CN101133066A - 从母液中回收cci-779 - Google Patents
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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Abstract
本发明提供一种从母液回收CCI－779的方法。
Description
发明背景
本发明涉及从母液中回收CCI-779。
CCI-779(与3-羟基-2-(羟甲基)-2-甲基丙酸的雷帕霉素(rapamycin)-42酯)是雷帕霉素的酯，其在体内和体外模型对于肿瘤的生长显示出重要的抑制效应。CCI-779结合到细胞质蛋白FKBP并与其一起形成复合物，其抑制一种酶，mTOR(雷帕霉素的哺乳动物靶，也就是已知的FKBP12-雷帕霉素联合蛋白[FRAP])。对mTOR激酶活性的抑制抑制了多种信号转导途径，包括细胞因子刺激的细胞增殖，用于调节细胞周期G1阶段的若干关键蛋白质的mRNA转译，和IL-2诱导的转录，导致抑制从G1到S的细胞周期进程。CCI-779在多种应用上显示出有效性，包括抑制中枢神经***癌症、白血病、乳腺癌、***癌、黑素瘤、神经胶质瘤和成胶质细胞瘤。
制备和使用雷帕霉素的羟基酯，包括CCI-779，公开在美国专利No.5362718中。美国专利No.6277983描述了CCI-779的区域选择性合成(regioselective synthesis)。但是，所得CCI-779的收率仅在70-80％范围内。在美国公开专利No.US2005-0033046A1中依然描述了其他区域选择性合成。为了获得用于临床应用的晶体产品，CCI-779的重结晶是必要的。
需要一种方法从作为CCI-779结晶副产物得到的母液中回收额外的结晶CCI-779。
发明概述
本发明提供一种从母液中回收CCI-779的方法。该方法包括浓缩母液、用缓冲液处理浓缩的CCI-779、干燥和浓缩有机层、和优选从醚中重结晶CCI-779。
在另外的实施方案中，从该方法获得的母液被用于该方法从而获得附加的收率。在其他实施方案中，该方法重复多次。
本发明的其他方面和优点从下面的发明详述中显而易见。
发明详述
本发明提供一种从母液中回收CCI-779的新方法。
CCI-779(与3-羟基-2-(羟甲基)-2-甲基丙酸的雷帕霉素-42酯)能够以下面方案2所示的两种异构体形式存在。
按照本发明从母液中回收的CCI-779通常包含大约95重量％的CCI-779异构体B和大约3重量％的异构体C。
如这里所用，术语联合收率或总联合收率指从所有重结晶步骤回收的总CCI-779，包括通过传统技术的初始重结晶和通过本发明的方法从母液中回收的CCI-779。
在一实施方案中，CCI-779是按照美国专利No.5362718所述制备的。在另一实施方案中，CCI-779是按照美国公开专利No.US2005-0033046A1所述制备的。
在另一实施方案中，CCI-779从雷帕霉素42-酯与2，2，5-三甲基[1.3-二烷]-5-羧酸的酸解获得。在一实施方案中，使用硫酸，随后进行硅胶色谱法来实现。美国专利No.6227983(Shaw等)描述了该酸解。此处方案1概括了酸解过程。酸解后，通过传统技术实现重结晶。在一实施方案中，采用醚进行重结晶。通常，重结晶得到的CCI-779具有大约30∶1到大约35∶1的B∶C异构体比率范围，和大约70％到大约80％，或大约72％到76％的收率范围。在一实施方案中，从重结晶得到的CCI-779具有大约32∶1的B∶C异构体比率和大约74％的收率。
方案1
雷帕霉素42-酯与 雷帕霉素42-酯与
2，2，5-三甲基[1，3-二烷] 2，2-双-(羟甲基)丙酸
-5-羧酸(WAY-130159) (CCI-779)
重结晶过程的副产物是含有额外CCI-779的母液。通常，重结晶后母液中存在的CCI-779的含量为产品的20％或更多。在一实施方案中，25-26％的CCI-779产品存在于母液中。此外，在这些母液中的CCI-779包含比通常在CCI-779中发现的更高比例的CCI-779异构体C，即，更低的B∶C比率。在一实施方案中，母液中B∶C异构体比率在大约1.5∶1到3∶1，大约1.5∶1到2.5∶1，大约2∶1或大约1.6∶1范围内。
与结晶CCI-779相反，母液中出现更高百分比的异构体C表明异构体C在结晶溶剂中有更高的溶解度。尽管不希望被理论所束缚，相信异构体C比异构体B少结晶，导致母液中异构体C的存在增加。申请者已经发现为了从母液中回收额外的收率，通过改变pH值可以增加异构体比率。方案2说明了希望的异构体转化。
方案2
异构体B 异构体C
从结晶CCI-779得到的母液，如上所述，首先减压浓缩。所得的泡沫与缓冲体系，即，pH调节缓冲液(缓冲溶液)和溶剂合并。在一实施方案中，缓冲液的pH值为大约5到6.5。在另一实施方案中，缓冲液的pH值为大约5到5.5。
