CN101959892B - (r),(r)-2,2’-二-甲基纳曲酮的制备和用途 - Google Patents
(r),(r)-2,2’-二-甲基纳曲酮的制备和用途 Download PDFInfo
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- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/24—Automatic injection systems
Abstract
本发明涉及如式(I)所示的(R),(R)-2,2’-二-MNTX的合成以及相关方法和产品。
Description
发明领域
本发明涉及(R),(R)-2,2’-二-甲基纳曲酮的合成以及相关方法和产物。
背景技术
甲基纳曲酮(MNTX)是阿片类拮抗剂纳曲酮的季胺衍生物。MNTX作为盐例如溴化物盐而存在。MNTX的溴化物盐在文献中也被称为:甲基纳曲酮溴化物、N-甲基纳曲酮溴化物、甲溴纳曲酮、纳曲酮甲基溴化物、MRZ 2663BR。如美国专利No.4,176,186中所述,在70年代中期由Goldberg等首次报道了MNTX。据信将甲基基团加到纳曲酮的环氮上形成带电化合物,所述带电化合物与纳曲酮相比具有更大的极性和更小的脂溶性,从而防止MNTX穿过人的血-脑屏障。因此,MNTX在外周神经系统而不是在中枢神经系统发挥其作用,具有不与阿片类物质对中枢神经系统的镇痛作用发生对抗的优点。
MNTX是手性分子,其中季氮可以具有(R)或(S)构型。例如,(R)-MNTX是指在季氮处具有(R)立体化学性的MNTX分子,而(S)-MNTX是指在季氮处具有(S)立体化学性的MNTX分子。文献中记载的MNTX的所有报道的功能显示MNTX是外周阿片类拮抗剂。这些拮抗剂功能的一部分记载于美国专利4,176,186、4,719,215、4,861,781、5,102,887、5,972,954、6,274,591、6,559,158和6,608,075,以及美国专利申请公开号2003/0022909A1、20040266806、20040259899和20050004155中。这些用途包括降低阿片类物质的副作用而不降低阿片类物质的镇痛作用。所述副作用包括恶心、呕吐、焦虑、瘙痒、尿潴留、肠蠕动缓慢、便秘、胃蠕动缓慢、胃排空延迟和免疫抑制。本领域中公开了MNTX不仅减少源自阿片类物质镇痛治疗的副作用,而且减少由单独的内源性阿片类物质(或与外源性阿片类物质联合治疗)所介导的副作用,例如胃肠功能紊乱,包括胃排空抑制,便秘,由于诸如手术、发炎或过度刺激迷走神经之类的任何原因引起的胃肠蠕动抑制,和其他包括但不限于上述那些的这类病症。 然而,从本领域中不清楚这些研究中所用的MNTX是否是(R)和(S)立体异构体的混合物或是单一的立体异构体。
本领域认为分离的化合物立体异构体有时可具有差别明显的物理和功能特性,尽管在任意特定情况下这是不可预知的。季胺麻醉拮抗剂表现出这种差别明显的物理和功能特性,使得开发分离和识别作为纯的(R)-MNTX或(S)-MNTX的MNTX的程序很重要。Goldberg等人的美国专利No.4,176,186以及最近Cantrell等人的WO 2004/043964A2描述了MNTX的合成方案,其涉及叔N-取代的吗啡喃生物碱利用甲基化试剂的季胺化作用。但是,Goldberg等人和Cantrell等人均没有提及关于合成产生的立体异构体。基于各自所述的合成方法,并不知道如此产生的MNTX是(R)或(S)或是二者的混合物。而且,纯形式的(S)-N-甲基纳曲酮((S)-MNTX)以及制备纯的(S)-MNTX的方法还没有在文献中描述过。因此,在缺少纯的(S)-MNTX作为标准物的情况下,研究者还不能确定无疑地表征和区别由Goldberg等人或Cantrell等人的合成获得的立体异构体。
除了季铵麻醉拮抗剂的各种立体异构体的分离和表征之外,还可以期望在药物组合物的制备中使拮抗剂与任意其他的杂质分离。通常,药物组合物也需要高水平的纯度以满足药品质量和纯度的管制标准。例如,在合成如上所述的MNTX合成中,常常形成杂质,包括降解物或制备的副产物,这可能妨碍MNTX的疗效和/或可能在足够高的量存在下具有毒性。这样,期望具有测定MNTX的立体化学构型和纯度的能力。为此,识别、分离以及化学表征杂质是重要的,其可以在色谱分析程序中用作标准物以确认MNTX的纯度。
发明内容
