CN114557977A - 一种治疗肠癌的药物的制备方法、制剂及纯度分析方法 - Google Patents
一种治疗肠癌的药物的制备方法、制剂及纯度分析方法 Download PDFInfo
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- CN114557977A CN114557977A CN202210345832.1A CN202210345832A CN114557977A CN 114557977 A CN114557977 A CN 114557977A CN 202210345832 A CN202210345832 A CN 202210345832A CN 114557977 A CN114557977 A CN 114557977A
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Abstract
本发明属于化学药物领域,具体涉及一种治疗肠癌的药物、制备方法、制剂、分析方法。该合成路线具有路线短、收率高、易产业化、成本低的优点,本发明制剂是一种康奈非尼合适的盐的固体分散体技术,可加快康奈非尼在肠胃的吸收,上述康奈非尼合适的盐是指康奈非尼双盐酸盐、康奈非尼双甲磺酸盐。本发明有助于缓解中国的抗肠癌药物的可及性问题。
Description
本申请是分案申请,母案申请的申请号为202210142332.8,申请日为2022年02月16 日、发明名称为“一种治疗肠癌的药物的制备方法、制剂及纯度分析方法”。
发明领域
本发明属于化学药物领域,具体涉及一种治疗肠癌的药物的制备方法、制剂、分析方法。
背景技术
由于体力劳动日益下降,由于高油、高脂、高糖的饮食习惯,由于肥胖,由于久坐、开车、熬夜、喝酒、抽烟等生活习惯,不少地区的肠癌发病率增加。
FDA批准了6种小分子药物治疗转移性黑色素瘤,均为针对MAPK级联信号通路[即小 GTP结合蛋白(RAS)-丝氨酸/苏氨酸蛋白激酶(RAF)-丝裂原活化蛋白激酶/激酶(MEK)-细胞外信号调节的蛋白激酶(ERK)]的小分子药物,分别是维莫非尼、达拉非尼、曲美替尼、考比替尼、康奈非尼和比美替尼(转移性黑色素瘤靶向和免疫治疗研究进展,医学研究生学报,2021 年3月,第34卷,第3期,韩利民综述,赵海龙审校)。
促分裂素原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号转导通路是细胞内最重要的信号通路之一,能调控细胞的生长、增殖和分化,尤其在多种肿瘤细胞中异常活跃。BRAF激酶是下游MAPK信号通路的最强激活剂,其过多表达或突变与肿瘤的发生密切相关。
2021年发表的最新美国肿瘤流行病学报告提示,结直肠癌发病率及死亡率均为所有癌肿的第3位。BRAF基因突变大约出现在15%的转移性结直肠癌中,这些患者预后尤其不良。而 V600突变是最常见的BRAF基因突变,携带BRAF V600E突变患者的死亡风险是携带野生型BRAF 基因患者的两倍。
康奈非尼Encorafenib(商品名Braftovi)由美国生物制药公司Array BioPharma研制,是一种激酶抑制剂,可在细胞试验中靶向BRAF V600E以及野生型BRAF和CRAF,IC50值分别为0.35,0.47和0.3nM。BRAF基因中的突变,例如BRAF V600E,可导致组成型活化的BRAF激酶,其可刺激肿瘤细胞生长。康奈非尼抑制表达BRAF V600E,D和K突变的肿瘤细胞系的体外生长。Inmice植入表达BRAF V600E的肿瘤细胞,康奈非尼诱导的肿瘤消退与RAF/MEK/ERK通路抑制相关。
NCCN指南已推荐康奈非尼联合西妥昔单抗方案,作为BRAF突变晚期经治结直肠癌患者新的标准治疗。用于治疗患有转移性结肠直肠癌(CRC)伴BRAF V600E突变,且曾经接受过系统治疗的成人患者。
康奈非尼的中文化学名称:甲基N-[(2S)-1-[(4-[3-[5-氯-2-氟-3-(甲磺酰胺)苯基]-1-(丙 -2-基)-1h-吡唑-4-基嘧啶-2-基)氨基]丙-2-基]氨基甲酸酯,分子式:C22H27ClFN7O4S,分子量: 540.01,CAS登记号:1269440-17-6,其化学结构式如下:
