CN107001280A - 环肌酸及其类似物的合成 - Google Patents
环肌酸及其类似物的合成 Download PDFInfo
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- CN107001280A CN107001280A CN201580047429.9A CN201580047429A CN107001280A CN 107001280 A CN107001280 A CN 107001280A CN 201580047429 A CN201580047429 A CN 201580047429A CN 107001280 A CN107001280 A CN 107001280A
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Abstract
本文提供了在反应中使用氰胺的用于制备式(I)化合物或其药学上可接受的盐的方法。
Description
发明领域
本发明涉及用于制备应用于治疗肌酸转运蛋白缺乏的环肌酸和相关环状肌酸类似物的化学方法。
以下引用或依托的所有文献通过引用明确并入本文。
背景技术
环肌酸((2-亚氨基咪唑啉-1-基)乙酸)用于治疗肌酸转运蛋白缺陷。在该基因疾病中,突变影响肌酸转运蛋白,从而阻止肌酸穿越血脑屏障(BBB),导致脑中该重要氨基酸的缺乏。肌酸是一种极性小分子且需要主动转运以穿越BBB。相反,环肌酸由于其两个额外的亚甲基而更为亲脂,且能够通过被动扩散穿越BBB,因此用作肌酸替代物。
首先在Rowley,G.L.;Greenleaf,A.L.;Kenyon,G.L.J.Am.Chem.Soc.1971,93,5542-5551中报道了环肌酸的合成。随后在WO2006/073923中描述了使用药学上可接受酸的环肌酸盐的合成和表征。环肌酸的Rowley合成起始自N-羧甲基-1,2-乙二胺的钠盐。将该中间体维持在溶液中并与溴化氰的甲醇溶液反应以提供粗产物,通过过滤将其从反应混合物中分离。进行最终的从水中重结晶以提供纯化产物。
然而,Rowley合成受限于低的总产率。此外,在规模化生产中使用溴化氰(一种高毒性以及反应性化合物)需要严格的工艺控制。更具体地,溴化氰是一种具有显著蒸汽压的低熔点固体(mp=50-53℃,bp=61-62℃),并具有吸入、皮肤暴露和口服毒性。事实上,2.5μg/mL的血浆水平在小鼠中引起抽搐和死亡。
因此,在本领域中存在对于具有更低毒性并以更高产率提供产物以及具有更低商业成本的环肌酸及其类似物的新合成方法的需求。
发明概述
本发明涉及用于制备式(I)化合物:
或其药学上可接受的盐的方法,其包括使式(II)化合物:
与式(III)化合物:
反应的步骤,其中:
Y是CH2CO2H、CH2CONR1R2或CH2CO2R1;
R1、R2各自独立地是氢、低级烷基、C7-C12烷基或低级环烷基;且
n是1、2、3、4或5。
发明详述
本发明涉及以更高的总产率和改善的安全性制备环肌酸和其它环状肌酸类似物的改善的合成方法。氰胺是易于获得的化学商品,且毒性显著低于溴化氰。
以下随附说明中描述了本发明的细节。虽然描述了示例性的方法和材料,但在实践或测试本发明时可使用与本文所述那些相似或等同的方法和材料。本发明的其它特征、目标和优点将通过说明书和权利要求书体现出来。在说明书和所附权利要求书中,除非上下文另有明确指出,否则单数形式也包括复数。除非另有定义,否则本文使用的技术和科学术语具有与本发明所属领域普通技术人员通常理解的相同的含义。
本发明中使用以下定义:
本公开中使用的冠词“一”和“一个”(“a”和“an”)是指一个或多于一个(即,至少一个)的冠词语法对象。举例来说,“一个元素”是指一个元素或多于一个元素。
