CN1321106C - 阿戈美拉汀的新合成方法、新晶型及其药物组合物 - Google Patents
阿戈美拉汀的新合成方法、新晶型及其药物组合物 Download PDFInfo
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Abstract
式(Ⅰ)化合物的工业合成方法及其新晶型:见右式以及药剂。
Description
本发明涉及工业合成式(I)所示的阿戈美拉汀(agomelatine)或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的方法:
本发明还涉及阿戈美拉汀的晶型II、其制备方法包含它的药物组合物。
阿戈美拉汀,或N-[2-(7甲氧基-1-萘基)乙基]乙酰胺,具有宝贵的药理性质。
实际上,它具有两方面的特征,一方面,它是褪黑激素能系统(melatoninergic system)受体的激动剂,另一方面,是一种5-HT2C受体的拮抗剂。这些性质使其在中枢神经系统具备活性,并尤其在严重抑郁症、季节性情感障碍、睡眠障碍、心血管疾病、消化系统疾病、飞行时差引起的失眠和疲劳、食欲紊乱和肥胖症的治疗中具有活性。
在欧洲专利说明书EP 0 447 285中已经描述了阿戈美拉汀、其制备及其治疗用途。
考虑到该化合物的药用价值,能够以一种有效的工业合成方法得到该化合物,即,可容易地转化为工业规模并以良好产率以及极高的纯度得到阿戈美拉汀的方法,是很重要的。
同样重要的是能够获得具有界限分明的晶型的、可重现性极好的、结果在过滤和易形成方面具有宝贵特性的阿戈美拉汀。
专利说明书EP 0 447 285描述了以7-甲氧基-1-四氢萘酮为起始原料、通过八个反应步骤合成阿戈美拉汀的方法,平均产率小于30%。
该方法包括溴乙酸乙酯的作用,其后进行芳构化和皂化以得到相应的酸,然后将它转化为乙酰胺,并随后脱水,得到(7-甲氧基-1-萘基)乙腈,随后进行还原,然后进行乙酰氯的缩合。
特别地,(7-甲氧基-1-萘基)乙腈的合成涉及6个反应步骤,并且在转化为工业规模时,很快就发现难以实施该方法,这主要是由第一步的再现性问题导致的。第一步包括溴乙酸乙酯按照Réformatsky反应对7-甲氧基-1-四氢萘酮发生作用,产生(7-甲氧基-3,4-二氢-1(2H)-萘撑基)乙酸乙酯。
此外,(7-甲氧基-3,4-二氢-1(2H)-萘撑基)乙酸乙酯的芳构化的后续步骤常常是不完全的,并且在皂化后得到难以纯化的产品混合物。
文献描述了一种三步法得到(7-甲氧基-1-萘基)乙腈的方法,包括:以7-甲氧基-1-四氢萘酮为起始原料,通过LiCH2CN作用,随后使用DDQ(2,3-二氯-5,6-二氰基-1,4-苯醌)脱氢,并最后在酸性介质中脱水(《合成通讯》(Synthetic Communication),2001,31(4),621-629)。总产率较一般(76%),然而,特别是在脱氢步骤中使用DDQ以及在第三个步骤中必须使用苯回流,从成本和环境方面考虑,这都不符合工业化生产的要求。
本申请人现已开发出了一种新的工业合成方法,该方法以可再现的方式进行,并且不需要进行繁琐的纯化,可得到具有能够将其用作药物活性成分所容许的纯度的阿戈美拉汀。
通过使氰基化合物与7-甲氧基-1-四氢萘酮直接缩合,获得了克服专利说明书EP 0 447 285所述方法中遇到的问题的又一方案。此外,不需要激烈的条件即可容易地对得到的缩合化合物进行芳构化得到(7-甲氧基-1-萘基)乙腈,并且可以使用在成本和环境方面符合工业化生产要求的试剂,这也是必要的。
显然(7-甲氧基-3,4-二氢-1-萘基)乙腈是一种满足直接由7-甲氧基-1-四氢萘酮进行合成这一需要的理想的合成中间体,并且是芳构化步骤中优良的底物。
在文献中已经描述了四氢萘酮与乙腈或乙腈化合物直接缩合的反应。特别地,专利说明书US 3 992 403描述了膦酸氰甲酯与6-氟-1-四氢萘酮的缩合,专利说明书US 3 931 188描述了乙腈与四氢萘酮缩合得到一种被直接用于后续反应的氰基中间体。