本发明涉及(R)-MNTX的杂质的识别、纯化和合成。已经发现,该化合物可以在(R)-MNTX的制备过程中作为杂质或者当(R)-MNTX的某些溶液在一定条件下储存时作为降解物而出现。该化合物为(R),(R)-2,2’-二-甲基纳曲酮。该化合物为盐,因而将具有反离子。该化合物也可以作为两性离子存在。因此,在本发明的一个方面中,提供一种式(I)的化合物,
其中X或Y为反离子。在一些实施方案中,各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。在特定实施方案中,Y可以独立地为相同或不同的反离子。在某一个实施方案中,可以存在X和Y的混合物。在一些实施方案中,X或Y可以是卤离子、硫酸根、磷酸根、磺酸根、硝酸根、羧酸根或有机物质。在一个特定的实施方案中,X为溴离子。在一些实施方案中,该化合物被分离为具有以至少0.5%的纯度,或者至少1%的纯度,或者至少5%的纯度,或者至少10%的纯度,或者至少15%的纯度,或者至少25%的纯度,或者至少50%的纯度、至少75%的纯度、至少95%的纯度,或者更优选至少97%的纯度。在一些实施方案中,所述化合物为固体。在其他实施方案中,所述化合物封装为在密封瓶中溶液。在一个实施方案中,所述化合物封装为在具有隔膜的密封瓶中的溶液。
根据本发明的另一方面,提供一种试剂盒,该试剂盒包含式(I)的化合物以及在试剂盒之中或之上指示所述化合物存在于试剂盒中的标记。在一些实施方案中,所述标记指示化合物的纯度。在一些实施方案中,所述标记通过提供化学式或者结构图来指示化合物的化学结构。在一些实施方案中,试剂盒包含第二化合物,其为(R)-甲基纳曲酮、(S)-甲基纳曲酮或另一种化合物。
本发明的另一方面提供合成(R),(R)-2,2’-二-MNTX的方法,其包括使第一分子(R)-甲基纳曲酮与第二分子(R)-甲基纳曲酮在其量足以形成式(I)的化合物的催化剂和氧化剂的存在下反应。在一些实施方案中,催化剂以相对于第一分子(R)-甲基纳曲酮的量为25摩尔%以下,或者更优选10摩尔%以下存在。在一些实施方案中,氧化剂以相对于第一分子(R)-甲基纳曲酮的量为化学计量存在。在一个实施方案中,催化剂为溴化铁。在一个实施方案中,氧化剂为过氧化氢。在一些实施方案中,所述方法还包括将该化合物分离为固体。在一些实施方案中,该化合物分离为具有至少0.5%的纯度,或者至少1%的纯度,或者至少5% 的纯度,或者至少10%的纯度,或者至少15%的纯度,或者至少25%的纯度,或者至少50%的纯度、至少75%的纯度、至少95%的纯度,或者更优选至少97%的纯度。在一些实施方案中,所述化合物为固体。
本发明还提供一种测定杂质的方法,其包括在一组条件下向HPLC柱中注入含有式(I)的化合物的参比溶液以获得第一HPLC色谱,其中参比溶液中存在的化合物的量和/或化学特性是已知的;在所述组条件下向HPLC柱中注入含甲基纳曲酮的样品溶液以获得第二HPLC色谱;并且测定所述化合物在样品溶液中的存在和/或量。在一些实施方案中,多次注入参比溶液。在一些实施方案中,所述测定包括比对第一HPLC色谱中的峰和第二HPLC色谱中的峰的保留时间以确定所述化合物在样品溶液中的存在。在其他实施方案中,所述测定包括量化HPLC色谱上样品溶液的峰面积和参比溶液的峰面积并且据此估算出化合物在样品溶液中的量。样品溶液可以包含(R)-甲基纳曲酮和/或(S)-甲基纳曲酮,或者(R)-甲基纳曲酮和(S)-甲基纳曲酮的混合物。在一些实施方案中,HPLC柱为反相柱并且所述柱用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。
本发明也提供测定在基本上由甲基纳曲酮构成的材料中的杂质的方法,其包括在一次或一系列注射中向HPLC柱中注入含有该材料并加入具有式(I)的已知化学结构的参比化合物的样品溶液;获得HPLC色谱;以及测定所述化合物在材料中存在和/或量。样品溶液可以包含(R)-甲基纳曲酮,或者(R)-甲基纳曲酮和(S)-甲基纳曲酮的混合物。在一些实施方案中,HPLC柱为反相柱并且所述柱用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。所述方法还可以包括以书面形式备案(documenting)所述化合物的化学特性和所述化合物作为杂质的量。