除非另有说明,否则在本公开中使用术语“和/或”表示“和”或者“或”。
“低级烷基”或“C1-C6烷基”是指包含1-6个碳原子的直链或支链饱和烃。低级烷基基团的实例包括但不限于,甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基和新戊基。
“C7-C12烷基”是指包含7-12个碳原子的直链或支链饱和烃。
术语“环烷基”是指包含3-6个碳原子的环状烃。环烷基基团的实例包括但不限于,环丙基、环丁基、环戊基和环己基。
应当理解,低级烷基、C7-C12烷基或环烷基上的任意可取代氢可独立地被一个或多个取代基(例如1个、2个或3个取代基)所取代。取代基的实例包括但不限于,卤素、C1-C3烷基、羟基、烷氧基、氧代和氰基。
“患者”是哺乳动物,例如人、小鼠、大鼠、豚鼠、狗、猫、马、奶牛、猪或非人灵长类,例如猴、黑猩猩、狒狒或猕猴,且术语“患者”和“受试者”在本文中可互换使用。
代表性的“药学上可接受的盐”包括例如,水溶性和非水溶性盐、例如醋酸盐、氨芪磺酸盐(4,4-二氨基芪-2,2–二磺酸盐)、苯磺酸盐、安息香酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、钙盐、依地酸钙盐、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、丙酸酯月桂硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐、六氟磷酸盐、己基间苯二酸盐、海巴盐、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、镁盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺盐、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(1,1-亚甲基-双-2-羟基-3-萘甲酸盐,einbonate)、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐、水杨酸盐、硬脂酸盐、次醋酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐、苏拉明酸盐(suramate)、单宁酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙基碘和戊酸盐。羧酸盐功能的另外的药学上可接受的盐形式包括锂盐、钠盐和钾盐。
当“治疗有效量”与环肌酸一同使用时,其是有效治疗或预防环肌酸调控的疾病或紊乱的量。
本领域普通技术人员将会理解,关于包含一个或多个取代基的任何基团,此类基团无意引入任何空间上不现实、合成上不可行和/或内在不稳定的取代或取代模式。此外,本文呈现的任何公式内的取代和/或变量的组合是允许的,只要此类组合得到稳定的化合物或有用的合成中间体,其中“稳定的”意味着生理条件下合理的药理相关性半衰期。
方案1
如以上方案I中所见,本发明提供了用于制备肌酸(7)各种环状类似物的方法,通过在适当溶剂中缩合二胺或其盐(6)和氰胺以得到7和氨或其盐。在本发明的一个实施方式中,6(X=H,Y=CH2CO2H,n=1)与氰胺在乙醇中于25-100℃下反应以得到7(X=H,Y=CH2CO2H,n=1)。二胺6可为纯化物质或者包含约20-95%6的混合物。在一些实施方式中,可通过从水或另一适当溶剂中结晶而进一步纯化产物7以得到化学纯度≥97%的7。7的替代实施方式可包括下式化合物:
或其药学上可接受的盐,其中R1、R2、R3、R4各自独立地可为氢、低级烷基或环烷基。
因此,在一个实施方式中,提供了用于制备式(I)化合物:
或其药学上可接受的盐的方法,其包括使式(II)化合物:
与式(III)化合物:
反应的步骤,其中:
Y是CH2CO2H、CH2CONR1R2或CH2CO2R1;
R1、R2各自独立地是氢、低级烷基、C7-C12烷基或低级环烷基;且
n是1、2、3、4或5。
在本发明的另一实施方式中,提供了用于制备式(I)化合物的方法,其中式(I)化合物括号内的碳任选被R3和R4取代,R3和R4各自独立地是氢、低级烷基或环烷基。
在本发明的另一实施方式中,提供了用于制备式(I)化合物的方法,其中n是1。
在本发明的另一实施方式中,提供了用于制备式(I)化合物的方法,其中式(I)化合物是环肌酸或其药学上可接受的盐。
在本发明的另一实施方式中,提供了用于制备式(I)化合物的方法,其中所述化合物是式(Ia)化合物:
或其药学上可接受的盐,其中:
Y是CH2CO2H、CH2CONR1R2或CH2CO2R1;
R1、R2、R3、R4各自独立地是氢、低级烷基、C7-C12烷基或环烷基。
在本发明的另一实施方式中,提供了用于制备式(I)化合物的方法,其进一步包括使乙二胺与氯乙酸反应以生产所述式(II)化合物的前体步骤。
在本发明的另一实施方式中,提供了用于制备式(I)化合物的方法,其中所述氰胺的浓度相对于氯乙酸的摩尔电荷为1-20摩尔当量。
实施例
通过以下实施例进一步描述本公开,其并非理解为将本公开的范围或精神限制至本文描述的具体步骤。应当理解的是,提供所述实施例以描述某些实施方式,并无意于限制本公开的范围。应当进一步理解的是,可采用各种其它实施方式、修饰及其等同物,而本领域技术人员能够在不脱离本公开的精神和/或所附权利要求的范围的情况下获得这些其它的实施方式、修饰及其等同物。
实施例1
在MTBE中制备中间体3
在500mL烧瓶中加入乙二胺(62.03g,1032mmol)。伴随磁力搅拌在22℃下经0.5小时加入氯乙酸(6.502g,68.80mmol)的甲基叔丁基醚(MTBE,30mL)溶液。加入期间内部温度升高至41℃。另外搅拌40分钟后,加入甲苯(100mL)并通过旋转蒸发浓缩混合物;再进行该程序两次并在高真空下进一步干燥所得残留物以得到16.4g粗产物。通过HPLC/MS评估,产物组成为3(37.3%)以及相应的二酸(62.7%)。
实施例2
在甲苯中制备中间体3
在具有塞子和磁力搅拌子的40mL小瓶中加入乙二胺(9.2g,153.7mmol)。在注射泵中加入氯乙酸(0.968g,10.24mmol)的PhMe溶液(总体积9.5mL)。将注射泵设置为以19.0mL/h的速率递送。在铝加热块中加热包含乙二胺的小瓶至70℃并在此时开始加入。加入(~30分钟)完成后,将小瓶自加热块移除并冷却至室温。通过移液管移除上清液并在高真空下蒸发残留物。残留物的HPLC/MS分析显示92.8%单酸3和7.2%二酸。
实施例3
由3和氰胺制备环肌酸
将实施例1中所述的3的粗批次的一部分(5.32g)以H2O(7.6mL)溶液的形式加入到具有搅拌子的100mL圆底烧瓶中。以固体形式加入固体氰胺(1.447g,34.41mmol)并将烧瓶配上回流冷凝器,置于70℃油浴中。搅拌20小时后,将混合物冷却至室温并将固体过滤,用H2O(2mL)洗涤并在高真空下干燥以得到粗环肌酸(1.161g,~23.5%产率)。该固体的HPLC/MS分析显示99.3%的环肌酸、0.7%的单酸3且无二酸。将粗产物(1.009g)加入小瓶并加入H2O(4.147g)。将混合物加热至沸腾,但这并未使得固体完全溶解。另外加入H2O(3.643g)并继续加热使其完全溶解(加入7.1mL/g水用于溶解)。加热3小时后冷却混合物并过滤所得固体,用H2O(2mL)洗涤。真空干燥得到纯环肌酸(0.498g,10.1%产率)。
实施例4
经由与氰胺反应制备环肌酸
