CN100594212C - N-[(r)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘苯基氨基)-苯甲酰胺的多晶型物 - Google Patents
N-[(r)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘苯基氨基)-苯甲酰胺的多晶型物 Download PDFInfo
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Abstract
本发明提供了N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的一种新多晶型物,以及药物组合物和利用该多晶型物的治疗方法。
Description
发明领域
本发明提供N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的一种新多晶型物IV,和该多晶型物的制备方法,以及药物组合物和使用该多晶型物的治疗方法。
发明背景
N-(2,3-二羟基-丙氧基)-3,4-二氟-2-[(2-氟-4-碘苯基)氨基]-苯甲酰胺记载于WO2002006213A2(Barrett等人)和EP1262176A1(Baragi等人)中。
发明概述
本发明包括具有下式的一种N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的新结晶多晶型物,
该多晶型的X-射线粉末衍射图有以2θ度表示的在大约4.6、7.2、14.6、19.9、23.2和26.5处的特征峰。
该N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺结晶多晶型物进一步特征在于,其X-射线粉末衍射图有以2θ度表示的在大约4.6、7.2、14.6、19.1、19.9、20.7、22.0、22.2、23.2、23.6、23.9、25.0、26.5、28.1、28.3、30.0、30.4、32.7、33.0、34.1、36.6、40.1、42.1、43.4和44.6处的峰。
附图简述
图1是IV型N-(2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的粉末X-射线衍射图(Y-轴=0-4,000cps)
发明详述
另外,本发明提供一种治疗需要所述治疗的患者增生性疾病的方法,包括给药药物或治疗有效量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的多晶型物IV。
本发明还提供了药物或治疗有效量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的新多晶型物IV用于制备治疗增生性疾病的药物的用途。
另外,本发明提供治疗需要所述治疗的患者癌症、再狭窄、牛皮癣、自身免疫性疾病、动脉粥样硬化、骨关节炎、类风湿性关节炎、心力衰竭、慢性疼痛、和神经性疼痛的方法,包括给药治疗有效量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的多晶型物IV。
可以用本发明的方法治疗的黑色素瘤包括浅表扩展性黑色素瘤(也称作克拉克黑素细胞痣)、结节性黑色素瘤、恶性雀斑样痣黑色素瘤(有时还称作哈钦森氏黑色素雀斑)、肢端雀斑样痣性黑色素瘤、眼黑色素瘤,包括结膜黑色素瘤和葡萄膜(脉络膜)黑色素瘤、和较少见的黑色素瘤,如口腔和生殖器区域的恶性黑色素瘤,例如外阴黑色素瘤、和粘膜黑色素瘤,包括***直肠黑色素瘤。
本发明还提供药物或治疗有效量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的新多晶型物IV用于制备治疗癌症、再狭窄、牛皮癣、自身免疫性疾病、动脉粥样硬化、骨关节炎、类风湿性关节炎、心力衰竭、慢性疼痛、和神经性疼痛的药物的用途。
此外,本发明提供一种治疗需要所述治疗的患者癌症的方法,包括给药治疗有效量的本发明所述多晶型物,以及联合放射治疗或至少一种化学治疗剂。
对本发明而言,术语“治疗”是指预防或防止、抑制、改善或消除指定的病症(一旦该病症已经形成),以及抑制或防止生理机制,该机制使病症发作和发展至该病症的症状或表现可被发现的程度。术语“药物有效量”或“治疗有效量”、或类似的术语应理解为至少最小量的活性药剂,该药剂将提供对本文所述的疾病或病症治疗或抑制。
所述公开的组合物可用作与MEK机能亢进有关的疾病或病症,以及由MEK级联调节的疾病或病症的预防和治疗剂。例子包括,但不限于中风、感染性休克、心力衰竭、骨关节炎、类风湿性关节炎、器官移植排斥、和各种肿瘤如卵巢瘤、肺瘤、胰腺瘤、脑瘤、***瘤、和结肠直肠瘤。