本发明还提供一种测定基本上由甲基纳曲酮构成的材料中的杂质的方法,其包括在一次或系列注射中向HPLC柱中注入溶解有该材料的溶液并获得HPLC色谱;测定已知具有式(I)结构的化合物在材料中的量;以及以书面形式备案所述化合物的化学特性和所述化合物作为杂质在材料中的量。在一些情况下,化合物在材料中的量是通过(i)在色谱上识别与已知具有式(I)结构的化合物的对照色谱上的峰相对应的峰,(ii)在色谱上识别与已知具有式(I)结构的化合物的相对保留时间相对应的峰,和/或(iii)在色谱上识别与已知具有式(I)结构的化合物的已知添加量相对应的峰来测定的。样品溶液可以包含(R)-甲基纳曲酮,或者(R)-甲基 纳曲酮和(S)-甲基纳曲酮的混合物。在一些实施方案中,HPLC柱为反相柱并且所述柱用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。
附图说明
图1示出根据本发明的一个实施方案合成(R),(R)-2,2’-二-甲基纳曲酮((R),(R)-2,2’-二-MNTX)的合成方案。
图2示出根据本发明的一个实施方案合成(R),(R)-2,2’-二-MNTX的替代合成方案。
具体实施方案
本发明提供合成(R),(R)-2,2’-二-甲基纳曲酮((R),(R)-2,2’-二-MNTX)的合成途径,以及相关的产物和方法。
(R),(R)-2,2’-二-MNTX具有式(I)的结构:
其中X或Y为反离子。在一些情况下,各X可以独立地为相同或不同的反离子。各X可以共价连接到其他X上。反离子可以为,例如卤离子(例如碘离子、溴离子、氯离子或氟离子)、硫酸根、磷酸根、硝酸根或带负电荷的有机物质(例如磺酸根如甲磺酸根、苯磺酸根、甲苯磺酸根、三氟甲磺酸根等,羧酸根如甲酸根、乙酸根、柠檬酸根、富马酸根等)。在一个实施方案中,反离子为卤离子,例如溴离子。
本发明提供合成(R),(R)-2,2’-二-MNTX的方法。图1示出根据本发明一个实施方案的(R),(R)-2,2’-二-MNTX的合成。第一(R)-MNTX分子的酚环可以与第二(R)-MNTX分子的另一个酚环在其量足以生成(R),(R)-2,2’-二-MNTX的催化剂和氧化剂的存在下偶联。或者,纳曲酮分子的酚环可以与第二纳曲酮的另一个酚环在类似的偶联条件下偶联,并且所得到的纳曲酮二聚体可以用甲基化试剂在N-取代的叔胺处进行烷基化以形成 (R),(R)-2,2’-二-MNTX,如图2中所示。
因为2,2’-二-MNTX含有两个手性季铵,所以基于偶联形成2,2’-二-MNTX二聚体的单独的MNTX分子的立体化学性,2,2’-二-MNTX可拥有多中不同的立体化学构型(例如(R),(R)-2,2’-二-MNTX、(S),(S)-2,2’-二-MNTX,或者(R),(S)-2,2’-二-MNTX)。本文所述的方法利用至少99.5%为(R)构型的MNTX作为原料,以使(R),(R)-2,2’-二-MNTX异构体为所形成的主要异构体。尽管2,2’-二-MNTX的其他异构体也可能形成,但它们的存在量将为极低或可忽略。2006年5月25日提交的美国专利申请11/441,395(公开号为US 2007-0099946A1),中描述了纯的(R)-MNTX的合成。(R)-MNTX的立体化学构型可以通过使用纯的(S)-MNTX作为参考标准进行测定。2006年5月25日提交的美国专利申请11/441,452,公布号为US 2007-0265293A1,中描述了纯的(S)-MNTX的合成。已经发现(R)-MNTX为阿片类拮抗剂,而(S)-MNTX为部分阿片类激动剂。
在一些情况下,本发明的方法包括偶联反应,例如芳基(例如酚)的氧化偶联。偶联反应可以涉及使用能够氧化催化两个分子例如两个芳基分子之间形成共价键的催化剂(例如溴化铁)。催化剂可以含有金属例如铁。催化剂的实例包括但不限于包括亚铁氰化钾、氯化铁和溴化铁的铁盐,或本领域技术人员已知的其他偶联剂。在一些实施方案中,优选催化剂相对于底物(例如MNTX、纳曲酮)以亚化学计量(例如催化量)存在于反应中。例如,催化剂可以相对于MNTX或纳曲酮的量为25摩尔%以下,更优选10摩尔%以下而存在。在一个实施方案中,催化剂为溴化铁且以10摩尔%存在于反应中。催化剂对于本领域技术人员而言是熟知的并且大量描述于专利文献和化学教科书中。本领域技术人员仅用常规技术即可选择适当的催化剂。
偶联反应中也可以包含氧化剂。在一个实施方案中,氧化剂为过氧化氢。不希望受到理论束缚,偶联反应的一个可能的机理可包括在二聚体分子(例如(R),(R)-2,2’-二-MNTX)形成之后通过氧化剂使催化物质再生。例如,催化剂在二聚体分子形成之后可被还原为无催化活性的分子。然后氧化剂可用于,例如氧化无催化活性的分子以再生催化剂的活性形式。在一些实施方案中,氧化剂可为过氧化氢。可以优选氧化剂以相对于底物(例如MNTX、纳曲酮)的化学计量(例如1摩尔当量)存在于反应中。任选地,可以使氧气鼓泡经过反应混合物以促进偶联反应。