在配有机械搅拌器的250mL烧瓶中加入乙二胺(28.08g,467.3mmol)并将烧瓶加热至70℃。将氯乙酸(2.944g,31.15mmol)的甲苯(28mL)溶液经30分钟加至反应。冷却混合物至环境温度并停止搅拌。移除包含甲苯和乙二胺的上层。将甲苯(15mL)加至反应并搅拌混合物。停止搅拌并移除上层。加入甲苯(15mL)并浓缩反应混合物。加入异丙醇(30mL),将混合物冷却至<0℃并维持3天。浓缩反应混合物并加入乙醇(20mL)。过滤所得浆料并用乙醇洗涤烧瓶和固体。通过高真空干燥固体以得到3(1.286g,27%)1H NMR(400MHz,D2O)δ3.32(s,2H),3.07(t,2H,J=6Hz),2.95(t,2H,J=6Hz)。通过NMR未检测到二酸异构体。在具有磁力搅拌子的40mL小瓶中加入化合物3(1.224g,7.918mmol)和水(8.7mL)。加入固体形式的氰胺(0.333g,7.918mmol)。将混合物加热至70℃并搅拌3.5小时。LCMS分析显示57%转化。加入更多氰胺(0.266g,6.327mmol)并在70℃下搅拌混合物24小时。将反应混合物冷却至0℃并过滤。用水(1mL)洗涤小瓶和固体。干燥固体以得到环肌酸2(0.655g,58%产率)。
实施例5
[(2-氨乙基)氨基]乙酸(3)的制备和分离
在配有磁力搅拌器、塞子和中隔的250mL三颈烧瓶中加入乙二胺(EDA,67mL,1003mmol)。在30mL注射器中加入氯乙酸(CSA,9.48g,100.3mmol)的DMSO溶液(总体积为26mL)。将注射器置于注射泵上,设置递送速度3.3mL/小时(总加入时间为8小时)。将注射器针头经由中隔***烧瓶并置于EDA液面下。在环境温度下进行加入。完成加入后在环境温度下搅拌反应混合物10小时。将反应混合物浓缩(60℃,~10毫巴)至47g。加入甲苯(50mL)并浓缩混合物以共沸EDA。加入更多甲苯(50mL)并将混合物浓缩至41g。加入DMSO(30mL),并在冰/水浴中冷却混合物30分钟。移除冷却浴并在环境温度下搅拌混合物30分钟。过滤混合物。相继用DMSO(50mL)、异丙醇(50mL)和甲基叔丁基醚(50mL)洗涤烧瓶和固体。真空干燥固体以得到白色粉末状的3(8.74g,62%)。1H NMR(400MHz,D2O)δ3.1 1(s,2H),2.90-2.70(m,4H)。MS[M+H]+m/z 119.1。
实施例6
由分离的3制备环肌酸2
在配有磁力搅拌器、回流冷凝器和塞子的250mL三颈烧瓶中加入3(8.74g,74mmol)和水(10mL)。加入氰胺溶液(4.4mL,50wt%水溶液)并在油浴中加热混合物至70℃4小时。停止加热并在环境温度下搅拌该混合物19小时。在冰/水浴中冷却混合物并搅拌2小时。过滤混合物并用冷水(5mL)洗涤烧瓶和固体。高真空下干燥固体以得到白色粉末状的2(2.88g,36%)。1H NMR(400MHz,D2O)δ3.78(s,2H),3.66-3.60(m,2H),3.57-3.51(m,2H)。MS[M+H]+m/z 144.1。
实施例7
制备环状肌酸类似物((2-亚氨基四氢嘧啶-1(2H)-基)乙酸)
将氯乙酸(1当量)的DMSO溶液经8小时时间加至丙-1,3–二胺(10当量)。通过真空蒸馏浓缩反应混合物并加入DMSO。将混合物冷却至0℃,然后加温回至环境温度。过滤所得浆料,并相继用DMSO、异丙醇和甲基叔丁基醚洗涤烧瓶和固体。干燥固体并将其溶入水中。加入氰胺(50wt%水溶液,1当量)并将混合物加热至70℃2小时。将反应冷却至0℃并过滤所得浆料。用水洗涤烧瓶和固体并干燥以得到8。
实施例8
替代实施方式