本发明还涉及治疗增生性疾病,如癌症、再狭窄、牛皮癣、自身免疫性疾病、和动脉粥样硬化的方法。本发明的其它方面包括治疗与MEK-相关的(包括ras-相关的)癌症(无论是实体还是造血癌)的方法。癌症的例子包括脑癌、乳腺癌、肺癌如非小细胞肺癌、卵巢癌、胰腺癌、***癌、肾癌、结肠直肠癌、子***、急性白血病、和胃癌。本发明的其它方面包括治疗或减轻异种移植物(细胞、皮肤、四肢、器官或骨髓移植)排斥、骨关节炎、类风湿性关节炎、囊性纤维化、糖尿病并发症(包括糖尿病性视网膜病和糖尿病性肾病)、肝肿大、心肥大、中风(如急性灶性缺血性中风和全脑缺血)、心力衰竭、感染性休克、哮喘、阿尔茨海默氏病、和慢性和神经性疼痛症状的方法。本发明化合物还可用作治疗病毒感染如HIV、肝炎(B)病毒(HBV)、人***状瘤病毒(HPV)、细胞巨化病毒(CMV)、和爱泼斯坦-巴尔病毒(EBV)的抗病毒剂。这些方法包括向需要这种治疗、或患有这种疾病或病症的患者给药治疗有效量的公开的化合物,包括结晶形式或其药物组合物的步骤。
对本发明而言,术语“慢性疼痛”包括,但不限于神经性疼痛、特发性疼痛、和与慢性酒精中毒、维生素缺乏、***、或甲状腺功能减退有关的疼痛。慢性疼痛与多种病症包括但不限于炎症、关节炎、和手术后疼痛有关。
本文所使用的术语“神经性疼痛”与下列多种病症有关,所述病症包括但不限于炎症、手术后疼痛、假肢痛、灼伤痛、痛风、三叉神经痛、急性疱疹和疱疹后疼痛、灼痛、糖尿病性神经病、丛撕脱伤(plexus avulsion)、神经瘤、血管炎、病毒感染、挤压伤、收缩损伤、组织损伤、截肢、手术后疼痛、关节炎痛、和外周神经***和中枢神经***间的神经损伤。
本发明还以联合治疗方法为特色,例如治疗癌症的方法,其中所述方法还包括向接受者提供药物有效量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的多晶型物IV和联合放射治疗或化学治疗,例如联合有丝***抑制剂如紫杉烷或长春花生物碱。有丝***抑制剂的例子包括紫杉醇、多西紫杉醇、长春新碱、长春碱、长春瑞滨、和长春氟宁。其它治疗联合包括本发明的MEK抑制剂和抗癌剂如顺铂、5-氟尿嘧啶或5-氟-2-4(1H,3H)-嘧啶二酮(5FU)、氟他胺和吉西他滨。
根据患者的需要,可以在给药所公开的化合物之前、同时或之后给予化学治疗或放射治疗。
根据已知的方法,考虑到诸如下述的因素:年龄、体重、一般健康状况、给药的化合物、给药途径、需要治疗的疼痛或病症的类型、和其它药物的存在,本领域技术人员将能够决定向患者给予本发明化合物的合适的治疗有效量或剂量。一般,N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的多晶型物IV的有效量或治疗有效量为约0.1-约1000mg/kg/天,优选约1-约300mg/kg体重,并且对于正常体重的成年患者而言,日剂量为约1-约500mg,优选约1mg-约50mg。由医学专业人员决定,成年人的日剂量范围可以是约1mg-约20mg,以单次剂量或分次剂量。根据已公开的方法,可以给药市售的如下规格的胶囊或其它制剂(例如液体和薄膜包衣的片剂),例如0.25mg、0.5mg、1mg、5mg、10mg、25mg、50mg、100mg、200mg、300mg、或400mg。
优选在给药之前使用N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺配制可药用制剂。因此,本发明的另一方面是一种药物组合物,其包含药物有效量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺和可药用载体。在制备本发明的组合物时,通常将活性成分-N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺与载体混合,或用载体稀释或密封于载体中。剂量单位形式或药物组合物包括片剂、胶囊、丸剂、粉剂、颗粒剂、含水和非水口服溶液和混悬液、和适于分装成单个剂量的包装于容器中的注射溶液。
剂量单位形式可适用于各种给药方法,包括控释制剂如皮下植入剂。给药方法包括口服、直肠、胃肠外(静脉内、肌内、皮下)、脑池内、***内、腹膜内、膀胱内、局部(滴剂、粉剂、软膏剂、凝胶剂、或乳膏)、和吸入(口腔或鼻腔喷雾)。