专利CN201080038197对康奈非尼的合成方法进行了报道。该专利涉及以化合物12、化合物16或17、化合物8a、8b、8c以及甲磺酰氯为起始原料采用多条路线进行康奈非尼的合成,其中涉及N-烷基化反应,Suzuki偶联反应,脱叔丁氧羰基和脱甲磺酰基反应,磺酰化反应等,合成路线如下所示:
CN201080038197公开的以上反应式中化合物16、17、化合物8a、8b、8c合成路线如下:
但以上路线如以化合物12、18、20为起始原料进行康奈非尼的合成,最短需要14步反应,存在路线太长,收率低,不易产业化等诸多问题。急需开发一条路线更短,收率高,容易产业化,且成本低的康奈非尼新的合成路线。
在另一方面,专利EP3449911公开了康奈非尼的固体分散体制剂。该专利指出康奈非尼为BCS II类药物,在弱酸性和中性pH下表现出较差的水溶性,这对药物口服生物利用度和治疗效果提出了挑战。康奈非尼表现出典型的弱碱溶解性,在低pH下因成盐高度溶解,在 pH 3.0左右时溶解度开始下降,在中性pH值范围内保持较低溶解度水平。当康奈非尼药物从胃排空后,由于肠道pH值升高导致的溶解度突然下降,康奈非尼有从溶液状态中快速沉淀析出的趋势。这显著降低了康奈非尼在肠道中吸收。
本发明的目的是提供康奈非尼的产业化合成路线和制剂,该合成路线具有路线短、收率高、易产业化、成本低的优点,本发明制剂是一种康奈非尼相应盐的固体分散体技术,可加快康奈非尼在肠胃的吸收,上述康奈非尼相应盐是指盐酸康奈非尼、甲磺酸康奈非尼。
因此,本发明有助于缓解中国的抗肠癌药物的可及性问题。
发明内容
本发明提供一种治疗肠癌的药物的新制备方法、制剂、分析方法。
本发明提供一种治疗肠癌的药物的新制备方法,涉及肠癌药物康奈非尼的新制备路线,该路线未有相关文献公开,路线化合物4和化合物3为起始原料,经suzuki偶联对接反应得到中间体2,必要时再经脱R1保护基得到康奈非尼关键中间体1,该中间体1与甲磺酰氯按 CN201080038197中反应操作可制备得到康奈非尼。合成路线如下:
其中:
X选自I,Br和Cl,根据反应活性,优选I。
R1选自氢、苄基(Bn)、对甲氧基苄基(PMB)、3,4二甲氧基苄基(DMB),根据保护基的价格、稳定程度及脱除难度,综合优选苄基(Bn)。由于苄基保护基作为氨基保护更加稳定,使得化合物2和化合物1的合成中杂质均较少。
本专利对化合物2合成反应的6种催化剂进行了考察,催化剂种类如下:四(三苯基膦) 钯(0)、双(三苯基膦)二氯化钯、双(三环己基膦)钯(0)、双(三-O-甲苯磷)钯(0),并通过产物转化率和收率进行评估,考察发现四(三苯基膦)钯(0)效果最好,且价格便宜,作为优选催化剂。另外本专利对化合物2合成反应中化合物3和化合物4的投料比进行考察,考虑到化合物3和化合物4如反应不完全,将直接影响纯度和收率,根据收率情况和实测纯度,最终优选投料比为1:1。
本专利同时提供康奈非尼新的合成路线中化合物4的制备路线,该化合物4的制备路线同样未有文献公开,为全新设计路线。该路线以化合物10为起始原料首先进行氨基保护得到化合物9,再进行Miyaura硼基化反应得到化合物8。然后化合物8和化合物7经suzuki偶联对接反应得到化合物6,经霍夫曼降解转化为5,最后化合物5中胺基转化卤代物得到化合物4。制备路线如下:
X1选自I,Br或Cl;根据反应活性,同时兼顾市场可获得性及价格,优选X1为Br。
X2选自I,Br或Cl;根据反应活性,优选X2为I。
X3选自I,Br或Cl;根据反应活性,优选X3为I。
R1选自氢、苄基(Bn)、对甲氧基苄基(PMB)或3,4二甲氧基苄基(DMB);据保护基的价格、稳定程度及脱除难度,综合优选苄基(Bn)。
上述化合物4的合成路线以常规化工品为起始原料,采用不同于CN201080038197专利中叔丁氧羰基保护基,以更稳定的苄基作为化合物10氨基保护基,能够经受更加苛刻的反应条件,如化合物5合成中霍夫曼降解反应,因此得以以最短路线进行化合物4的制备。
本专利同时提供康奈非尼新的合成路线中化合物3的制备路线,该化合物3的制备路线同样未有文献公开,为全新设计路线。该路线中化合物3以化合物12和13(4-溴-2-氯嘧啶) 为起始原料,经对接反应转化为化合物11,再经Miyaura硼基化反应转化为化合物3,具体制备路线如下:
上述涉及的新的康奈非尼合成路线,如以化合物7、12、13、10为起始原料,不仅起始原料价廉易购,且仅需10步即可获得康奈非尼产品,由于更稳定性氨基保护基苄的使用,更能有效控制产品杂质水平,经自拟有关物质HPLC检测方法确认,产品纯度大于99%,单个杂质小于0.10%。
本品专利还提供一种康奈非尼及其盐的新的制剂形式,尤其提供了康奈非尼双盐酸盐和康奈非尼双甲磺酸盐的固体分散体胶囊制剂,该制剂大大改善了康奈非尼在胃肠内的吸收,同时减少胃排空进行肠内的药物。
一种治疗肠癌的药物的制剂,其特征在于:采用康奈非尼或康奈非尼合适的盐进行固体分散体制剂制备,其中:康奈非尼合适的盐选自康奈非尼双盐酸盐或康奈非尼双甲磺酸盐,优选康奈非尼双盐酸盐;
固体分散体的载体选自共聚维酮和泊洛沙姆的高分子化合物组合,聚乙二醇6000和维生素E 聚乙二醇琥珀酸酯的高分子化合物组合,优选共聚维酮和泊洛沙姆的高分子化合物组合。
一种治疗肠癌的药物的制剂,其特征在于:采用康奈非尼或康奈非尼合适的盐进行固体分散体制剂制备的处方如下:
康奈非尼双盐酸盐:5-60g(按康奈非尼计);
共聚维酮Kollidon VA64:10-120g;
泊洛沙姆188:1-15g;
海藻糖:3-45g;
琥珀酸:3-36g;
微晶纤维素:1-33g;
交联聚维酮:1-12g;
硬脂酸镁:0.1-2g;
胶态二氧化硅:0.1-2g。康奈非尼盐酸盐或替换为康奈非尼或康奈非尼双甲磺酸盐,填充至明胶胶囊中。优选按50mg或75mg剂量填充至明胶胶囊中。
本发明涉及的康奈非尼及其盐纯度的分析方法如下:
检测色谱条件如下:
色谱柱:用十八烷基硅烷键合硅胶为填充剂(Agilent ZORBAX SB-C18,150×4.6mm,3.5 μm,或效能相当的色谱柱);
流动相:流动相A为0.05%(v/v)三氟乙酸溶液,流动相B为含0.05%(v/v)三氟乙酸的甲醇溶液-乙腈(90:10),按下表进行梯度洗脱;
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 65 | 35 |
20 | 40 | 60 |
50 | 0 | 100 |
60 | 0 | 100 |
61 | 65 | 35 |
70 | 65 | 35 |
检测波长:225nm;
流速:1.0ml/min;
进样体积:10μl。
供试品溶液:精密称取本品适量,加甲醇溶解并定量稀释制成每1ml中约含康奈非尼1mg 的溶液。
附图说明
图1:溶出曲线对比图
具体实施方式
实施例:
本发明可进一步地通过以下中间体和实施例进行例证,阐述根据本发明的康奈非尼的新的制备路线,但并不限于此。
使用的缩略语如下:苄基(Bn);三乙胺(TEA);1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(PdCl2(dppf)-CH2Cl2);四(三苯基膦)钯(0)(Pd(PPh3)4);甲基磺酰氯(MsCl);对甲苯磺酸(TsOH);液溴(Br2);亚硝酸钠(NaNO2);碘化钾(KI);钯炭(Pd/C)。
实施例1:
化合物3:S-甲基-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)嘧啶-2-基) 氨基)丙烷-2-基)氨基甲酸酯
步骤1:化合物11(S)-(1-((4-溴嘧啶-2-基)氨基)丙-2-基)氨基甲酸甲酯。将化合物 13 4-溴-2-氯嘧啶(96.5g,0.5mol)、化合物12(S)-1-氨基丙-2-基氨基甲酸甲酯(79g,0.6mmol)、三乙胺(101g,1mol)以及二氧六环1.5L置于三口烧瓶中,回流反应24h,减压浓缩反应液,向残留物中加入碳酸氢钠水溶液。用乙酸乙酯萃取水相,有机相用无水硫酸钠干燥。浓缩,残留物用甲醇重结晶,烘干得到121g类白色固体,收率83.7%,MS m/z 289.0(M+1)。1H NMR(d6-DMSO):δ1.31(d,3H),3.13~3.38(m,2H),3.60(s,3H),3.67(q,1H),6.70(s,1H),6.97(d,1H),8.73(d,1H)。