除了最终纯化以外,该合成与生产过程相似,其中进行两个额外的纯化操作:额外的水性浆料以及从水中重结晶。在第一步中,将氯乙酸(CAA,1)的DMSO溶液加至10倍摩尔过量的乙二胺(EDA,2)以得到单酸(3),其作为游离碱(或两性离子)被分离。在该缩合中产生一当量的HCl。第二步是将氰胺水溶液加至中间体单酸(3)中以在失去氨后获得环肌酸(5)。在生产过程中产物通过水浆料纯化。
方案1.制备环肌酸的参照标准
步骤1,运行1
制备[(2-氨乙基)氨基]乙酸3
在1L爱伦美氏烧瓶中加入CAA(1)(500.7g,5.30mol,1.0当量,Sigma-Aldrich)和DMSO(520.7g)。通过间歇性旋动烧瓶获得溶液。在配有氮入口、机械搅拌器、热电偶和蠕动计量泵的5L烧瓶中加入EDA(2,3182g,52.9mol)。开始冷却5L烧瓶(冰/水)。经由计量泵开始加入1的DMSO溶液。细节见表1。
表1.加入数据
过夜加入后传输线中仍残留一些溶液。将该溶液转移至5L烧瓶。通过旋转蒸发(53至60℃,10至21托)浓缩反应混合物以除去EDA。收集的馏出物总量为2376g。使用DMSO(3010g)作为洗液将残留物(1800g)转移回5L烧瓶。内部温度为27℃且该混合物变浑浊。开始冷却5L烧瓶(冰/水)。将混合物搅拌过夜。通过滤纸真空过滤所得悬浮液。过滤花费36分钟。用DMSO(507.6g,501.7g)洗涤烧瓶和固体两次。用异丙醇(IPA,448.4g,430.1g)洗涤固体两次。用甲基叔丁基醚(TBME,395.0g,406.3g)洗涤固体两次。在低真空(house vacuum)下采用氮气流在~35℃下干燥固体3天。回收的3(白色固体)为462.9g(3.92mol,74%)。1HNMR(400MHz,D2O)δ3.13(s,2H),2.89(表观t,2H,J=6Hz),2.76(表观t,2H,J=6Hz)。
步骤1,运行2
制备[(2-氨乙基)氨基]乙酸3
在1L爱伦美氏烧瓶中加入CAA(1)(499.1g,5.28mol,1.0当量,Sigma-Aldrich)和DMSO(528.9g)。通过间歇性旋动烧瓶获得溶液。在配有氮入口、机械搅拌器、热电偶和蠕动计量泵的5L烧瓶中加入EDA(2,3186g,53.0mol)。开始冷却5L烧瓶(冰/水)。经由计量泵开始加入1的DMSO溶液。细节见表2。
表2.加入数据
记录 | 时间 | 加入量,g | 温度,℃ | 加入速率,g/hr |
1 | 1343 | 0 | 14.6 | NA |
2 | 1358 | 40 | 12.4 | 160 |
3 | 1417 | 92 | 10.0 | 164 |
4 | 1458 | 208 | 11.1 | 170 |
5 | 1540 | 326 | 9.7 | 169 |
6 | 1610 | 404 | 9.5 | 156 |
7 | 0839(第二天) | 988 | 22.2 | NA |
过夜加入后传输线中仍残留一些溶液。将该溶液转移至5L烧瓶。通过旋转蒸发(53至60℃,10至21托)浓缩反应混合物以除去EDA。使用DMSO(3002g)作为洗液将残留物(2106g)转移回5L烧瓶。内部温度为26℃且该混合物变浑浊。开始冷却5L烧瓶(冰/水)。将混合物搅拌过夜。通过滤纸真空过滤所得悬浮液。过滤花费22分钟。用DMSO(498g,498g)洗涤烧瓶和固体两次。用IPA(384g,400g)洗涤固体两次。用TBME(360g,300g)洗涤固体两次。在低真空(house vacuum)下采用氮气流在~40℃下干燥固体22小时。回收的3(白色固体)为454g(3.84mol,73%)。1H NMR(400MHz,D2O)δ3.13(s,2H),2.89(表观t,2H,J=6Hz),2.76(表观t,2H,J=6Hz)。
步骤2
制备(2-亚氨基咪唑啉-1-基)乙酸(5)