胃肠外制剂包括可药用含水或非水溶液、分散液、混悬液、乳剂和用于其制备的无菌粉末。载体的例子包括水、乙醇、多元醇类(丙二醇、聚乙二醇)、植物油、和可注射的有机酯如油酸乙酯。通过使用诸如卵磷脂、表面活性剂的包衣、或通过保持合适的颗粒大小来保持流动性。固体剂型的载体包括(a)填料或膨胀剂,(b)粘合剂,(c)湿润剂,(d)崩解剂,(e)溶液阻滞剂,(f)吸收促进剂,(g)吸附剂,(h)滑润剂,(i)缓冲剂,和(j)推进剂。
组合物还可以含有辅剂如防腐剂、湿润剂、乳化剂、和分散剂;抗微生物剂如对羟基苯甲酸酯类、三氯叔丁醇、苯酚、和山梨酸;等渗剂如糖或氯化钠;吸收延长剂如硬脂酸(二羟基)铝和明胶;和吸收增强剂。
硬明胶胶囊中的口服制剂的具体例子可包括例如每个胶囊0.1mg至50mg的剂量。所述组合物可包括活性药物IV型,N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺、稀释剂如微晶纤维素、和崩解剂如交联羧甲基纤维素钠。所述组合物还可含有滑润剂,如硬脂酸或硬脂酸镁。
硬明胶胶囊中的这些口服制剂的例子包括那些以重量计,活性药物占制剂的约0.1-20%、稀释剂占约75-95%、崩解剂占约3-7%和任选地滑润剂占约0.1-2%的制剂。
以重量计,0.25mg胶囊可含有约0.15-约0.25%IV型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺、约93-95%微晶纤维素、约4-6%交联羧甲基纤维素钠和任选地约0.5-1.5%硬脂酸镁。
以重量计,1mg胶囊可含有约0.7-约0.85%IV型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺、约92.5-95%微晶纤维素、约4-6%交联羧甲基纤维素钠和任选地约0.5-1.5%硬脂酸镁。
以重量计,5mg胶囊可含有约4%-约6%IV型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺、约87-93%微晶纤维素、约4-6%交联羧甲基纤维素钠和任选地约0.5-1.5%硬脂酸镁。
以重量计,25mg胶囊可含有约14%-约17%IV型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺、约76-83%微晶纤维素、约4-6%交联羧甲基纤维素钠和任选地约0.5-1.5%硬脂酸镁。
刚才描述的这类硬明胶胶囊口服制剂可以按照现有技术已知的方法制备。例子包括将活性药物与所需量的崩解剂如交联羧甲基纤维素钠、和一半所需量的稀释剂如微晶纤维素一起混合和研磨。然后将另一半稀释剂与最初的活性剂、稀释剂和崩解剂的混合物一起研磨和混合,并混合所得组合物。然后可以加入任选的滑润剂如硬脂酸镁并再混合。然后称量总组合物并放置于硬明胶胶囊中。另外,可以使用压片机将干组合物压成片,然后再研磨所得片。然后将最终的混合物分成合适的剂量并密封于硬明胶胶囊中。
将理解的是,利用现有技术已知的方法,可以容易地制备N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺。例如,可以按照WO2002006213A2(Barrett等人)所述的方法制备:在有机碱如二异丙基氨基锂存在下,2-氟-4-碘-苯胺(登记号367-25-9)和2,3,4-三氟-苯甲酸(登记号61079-72-9)反应,形成3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酸,然后该化合物可与(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺反应。所得产物可以用酸水溶液水解,得到N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟4-碘-苯基氨基)-苯甲酰胺。
对比实施例1
N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺(I
型)
步骤A:在氮气氛下,向3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酸(39.3g,100.0mmo1)的无水四氢呋喃(500mL,0.2M)溶液中加入(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺(14.7g,100.0mmol),然后加入N-甲基吗啉(27.5mL,0.25摩尔)。用冰水浴冷却橙色溶液。滴加二苯基膦酰氯(22.9mL,0.12摩尔)。形成一些固体。将该混合物升温至室温并搅拌18小时。加入水淬灭反应,并真空蒸发四氢呋喃。将残留油状物溶解于乙酸乙酯(500mL),用饱和盐水和饱和碳酸氢钠(1∶1)的混合物洗涤两次。除去乙酸乙酯,粗油状固体经快速色谱(硅胶,己烷-丙酮/2∶1)纯化,在40℃的真空烘箱中干燥20小时后得到N-((R)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺,灰白色固体:41.7g(79.8%),熔点124-125℃。合并不纯的馏分并使用同样的条件,经第二次柱色谱纯化,得到第二批产物:6.4g(12.3%),熔点124-125℃,总产量48.1g(92.1%)。