偶联反应可以在任何有机溶剂、有机溶剂的混合物,或者有机溶剂与 水的混合物中进行。在一些实施方案中,反应可以在酸性条件下进行。在一些实施方案中,反应可以在碱性条件下进行。在一个实施方案中,偶联反应在水、甲醇和三氟乙酸的混合物中进行。偶联反应也可以在0℃到室温之间的任何温度下进行。在一些情况下,可以在0℃下在一段时间内向反应混合物中加入第二试剂,并且将所得的混合物升温至室温。偶联反应可以进行1小时到约10小时,优选约1小时到约5小时,更优选约1到2.5小时,最优选约1.5小时。反应可以使用高效液相色谱(HPLC)进行监控。
在一些情况下,本发明的方法还可以包括甲基化反应,例如纳曲酮二聚体的N-取代叔胺的甲基化(图2)。甲基化反应可涉及甲基化试剂如甲基溴的使用。如本文所用的术语“甲基化试剂”是指能够在纳曲酮的氮原子处引入甲基以与其形成共价键的具有亲电性的活性物质。示例性的甲基化试剂可由式CH3Z来表示,其中“Z”为离去基团,使得在其离开后能够在甲基和纳曲酮的氮原子之间形成共价键,从而形成MNTX。甲基化试剂和离去基团对于本领域技术人员而言是熟知的并且大量描述于专利文献和化学教科书中。合适的Z基团包括但不限于F、Cl、Br、I、-OSO2CF3、CH3OSO2O-、-OSO2CH3、-OSO2C6H4-p-CH3、-OSO2C6H4-p-Br。
所述方法还可涉及使用至少一种纯化技术例如色谱法或结晶法来提纯(R),(R)-2,2’-二-MNTX。色谱法可为反相色谱法、正相色谱法,和/或离子交换色谱法。在一些实施方案中,正相色谱法可涉及氧化铝或硅胶柱的使用。在一些情况下,本发明的方法可涉及使用反相HPLC柱,随后使用离子交换色谱法。对于反相色谱法,可以使用含有水、甲醇、三氟乙酸或其混合物的移动相对HPLC柱进行洗脱。结晶溶剂可以为有机溶剂、有机溶剂的混合物,或者有机溶剂与水的混合物。优选的溶剂可以为醇,例如甲醇。色谱分析和结晶的方法均为本领域技术人员已知的。
在一些情况下,HPLC柱为反相柱并且所述柱用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。
在一个示例性的实施方案中,使用催化量的溴化铁和化学计量的过氧化氢进行偶联反应。用8.5g的(R)-MNTX进行该程序,在反相色谱分离、接着进行离子交换色谱以及从甲醇中结晶之后,生成660mg的纯度>97%的产物,产率为7.8%,如下详述。应当理解,本领域技术人员可以优化本文所述的方法以获得更高纯度和/或更高产率的(R),(R)-2,2’-二-MNTX,其中结晶产物的纯度大于99%,或者甚至大于99.9%。如通过本文所述 的HPLC方法B测定的(R),(R)-2,2’-二-MNTX、(R)-MNTX和(S)-MNTX的相对保留时间分别为1.55、1.00和0.89。
对于固体的纯度而言,纯度为固体中的(R),(R)-2,2’-二-MNTX的重量百分比相对其他化合物的重量百分比。对于溶液的纯度而言,所述纯度为溶液中的(R),(R)-2,2’-二-MNTX的重量百分比相对其他化合物的重量百分比。纯度可通过HPLC测定,其中化合物的百分纯度是指溶液中存在的化合物的重量百分比相对于相同溶液中存在的其他化合物的重量百分比。
本发明可以有利地提供足够纯度的(R),(R)-2,2’-二-MNTX,以使其能够在不同的分析方法(例如HPLC)中用作参比物或者标准物,如下详述。在一些实施方案中,(R),(R)-2,2’-二-MNTX可以分离为具有至少0.5%的纯度、至少1%的纯度、至少5%的纯度、至少10%的纯度、至少15%的纯度、至少25%的纯度、至少50%的纯度、至少75%的纯度、至少95%的纯度,更优选至少97%的纯度。在一些实施方案中,(R),(R)-2,2’-二-MNTX可作为固体分离和/或封装。在一些实施方案中,(R),(R)-2,2’-二-MNTX可作为溶液封装在诸如密封瓶或小瓶,或包括隔膜的密封瓶之类的容器中。