步骤2:化合物3S-甲基-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)嘧啶-2- 基)氨基)丙烷-2-基)氨基甲酸酯。将化合物11(S)-(1-((4-溴嘧啶-2-基)氨基)丙-2-基) 氨基甲酸甲酯(120g,0.42mol)、醋酸钾(81.5g,0.83mol)、联硼酸频那醇酯(158g,0.62mmol)、 PdCl2(dppf)-CH2Cl2(15.5g,21mmol)和二氧六环1.5L置于三口瓶中,回流反应12h。冷却,反应液中加入乙酸乙酯,用碳酸氢钠水溶液和盐水依次洗涤。有机相用硫酸钠干燥,过滤并浓缩,得到134g油状的标题化合物3,收率96.4%。MS m/z 254.1(M-频那醇)。
实施例2:
化合物4a:N-苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺
步骤1:化合物8a(S)-(1-((4-溴嘧啶-2-基)氨基)丙烷-2-基)氨基甲酸甲酯。将苄溴 (341g,1mol)、三乙胺(121g,0.6mol)以及二氯甲烷3L置于三口烧瓶中,室温滴加化合物9a 3-溴-5-氯-2-氟苯胺(112g,0.5mmol)和500ml二氯甲烷的溶液,滴完,继续反应4h,向反应液中加入0.1N盐酸,分液,水相再用二氯甲烷萃取,水相加入碳酸氢钠水溶液调ph至 7-9,析出固体,过滤,烘干得到146g白色固体,收率93.0%,Ms m/z 314.0(M+1)。
步骤2:化合物7a N-苄基-5-氯-2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基) 苯胺。将化合物8a(S)-(1-((4-溴嘧啶-2-基)氨基)丙烷-2-基)氨基甲酸甲酯(142g, 0.45mol)、醋酸钾(88g,0.9mol)、联硼酸频那醇酯(31.6g,0.125mmol)、 PdCl2(dppf)-CH2Cl2(47.4g,64mmol)和二氧六环2L置于三口瓶中,回流反应18h。冷却,反应液中加入乙酸乙酯,用碳酸氢钠水溶液和盐水依次洗涤。有机相用硫酸钠干燥,过滤并浓缩,得到149.8g油状物,收率92.1%。Ms m/z 279.1(M-频那醇)。
步骤3:化合物6a 3-(3-(苄基氨基)-5-氯-2-氟苯基)-1-异丙基-1H-吡唑-4-甲酰胺。将化合物7a N-苄基-5-氯-2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺(145g, 0.4mol)、化合物10a 3-碘-1-异丙基-1H-吡唑-4-甲酰胺(112g,0.4mol)、四(三苯基膦)钯 (0)(23.1g,0.02mol)、2mol/L的碳酸氢钠水溶液(100ml)、甲苯1L和乙醇100ml置于三口烧瓶中,回流反应12h。冷却,反应液用乙酸乙酯萃取,合并的有机物用盐水洗涤。有机相用硫酸钠干燥并浓缩。粗品用无水乙醇重结晶,烘干得到119.6g类白色固体,收率77.3%。 Ms m/z 387.11(M+1)。1H NMR(d6-DMSO):δ1.35(d,6H),3.92(q,1H),4.31(s,2H),6.96(d, 1H),7.29~7.37(m,6H),8.80(s,1H)。
步骤4:化合物5a 3-(3-(苄基氨基)-5-氯-2-氟苯基)-1-异丙基-1H-吡唑-4-胺。
于0℃以下将液溴(71.9g,0.45mol)滴加到360mL氢氧化钠溶液(10%)和乙醇300ml的混合溶液中,得到的溶液。控温0℃以下将化合物6a 3-(3-(苄基氨基)-5-氯-2-氟苯基)-1- 异丙基-1H-吡唑-4-甲酰胺(115g,0.3mol)加入上述溶液中,回温至室温继续反应0.5h,再加热至70~75℃,反应2h后冷却反应液,用盐酸调pH至中性,加入乙酸乙酯萃取,合成有机相,再用盐水洗涤,有机相干燥,浓缩,烘干,得到96g浅棕色固体,收率89.2%,Msm/z 359.1(M+1)。1H NMR(d6-DMSO):δ1.37(d,6H),3.90(q,1H),4.32(s,2H),6.95(d,1H),7.29~7.37(m,6H),7.13(s,1H)。
步骤5:化合物4a N-苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺。
