CN1443182A - 一种可降低二聚体杂质水平的提纯洛伐他汀和辛伐他汀的方法 - Google Patents
一种可降低二聚体杂质水平的提纯洛伐他汀和辛伐他汀的方法 Download PDFInfo
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- CN1443182A CN1443182A CN01808689A CN01808689A CN1443182A CN 1443182 A CN1443182 A CN 1443182A CN 01808689 A CN01808689 A CN 01808689A CN 01808689 A CN01808689 A CN 01808689A CN 1443182 A CN1443182 A CN 1443182A
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- mixture
- lovastatin
- solvent
- simvastatin
- alcohol
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- 229960004844 lovastatin Drugs 0.000 title claims description 54
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 title claims description 54
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Abstract
一种将抑制素中二聚体杂质含量降低到低于0.08％的方法，通过在一种合适的溶剂混合物中用一种温和碱处理含有多于0.08％二聚体杂质的抑制素。
Description
相关申请的交叉参考
本申请要求2000年3月3日提交的美国临时申请No.60/186868的优先权，其内容在此引入作为参考。
发明领域
本发明涉及一种提纯洛伐他汀或辛伐他汀的方法，其降低了终产品中二聚体杂质的水平。
发明背景
洛伐他汀及其类似物，例如辛伐他汀，是有效的抗高胆固醇血症的试剂，通过限制胆固醇的生物合成发挥作用。洛伐他汀是已知的降胆固醇试剂中最重要的一种。洛伐他汀(CAS注册号75330-75-5)也被称作美维诺林或莫纳可林K，其化学名称是β，β-二羟基-7-[1，2，6，7，8，8a-六氢-2，6-二甲基-8-(2-甲基-丁酰氧基)-1-萘-1-基]-庚酸β-内酯，分子式：
洛伐他汀
洛伐他汀，是一类化合物中的一种，其通常被称为抑制素，已知以开环羟基酸和内酯形式存在。洛伐他汀的内酯形式如上所示。
洛伐他汀及其类似物抑制3-羟基-3-甲基-戊二酸辅酶A还原酶(“HMG-CoA还原酶”)。HMG-CoA还原酶催化甲羟戊酸，一种胆固醇生物合成的早期中间体，的形成。洛伐他汀是非常有利的，这是由于应用它的结果是，形成于生物合成后期的具有有毒的类固醇骨架的生物合成中间体不能积累。洛伐他汀也可以增加细胞膜表面上的LDL受体的数量，其可以去除血液循环中的LDL胆固醇，因此降低了血浆中胆固醇的含量。
洛伐他汀常规地通过发酵生产。GB 2,046,737公开了洛伐他汀可以用一些属于红曲霉菌属的菌株，例如，通过在7到40℃培养红色红曲霉菌(M.ruber)1005生产。作为培养基，使用葡萄糖，蛋白胨，玉米浆和氯化铵的水溶液。在需氧状态下发酵10天，从5升肉汤培养基滤液中得到87毫克洛伐他汀。
美国专利4,294,926公开了洛伐他汀优选地生物合成的方法：在包含碳水化合物，例如，葡萄糖，果糖，麦芽糖作为碳源；氮源，例如，酵母，水解酵母，水解酪蛋白，玉米浆，和无机盐，例如，碳酸钙，硫酸镁，钴，铁，和锰盐的培养基上，在20-37℃下使用属于土曲霉菌种的保藏号为ATCC20541或20542的微生物。类似的方法在美国专利4,420,491；4,342,767；4,319,039和4,294,846中也有描述，其中，在包含1-6％碳水化合物和0.2-6％氮源的培养基上发酵3-5天。
德国专利4,402,591公开了洛伐他汀的生物合成方法：通过在25-35℃表面或浸没培养属于侧耳属的微生物，例如，糙皮侧耳(P.ostreatus)，紫孢侧耳(P.sapidus)和凤尾菇(P.saca)，培养时间为7-14天。