1H NMR(d6-DMSO):δ11.9(s,br,1H),8.7(s,br,1H),7.6(d,1H,J=10.99Hz),7.4(m,2H),7.2(m,1H),6.7(m,1H),4.2(m,1H),4.0(t,1H,J1=8.3Hz,J2=6.8Hz),3.8(m,2H),3.7(m,1H),1.3(s,3H),1.2(s,3H);19FNMR(d6-DMSO):δ-128.0,-133.1,-144.3;MS:523(M++1)。
步骤B:将N-((R)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺(22.3g,42.7mmol)混悬于甲醇(223mL,10mL/g)中,然后加入pTsOH·H2O(4.1g,21.35mmol)的水(22.3mL)溶液。在室温下搅拌该混合物18小时,其间所有的固体均溶解得到无色澄清的溶液。浓缩该溶液并用乙酸乙酯(2×300mL)萃取。用碳酸氢钠洗涤有机溶液,MgSO4干燥。过滤后,浓缩滤液,并与庚烷共蒸发,得到泡沫状固体。向该固体中加入己烷-CH2Cl2(1∶1,100mL)并搅拌该混合物30分钟。形成白色固体,将其过滤,并用己烷洗涤。由己烷-AcOEt中重结晶该固体,得到白色结晶的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺,在60℃的真空烘箱中干燥3天后得到13.57g(65.9%)产物。由同样的溶剂***重结晶之后,从母液中得到第二批产物5.05g。总产量为18.62g(90.4%),熔点89-90℃(化合物B的II型)。用研钵将合并的结晶粉碎并研磨成细粉末,并在60℃的真空烘箱中干燥3天:熔点117-118℃(化合物B的I型);
[α]=-2.05°(c=1.12,甲醇);
分析:计算值:C16H14F3I1N2O4:C,39.85;H,2.93;N,5.81;F,11.82,I,26.32.测定值:C,39.95;H,2.76;N,5.72;F,11.71;I,26.53。
1NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.69(s,1H),7.54(dd,1H,J=10.9,1.5),7.32-7.38(m,2H),7.17(dd,1H,J=16.8,9.0),6.61-6.66(cm,1H),4.82(bs,1H),4.58(bs,1H),3.84-3.85(m,1H),3.71-3.64(cm,2H),3.33(2H,部分被HDO遮掩)。
对比实施例2
N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺
(II型)
步骤A:在氮气氛下,在-15℃向3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酸(2.25g,5.10mmol)的无水四氢呋喃溶液中滴加入二苯基膦酰氯(1.26mL.6.63摩尔)。搅拌20分钟之后,加入N-甲基吗啉(0.70mL,6.375mmol)并再搅拌反应物20分钟。加入(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺(0.748g,5.1mmol)并搅拌反应物1小时,此时加入N-甲基吗啉(0.7mL,6.37mmol)。将该混合物升温至室温并搅拌12小时。真空浓缩反应混合物,然后用EtOAc稀释。有机层用饱和NaHCO3(2×)、盐水(1×)洗涤,Na2SO4干燥,过滤并浓缩。粗产物经SiO2纯化,使用4∶1己烷/EtOAc作为洗脱剂,得到1.82g(68%)的褐红色固体。