根据图1,在将其应用于7-甲氧基-1-四氢萘酮时,乙腈的缩合得到了异构体混合物,其中外型(exo)占大部分,而内型(endo)占小部分,
图1
较多部分的“外型”较少部分的“内型”
得到的混合物随后需要剧烈的芳构化条件,而这些条件与进行阿戈美拉汀合成的工业化需要是不相容的。
本申请人现已开发了一种新的工业合成方法,该方法可以以一种可重现的方式、无需进行繁琐的纯化、通过使用不含式(II)所示的“外型”杂质的(7-甲氧基-3,4-二氢-1-萘基)乙腈作为合成中间体,在仅两个步骤中由7-甲氧基-四氢萘酮得到(7-甲氧基-1-萘基)乙腈:
该杂质在与进行阿戈美拉汀合成的工业化需要相容的操作条件下,不能进行随后的芳构化。
更具体地说,本发明涉及工业合成式(I)所示化合物的方法:
其特征在于式(III)的7-甲氧基-1-四氢萘酮:
与式(IV)的氰基乙酸反应,
条件是除去形成的水,且存在催化量的式(V)的化合物:
其中R与R’可以是相同的或者不同的,分别表示直链或者支链的(C3-C10)烷基、未取代或取代的芳基、未取代或取代的直链或支链的芳基(C1-C6)烷基,优选R代表己基,R′代表苄基。
过滤以及用碱液洗涤后,生成如式(VI)所示的(7-甲氧基-3,4-二氢-1-萘基)乙腈:
式(VI)所示的化合物在烯丙基化合物存在下与氢化催化剂进行反应,生成式(VII)所示的化合物:
在含氨的乙醇介质中在阮内镍的存在下用氢对其进行还原,随后使用盐酸将其转化为盐,生成式(VIII)所示的化合物:
接连用乙酸钠和乙酸酐对其发生作用,生成式(I)所示的化合物,并以固体的形式分离出来。
其中:
-芳基被理解为指苯基、萘基和联苯基,
-用于限定“芳基”和“芳基烷基”的术语“取代的”表示这些基团的芳基残基可被选自直链或支链(C1-C6)烷基、羟基和直链或支链的(C1-C6)烷氧基的1至3个相同或不同的基团所取代,
-“烯丙基化合物”被理解为任何含有3至10个碳原子、并含有至少1个-CH2-CH=CH2基团的分子,其可另外含有1至5个氧原子。
更特别地,在式(III)所示化合物转化为式(VI)所示化合物的反应中,通过蒸馏除去形成的水。优选使用沸点温度高于或等于水的反应溶剂,更优选与水形成共沸物的反应溶剂,例如二甲苯、甲苯、苯甲醚、乙苯、四氯乙烯、环己烯或1,3,5-三甲苯。
优选在甲苯或二甲苯回流的条件下、更优选在甲苯回流的条件下实现式(III)所示化合物向式(VI)化合物的转化。
在由式(III)所示化合物转化为式(VI)所示化合物的反应中,适宜的是,所用催化剂的R或R’基团中的一个表示直链或支链的(C3-C10)烷基,且另一个表示芳基或芳基烷基。更特别地,优选的催化剂为式(Va)所示的催化剂:
其中R’a表示未取代的或被一个或多个直链或支链(C1-C6)烷基取代的苯基,n为0或1,Ra表示直链(C3-C10)烷基。
适宜的是,R’a表示未取代或取代的苯基,更特别地,表示未取代的苯基。
优选的基团Ra为己基。
N优选的值为1。
根据本发明的方法,在由式(III)所示化合物转化为式(VI)化合物的反应中,所用催化剂优选为式(IX)所示的庚酸苄基铵:
有利地,在过滤以及使用无机或有机碱溶液,例如NaOH、KOH、Ca(OH)2、Sr(OH)2或NH4OH,并特别优选使用氢氧化钠溶液洗涤之后,得到式(VI)所示化合物。
优选在甲苯或二甲苯回流的条件下、更优选在甲苯回流的条件下实现式(VI)所示化合物向式(VII)所示化合物的转化。
在由式(VI)所示化合物向式(VII)所示化合物的转化中,优选使用的催化剂是氧化物形式,或者是被负载的例如钯、铂、镍、Al2O3,更特别是钯。宜使用1至20%的碳载钯(氢化催化剂),更特别是5%或10%的碳载钯。以催化剂的重量相对于底物的重量计,所用碳载钯(氢化催化剂)的量优选为1至10重量%,更特别是5%。