在另一个方面,本发明提供测定样品(例如含(R)-MNTX的样品)中(R),(R)-2,2’-二-MNTX的存在和/或量的方法。例如,(R),(R)-2,2’-二-MNTX可以在(R)-MNTX的合成过程中作为杂质形成。本文所用的术语“杂质”可以指(R)-MNTX的储存过程中出现的降解物和/或制备(R)-MNTX的化学反应中形成的副产物。在一个实施方案中,所述方法包括在一组条件下向HPLC柱中注入含有(R),(R)-2,2’-二-MNTX的参比溶液以获得第一HPLC色谱,其中参比溶液中存在的(R),(R)-2,2’-二-MNTX的量和/或化学特性是已知的;在相同组的条件下向HPLC柱中注入含MNTX的样品溶液以获得第二HPLC色谱;并且将第一HPLC色谱和第二HPLC色谱进行比对以确定杂质的存在和/或量。参比溶液可以通过将(R),(R)-2,2’-二-MNTX的样品(例如固体样品)溶解于第一溶剂中而形成,而样品溶液可以通过将固体样品溶解于第二溶剂中而形成。在一些实施方案中,参比溶液可以含有其他的化合物,其中所述其他的化合物的量和/或特性也是已知的。在一个实施方案中,样品(例如样品溶液)可以含有(R)-MNTX。应当理解,本发明可以包括疑似含有(R),(R)-2,2’-二-MNTX的其他样品。
在一个实施方案中,(R),(R)-2,2’-二-MNTX在样品溶液中的存在可以 通过比对第一HPLC色谱中峰的保留时间与第二HPLC色谱中峰的保留时间进行测定。例如,含有(R),(R)-2,2’-二-MNTX的标准溶液可以产生具有对应于(R),(R)-2,2’-二-MNTX且具有特定保留时间的峰的色谱。然后在与标准溶液相同的条件下将样品溶液注入HPLC柱,并且研究所得的色谱以确定在与标准溶液的HPLC色谱中对应于(R),(R)-2,2’-二-MNTX的峰的相同保留时间是否存在峰。这样的峰的存在可以表明样品中存在(R),(R)-2,2’-二-MNTX。在另一个实施方案中,通过比对第一HPLC色谱中的峰面积与第二HPLC色谱中的峰面积并且据此计算(R),(R)-2,2’-二-MNTX在样品溶液中的含量,可以确定(R),(R)-2,2’-二-MNTX在样品溶液中的量。
在一些实施方案中,本发明提供测定在基本上由甲基纳曲酮构成的材料中的杂质的方法,其中将含有该材料且加入具有如本文所述的式(I)的已知化学结构的参比化合物的样品溶液注入HPLC柱中,并获得HPLC色谱以测定所述化合物在材料中的存在和/或量。
本发明的方法还可以包括以书面形式备案所述化合物的化学特性和所述化合物作为杂质在材料中的量。
在其他实施方案中,本发明提供测定在基本上由甲基纳曲酮构成的材料中的杂质的方法,其中将溶解该材料的溶液注入HPLC柱中并获得HPLC色谱以测定已知具有如本文所述的式(I)结构的化合物在该材料中的量。然后可以以书面形式备案所述化合物的化学特性以及所述化合物作为杂质在材料中的量。化合物在材料中的量可如下测定:(i)在色谱上识别与对照色谱上的峰相对应的峰,(ii)在色谱上识别与已知具有式(I)结构的化合物的相对保留时间相对应的峰,和/或(iii)在色谱上识别与已知具有式(I)结构的化合物的已知添加量相对应的峰量。
本发明的一些实施方案可以用来测定(R),(R)-2,2’-二-MNTX在含有(R)-MNTX的样品中的量和/或存在。该样品可以是新鲜制备的材料的样品,或者该样品可以是储存了规定时间的样品。在一个实施方案中,(R)-MNTX的样品可以储存并且使用本文所述的方法进行周期性分析以测定可能已通过例如(R)-MNTX的降解而形成的(R),(R)-2,2’-二-MNTX在样品中的存在和/或量。在一些情况中,样品可以置于有意促进(R)-MNTX降解的条件下,其中使用本文所述的方法对样品进行周期性分析以测定(R),(R)-2,2’-二-MNTX在样品中的存在和/或量。样品溶液也可以含有(R)-MNTX、(S)-MNTX或其混合物。在一个实施方案中,样品溶液含有 (R)-MNTX和/或(S)-MNTX。在另一个实施方案中,样品溶液含有(R)-MNTX和(S)-MNTX的混合物。
在本发明的一个方面中,提供包含(R),(R)-2,2’-二-MNTX的试剂盒。例如,可以提供含有(R),(R)-2,2’-二-MNTX的试剂盒用于产生分析方法例如HPLC用的标准物。在一个实施方案中,试剂盒可以含有(R),(R)-2,2’-二-MNTX和在试剂盒之内或之上指示该试剂盒中存在(R),(R)-2,2’-二-MNTX的标记。在一些情况下,该标记指示(R),(R)-2,2’-二-MNTX的纯度。该标记也可以通过提供化学式或结构图来指示化合物的化学结构。在一些情况下,试剂盒可以包含第二化合物,其为(R)-MNTX、(S)-MNTX或另一化合物。该标记可以指示第二化合物存在于试剂盒中,或者可以指示第二化合物的纯度或者通过提供化学式或结构图而指示第二化合物的化学结构。应当理解,试剂盒也可以包含另外的化合物,类似地通过标记进行标识。