加拿大专利2,129,416公开了洛伐他汀的制备方法：用属于盾壳霉菌属的微生物，例如，保藏号为蔷薇盾壳霉菌(Coniothyriumfuckelii)ATCC 74227在包含3-15％葡萄糖，0.5-4％蛋白胨，0.5-5％淀粉酶，0.2-1％硫酸铵，0.01-0.1％硫酸镁，0.05-0.2％消泡剂，0.2-1.5％L-异亮氨酸，0.2-1.5％天冬氨酸的培养基上，在pH值为5-6之间培养。根据实施例，肉汤中活性成分的浓度为19-430毫克/升。
匈牙利专利HU 208,997公开了编号为MV-1，保藏号为NCAIM(P)F001189的主模式标本(holotype)菌株黑曲霉菌(Aspergillus obscurus)的应用。发酵优选在包含酵母浸出物和/或蛋白胨和/或酪蛋白作为氮源和葡萄糖和/或麦芽糖或蔗糖作为碳源的培养基上进行。在实验室规模培养的最后，肉汤的活性为400-850毫克/升。
辛伐他汀是洛伐他汀的一种合成类似物，其中8-酰基部分是2，2-二甲基丁酰。辛伐他汀是一种甚至比洛伐他汀更加有效的HMG-CoA还原酶抑制剂。辛伐他汀的化学名称是2，2-二甲基丁酸(4R，6R)-6-[2(1S，2S，6R，8S，8aR)-1，2，6，7，8，8a-六氢-2，6-二甲基-1-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1-萘基酯(CAS注册号79902-63-9)。辛伐他汀的化学结构如下：
辛伐他汀
注册号79902-63-9
辛伐他汀现在在一些市场上可以ZOCOR商品化得到。辛伐他汀的制备最初描述于美国专利4,444,784中。方法包括洛伐他汀的脱酰基化及随后用2，2-二甲基丁酰部分酰基化。如美国专利4,582,915和4,820,850所述，辛伐他汀也已经通过洛伐他汀酯部分的α烷基化来制备。
发酵完毕之后，洛伐他汀以内酯和酸的形式存在于肉汤中。抑制素的开环羟基酸形式是其有生物活性的形式。然而，抑制素一般是以内酯的形式给病人用药，其在体内被转化为它的活性代谢物羟基酸形式。因此，因为只有内酯形式才是有商业利益的，酸形式就通过一种叫做内酯化的过程转化为内酯形式。内酯化过程是一个平衡反应，由此开环的二羟基酸形式被转化为闭环的内酯形式。因为内酯化是一个平衡过程，为了达到内酯产物高的产率，必须采用一些方法使平衡向内酯方向移动。该平衡方程可以描述如下：
内酯化是一种分子内的酯化。导致二聚体形成和更高的寡聚体种类的分子间酯化与内酯化相竞争：
内酯化的方法为本领域所熟知并且许多这样的方法将在下面讨论。在洛伐他汀的内酯化或合成辛伐他汀之后，应用本领域熟知的结晶技术分离抑制素。
文献报道的游离羟基酸或其盐的内酯化方法或者在高温条件下进行，即用惰性溶剂回流，或者当内酯化在环境温度下进行时用强酸催化。美国专利4,820,850公开的方法包括：在高沸点烃类化合物溶剂如甲苯中加热游离酸或其盐，例如铵盐，至回流温度(通常100-110℃)7-8小时。在此高温下，酸的环境酸性据信是内酯化反应的主要因素。另外，作为反应副产物形成的水用共沸蒸馏不断的除去可以迫使反应接近完全(平衡向内酯方向移动)。在加热回流条件下的内酯化过程由于形成二聚体杂质而复杂化，这会降低最终内酯产物的质量。一旦形成，该二聚体杂质很难除去并且其经常占产物的0.4到0.08％。为了使二聚体形成最小化，在内酯化反应中经常采用高稀释度，代价是反应和过程的效率，这对工业化规模生产是不利的。
美国专利4,916,239公开了在室温下进行内酯化的方法：在强酸催化剂存在下，在乙酸和水的混合物中处理莫维诺林酸的游离铵盐。在游离羟基酸-内酯平衡建立之后(反应进行到50％转化率)，逐渐加入水，其用量足以将内酯从反应介质中结晶出来。从溶液中取出内酯有利于内酯的形成并因此促使内酯化作用完全。由于内酯不断从溶液中取出，二聚体的形成也最小化。该方法的缺点在于在大规模合成中不便使用强酸催化剂。强酸催化剂(例如，甲酸，磷酸，三氟乙酸，硫酸，盐酸，对-甲苯酸，磺酸，甲磺酸)的用量经常在1.2到1.5摩尔当量之间变化，难以操作并且造成环境不接受的处理问题，尤其是在工业化规模。此外，所使用的过量酸催化剂需要在过滤产物之前通过加入强碱中和掉。另外，内酯化反应在达到平衡后仅仅完成了大约50％。任何过快或过早地加入水都会导致严重的结晶和过滤问题。此外，反应及随后的处理工作需要大约9-12个小时才能完成，因此降低了方法的效率。