在由式(VI)所示化合物转化为式(VII)所示化合物的反应中,所用的氢受体优选为烯丙基化合物,更特别是丙烯酸烯丙酯或者烯丙基缩水甘油醚。本发明方法优选的丙烯酸烯丙酯为甲基丙烯酸烯丙酯。
根据本发明的方法,式(VII)所示化合物转化为式(VIII)所示化合物的反应宜在20至40℃下进行,更特别在30至40℃下进行,甚至更宜在40℃下进行。
式(VIII)所示化合物转化为式(I)所示化合物的反应宜在醇介质中进行,并更特别在乙醇介质中进行。
该方法是特别有利的,这是因为:
-该方法能够以工业规模唯一地获得“内型”的式(VI)所示化合物。考虑到在该类型的反应方面,文献中通常大都报导获得的是内型/外型混合物(Tetrahedron,1966,22,3021-3026),这一结果更是令人惊讶的。该种结果的原因是使用了式(V)的化合物作为反应催化剂,而不是目前在这种反应中使用的乙酸铵(Bull.Soc.Chim.Fr.,1949,884-890)。
-式(III)的化合物转化为式(VI)的化合物的转化率非常高,超过了97%,而不象使用乙酸的那样转化率不超过75%。
-和目前所用的苯醌不同,在烯丙基化合物的存在下使用氢化催化剂用于由式(VI)所示化合物向式(VII)所示化合物的转化,在成本及环境方面,完全符合工业化生产的要求。
-此外,该方法能够以工业规模唯一地获得式(VII)化合物,特别是不含式(X)结构的相应的还原产物:
-最后,观察到的式(VI)化合物向通式(VII)化合物的转化率较高,超过了90%。
-在阮内镍催化剂存在下于含氨的乙醇介质中进行式(VII)化合物的氢化反应已有描述(J.Med.Chem.,1994,37(20),3231-3239),但该反应所需条件很难应用到工业规模上:该反应于60℃下进行15小时,最终产率少于90%。此外,该反应的主要缺点是还伴随生成如式(XI)的“双”化合物:
而且很难控制杂质的转化率。由本发明者开发的方法可以在实验条件下制取杂质水平降至低于4%的式(VIII)所示化合物,所述实验条件符合工业化要求,因为该反应在30至40℃下进行,产率超过90%,化学纯度超过99.5%。
-酰胺化作用是在醇类溶剂中、更特别在乙醇溶剂中进行的,这使得式(I)所示化合物可以非常容易地以定量产率分离出来,这一结果令人非常吃惊,因为预计该溶剂对乙酸酐有竞争性的消耗,因而并不是非常适于这种类型的反应。
根据本发明方法得到的式(VI)所示化合物是新颖的,并且可用作合成阿戈美拉汀的中间体。在所述合成过程中,对式(VI)所示化合物进行芳构化,然后还原,再与乙酸酐进行偶联。
本发明还涉及根据上述方法获得的阿戈美拉汀的晶型II。实际上,获得界限分明且可再现性极好的晶型是非常重要的。
现有文献EP 0 447 285以及Yous等人(Journal of MedicinalChemistry,1992,35(8),1484-1486)可以制得特殊晶型的阿戈美拉汀,这种晶型已由Tinant等人(Acta Cryst.,1994,C50,907-910)描述。
本发明者开发出了制备阿戈美拉汀的方法,其具有界限分明且可再现性极好的晶型,因而在过滤和易形成方面具有宝贵的特性。
更具体地说,本发明涉及阿戈美拉汀的晶型II,其特征可以用下列参数表示,这些参数是由使用Bruker AXS D8高分辨率衍射仪得到的粉末图获得的,该衍射仪的2θ角范围是3°-90°,步进为0.01°,每步进30s:
-单斜晶晶格
-晶格参数:a=20.0903,b=9.3194,c=15.4796,β=108.667°
-空间群:P21/n
-单位晶格中的分子数:8
-单位晶格体积:V单位晶格=2746.7423
-密度:d=1.13g/cm3。
获得这种晶型的优点是,可以对它极为快速和有效地过滤,而且药物制剂的制备物具有一致且可再生的组分,当该药物制剂用于口服时这是极为有利的。