在配有氮喷雾、回流冷凝器、机械搅拌器、热电偶和加热罩的5L烧瓶中加入化合物3(916g,7.75mol,1.00当量)和去离子水(918g)。加热所得浆料,目标温度为60℃。根据表3加入氰胺(4,50wt%水溶液,656g,7.80mol,1.01当量)。
表3.加入数据
60℃下搅拌反应3小时。LCMS分析显示消耗了3且不存在质量为160的中间体。关掉加热并允许反应伴随搅拌冷却过夜。通过滤纸真空过滤混合物。过滤花费1.3小时。用去离子水(302g)洗涤烧瓶和固体。将湿固体转移至洁净的5L烧瓶。加入去离子水(917.4g)并在环境温度下搅拌稠浆料2小时。通过滤纸真空过滤混合物(过滤花费45分钟)。用IPA(696.1g)洗涤烧瓶和固体。将湿固体转移至洁净的5L烧瓶用于第二浆料。加入去离子水(916g)并在环境温度下搅拌稠浆料2小时。通过滤纸真空过滤混合物(过滤花费1.3小时)。用IPA(380g)洗涤烧瓶和固体。在滤器上晾干产物1小时,然后在真空干燥箱(45℃,25Hg,2天)中干燥以得到白色固体状的5(543.9g,3.80mol,49%)。1H NMR(400MHz,D2O)δ3.53(s,2H),3.62-3.55(m,2H),3.53-3.46(m,2H)。
重结晶(2-亚氨基咪唑啉-1-基)乙酸(5)
在配有回流冷凝器、机械搅拌器、热电偶和加热罩的5L烧瓶中加入两次重悬的化合物5(141.8g)和去离子水(1414.5g)。加热所得浆料,目标温度为100℃。当温度达到99.1℃时,所有固体看起来已溶解。通过滤纸真空过滤所得热溶液。约5分钟后滤液中开始形成固体。经23.5小时将所得悬浮液冷却至环境温度。通过滤纸真空过滤悬浮液。用去离子水(104.7g)洗涤烧瓶和固体。在真空干燥箱(~40℃,~27Hg)中干燥固体21.2小时,直至达到恒定重量。回收的5为113.9g(80.3%)。
实施例9
制备环肌酸的替代实施方式
制备[(2-氨乙基)氨基]乙酸3
通过将1(500.0g,5.29mol,1.0当量)溶解在DMSO(515.6g)中制备氯乙酸(1)的溶液。在配有氮入口、机械搅拌器、热电偶和蠕动计量泵的5L烧瓶中加入乙二胺(2,EDA,3537mL,52.9mol)。开始冷却(冰/水)。经由计量泵开始加入1的DMSO溶液。加入时间、温度和残留体积见表1。
表1
记录 | 时间 | 温度,℃ | 1的残留体积 |
1 | 10:51 | 17 | |
2 | 11:28 | 18 | |
3 | 12:18 | 16 | 720 |
4 | 13:38 | 11 | 625 |
5 | 14:35 | 12 | 550 |
6 | 15:17 | 10 | 490 |
7 | 16:08 | 8 | 420 |
8 | 8:59(第二天) | 19 | 0 |
通过旋转蒸发(50至60℃,14至21托)浓缩反应混合物以除去EDA。收集的馏出物总量为2400mL。将甲苯(900mL)加至残留物并通过旋转蒸发(60℃,30托)浓缩混合物以共沸任何残留的EDA。使用DMSO(3kg)作为洗液将残留物转移回5L烧瓶。内部温度为28℃且该混合物变浑浊。开始冷却(冰/水)。将混合物搅拌过夜。通过滤纸过滤所得悬浮液。过滤花费25分钟。用DMSO(2x 500mL)洗涤烧瓶和固体。用异丙醇(IPA,2x 500mL)洗涤固体。用甲基叔丁基醚(TBME,2x 500mL)洗涤固体。在高真空和环境温度下干燥固体18小时。回收的3(白色固体)为480.4g(59%)。NMR分析显示92.4mol%3、6.4mol%EDA和1.1mol%EDA的N,N'-二乙酸。1H NMR(400MHz,D2O)δ3.13(s,2H),2.89表观t(2H,J=6Hz),2.76(表观t,2H,J=6Hz)。