美国专利5,917,058公开了一种不用强腐蚀性酸和剧烈加热条件的内酯化方法。该方法包括：在惰性的无水环境中在室温或适度温度下用乙酸处理抑制素的开环羟基酸形式，优选其铵盐形式。乙酸既是溶剂又是催化剂。内酯化过程无需加入强酸催化剂。反应结束后通过加入反溶剂将内酯化的产物结晶分离出来。公开的反溶剂是水，己烷，庚烷，或环己烷。因为内酯化是一个平衡反应，反应副产物-水和氨必须被除去以使平衡向内酯方向移动。该方法中使用的乙酸原位消耗氨，导致形成乙酸铵。乙酸铵吸收另外一种副产物-水，因为它本质是吸湿的。据报道该方法产率达85-95％且纯度达95-98％。
美国专利5,939,564也公开了一种不用强腐蚀性酸的内酯化方法。在有机溶剂中无水条件下，盐形式的开环羟基酸被加热至从室温到溶剂回流的温度。该混合物随后在从室温到50℃的温度下用温和的催化剂处理。温和的催化剂是有机碱和无机或有机酸的盐，例如吡啶氢溴化物，吡啶盐酸盐，或吡啶对甲苯磺酸盐。内酯化产物然后通过加入水沉淀，最后从混合物中收集结晶的产物。该方法最多可制得98.7％纯度的洛伐他汀。
尽管上述各种内酯化方法降低了环境负担并提高了产率和纯度，但是这些方法仍然导致明显产生洛伐他汀二聚体。另外，在从洛伐他汀合成辛伐他汀的过程中，在内酯化过程中形成二聚体杂质。因此，仍然需要一种可以降低二聚体杂质水平的纯化方法。本发明正是解决这种需要的。
发明简述
目前已经发现通过用温和碱处理可以将二聚体杂质从洛伐他汀或辛伐他汀中除去，碱可以选择性地水解该二聚体但不会同时打开辛伐他汀或洛伐他汀的内酯环。
优选的温和碱包括脂肪族单或双或三胺，芳香族胺，氢氧化铵，氨气和上述试剂的水溶液。
使用本发明的纯化方法，可以得到包含低于约0.08％二聚体杂质的洛伐他汀或辛伐他汀。因此，本发明的另一个方面是提供化合物，含有低于约0.08％二聚体杂质的洛伐他汀和辛伐他汀。
发明详述
如上面所讨论，已知的合成辛伐他汀的方法或洛伐他汀的内酯化方法都会形成不想要的二聚体杂质。由于它们会和洛伐他汀及辛伐他汀共结晶，因此二聚体杂质很难去除。本发明提供一种洛伐他汀或辛伐他汀的纯化方法，其可以降低这些二聚体杂质的水平。本发明提供一种得到基本上纯内酯形式的纯化洛伐他汀或辛伐他汀的方法。本发明的方法可生产具有低于0.08％二聚体杂质的洛伐他汀或辛伐他汀。
本发明方法利用包含洛伐他汀或辛伐他汀的溶剂混合物在微碱性条件可以水解洛伐他汀二聚体或辛伐他汀二聚体和其他酯类杂质，而不会同时使内酯开环。一种0.4摩尔当量或更少的温和碱试剂被加到溶剂混合物中以得到碱性条件。优选的温和碱试剂包括脂肪族单或双或三胺，芳香族胺，氢氧化铵，氨气和上述试剂的水溶液和它们的混合物。最优选的温和碱试剂是氢氧化铵。
辛伐他汀或洛伐他汀的内酯形式(“抑制素内酯”)与羟基酸形式的溶解度有很大不同，因此可以被分开。洛伐他汀二聚体可被水解为洛伐他汀羟基酸，脱水洛伐他汀，和洛伐他汀内酯。脱水洛伐他汀与洛伐他汀的测定比例取决于水的量。水的量是受到限制的因为它有助于内酯形式的开环。抑制素内酯从溶剂混合物中回收。回收抑制素内酯可以用本领域熟知的方法通过从一种合适的溶剂中结晶出来。结晶可通过冷却用于水解内酯的溶剂混合物实现。或者，水解用溶剂混合物可以被蒸发，固体重新悬浮于结晶溶液中。优选结晶用溶剂包括乙酸异丁酯，乙醇，乙酸丁酯，乙腈，上述溶剂的混合物，乙醇和水的混合物，甲醇和水的混合物。优选的混合溶剂是乙酸异丁酯与乙醇以约3∶1混合。用乙醇和水结晶时，优选比例是0.8∶1.1。用甲醇和水结晶时，优选比例是0.7∶1.0。结晶优选在大约-20℃到大约+25℃之间进行。结晶更优选在大约-15℃到大约+15℃之间进行，最优选在大约-15℃到大约+5℃之间进行。
本发明另外的一个方面涉及用来纯化洛伐他汀或辛伐他汀的溶剂混合物。在本发明的一个方面，溶剂混合物包括一种醇和另一种或多种溶剂成分。溶剂混合物中的醇可以是任何一种烷基醇，芳香族醇，或这些醇的混合物。优选的醇包括，但不限于，甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇或它们的混合物。最优选的醇是甲醇和乙醇。本发明优选的溶剂混合物包含1-70v/v％的醇。更优选包含5-50v/v％的醇，最优选10-30v/v％的醇。