在一实施方案中，缓冲溶液包含醋酸钠。在其他实施方案中，缓冲溶液包含醋酸钾或醋酸锌。在其他实施方案中，缓冲溶液包含醋酸钠、醋酸钾，和/或醋酸锌的混合物。在一实施方案中，溶剂为有机溶剂。在另外的实施方案中，有机溶剂是丙酮。在其他实施方案中，有机溶剂是四氢呋喃、乙腈或乙酸。在其他实施方案中，溶剂是溶剂的混合物，例如，丙酮、四氢呋喃、乙腈和/或丙酸的混合物。在一实施方案中，溶剂和缓冲液的体积比率为1.5-1.1∶1.0之间。在另一实施方案中，体积比率是1.1∶1.0。其它用来调节pH的缓冲体系、溶液、溶剂和体积比率为本发明所预期，为本领域的技术人员所知。
混合缓冲体系(即，缓冲溶液和溶剂)和来自母液的残留泡沫的溶液。在一实施方案中，溶液在大约20到25℃，氮气下混合24小时。在其他实施方案中，溶液被混合48小时。为了最大化异构体B对异构体C的比率，时间长度可调。在另一实施方案中，在混合过程中该比率被监控，例如，通过HPLC。
在混合之后，通过传统的方法分离产品。在一实施方案中，混合物用乙酸乙酯稀释并用盐水溶液洗涤。然后用水和盐水洗涤有机层(或合并的有机层)。有机层然后被硫酸钠干燥并减压浓缩，生成泡沫。其他的产品分离方法应为该领域技术人员所知，并为本发明所预期。分离产品的方法包含加入有机介质以形成有机层。分离后，泡沫通过传统技术被重结晶，所述传统技术例如为沉淀。在一实施方案中，泡沫从醚中重结晶。在此外的实施方案中，所述醚是二***，或叔丁基甲基醚。作为用于此处重结晶的溶剂，也可使用乙腈，醚与和己烷或庚烷的混合物，或叔丁基甲基醚与己烷或庚烷的混合物。在进一步的实施方案中，所述醚为二***。在一实施方案中，例如，可在真空下通过传统技术干燥沉淀的CCI-779。
在一实施方案中，重结晶的CCI-779具有大于约30∶1的B∶C异构体比率。在其他实施方案中，重结晶的CCI-779具有约45∶1，或大约49∶1，或更大的B∶C异构体比率。在进一步的实施方案中，重结晶的CCI-779具有大约55∶1，或大约57∶1，或更大的B∶C异构体比率。
在其他实施方案中，使用从所述方法得到的母液来重复该方法以获得期望的CCI-779总收率。在一实施方案中，通过本发明的方法实现的总联合收率为大约90％，或大约95％，或更大。在其他实施方案中，实现的总联合收率为大约98％，或更大。下面的方案3说明这一方法。
方案3
下面的实施例是本发明的示例性说明，但不局限于此。
实施例
从母液回收CCI-779
通过向合适的容器中加入400mL水，然后加入5.5g醋酸钠并搅拌形成溶液来制备醋酸盐缓冲液(pH5-5.5)。向该溶液中加入0.05M醋酸(300mL)并搅拌形成醋酸盐缓冲液(pH5-5.5)。向2L的烧瓶中加入600mL丙酮，然后加入545mL醋酸盐缓冲液(pH5-5.5)。搅拌混合物形成均匀溶液的1.1∶1丙酮-醋酸盐缓冲液(pH5-5.5)。
向1L烧瓶中加入500g CCI-779母液(二***溶剂)(化验包含7.9％CCI-779，异构体比率B∶C＝1.6∶1)。母液减压浓缩得到49.85g泡沫产品。泡沫溶于750mL 1.1∶1丙酮-醋酸盐缓冲液，在20-25℃氮气下混合至少24小时，并用HPLC监控反应过程。一天后，经后处理的(work-up)样品的B∶C比率为8.1∶1和48小时后为9∶1。两种异构体比率在48小时后保持不变。
用1200mL乙酸乙酯稀释反应混合物并用300mL盐水洗涤。水层被分离并用300mL乙酸乙酯萃取。有机层被合并，并用水(300mL)和盐水(300mL)洗涤。有机层用硫酸钠干燥，然后减压浓缩得到45.45g浅黄色泡沫产品。泡沫从醚(180mL)中重结晶。产品在真空烘箱中于50-55℃干燥至恒重得到22.5g白色结晶固体产品，其纯度93.2％(异构体B+C)和异构体比率B∶C＝57∶1。回收收率为57％。
减压浓缩母液得到19.5g亮黄色泡沫产品，B∶C异构体约3.3∶1。用300mL丙酮-醋酸盐缓冲液在20到25℃处理泡沫48小时。用450mL乙酸乙酯稀释反应混合物并用150mL盐水洗涤。水层被分离并用150mL乙酸乙酯萃取。有机层被合并，用水(200mL)和盐水(200mL)洗涤，经硫酸钠干燥。减压浓缩后得到17.24g亮黄色泡沫产品，B∶C异构体比率为9∶1。该物质可以从醚中重结晶，以获得更多的结晶CCI-779，如工艺循环中所描述。
所有的专利、出版物和其他此处标明的文件都作为参考引入。本领域的技术人员应该意识到对在这里描述的特定实施方案中描述的条件和技术进行小的修改变动，而不会背离本发明。这样的小修改和变动在根据下面权利要求限定的本发明的范围内。
Claims (15)
1.一种从母液中回收CCI-779的方法，包含：
(a)浓缩母液；
(b)用具有pH范围为大约5到大约5.5的pH调节缓冲液来进行对通过浓缩母液得到的CCI-779的处理；