在一些情况下,试剂盒包含(R),(R)-2,2’-二-MNTX的溶液。在一些情况下,试剂盒包含(R),(R)-2,2’-二-MNTX的固体样品。本文所用的“试剂盒”,通常定义为含有一种或更多种本发明的组合物,和/或与本发明相关的其他材料例如溶剂的封装体或组合件。可以以液体形式(例如溶液中)或以固体形式提供试剂盒的每一种组合物。在某些情况下,一些组合物可以是可稀释配制的(constitutable)或可以其他方式处理的,例如通过添加可以或不可与试剂盒一起提供的合适溶剂或其他物质。与本发明相关的其他组合物或部件的实例包括但不限于溶剂、表面活性剂、稀释剂、盐类、缓冲液、乳化剂、螯合剂、抗氧化剂、干燥剂、针、注射器、封装材料、管、瓶、烧瓶、烧杯、碟、玻璃料、过滤器、环形物、夹具、包裹物、盖板、容器等,例如为了特定用途,例如对样品进行使用、修饰、组装、储存、封装、制备、混合、稀释,和/或保存组合物、部件。
本发明的试剂盒在一些情况下可以包括与本发明的组合物一起提供的任意形式的说明书,以此方式,本领域技术人员将认识到该说明书与本发明的组合物相关。例如,说明书可以包括组合物和/或与试剂盒相关的其他组合物的使用、修饰、混合、稀释、保存、组装、储存、封装和/或制备的说明。在一些情况下,说明书也可以包括例如为了特定用途,对例如样品进行组合物的运输的说明。说明书可以以本领域技术人员可认知的任意形式进行提供,同时以任意方式提供包括这类说明的合适媒介物例如书写或出版的、口头的、可听的(例如用电话传送的)、数字的、光学的、 可视的(例如录像带、DVD等)或电子通讯(包括互联网或基于网络的通信)。
本文所用的“说明书”可以定义说明用途的组成部分(例如,指导、指南、警告、标志、注意事项、常见问题解答(FAQ)或者“常见问答”等),并且通常涉及与本发明和/或与本发明的化合物的封装有关或相关的书面说明。说明书也可以包括以任意方式提供的任意形式(例如、口头的、电子的、可听的、数字的、光学的、可视的等)的指导通讯,使得用户清楚地认识到说明书与本发明的化合物相关。
实施例
实施例1:(R),(R)-2,2’-二-MNTX的合成
在40mL的水∶甲醇∶三氟乙酸(94.9∶5∶0.1)中的(R)-MNTX(8.5g,0.0195mol)溶液和溴化铁(0.57g,1.95mmol)在冰/水浴中冷却。在30分钟的时间内向溶液中加入在10mL水中的过氧化氢(0.66g,0.0195mol)溶液。在冰浴中搅拌30分钟后,通过HPLC分析,溶液中含74%的(R)-MNTX和16%的(R),(R)-2,2’-二-MNTX。从冰浴中取出溶液并升温至室温。30分钟后,HPLC分析表明溶液中含44%的(R)-MNTX、27%的(R),(R)-2,2’-二-MNTX以及在更长保留时间处的2%的杂质。再一个小时后,HPLC分析表明溶液中含27%的(R)-MNTX、35%的(R),(R)-2,2’-二-MNTX和6.2%的杂质,外加其他杂质。
实施例2:(R),(R)-2,2’-二-MNTX的纯化
将反应混合物直接装载到制备性反相柱(Biotage 40M C18)上并用2.4L具有恒定TFA浓度、线性溶剂梯度的水∶甲醇(在12mL级分中,95∶5的水∶甲醇至82.5∶17.5的水∶甲醇)洗脱。级分通过HPLC进行分析,根据纯度将类似组成的级分合并成两份。在保持浴温低于34℃的同时,通过在抽吸压力下且随后在高真空下的旋转蒸发除去溶剂。
两份随后单独地均在使用2.4L线性梯度为95∶5∶0.1到70∶30∶0.1的水∶甲醇∶TFA的Biotage 40M C18柱上通过反相色谱法进行纯化。级分通过HPLC进行分析并且根据纯度合并成两份。在保持浴温低于34℃的同时,通过在抽吸压力下且随后在高真空下的旋转蒸发从不纯的级分中除去溶剂,并且再次进行如上所述的色谱分析,色谱分析总共重复4次。
合并纯的级分并且如上所述除去溶剂,得到1.0g如黄色玻璃的(R),(R)-2,2’-二-MNTX。通过用500mL的1M的HBr然后用4L的蒸馏水 进行洗脱,直至洗脱剂的pH大致为6为止,来制备Bio-Rad AG-1-X8离子交换柱(60g)。将产物溶于15mL的水∶甲醇(95∶5)中并且装载到新鲜制备的离子交换柱中。使用蒸馏水作为洗脱剂对产物进行纯化。产物在第一份100mL的蒸馏水中洗脱出来。合并级分,并且在维持在34℃的浴温下通过在抽吸压力下的旋转蒸发除去溶剂。所得的残余物在高真空线上干燥并且自10mL甲醇中结晶,在高真空干燥后得到产率为7.8%的黄色晶体(660mg,纯度>97%)。
