CN101443341A - 制造二膦酸的方法 - Google Patents
制造二膦酸的方法 Download PDFInfo
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- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
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- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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- C07F9/58—Pyridine rings
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- C07F9/02—Phosphorus compounds
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- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract
本发明提供用于制备二膦酸,特别是唑来膦酸的制造方法,其中使用二甘醇二甲醚、一甘醇二甲醚或其混合物来生产均质的、水溶性的固体反应物料,在冷却时,溶于水和进行洗提导致获得高纯度产物并具有比较好的产率。其中R1选自以下所组成的组。
Description
发明背景
本发明涉及用于制备二膦酸及其药理学活性盐,特别是通常被称为唑来膦酸的1-羟基-2-(咪唑-1-基)亚乙基-1,1-二膦酸的改进的工业方法。本文所描述的二膦酸适用于骨骼系统的疾病的治疗以及适用于在骨形成和/或钙代谢已经紊乱时的情况,例如骨移位的治疗。
本文所描述的二膦酸具有以下结构:
式中,M1、M2、M3和M4选自氢和一价阳离子,R1选自下面中的一种:
CH3 依替膦酸
米诺膦酸
伊班膦酸
美国专利4,939,130和4,777,163公开了用于制造二膦酸的方法,该方法基于由Kabachnick等人出版的[Izv.Akad.Nauk.USSR,Ser.Khim.,2,433-437,(1987)]已知方法。该合成基本上包括:将适合的ω-氨基酸与亚磷酸和氯化三磷(three phosphorus chloride)、三氯化磷、三氯氧化磷或五氯化磷中的一种的混合物进行反应,然后用水或非氧化性酸水溶液对反应混合物进行淬冷,之后加热以将磷中间产物水解为最终产物。
该方法的一个问题涉及反应熔体的固化。该方法从两相体系开始,该两相体系逐渐稠化成不能搅拌的物质。在加拿大专利2,018,477和2,044,923中也提及该问题,其中发明人利用甲磺酸使反应组分溶解,并且保持流体形式直到反应完成。不幸的是,甲磺酸与三氯化磷发生反应,并且在绝热条件下,该方法在85℃下自然发热,在>140℃下发生不受控的放热。
其它人也尝试利用各种溶剂体系来解决固化问题。例如美国专利6,201,148使用N-保护的衍生物和磷酸作为溶剂;US专利6,573,401描述了使用甲磺酸酐;公开的美国专利申请2005288509描述了使用包括铵、锍或膦盐的离子溶剂。然而,这些体系具有各种缺点,包括安全问题、高成本、产品污染、和/或附加的处理步骤。
在制备阿仑膦酸过程中解决固化问题的现有技术溶剂体系的另一实例是美国专利5,908,959,其描述了利用高分子量聚二醇或其衍生物的方法。然而,当使用该发明的方法时,其产率和纯度是令人不满意的低。
发明概述
因此,本发明提供用于制备二膦酸,特别是唑来膦酸的制造方法。尽管随后的描述具体涉及生产唑来膦酸,但是该方法可以通过选择适合的原料容易适于生产其它的二膦酸。
发明的详细描述
所述制造方法的第一步骤是由咪唑和叔氯乙酸丁酯制备叔丁基咪唑乙酸酯,这描述在US专利4,584,008中,在此通过适用法条允许的程度整体引入作为参考。
反应温度可以从约0℃到约100℃,或者从约50℃到约70℃范围内变化。反应物料可以搅拌和/或回流约1小时到约24小时。通常,每摩尔氯乙酸叔丁酯使用约0.5-5摩尔,或者约2-3摩尔的咪唑。在适合的惰性无机溶剂,例如氯仿中进行所述反应。可以用于该步骤的其它适合的惰性有机溶剂包括例如二氯甲烷、四氯化碳、苯、甲苯等及其互溶的混合物。
在完成后,将反应物料冷却到室温,在减压下萃取、清洗和洗提有机相,以制备叔丁基咪唑-1乙酸酯。
该制造方法的第二步骤是将叔丁基咪唑-1乙酸酯水解为咪唑-1乙酸。
通过溶解在约20-约40摩尔当量,或者约30-约35摩尔当量的水中并加热到约100℃,使叔丁基咪唑-1乙酸酯水解。分离副产物叔丁醇,并且在将反应混合物冷却到约室温时在真空下洗提反应混合物,而咪唑-1乙酸以固态产物形式保留。