步骤B:将N-((R)-2,2-二甲基-[1,3]二氧戊环-4-基甲氧基)-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺(0.210g,0.40mmol)混悬于10∶1甲醇/H2O中并加入pTsOH·H2O(0.008g,0.04mmol)。在室温下搅拌该混合物18小时,其间所有的固体均溶解得到无色澄清的溶液。用EtOAc稀释该溶液。用碳酸氢钠(2×)、盐水(1×)洗涤有机溶液并经Na2SO4干燥。过滤后,浓缩滤液,并由EtOAc和庚烷中重结晶。用己烷-CH2Cl2(1∶1)洗涤该固体并在60℃真空干燥,得到白色固体的N-((R)-2,3-二羟基-丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺(0.136g,70%)。产物在90.8℃缩减,在115-117℃熔化。
分析显示:C 40.92,H 3.16,N 5.41,F 11.30,I 23.92(6.75%EtOAc,0.96%庚烷)。
IV型N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺可以按照包括以下步骤的方法制备:
a)在高于约30℃至约40℃的温度下,将一定量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺加入一定体积的C1-C4低级烷醇和水中,其中乙醇与水的比例为约1∶7至约1∶13;
b)搅拌步骤a)的组分,生成N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺在烷醇和水中的混合物;
c)将N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺在烷醇和水中的混合物冷却至约20℃至低于约30℃;
d)从烷醇和水中分离出N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺。
在该方法中,上面讨论的参数是如下制备多晶型物IV的步骤:
a)在约32℃至约38℃的温度下,将一定量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺加入一定体积的C1-C4低级烷醇和水中,其中乙醇与水的比例为约1∶9至约1∶11;
b)搅拌步骤a)的组分,生成N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺在烷醇和水中的混合物;
c)将N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺在烷醇和水中的混合物冷却至约22℃至约28℃;
d)从烷醇和水中分离出N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺。
该方法中可以使用的C1-C4低级烷醇包括甲醇、乙醇、丙醇、异丙醇等,其中乙醇是优选的烷醇。在本文中所述的方法是将约0.1-约5kg的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺混合于体积为约7.5-约15升的烷醇和水的混合物中。
实施例1
N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺
(IV型)
在氮气氛下,向装有3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酸(2.6Kg,6.6mol)和N’,N-羰基二咪唑(1.1Kg,6.8mol)的烧瓶中加入12L干燥的乙睛。在22±5℃搅拌约90分钟之后,加入(R)-O-(2,2-二甲基-[1,3]二氧戊环-4-基甲基)-羟胺的甲苯溶液(总体积为8.5L,约8摩尔胺)。在22±5℃搅拌该溶液至少6小时。加入盐酸水溶液(9L,1.5摩尔),搅拌约5分钟后分层。将盐酸水溶液(9L,1.5摩尔)加入保持的上层中,搅拌约20小时之后分层。真空蒸馏浓缩保持的上层,然后用15L甲苯和2L乙醇稀释。将混合物升温至35-45℃并用20L温水稀释,然后冷却至0-5℃。过滤收集产物,用2L甲苯洗涤。通过将产物溶解于12L甲苯和2L乙醇(50±5℃),加入10L水并冷却至0-5℃来进行重结晶。过滤收集产物之后,用甲苯洗涤,在真空烘箱中干燥产物,得到2.6Kg的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺。
在35±5℃下,在10L水和1L乙醇的混合物中搅拌2.4Kg不同结晶形式的混合物的上述化合物20-30小时,然后冷却至25±5℃。过滤收集产物并用1L水洗涤,然后在65℃的真空烘箱中干燥。得到2.3Kg产物,其中IV型大于90%。提示:DSC分析显示在110℃开始熔化,仅有少量峰在117℃开始熔化。
本发明晶型的X-射线衍射图是在有CuKa辐射的Rigaku Ultima+衍射仪上测定的。