观察到产物在中性水溶液中不稳定。当溶于d4-甲醇/D2O中时,产物转化为具有稍短保留时间的化合物。然而,当在水∶甲醇∶TFA(94.9∶5∶0.1)中储存过夜时,产物保持稳定。
使用本文所述的HPLC方法A,在Hewlett Packard 1100series上进行HPLC分析。
HPLC方法A:
柱:Phenomonex Intersil ODS-3柱(C18,5μ,150 X 4.6mm)
流速:1.5mL/分钟
柱温:50℃
检测器:二极管阵列检测器,在280nm监控
洗脱:线性梯度
时间(分钟) | %A | %B | %C | 曲线 |
0 | 0 | 90 | 10 | 初始 |
45 | 30 | 60 | 10 | 线性 |
45.1 | 0 | 90 | 10 | 线性 |
50 | 0 | 90 | 10 | 保持 |
A=甲醇
B=水
C=水∶甲醇∶TFA(49.5∶49.5∶1)
HPLC方法B:
在美国公布号US 2007-0099946A1(美国专利申请号11/441,395)中作为“HPLC方法II”描述了HPLC方法B。
Claims (73)
2.权利要求1的化合物,其中各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。
3.权利要求1的化合物,其中X或Y为除溴离子之外的卤离子、硫酸根、硝酸根、或有机物质。
4.权利要求1的化合物,其中X为羧酸根或磺酸根。
6.权利要求5的化合物,具有至少1%的纯度。
7.权利要求5的化合物,具有至少5%的纯度。
8.权利要求5的化合物,具有至少10%的纯度。
9.权利要求5的化合物,具有至少15%的纯度。
10.权利要求5的化合物,具有至少25%的纯度。
11.权利要求5的化合物,具有至少50%的纯度。
12.权利要求5的化合物,具有至少75%的纯度。
13.权利要求5的化合物,具有至少95%的纯度。
14.权利要求5的化合物,具有至少97%的纯度。
15.权利要求1到14中任一项的化合物,其中所述化合物为固体。
17.权利要求16的溶液,其中所述密封瓶含隔膜。
19.权利要求18的试剂盒,其中各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。
20.权利要求18的试剂盒,其中X或Y为除了溴离子之外的卤离子、硫酸根、硝酸根、或有机物质。
21.权利要求18的试剂盒,其中X为羧酸根或磺酸根。
22.权利要求18的试剂盒,其中所述标记指示所述化合物的纯度。
23.权利要求18的试剂盒,其中所述标记通过提供化学式或结构图指示所述化合物的化学结构。
24.一种合成权利要求1的化合物的方法,其包括:
使第一分子(R)-甲基纳曲酮与第二分子(R)-甲基纳曲酮在其量足以形成权利要求1的化合物的催化剂和氧化剂的存在下反应,其中X或Y为反离子并且其中X不是溴离子。
25.权利要求24的方法,其中各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。
26.权利要求24的方法,其中X或Y为除了溴离子之外的卤离子、硫酸根、硝酸根、或有机物质。
27.权利要求24的方法,其中X为羧酸根或磺酸根。
28.权利要求24的方法,其中所述催化剂以相对于所述第一分子(R)-甲基纳曲酮的量为25摩尔%以下存在。
29.权利要求24的方法,其中所述催化剂以相对于所述第一分子(R)-甲基纳曲酮的量为10摩尔%以下存在。
30.权利要求24的方法,其中所述氧化剂以相对于所述第一分子(R)-甲基纳曲酮的量为化学计算量存在。
31.权利要求24的方法,其中所述催化剂为溴化铁。
32.权利要求24的方法,其中所述氧化剂为过氧化氢。
33.权利要求24的方法,还包括分离作为固体的所述化合物。
34.权利要求24的方法,还包括通过色谱法或通过结晶法来提纯所述化合物。
35.权利要求34的方法,其中所述化合物通过反相色谱法、正相色谱法,和/或离子交换色谱法来提纯。
36.权利要求35的方法,其中所述化合物提纯为具有至少0.5%的纯度。
37.权利要求35的方法,其中所述化合物提纯为具有至少1%的纯度。
38.权利要求35的方法,其中所述化合物提纯为具有至少5%的纯度。
39.权利要求35的方法,其中所述化合物提纯为具有至少10%的纯度。
40.权利要求35的方法,其中所述化合物提纯为具有至少15%的纯度。
41.权利要求35的方法,其中所述化合物提纯为具有至少25%的纯度。
42.权利要求35的方法,其中所述化合物提纯为具有至少50%的纯度。