咪唑-1乙酸的磷酸化是本发明方法的最终步骤,也是发生上述固化问题的步骤。不是通过试图保持反应物料的连续溶解性来解决固化问题,而是使用二甘醇二甲醚(1,2-二甲氧基乙烷)、一甘醇二甲醚(双(2-甲氧基乙基)醚)或它们的混合物以生成能够容易分散在水中的均匀固体物。
咪唑-1乙酸与约1-约5或者约2-约4摩尔当量的三氯化磷和约1-约2摩尔当量的磷酸混合。可以使用化学计量的磷酸。将反应物与足量体积的二甘醇二甲醚或一甘醇二甲醚进行混合,以确保咪唑-1乙酸基本上溶解,例如约1-约5摩尔当量,或者约2-约4摩尔当量。在约40-约80℃的受控温度下搅拌反应物料直到停止释放出氯化氢,之后反应物料在较高的温度,例如约60-约90℃下进行搅拌。在较高的温度下,形成不能再进行搅拌的固体均质物料,但进一步加热例如约1-约10小时以使产率最大化。
允许均质物料冷却到例如约室温或更低。然后缓慢添加水溶解均质物料,之后将溶液进行回流、冷却、洗提、在水中再次溶解直到所有固体溶解。然后可以通过常规方法即晶种结晶从获得的溶液中收集唑来膦酸。
实施例1
制备咪唑乙酸:
在50L反应器中装入氯仿(54kg)、咪唑(6.13kg,90.04mol)和氯乙酸叔丁酯(5.48kg,36.4mol)。在超过2小时使温度升高到60℃,在60℃下另外保温24小时。将反应物料冷却到室温。连续使用4份水(每份7.2kg)清洗氯仿相,以除去咪唑鎓盐和过量的咪唑。
添加水(15.1kg),使用迪安-斯塔克分离器(Dean-Stark trap)通过60-65℃的加热套温度(共沸混合物沸点为53℃)的蒸馏来除去氯仿,以回收水相。在除去氯仿后,反应器的加热套温度缓慢升高到115℃,在此期间叔丁醇和水进行共蒸馏(共沸混合物沸点为80℃)。在除去醇后,冷却水溶液,并且从反应器中排出,生成17.54kg的含有咪唑乙酸(通过NMR分析:3.77kg、29.9mol,产率82.2%)的溶液。
实施例2
分离咪唑乙酸:
将实施例1中的部分溶液(1.13kg)旋转蒸发,获得固体浆料(0.38kg),添加丙酮(234g)以完成结晶。将固体进行过滤、用丙酮清洗、用氮气流进行干燥。将蒸发器冷凝物再次蒸发、清洗和干燥以获得第二晶体产物;与第一结晶产物结合,以获得咪唑乙酸(通过NMR测定分析:219g,回收率91%,纯度98.9wt%)。1H NMR(D20):8.68(s,1H);7.42(s,2H);4.83(s,2H);4.79(br s,1H)。
实施例3
制备唑来膦酸:
在1.5升罐式反应器中装入咪唑乙酸(100g,0.793mol)、一甘醇二甲醚(400ml)和85%磷酸(55ml),该罐式反应器装备有加热套、机械搅拌器、滴液漏斗、热电偶和具有氮入口适配器的冷凝器。在反应物料中缓慢添加三氯化磷(330g,2.41mol),放出热量并产生氯化氢。允许温度升高到70℃,搅拌该溶液直到停止生成HCl。反应物料的温度升高到85℃,开始形成白色固体物,漂浮并粘附到搅拌器轴上。约1小时后,不可能再进行搅拌,搅拌发动机停止。将反应物料在85℃下加热5小时或更长时间,然后冷却到室温,生成固体均匀的白色物料。
在白色物料中缓慢添加水(320ml)导致放热并生成HCl。水以逐步和均匀的方式缓慢溶解物料,最终解放搅拌器。在物料基本上溶解后,回流该溶液5小时,然后冷却,通过旋转蒸发器洗提成粘胶(gum),收集420g水(pH0.65)。添加更多水(250ml),进行洗提,收集166g水(pH1.87)。再次添加水(250ml)并且洗提,收集316g水(pH2.14)。从旋转蒸发器移出烧瓶,添加水(150ml),将混合物加热到90-95℃,在此期间所有固体物溶解。在该溶液中下籽晶唑来膦酸一水合物晶体,并且缓慢冷却到室温,然后使用冰浴冷确到3℃。将所获得的结晶固体物进行过滤,用丙酮(200+100ml)进行清洗,在氮气流下干燥,获得52.4g的产量。也在滤液添加丙酮(200ml),将该溶液保留在冰箱中整夜,获得第二晶体产物(12.0g),用丙酮清洗后,干燥,与第一产物组合,总产率为64.4g(28%)。NMR表明具有痕量一甘醇二甲醚、丙酮和H3PO3杂质。
实施例4:
制备唑来膦酸:
5升圆柱形夹套反应器配备有机械搅拌器、热电偶、氮入口适配器和具有碱洗气器的冷凝器。在该夹套反应器中装入咪唑乙酸(0.333kg,2.64mol)和一甘醇二甲醚(1.001)。将该浆料加热到50℃,同时在缓慢的氮气吹扫下(1L/min)搅拌(100rpm)。在反应物料中添加另外的一甘醇二甲醚(0.26L)和85%磷酸(0.304kg)。在磷酸中水完全耗尽后,使用Masterflex泵和特富龙管,将三氯化磷(总共1.04kg,7.57mol)首先以缓慢速率(2ml/min)然后以增加的速率(40ml/min)泵吸到反应物料中。在添加PCl3过程中,温度升高到约65℃,白色物料逐渐形成,使得搅拌器被束缚。加热套温度升高到85℃,使PCl3回流。回流减速,然后在白色物料膨胀时停止。允许反应器在约80℃保温4小时,之后加热套温度设定在15℃整夜。