于0℃以下将化合物5a 3-(3-(苄基氨基)-5-氯-2-氟苯基)-1-异丙基-1H-吡唑-4-胺 (95g,0.265mol)、对甲苯磺酸(91.2g,0.53mol)溶解在1.5L的乙腈,控温滴加亚硝酸钠 (32.9g,0.477mol)、碘化钾(88.0g,0.53mol)的800ml水溶液。滴加完毕,继续控温反应1h,回温至室温并搅拌5h。将反应液浓缩,然后用水稀释,并用碳酸钠水溶液中和至pH 7 至8,用乙酸乙酯萃取。合并的有机层用硫代硫酸钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残留物用无水乙醇重结晶,烘干,得到84.3g浅棕黄色固体状的标题化合物4a,收率69.2%。Ms m/z 470.0(M+1)。1H NMR(d6-DMSO):δ1.36(d,6H),3.91(q,1H),4.33(s,2H),6.97(d,1H),7.29~7.37(m,6H),7.85(s,1H)。
化合物4b:N-对甲氧基苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺
严格按“化合物4a:N-苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺”5步合成操作,仅将其步骤1反应中起始物料由苄溴替换为对甲氧基苄溴即得化合物4b。Msm/z 500.0(M+1)。1H NMR(d6-DMSO):δ1.37(d,6H),3.81(s,3H),3.90(q,1H),4.32(s,2H),6.96(d,1H),6.90(d,2H),7.12(d,2H),7.86(s,1H)。
化合物4c:N-3,4-二甲氧基苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺
严格按“化合物4a:N-苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺”5步合成操作,将其步骤1反应中起始物料由苄溴替换为3,4-二甲氧基苄溴即得化合物4c。Msm/z 530.0(M+1)。1H NMR(d6-DMSO):δ1.36(d,6H),3.76~3.83(d,6H),3.90(q,1H),4.31(s,2H),6.80~6.98(m,4H),7.87(s,1H)。
化合物4d:N-苄基-5-氯-2-氟-3-(4-溴-1-异丙基-1H-吡唑-3-基)苯胺
严格按“化合物4a:N-苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺”5步合成操作,将其步骤5反应中碘化钾替换为溴化钾即得。Ms m/z 422.0(M+1)。1H NMR(d6-DMSO):δ1.36(d,6H),3.91(q,1H),4.33(s,2H),6.97(d,1H),7.29~7.37(m,6H),8.05(s,1H)。
实施例3:
化合物1:N-[(2S)-1-({4-[3-(5-氯-2-氟-3-氨基苯基)-1H-吡唑-4-基]嘧啶-2-基}氨基) 丙-2-基]氨基甲酸甲酯
步骤1:化合物2a N-[(2S)-1-({4-[3-(5-氯-2-氟-3-苄基氨基苯基)-1H-吡唑-4-基]嘧啶-2-基}氨基)丙-2-基]氨基甲酸甲酯。
方法1:将化合物4a N-苄基-5-氯-2-氟-3-(4-碘-1-异丙基-1H-吡唑-3-基)苯胺(80g, 0.17mol)、化合物3S-甲基-(1-((4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)嘧啶-2- 基)氨基)丙烷-2-基)氨基甲酸酯(57.3g,0.17mol)、四(三苯基膦)钯(0)(9.8g,0.085mol)、2mol/L的碳酸氢钠水溶液(50ml)、甲苯800ml和乙醇80ml置于三口烧瓶中,回流反应12h。冷却,反应液用乙酸乙酯萃取,合并的有机物用盐水洗涤。有机相用硫酸钠干燥并浓缩,加入无水乙醇重结晶,过滤,烘干得到82.8g浅黄色固体化合物2a,收率88.3%。Ms m/z 552.2(M+1)。
方法2:严格按照化合物2a法1的合成操作,将反应物料由化合物4a替换为化合物4d,同样可获得化合物2a。
另外本专利化合物2a合成中按照方法1操作固定其他反应条件考察了6种相同当量不同钯催化剂和不用主物料投料比的对反应的影响,并采用康奈非尼成品HPLC检查方法进行化合物2a转化率和纯度检查,结果及表1和表2,通过考察发现四(三苯基膦)钯(0)反应效果最好,且价格便宜,作为优选催化剂。化合物2合成反应中化合物3和化合物4的投料比为 1:1,产品纯度和收率均最高,作为优选投料比。