43.权利要求35的方法,其中所述化合物提纯为具有至少75%的纯度。
44.权利要求35的方法,其中所述化合物提纯为具有至少95%的纯度。
45.权利要求35的方法,其中所述化合物提纯为具有至少97%的纯度。
47.权利要求46的方法,其中各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。
48.权利要求46的方法,其中X或Y为卤离子、硫酸根、硝酸根、或有机物质。
49.权利要求46的方法,其中X为溴离子。
50.权利要求46的方法,其中X为羧酸根或磺酸根。
51.权利要求46的方法,其中所述测定包括比对所述第一HPLC色谱中的峰和所述第二HPLC色谱中的峰的保留时间,以确定所述化合物在所述样品溶液中的存在。
52.权利要求46的方法,其中所述测定包括量化所述HPLC色谱上的所述样品溶液的峰面积和所述参比溶液的峰面积并且据此估算所述化合物在所述样品溶液中的量。
53.权利要求46的方法,其中所述样品溶液含有(R)-甲基纳曲酮和/或(S)-甲基纳曲酮。
54.权利要求46的方法,其中所述样品溶液含有(R)-甲基纳曲酮和(S)-甲基纳曲酮的混合物。
55.权利要求46的方法,其中所述HPLC柱为反相柱并且所述柱使用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。
56.权利要求46的方法,还包括以书面形式备案所述化合物的化学特性和所述化合物作为杂质的量。
58.权利要求57的方法,其中各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。
59.权利要求57的方法,其中X或Y为卤离子、硫酸根、硝酸根、或有机物质。
60.权利要求57的方法,其中X为溴离子。
61.权利要求57的方法,其中X为羧酸根或磺酸根。
62.权利要求57的方法,其中所述样品溶液含有(R)-甲基纳曲酮。
63.权利要求57的方法,其中所述样品溶液含有(R)-甲基纳曲酮和(S)-甲基纳曲酮的混合物。
64.权利要求57的方法,其中所述HPLC柱为反相柱并且所述柱使用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。
65.权利要求57的方法,还包括以书面形式备案所述化合物的化学特性和所述化合物作为杂质的量。
67.权利要求66的方法,其中各X可以独立地为相同或不同的反离子,或者各X可以共价连接到其他X上。
68.权利要求66的方法,其中X或Y为卤离子、硫酸根、硝酸根、或有机物质。
69.权利要求66的方法,其中X为溴离子。
70.权利要求66的方法,其中X为羧酸根或磺酸根。
71.权利要求66的方法,其中所述样品溶液含有(R)-甲基纳曲酮。
72.权利要求66的方法,其中所述样品溶液含有(R)-甲基纳曲酮和(S)-甲基纳曲酮的混合物。
73.权利要求66的方法,其中所述HPLC柱为反相柱并且所述柱使用含有水、甲醇、三氟乙酸或其混合物的移动相进行洗脱。
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KR101581480B1 (ko) | 2015-12-30 |
US20130296570A1 (en) | 2013-11-07 |
US8916706B2 (en) | 2014-12-23 |
WO2009099411A1 (en) | 2009-08-13 |
KR20100110387A (ko) | 2010-10-12 |
CA2713568C (en) | 2016-09-20 |
CN101959892A (zh) | 2011-01-26 |
JP5358587B2 (ja) | 2013-12-04 |
JP2011511064A (ja) | 2011-04-07 |
EP2240489A1 (en) | 2010-10-20 |
AU2008349873A1 (en) | 2009-08-13 |
CA2713568A1 (en) | 2009-08-13 |
EP2730578A1 (en) | 2014-05-14 |
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AU2008349873B2 (en) | 2014-02-13 |
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