(c)对混合物进行溶剂萃取；
(d)干燥和浓缩得到的有机层；和
(e)重结晶CCI-779。
2.根据权利要求1所述的方法，其中用从步骤(e)得到的母液来重复步骤(a)到(d)。
3.根据权利要求2所述的方法，其中最后的联合收率超过95％。
4.根据权利要求2所述的方法，其中最后的联合收率超过98％。
5.根据权利要求1到4任意一项所述的方法，其中pH调节缓冲液包含醋酸钠、醋酸钾或醋酸锌。
6.根据权利要求5所述的方法，其中pH调节缓冲液包含醋酸钠。
7.根据权利要求1到6任意一项所述的方法，其中pH调节缓冲液使用丙酮、四氢呋喃、乙腈或醋酸作为溶剂。
8.根据权利要求7所述的方法，其中pH调节缓冲液使用丙酮作为溶剂。
9.根据权利要求1到8任意一项所述的方法，其中醚被用于重结晶。
10.根据权利要求1到6任意一项所述的方法，其中二***、叔丁基甲基醚、乙腈、醚与己烷或庚烷的混合物，或叔丁基甲基醚与己烷或庚烷的混合物作为溶剂用于重结晶。
11.根据权利要求10所述的方法，其中溶剂是二***。
12.根据权利要求1到11任意一项所述的方法，进一步包含步骤：
(f)沉淀CCI-779；和
(g)真空干燥CCI-779。
13.根据权利要求1到12任意一项所述的方法，其中所述由此产生的CCI-779具有大于30∶1的B∶C异构体比率。
14.根据权利要求1到12任意一项所述的方法，其中所述由此产生的CCI-779具有大于45∶1的B∶C异构体比率。
15.根据权利要求1到12任意一项所述的方法，其中乙酸乙酯作为溶剂用于溶剂萃取。
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| WO2007067560A2 (en) * | 2005-12-07 | 2007-06-14 | Wyeth | Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate |
| KR20080077147A (ko) * | 2005-12-07 | 2008-08-21 | 와이어쓰 | 결정성 라파마이신의 제조 방법 및 시차 주사 열량계를사용하는 라파마이신 화합물의 결정화도의 측정 방법 |
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| US5362718A (en) * | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
| US6277983B1 (en) | 2000-09-27 | 2001-08-21 | American Home Products Corporation | Regioselective synthesis of rapamycin derivatives |
| BRPI0412659A (pt) | 2003-07-16 | 2006-09-26 | Wyeth Corp | isÈmero c de cci-779, seu processo de preparação, composição farmacêutica compreendendo o mesmo e pacote farmacêutico contendo o referido composto |
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| TW200643023A (en) | 2006-12-16 |
| CR9325A (es) | 2008-01-21 |
| NO20074101L (no) | 2007-09-26 |
| KR20070107072A (ko) | 2007-11-06 |
| PE20061293A1 (es) | 2006-12-22 |
| AU2006218916A1 (en) | 2006-09-08 |
| JP2008531685A (ja) | 2008-08-14 |
| CA2599580A1 (en) | 2006-09-08 |
| MX2007010715A (es) | 2007-10-12 |
| ZA200707526B (en) | 2010-02-24 |
| GT200600095A (es) | 2006-10-25 |
| IL185078A0 (en) | 2007-12-03 |
| AR053151A1 (es) | 2007-04-25 |
| WO2006093743A1 (en) | 2006-09-08 |
| US7288647B2 (en) | 2007-10-30 |
| EP1853611A1 (en) | 2007-11-14 |
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