表1不同钯催化剂的考察
钯催化剂种类 | 用量 | 转化率 | 收率 |
四(三苯基膦)钯(0) | 0.05eq | 96% | 88.3% |
双(三苯基膦)二氯化钯 | 0.05eq | 72% | 60.3% |
双(三环己基膦)钯(0) | 0.05eq | 89% | 78.5% |
双(三-O-甲苯磷)钯(0) | 0.05eq | 83% | 70.1% |
表2不同投料比的考察
化合物4a:化合物3投料比 | 化合物2a纯度 | 收率 |
1:1.0 | 98.3% | 88.3% |
1:1.1 | 95.6%,主要杂质为化合物3 | 77.3% |
1:1.05 | 97.5%,主要杂质为化合物3 | 85.5% |
1:0.95 | 96.9%,主要杂质为化合物4a | 84.6% |
1:0.9 | 94.3%,主要杂质为化合物4a | 78.1% |
化合物2b N-[(2S)-1-({4-[3-(5-氯-2-氟-3-(4-甲氧基苄基)氨基苯基)-1H-吡唑-4-基] 嘧啶-2-基}氨基)丙-2-基]氨基甲酸甲酯。
严格按照化合物2a方法1的合成操作,将反应物料由化合物4a替换为化合物4b,即得。 MS m/z 582.2(M+1)。
化合物2c N-[(2S)-1-({4-[3-(5-氯-2-氟-3-(3,4-二甲氧基苄基)氨基苯基)-1H-吡唑 -4-基]嘧啶-2-基}氨基)丙-2-基]氨基甲酸甲酯。
严格按照化合物2a方法1的的合成操作,将反应物料由化合物4a替换为化合物4c,即得。MS m/z 612.2(M+1)。
步骤2:化合物1N-[(2S)-1-({4-[3-(5-氯-2-氟-3-氨基苯基)-1H-吡唑-4-基]嘧啶-2- 基}氨基)丙-2-基]氨基甲酸甲酯
方法1:将化合物2a N-[(2S)-1-({4-[3-(5-氯-2-氟-3-苄基氨基苯基)-1H-吡唑-4-基] 嘧啶-2-基}氨基)丙-2-基]氨基甲酸甲酯(80g,0.145mol)、10%钯/炭5g、无水乙醇900ml 以及二氯甲烷600ml置于三口烧瓶中,控制30-45℃,常压通入H2反应12h,过滤,滤液浓缩至析出大量固体,过滤,滤饼用甲苯重结晶,烘干,得到49.0g类白色固体标题化合物1,收率73.2%。Ms m/z 462.2(M+1)。1H NMR(d6-DMSO):δ1.31(d,3H),1.37(d,6H),3.14, 3.38(m,2H),3.61(m,4H),3.90(q,1H),7.10(d,1H),7.36~7.41(m,2H),7.95(s,1H), 8.56(d,1H)。
方法2:严格按照化合物1方法1的合成操作,将反应物料由化合物2a替换为化合物2b,即得化合物1。
方法3:严格按照化合物1方法1的合成操作,将反应物料由化合物2a替换为化合物2c,即得化合物1。
另外本专利对采用不同氨基保护基的化合物4a、4b、4c进行化合物1合成的影响进行了考察,并采用康奈非尼成品HPLC检查方法进行化合物1的纯度检查,结果及表3,通过考察最终发现苄基(Bn)效果最好,作为优选保护基。
表3不同保护基影响的考察
保护基种类 | 对应化合物 | 化合物1纯度 | 两步收率 |
苄基(Bn) | 化合物4a | 98.5% | 88.3%,73.2% |
对甲氧基苄基(PMB) | 化合物4b | 97.2% | 83.0%,70.5% |
3,4二甲氧基苄基(DMB) | 化合物4c | 97.8% | 85.2%,71.2% |
实施例4:
化合物:康奈非尼
方法1:按照CN201080038197专利操作,将化合物1N-[(2S)-1-({4-[3-(5-氯-2-氟-3- 氨基苯基)-1H-吡唑-4-基]嘧啶-2-基}氨基)丙-2-基]氨基甲酸甲酯(45g,0.097mol)、三乙胺(19.6g,0.194mol)、二氯甲烷500ml,室温滴加甲磺酰氯(11.1g,0.097mol),滴加完毕,继续反应18h,反应液中加入碳酸氢钠溶液调pH至7-8,分液,盐水洗涤,有机相浓缩至干,柱层析纯化得到41.0g类白色固体,收率78.3%,MS m/z 540.1(M+1)。