由此得到的晶型足够稳定,因而可以长期储存,无需限制特殊的温度、光线、湿度或氧含量条件。
对由此得到的晶型的药理学研究表明,其对于中枢神经系统和微循环系统具有显著的活性,因而可以肯定阿戈美拉汀的晶型II可用于治疗紧张、睡眠障碍、焦虑症、严重抑郁症、季节性情感障碍、心血管疾病、消化系统疾病、飞行时差引起的失眠和疲劳、精神分裂症、恐惧症、忧郁症、食欲紊乱、肥胖症、失眠症、疼痛、精神错乱、癫痫症、糖尿病、帕金森氏病、老年痴呆症、与正常的或病理性老化相关的各种疾病、偏头痛、失忆症、阿耳茨海默氏病、以及大脑循环疾病。在另一活性领域,阿戈美拉汀的晶型II可用于治疗性功能障碍,其具有抑制排卵和调节免疫的性质,而且其可用于治疗癌症。
阿戈美拉汀的晶型II优选用于治疗严重抑郁症、季节性情感障碍、睡眠障碍、心血管病状、飞行时差引起的失眠和疲劳、食欲紊乱和肥胖症。
本发明还涉及药物组合物,其包含阿戈美拉汀的晶型II作为活性组分,同时还包含一种或多种惰性、无毒的适宜赋形剂。在根据本发明的药物组合物中,可以提及的是,更为特别地,适于口服、不经消化道的(静脉内或皮下)注射或通过鼻内使用的那些,片剂或糖衣丸、颗粒、舌下片、胶囊、锭剂、栓剂、乳剂、软膏、涂肤胶、注射制剂、口服液以及可分解糊。
本发明还涉及上述药物组合物的用途,用于生产治疗褪黑激素能系统疾病的药物。
应根据疾病的特征和严重程度、服用途径以及患者的年龄和体重来选择服用的剂量,每天分一次或多次服用0.1mg到1g的剂量。
下列实施例用于阐述本发明,但决不是限制本发明。
实施例1:N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
步骤A:(7-甲氧基-3,4-二氢-1-萘基)乙腈
在12.7kg苄胺的存在下,将85.0kg7-甲氧基-1-四氢萘酮、60.3kg氰基乙酸和15.6kg溶于甲苯的庚酸加入670升的反应器中。在回流下加热该混合物。当全部起始底物消失后,冷却该溶液并过滤。使用甲苯洗涤得到的沉淀,并然后使用2N的氢氧化钠溶液洗涤得到的滤出液,并随后用水洗涤直至中性。通过蒸发除去溶剂,然后在乙醇/水(80/20)的混合物中重结晶所获固体,以90%的产率和超过99%的化学纯度得到标题产物。
熔点:48-50℃
步骤B:(7-甲氧基-1-萘基)乙腈
向670升的反应器中加入12.6kg 5%的溶于甲苯的碳载钯,在回流下加热;然后加入96.1kg溶于甲苯的(7-甲氧基-3,4-二氢-1-萘基)乙腈和63.7kg甲基丙烯酸烯丙酯。在回流条件下继续反应,然后进行气相色谱分析。当全部起始底物消失后,冷却该溶液至室温,然后过滤。通过蒸发除去甲苯,然后在乙醇/水(80/20)的混合物中重结晶所获固体残留物,以91%的产率和超过99%的化学纯度得到标题产物。
熔点:83℃
步骤C:2-(7-甲氧基-1-萘基)乙胺盐酸盐
将80.0kg步骤B所得化合物、24.0kg溶于乙醇的阮内镍以及170升氢氧化铵加入1100升反应器中。混合物在30巴的氢气压下搅拌,然后加热到40℃。当全部起始底物消失后,蒸除溶剂,所得残余物再溶解于乙酸乙酯中,加入41.5升11N盐酸溶液。过滤后,用乙酸乙酯洗涤所获沉淀,在烘箱中干燥,以95.3%的产率和超过99.5%的化学纯度得到标题产物。
熔点:243℃
步骤D:N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
将173kg步骤C所得化合物和66kg乙酸钠的乙醇溶液加入1600升反应器中,搅拌混合物,然后加入79kg乙酸酐。对反应混合物加热回流,加入600升水。将反应混合物回复至室温,滤出所获沉淀物,用35/65的乙醇/水混合液进行洗涤,以92.5%的产率和超过99%的化学纯度得到标题产物。
熔点:108℃
实施例2:N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
步骤A:(7-甲氧基-3,4-二氢-1-萘基)乙腈