反应器管套温度升高到50℃,使用Masterflex泵缓慢(2-5ml/min)添加水。通过接触使水溶解白色物料,在放热反应中释放出HCl。在将约250g水添加到反应物料后,搅拌器未被束缚,重新开始搅拌(100rpm)。将水的添加速率缓慢增加到40ml/min。然后将反应物料在约100℃下加热4小时,然后冷却到室温。
取出反应物料,旋转蒸发以生成粘胶。在粘胶中添加水,洗提几次直到镏出液pH值高于1。获得的水溶液(1.2kg,1.6L)在烧杯中进行搅拌,缓慢添加丙酮(1.5L)。允许混合物静置16小时以完成结晶。过滤固体物,用丙酮彻底清洗,在氮气流中干燥,以获得未处理的唑来膦酸(0.202g,0.74mol,产率28%)。
实施例5
唑来膦酸一水化物的再结晶:
在装配有搅拌器、热电偶和氮适配器的3升管套烧瓶中装入水(1.5L)、64.4g未处理的唑来膦酸一水化物。将含水混合物加热到85℃,使所有固体溶解,获得pH值为1.7。向含水的混合物中添加无水乙醇(500ml)和唑来膦酸一水化物晶种,获得浆料,通过搅拌缓慢冷却。在38℃下,通过盐酸将pH值从3.7调节到1.7。在18℃下,将含水混合物的pH值调节至大于2。在0℃下搅拌该浆料约4小时,然后过滤固体物,用乙醇清洗(2×200ml),用氮气干燥,获得58.64g唑来膦酸一水化物。将该产物在50℃真空干燥烘箱中进一步干燥,1-2入口的氮气(1-2in,nitrogen),损失0.28wt%。NMR分析表明产物纯度为92.2wt%(基于无水干重)。Karl-Fischer滴定表明有6.46%水,相当于98.7%的唑来膦酸水合物,水和唑来磷酸摩尔比为1.06:1。1H NMR(D2O/NaOD):7.75(s,1H);7.23(s,1H);6.90(s,1H);4.82(O-H,7.35H);4.46(m,2H);31P(共轭H,D2O/NaOD):16.83(m)。
实施例6
(比较例)在PEG 400中制备唑来膦酸:
使用PEG-400(400ml)替代一甘醇二甲醚重复实施例3。在添加三氯化磷并且升高反应物料的温度之后,通过进一步加热形成最终返回到溶液中的固体物。唑来膦酸的产率是7%(分离产率)。1H NMR(D2O/NaOD):7.72(s,1H);7.22(s,1H);6.87(s,1H);4.82(O-H,7.02H);4.45(m,2H)。31P NMR(D2O/NaOD):17.0(m)。不仅产率显著降低,而且产物纯度也降低。
尽管已经以优选的实施方案方式描述了本发明的组成和方法,但是对本领域技术人员是显而易见的是,可以对组成、方法和/或过程进行变化,对此描述方法的步骤或步骤顺序进行改变,而没有脱离本发明的构思和范围。更具体地,某些化学和生理上相关的试剂可代替在此描述的试剂,而获得相同或相似结果也是显而易见的。所有这些对本领域技术人员显而易见的相似代替和改变认为在本发明的范围和构思内。
Claims (9)
2.用于制备唑来膦酸及其盐的方法,包括咪唑乙酸与选自磷酸、亚磷酸或者磷酸与亚磷酸的混合物的酸以及三氯化磷进行反应,其特征在于,在二甘醇二甲醚、一甘醇二甲醚或二甘醇二甲醚和一甘醇二甲醚的混合物中进行所述反应。
3.权利要求2的方法,其中,所述反应在约40℃-约90℃的温度下进行,该反应的特征在于:形成水溶性固体。
4.权利要求2的方法,其中,所述反应在约40℃-约80℃的起始反应温度下进行,并且升高到约60℃-约90℃的随后反应温度,该反应的特征在于:形成水溶性固体。
5.权利要求4的方法,其中,保持所述随后反应温度约1-约10小时。
6.权利要求5的方法,其中,三氯化磷的量在约1-约5摩尔当量范围内。
7.权利要求6的方法,其中,三氯化磷的量在约2-约4摩尔当量范围内。
8.权利要求5的方法,其中,使用化学计量比的酸。
9.权利要求5的方法,还包括将水溶性固体冷却到室温或低于室温;添加水以溶解所述水溶性固体;以及收集唑来膦酸产物。
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CN102372741A (zh) * | 2011-11-15 | 2012-03-14 | 海南锦瑞制药股份有限公司 | 一种唑来膦酸晶体及其冻干粉针剂 |
CN106699809A (zh) * | 2016-12-07 | 2017-05-24 | 河北仁合益康药业有限公司 | 一种唑来膦酸的合成工艺 |
CN107011380A (zh) * | 2016-01-28 | 2017-08-04 | 臧伟 | 一种二膦酸衍生物及含二膦酸衍生物的组合物治疗骨折的应用 |