方法2:严格按照CN201080038197中实施例6中步骤19和步骤20操作,先制备化合物 15,再氢氧化钠水解制备得到康奈非尼。
采用HPLC法对上述新路线制备的康奈非尼进行检测,纯度大于99.0%,单个杂质小于 0.10%,检测色谱条件如下:
色谱柱:用十八烷基硅烷键合硅胶为填充剂(Agilent ZORBAX SB-C18,150×4.6mm,3.5 μm,或效能相当的色谱柱);
流动相:流动相A为0.05%(v/v)三氟乙酸溶液,流动相B为含0.05%(v/v)三氟乙酸的甲醇溶液-乙腈(90:10),按下表进行梯度洗脱;
时间(min) | 流动相A(%) | 流动相B(%) |
0 | 65 | 35 |
20 | 40 | 60 |
50 | 0 | 100 |
60 | 0 | 100 |
61 | 65 | 35 |
70 | 65 | 35 |
检测波长:225nm;
流速:1.0ml/min;
进样体积:10μl。
供试品溶液:精密称取本品适量,加甲醇溶解并定量稀释制成每1ml中约含康奈非尼1mg 的溶液。
化合物:康奈非尼双盐酸盐
取康奈非尼20g(0.037mol),加入300ml甲醇,加热至40℃溶解,缓慢滴加3.5ml浓盐酸,析出量白色固体,过滤,烘干,得到19g康奈非尼双盐酸,盐,收率83.8%,采用HPLC 检查,纯度99.8%,最大单杂0.05%。
化合物:康奈非尼双甲磺酸盐
将上述康奈非尼20g(0.037mol),加入300ml甲醇,加热至40℃溶解,缓慢滴加加入7.5g甲磺酸(0.078mol),析出量白色固体,过滤,烘干,得到22g康奈非尼双甲磺酸盐,收率81.2%,采用HPLC检查,纯度99.8%,最大单杂0.04%。
实施例5:
a、康奈非尼的固体分散体胶囊之处方1如下:
康奈非尼:15g;
共聚维酮Kollidon VA64:40g;
泊洛沙姆188:5g;
海藻糖:15g;
琥珀酸:9g;
微晶纤维素:11g;
交联聚维酮:4g;
硬脂酸镁:0.5g;
胶态二氧化硅:0.5g;称取所需量的康奈非尼、共聚维酮Kollidon VA64和泊洛沙姆188 混合均匀,在加热控温在双螺杆挤出机上挤出共混物,研磨挤出物,添加琥珀酸、海藻糖、纤维素微晶混合均匀,再添加交聚维酮和胶态二氧化硅混合均匀,再添加预筛分硬脂酸镁混合均匀,最终填充至明胶胶囊中,药物剂量分别为50和75mg。
b、康奈非尼双盐酸盐的固体分散体胶囊之处方1如下:
康奈非尼双盐酸盐:15g(以康奈非尼计);
共聚维酮Kollidon VA64:40g;
泊洛沙姆188:5g;
海藻糖:15g;
琥珀酸:9g;
微晶纤维素:11g;
交联聚维酮:4g;
硬脂酸镁:0.5g;
胶态二氧化硅:0.5g;称取所需量的康奈非尼双盐酸盐、共聚维酮Kollidon VA64和泊洛沙姆188混合均匀,在加热控温在双螺杆挤出机上挤出共混物,研磨挤出物,添加琥珀酸、海藻糖、纤维素微晶混合均匀,再添加交聚维酮和胶态二氧化硅混合均匀,再添加预筛分硬脂酸镁混合均匀,最终填充至明胶胶囊中,药物剂量分别为50和75mg:
c、康奈非尼双甲磺酸盐的固体分散体胶囊之处方1如下:
康奈非尼的甲磺酸盐:15g(以康奈非尼计);
共聚维酮Kollidon VA64:40g;
泊洛沙姆188:5g;
海藻糖:5g;
琥珀酸:9g;
微晶纤维素:11g;
交联聚维酮:4g;
硬脂酸镁:0.5g;
胶态二氧化硅:0.5g;称取所需量的康奈非尼双甲磺酸盐、共聚维酮KollidonVA64和泊洛沙姆188混合均匀,在加热控温在双螺杆挤出机上挤出共混物,研磨挤出物,添加琥珀酸、海藻糖、纤维素微晶混合均匀,再添加交聚维酮和胶态二氧化硅混合均匀,再添加预筛分硬脂酸镁混合均匀,最终填充至明胶胶囊中,药物剂量分别为50和75mg。
实施例6:
a、康奈非尼双盐酸盐的固体分散体胶囊之处方2如下:
康奈非尼双盐酸盐:25g(以康奈非尼计);
维生素E聚乙二醇琥珀酸酯:45g;
聚乙二醇6000:5g;
羟丙基甲基纤维素:5g;
琥珀酸:7g;
聚丙烯酸树脂S100:11g;
滑石粉:2g;称取所需量的康奈非尼双盐酸盐、维生素E聚乙二醇琥珀酸酯、聚乙二醇 6000混合均匀,在加热控温在双螺杆挤出机上挤出共混物,研磨挤出物,添加琥珀酸、羟丙基甲基纤维素混合均匀,再添加聚丙烯酸树脂S100和滑石粉混合均匀,最终填充至明胶胶囊中,药物剂量分别为50和75mg:
b、康奈非尼双甲磺酸盐的固体分散体胶囊之处方2如下:
康奈非尼双甲磺酸盐:25g(以康奈非尼计);
维生素E聚乙二醇琥珀酸酯:45g;
聚乙二醇6000:5g;
羟丙基甲基纤维素:5g;
琥珀酸:7g;
聚丙烯酸树脂S100:11g;
滑石粉:2g;称取所需量的康奈非尼双甲磺酸盐、维生素E聚乙二醇琥珀酸酯、聚乙二醇6000混合均匀,在加热控温在双螺杆挤出机上挤出共混物,研磨挤出物,添加琥珀酸、羟丙基甲基纤维素混合均匀,再添加聚丙烯酸树脂S100和滑石粉混合均匀,最终填充至明胶胶囊中,药物剂量分别为50和75mg。
实施例7:
康奈非尼相关固体分散体胶囊制剂的溶出曲线评估:
对实施例5和实施例6中5个康奈非尼相关固体分散体制剂75mg处方进行溶出曲线评估,溶出条件如下:
溶出介质:0.1N盐酸;
介质体积:900ml;
溶出方法:篮法;
转速:75转;
检测方法:HPLC法,254nm;
取样时间:5min、10min、15min;
供试品溶液:取溶出液10ml过0.45um滤膜,取续滤液作为供试品溶液。
溶出曲线对比结果显示:康奈非尼双盐酸盐和双甲磺酸盐胶囊处方的溶出速率均较康奈非尼胶囊处方更快,尤其是采用康奈非尼双盐酸盐胶囊处方溶出更快;另外相同康奈非尼盐但不同固体分散体的载体的溶出结果显示,采用共聚维酮和泊洛沙姆的高分子化合物组合为载体的处方较聚乙二醇6000和维生素E聚乙二醇琥珀酸酯的高分子化合物组合为载体处方的溶出更快。康奈非尼双盐酸盐采用共聚维酮和泊洛沙姆的高分子化合物组合为载体的固体分散体胶囊制剂呈现最快的溶出行为。
具体溶出曲线见图1。
实施例8:
BALB/c雄性小鼠适应性喂养1周后,小鼠体重20-22克,取对数增殖期的小鼠结肠癌C26 瘤细胞约1×106个细胞/只),按1∶3的比例在生理盐水稀释,悬液接种于BALB/c雄性小鼠腋窝的皮下,0.2ml/只,按照康奈非尼、康奈非尼双盐酸盐、康奈非尼双甲磺酸盐、对照组,随机分组,n=6只/组。
接种72小时后,灌胃给药,持续7天,2.5mg/kg,溶剂是75%PEG300。对照组给予生理盐水。实验第12天测量肿瘤体积,按肿瘤体积计算抑瘤率。
小鼠自发性活动采用视频记录分析系统检测。肿瘤体积按公式计算。
康奈非尼、康奈非尼双盐酸盐、康奈非尼双甲磺酸盐的抑瘤率分别为52.7%,75.3%和 78.9%。
对照组组出现精神萎靡,毛发粗糙、自发性活动减少的恶病质状态,康奈非尼双盐酸盐组、康奈非尼双甲磺酸盐组的恶病质状态有明显的改善。
Claims (4)
1.一种治疗肠癌的药物的制剂,其特征在于:所述治疗肠癌的药物的制剂采用康奈非尼或康奈非尼合适的盐进行固体分散体制剂制备,
其中:康奈非尼合适的盐选自康奈非尼双盐酸盐或康奈非尼双甲磺酸盐;
固体分散体的载体选自共聚维酮和泊洛沙姆的高分子化合物组合或聚乙二醇6000和维生素E聚乙二醇琥珀酸酯的高分子化合物组合。
2.根据权利要求1所述的治疗肠癌的药物的制剂,其特征在于:采用康奈非尼或康奈非尼合适的盐进行固体分散体制剂制备的组分如下:
康奈非尼双盐酸盐:5-60g;
共聚维酮Kollidon VA64:10-120g;
泊洛沙姆188:1-15g;
海藻糖:3-45g;
琥珀酸:3-36g;
微晶纤维素:1-33g;
交联聚维酮:1-12g;
硬脂酸镁:0.1-2g;
胶态二氧化硅:0.1-2g。
3.根据权利要求1所述的治疗肠癌的药物的制剂,其特征在于:将康奈非尼或康奈非尼合适的盐的固体分散体制剂,填充至明胶胶囊中得到。
4.一种治疗肠癌的药物的纯度分析方法,其特征在于:应用于所述的治疗肠癌的药物的制备方法制备得到的药物;所述治疗肠癌的药物的纯度分析方法采用色谱法分析药物纯度;
检测采用的色谱条件如下:
色谱柱用十八烷基硅烷键合硅胶为填充剂;
色谱检测的流动相A为0.05%(v/v)三氟乙酸溶液,流动相B为含0.05%(v/v)三氟乙酸的甲醇溶液与乙腈按照90∶10的体积比混合的混合液;
色谱检测按以下条件进行梯度洗脱:
检测波长为225nm;
流速为1.0ml/min;
进样体积为10μl;
供试品溶液按照如下方法配制得到:取待测的所述治疗肠癌的药物,加甲醇溶解并定量稀释制成每1ml中含康奈非尼1mg的溶液。
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