在11.0kg苯胺的存在下,将85.0kg的7-甲氧基-1-四氢萘酮、60.3kg氰基乙酸以及溶于甲苯中的15.6kg庚酸加入到670升反应器中,混合物加热回流。当全部起始底物消失后,冷却并过滤溶液。所得沉淀物用甲苯洗涤,所得滤液用2N氢氧化钠溶液洗涤,然后用水洗涤至中性。蒸发除去溶剂,所得固体在乙醇/水(80/20)混合物中重结晶,得到标题产物,其产率为87%,化学纯度超过99%。
熔点:48-50℃
步骤B:(7-甲氧基-1-萘基)乙腈
该操作与实施例1中的步骤B相同。
熔点:83℃
步骤C:2-(7-甲氧基-1-萘基)乙胺盐酸盐
该操作与实施例1中的步骤C相同。
熔点:243℃
步骤D:N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
该操作与实施例1中的步骤D相同。
熔点:108℃
实施例3:N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的晶型II
使用Bruker AXS D8高分辨率衍射仪记录数据,该衍射仪参数如下:2θ角范围为3°-90°,步进为0.01°,每步进30s。实施例中得到的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺粉末放置在传输台座支撑上。X射线源为铜管(λCuKα1=1.54056)。该台座包括前单色仪(Ge(111)晶体)和能量分解固态检测器(MXP-D1,Moxtec-SEPH)。
该化合物得结晶良好:半高射线宽度为约0.07°(2θ)。下列参数确定为:
-单斜晶晶格
-晶格参数:a=20.0903,b=9.3194,c=15.4796,β=108.667°
-空间组:P21/n
-单位晶格中的分子数:8
-单位晶格体积:V单位晶格=2746.7423
-密度:d=1.13g/cm3
实施例4:药物组合物
1000片制剂,每片含有25mg剂量,其配方如下:
实施例3的化合物25g
乳糖一水合物62g
硬脂酸镁1.3g
玉米淀粉26g
麦芽糊精9g
硅石,无水胶体0.3g
A型淀粉甘醇酸钠4g
硬脂酸2.6g
实施例5:药物组合物
1000片制剂,每片含有25mg的剂量,其配方如下:
实施例3的化合物25g
乳糖一水合物62g
硬脂酸镁1.3g
聚维酮9g
硅石,无水胶体0.3g
纤维素甘醇酸钠30g
硬脂酸2.6g
Claims (19)
2.工业合成权利要求1所述式(I)的阿戈美拉汀的晶型II的方法:
其特征在于式(III)所示的7-甲氧基-1-四氢萘酮:
与式(IV)所示的氰基乙酸反应:
条件是除去形成的水,且存在催化量的式(V)所示的化合物:
其中R与R’可以是相同的或者不同的,分别表示直链或者支链的C3-C10烷基、未取代或取代的芳基、未取代或取代的直链或支链的芳基C1-C6烷基,
过滤及用碱液洗涤后,生成如式(VI)所示的(7-甲氧基-3,4-二氢-1-萘基)乙腈:
式(VI)所示的化合物在烯丙基化合物存在下与氢化催化剂进行反应,生成式(VII)所示的化合物:
在含氨的乙醇介质中在阮内镍的存在下用氢对其进行还原,随后使用盐酸将其转化为盐,生成式(VIII)所示的化合物:
接连用乙酸钠和乙酸酐对其发生作用,生成式(I)所示的化合物,并以固体的形式分离出来,
其中:
-芳基被理解为指苯基、萘基和联苯基,
-用于限定“芳基”和“芳基烷基”的术语“取代的”表示这些基团的芳基残基可被选自直链或支链C1-C6烷基、羟基和直链或支链的C1-C6烷氧基的1至3个相同或不同的基团所取代,
-“烯丙基化合物”被理解为任何含有3至10个碳原子、并含有至少1个-CH2-CH=CH2基团的分子,其可另外含有1至5个氧原子。
3.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于由式(III)化合物向式(VI)化合物的转化是在甲苯的回流下进行的。