混合物中另外一种溶剂成分据信可以防止洛伐他汀或辛伐他汀水解或内酯开环。优选的溶剂成分，除了溶剂混合物中的醇以外，包括烷烃，烷基衍生物溶剂，和酯衍生物溶剂。优选的溶剂包括：二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，和丁基-甲基酮，乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，甲酸丙酯和它们的混合物。最优选的溶剂是醇类，例如甲醇和乙醇和乙酸酯，例如乙酸异丁酯，和乙酸乙酯。
本发明的另外一个优点是溶剂混合物比纯溶剂更容易溶解洛伐他汀和辛伐他汀并且也可以用于结晶。因此，本方法与本领域已知的以前的方法相比可以提高洛伐他汀和辛伐他汀的产率。
本发明的方法制备的洛伐他汀和辛伐他汀包含低于约0.08％的二聚体杂质。因此，本发明另外一个方面就是关于二聚体杂质含量低于0.08％的洛伐他汀和辛伐他汀化合物。
实施例买施例1
100-220克洛伐他汀(以其内酯形式)溶于1升以3∶1比例混合的乙酸异丁酯和乙醇的溶剂混合物中。该混合物加热到40-70℃。浓氢氧化铵溶液以1.0-2.0％(以活性物质计算)的比例加到该溶液中。溶液在40-85℃混合1-6小时，然后在1-3小时内冷却到20-30℃。在-5到+10℃悬浮液进一步冷却2-10小时。最后在-5到-20℃冷却15-24小时。产率为90％。HPLC分析显示洛伐他汀二聚体降低到了低于0.08％。
实施例2
100-220克辛伐他汀(以其内酯形式)溶于1升以3∶1比例混合的乙酸异丁酯和乙醇的溶剂混合物中。该混合物加热到40-70℃。浓氢氧化铵溶液(0.1-3.0％，以活性物质计算)被加到该溶液中。溶液在40-70℃混合1-6小时，然后在1-3小时内冷却到20-30℃。在-5到+10℃悬浮液进一步冷却2-10小时。最后在-5到-20℃冷却15-24小时。产率为90％。HPLC分析显示洛伐他汀二聚体降低到了低于0.08％。
实施例3
如上进行实施例1或2的方法，只是溶剂混合物改变如下。乙酸异丁酯被以下溶剂之一或其混合物代替：二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，环己酮和丁基-甲基酮，乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，甲酸丙酯或另一种酯。另外，乙醇被下面的一种醇或其混合物代替：烷基和芳香族醇，包括甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇。在40-85℃混合后真空蒸发掉水解用溶剂混合物。固体溶解于加热到50℃的20倍乙醇中。通过冷却到10-25℃并加入28倍水沉淀出抑制素。晶体被过滤并干燥。
实施例4
作如下修改进行实施例1或2的方法：氢氧化铵被一种脂肪族单-或二-或三胺或者芳香族胺或者上述胺的水溶液或者氨气代替。
实施例5
进行实施例1或2的方法，只是醇在溶剂混合物中占1-70v/v％。在5％乙醇含量时，产率是94％。HPLC分析显示洛伐他汀二聚体低于0.08％。
Claims (19)
1.一种降低洛伐他汀或辛伐他汀中二聚体杂质的方法，包括：
a)在一种溶剂混合物中溶解或悬浮含大于0.08％二聚体杂质的洛伐他汀或辛伐他汀；
b)用一种温和碱处理所述的溶液或悬浮液；和
c)分离包含低于约0.08％二聚体杂质的洛伐他汀或辛伐他汀。
2.权利要求1的方法，其中通过搅拌所述溶剂混合物或者混合所述溶液将所述温和碱加到所述溶剂混合物中。
3.权利要求1的方法，进一步包括通过结晶从所述溶剂混合物中分离洛伐他汀或辛伐他汀的步骤。
4.权利要求2的方法，其中所述搅拌或混合步骤在从约5℃到所述溶剂混合物的沸点温度下进行。
5.权利要求2的方法，其中所述搅拌或混合步骤进行1到10个小时。
6.权利要求3的方法，其中所述结晶在大约-20℃到+25℃温度下进行。
7.权利要求1的方法，其中溶剂混合物包含一种醇和另外一种溶剂成分。
8.权利要求7的方法，其中溶剂混合物包含醇的量为大约1-大约70v/v％。
9.权利要求7的方法，其中所述醇选自链烷醇，芳族醇或所述醇的混合物。
10.权利要求7的方法，其中所述醇选自甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇或它们的混合物。
11.权利要求7的方法，其中所述溶剂成分选自酯或酯混合物，乙腈，一种酯和其它溶剂成分的混合物，乙腈和其它溶剂成分的混合物，一种酯和乙腈的混合物，多种酯和乙腈的混合物，或酯和其它溶剂成分的混合物。
