixture was quenched by water(1L).The mixture was thendiluted with water(12L)and MTBE(8L).The two layerswere separated and the aqueous layer was extracted withMTBE(8L).The combined organic layers were washedwith water(2×4L)and brine(4L)and dried over sodiumsulfate(Na2SO4).The solvents were removed under reducedUS2009/233903;(2009);(A1)English;US2010/190981;(2010);(A1)English;WO2013/36611;(2013);(A1)Englishpressure.The residue was then dissolved inheptane (2L),filtered and loaded onto a silica gel (SiO 2,3.5Kg)column eluding with heptane (6L),95%heptane/ethyl acetate (12L),90%heptane/ethyl acetate (10L),and finally 80%heptane/ethyl acetate (10L).The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2-(trimethylsilyl)-ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 3(987g,1109.8g theoretical,88.9%yield)as a pale yellow oil which partially solidified to an oily solid on standing at room temperature.操作方法七To a mixture of sodium hydride (60%dispersion in mineral oil;276mg;6.89mmol)in DMF (10mL)at 0°C was added drop-wise a solution of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine 1(1.145g;5.74mmol)in anhydrous DMF (20mL).When the addition was complete,2-(trimethylsilyl)ethoxymethyl chloride 2(1.32ml;7.46mmol)was added drop-wise and the reaction mixture was stirred at 0°C for 1.5h then allowed to warm to ambient temperature.The reaction mixture was partitioned between water (100mL)and ethyl acetate (100mL).The organic phase was separated,dried over Na 2SO 4and then filtered and the filtrate solvents evaporated in vacuo.The crude product was purified by flash chromatography on silica gel (70g)eluting with a solvent gradient of 05%ethyl acetate in hexane to afford the title compound 3(1.73g,91%)as a colourless oil.Bioorganic and Medicinal Chemistry ;vol.20;nb.22;(2012);p.6770-6789.(二)Ruxolitinib （鲁索替尼）中间体5的合成（路线一）合成方法实验步骤参考文献To a flask equipped with a reflux condenser,a nitrogen inlet,mechanical stirrer,and a thermowell was added 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 3(817g,2.88mol)and dioxane (8L).To this solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole 4(728g,3.75mol,1.30equiv)followed by a solution of potassium carbonate (K 2CO 3,1196g,8.67mol,3.0equiv)in water (4L).The solution was degassed by passing a stream of nitrogen through the。