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US8071574B2 (en) | 2005-02-22 | 2011-12-06 | John Dennis Bobyn | Implant improving local bone formation |
PT103600B (pt) * | 2006-11-06 | 2009-01-30 | Hovione Farmaciencia Sa | Processo para a preparação de ácidos biosfónicos e seus sais farmaceuticamente aceitáveis |
WO2008157050A1 (en) * | 2007-06-19 | 2008-12-24 | Albemarle Corporation | Processes for manufacturing bisphosphonic acids |
CN102124016A (zh) * | 2008-07-11 | 2011-07-13 | 斯索恩有限公司 | 制备1-羟基亚烷基-1,1-双膦酸的方法 |
PL213599B1 (pl) * | 2008-10-31 | 2013-03-29 | Politechnika Gdanska | Sposób otrzymywania kwasu [1-hydroksy-2-(1H-imidazol-1-ilo)-etylideno] bisfosfonowego |
US20160016982A1 (en) | 2009-07-31 | 2016-01-21 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
CA2769633C (en) | 2009-07-31 | 2017-06-06 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
US9340565B2 (en) | 2010-11-24 | 2016-05-17 | Thar Pharmaceuticals, Inc. | Crystalline forms |
HU230718B1 (hu) | 2011-02-08 | 2017-11-28 | Richter Gedeon Nyrt. | Új eljárás dronsavak gyógyszeripari előállítására |
US10195218B2 (en) | 2016-05-31 | 2019-02-05 | Grunenthal Gmbh | Crystallization method and bioavailability |
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TR200101250A2 (tr) * | 2001-05-10 | 2003-04-21 | E�S Eczaciba�I �Zg�N K�Myasal �R�Nler Sanay� A.�. | 4-amino-1-hidroksibutiliden-1,1-bifosfonik asit veya tuzlarının hazırlanmasına ilişkin proses |
DK1656386T3 (da) * | 2003-08-21 | 2010-04-19 | Sun Pharmaceuticals Ind Ltd | Fremgangsmåde til fremstilling af bisphosphonsyreforbindelser |
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CN102372741A (zh) * | 2011-11-15 | 2012-03-14 | 海南锦瑞制药股份有限公司 | 一种唑来膦酸晶体及其冻干粉针剂 |
CN102372741B (zh) * | 2011-11-15 | 2013-10-16 | 海南锦瑞制药股份有限公司 | 一种唑来膦酸晶体及其冻干粉针剂 |
CN107011380A (zh) * | 2016-01-28 | 2017-08-04 | 臧伟 | 一种二膦酸衍生物及含二膦酸衍生物的组合物治疗骨折的应用 |
CN106699809A (zh) * | 2016-12-07 | 2017-05-24 | 河北仁合益康药业有限公司 | 一种唑来膦酸的合成工艺 |
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