12.权利要求11的方法，其中酯选自乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，和甲酸丙酯及其混合物。
13.权利要求11的方法，其中溶剂成分选自二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，和丁基-甲基酮及其混合物。
14.权利要求1的方法，其中所述碱性试剂选自脂肪族单-或二-或三胺，芳香族胺，氢氧化铵，氨气，上述任何一种的水溶液，和它们的混合物。
15.包含低于约0.08％二聚体杂质的洛伐他汀，用权利要求1的方法制备。
16.包含低于约0.08％二聚体杂质的辛伐他汀，用权利要求1的方法制备。
17.一种制备选自洛伐他汀或辛伐他汀的抑制素的方法，包括：
a)将抑制素溶解或悬浮在一种溶剂中，该溶剂包含1-70％的醇，选自甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇和它们的混合物；和第二溶剂，选自二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，丁基-甲基酮，乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，甲酸丙酯；和所述溶剂的混合物；
b)添加一种温和碱，选自脂肪族单-或二-或三胺，芳香族胺，氢氧化铵，氨气，上述任何一种的水溶液，和它们的混合物；
c)处理该溶液；和
d)通过结晶或沉淀从所述溶剂混合物中分离洛伐他汀或辛伐他汀，在大约-20℃到+25℃。
18.用权利要求17的方法制备的洛伐他汀，含有低于约0.08％二聚体杂质。
19.用权利要求17的方法制备的辛伐他汀，含有低于约0.08％二聚体杂质。
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| US20070015779A1 (en) * | 2005-04-29 | 2007-01-18 | John Griffin | Compositions and treatments for inhibiting kinase and/or hmg-coa reductase |
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| CA2388182A1 (en) | 1999-10-27 | 2001-05-03 | Merck & Co., Inc. | Lactonization process |
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| IL151583A0 (en) | 2003-04-10 |
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| AU4183301A (en) | 2001-09-17 |
| DE01913139T1 (de) | 2005-03-31 |
| EP1265884A1 (en) | 2002-12-18 |
| TR200403001T3 (tr) | 2005-02-21 |
| EP1265884A4 (en) | 2003-05-21 |
| HUP0301214A2 (hu) | 2003-08-28 |
| SK13782002A3 (sk) | 2004-02-03 |
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| US6521762B2 (en) | 2003-02-18 |
| IS6533A (is) | 2002-08-29 |
| HRP20020730A2 (en) | 2004-12-31 |
| PL357533A1 (en) | 2004-07-26 |
| US20020002288A1 (en) | 2002-01-03 |
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| CZ20023201A3 (cs) | 2003-09-17 |
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