装置
Rigaku Ultima+衍射仪,其具有IBM兼容界面并装备有6个方位自动取样器,软件为RigMeas v2.0(Rigaku,1995年12月)和JADE 3.1(MaterialsData,Inc.)。
方法
连续θ/2θ偶合扫描:3.00°-45.00°2θ,扫描速率0.2°/分钟:15.0秒/0.05°步。
将样品从瓶中敲打出并在铝固定器中压在零背景的硅上。样品宽5mm。
样品在室温下储存和测试。
数据收集期间,样品以40rpm绕垂直轴旋转。
表1列出了化合物A的晶型IV的X-射线粉末衍射图,以2-θ(“2θ”)、d-间距或d(A)、和相对强度>10%的峰面积相对强度来表示,在有CuKa辐射的Ultima+衍射仪上测定。
表1
Claims (2)
1.N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的结晶多晶型物,该多晶型物的X-射线粉末衍射图有以2θ度表示的在4.577、7.245、14.584、19.091、19.894、20.697、21.964、22.245、23.157、23.648、23.884、25.006、26.491、26.905、28.103、28.296、29.962、30.393、32.653、33.008、34.054、36.593、40.093、42.098、43.360和44.554处的峰。
2.一种根据权利要求1的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的结晶多晶型物的制备方法,该方法包括下列步骤:
a)在高于30℃至40℃的温度下,将一定量的N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺加入一定体积的乙醇和水中,其中乙醇与水的比例为1∶7至1∶13;
b)搅拌步骤a)的组分,生成N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺在乙醇和水中的混合物;
c)将N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺在乙醇和水中的混合物冷却至温度20℃至低于30℃;
d)从乙醇和水中分离出N-[(R)-2,3-二羟基-丙氧基]-3,4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103841976A (zh) * | 2011-04-01 | 2014-06-04 | 基因泰克公司 | Akt和mek抑制剂化合物的组合及其使用方法 |
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TW200524584A (en) | 2005-08-01 |
EP1682495A1 (en) | 2006-07-26 |
US7060856B2 (en) | 2006-06-13 |
NZ546011A (en) | 2009-09-25 |
RU2352558C2 (ru) | 2009-04-20 |
NO20062090L (no) | 2006-07-12 |
JP2007509125A (ja) | 2007-04-12 |
KR20060080230A (ko) | 2006-07-07 |
US20050085550A1 (en) | 2005-04-21 |
RU2006113437A (ru) | 2006-08-27 |
AR046124A1 (es) | 2005-11-23 |
CA2542210A1 (en) | 2005-05-06 |
KR101013932B1 (ko) | 2011-02-14 |
WO2005040098A1 (en) | 2005-05-06 |
ZA200602250B (en) | 2007-05-30 |
MXPA06004363A (es) | 2006-06-14 |
IL174367A0 (en) | 2006-08-01 |
HK1093483A1 (en) | 2007-03-02 |
BRPI0415710A (pt) | 2006-12-19 |
AU2004283148A1 (en) | 2005-05-06 |
CO5690569A2 (es) | 2006-10-31 |
CN1867543A (zh) | 2006-11-22 |
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