4.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于R代表己基。
5.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于R′代表苄基。
8.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于由式(VI)化合物向式(VII)化合物的转化是在甲苯的回流下进行的。
9.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于在由式(VI)化合物向式(VII)化合物的转化中所用氢化催化剂为钯。
10.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于在由式(VI)化合物向式(VII)化合物的转化中所用氢化催化剂为5%的碳载钯。
11.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于在由式(VI)化合物向式(VII)化合物的转化中,以催化剂的重量相对于底物的重量计,所用氢化催化剂的量为5重量%。
12.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于由式(VII)化合物向式(VIII)化合物的转化在40℃下进行。
13.如权利要求2的合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于由式(VIII)化合物向式(I)化合物的转化是在乙醇中进行的。
14.以式(VI)化合物为原料合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于对式(VI)化合物进行芳构化,然后还原,并用乙酸酐进行偶联。
16.以式(VIII)化合物为原料合成式(I)的阿戈美拉汀的晶型II的方法,其特征在于用乙酸钠和乙酸酐对式(VIII)化合物发生作用。
17.一种药物组合物,其含有如权利要求1的阿戈美拉汀的晶型II作为活性剂,同时含有一种或多种药理上可接受的、惰性的、无毒赋形剂。
18.如权利要求17的药物组合物的用途,用于生产治疗褪黑激素能系统疾病的药物。
19.如权利要求17的药物组合物的用途,用于生产治疗下列疾病的药物:睡眠障碍、紧张、焦虑症、季节性情感障碍或严重抑郁症、心血管疾病、消化系统疾病、飞行时差引起的失眠和疲劳、精神分裂症、恐惧症、忧郁症、食欲紊乱、肥胖症、失眠症、精神错乱、癫痫症、糖尿病、帕金森氏病、老年痴呆症、与正常的或病理性老化相关的各种疾病、偏头痛、失忆症、阿耳茨海默氏病、大脑循环疾病以及性功能障碍,用作排卵抑制剂和免疫调节剂,用于治疗癌症。
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US3992403A (en) * | 1975-05-30 | 1976-11-16 | Schering Corporation | 2-Imidazolines and their use as hypoglycemic agents |
EP0447285B1 (fr) * | 1990-02-27 | 1993-05-12 | Adir Et Compagnie | Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
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CN101638376B (zh) * | 2008-07-29 | 2011-04-27 | 江苏恩华药业股份有限公司 | 阿戈美拉汀的制备方法及其中间体 |
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