制备(2-亚氨基咪唑啉-1-基)乙酸(5)
在配有氮入口、回流冷凝器、机械搅拌器、热电偶和加热罩的5L烧瓶中加入化合物3(478.4g,4.05mol,1.00当量)和去离子水(484.5g)。在环境温度(22℃)下搅拌所得浆料。一次性加入氰胺(4,50wt%水溶液,340.5g,4.05mol,1.00当量)。加入***液使得内部温度降低至15℃。反应混合物变为溶液。开始加热。目标温度为40℃。22分钟后内部温度升至62℃。停止加热。表2显示了放热和反应的进展。
表2
记录 | 时间 | 温度,℃ |
1 | 9:28 | 15 |
2 | 9:50 | 62 |
3 | 9:56 | 70 |
4 | 10:01 | 80 |
5 | 10:08 | 84 |
6 | 11:48 | 71 |
7 | 13:05 | 70 |
LCMS分析显示消耗了3且不存在质量为160的中间体。关掉加热并在冰/水浴中冷却反应。将混合物搅拌过夜。通过滤纸过滤混合物。过滤花费25分钟。用去离子水(150mL)洗涤烧瓶和固体。将湿固体转移至配有机械搅拌器的2L烧瓶。加入去离子水(450mL)并在环境温度下搅拌稠浆料3小时。通过滤纸过滤混合物(过滤花费45分钟)。用IPA(450mL)洗涤烧瓶和固体。在滤器上晾干产物1小时,然后在真空干燥箱(40℃,25Hg,3天)中干燥以得到白色固体状的5(248.9g,56%)。1H NMR(400MHz,D2O)δ3.53(s,2H),3.62-3.55(m,2H),3.53-3.46(m,2H)。
***
应当理解的是,本发明不限于以上所述的本发明特定实施方式,因为可进行特定实施方式的变化,并仍落入所附权利要求的范围内。
Claims (7)
1.一种用于制备式(I)化合物:
或其药学上可接受的盐的方法,所述方法包括使式(II)化合物:
与式(III)化合物:
反应的步骤,其中:
Y是CH2CO2H、CH2CONR1R2或CH2CO2R1;
R1、R2各自独立地是氢、低级烷基、C7-C12烷基或低级环烷基;且
n是1、2、3、4或5。
2.根据权利要求1所述的方法,其中所述式(I)化合物括号内的碳任选被R3和R4取代,所述R3和R4各自独立地是氢、低级烷基或环烷基。
3.根据权利要求1所述的方法,其中n是1。
4.根据权利要求1所述的方法,其中所述式(I)化合物是环肌酸或其药学上可接受的盐。
5.根据权利要求2所述的方法,其中所述化合物是式(Ia)化合物:
或其药学上可接受的盐,其中:
Y是CH2CO2H、CH2CONR1R2或CH2CO2R1;
R1、R2、R3、R4各自独立地是氢、低级烷基、C7-C12烷基或环烷基。
6.根据权利要求1所述的方法,其进一步包括使乙二胺与氯乙酸反应以生产所述式(II)化合物的前体步骤。
7.根据权利要求6所述的方法,其中所述氰胺的浓度相对于所述氯乙酸的摩尔电荷为1-20摩尔当量。
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Cited By (1)
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CN107529753A (zh) * | 2015-03-11 | 2018-01-02 | 卢莫斯制药公司 | 环肌酸及其类似物的合成 |
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JP2017525748A (ja) | 2017-09-07 |
AU2015312159B2 (en) | 2019-03-07 |
WO2016036699A1 (en) | 2016-03-10 |
EP3194370A1 (en) | 2017-07-26 |
EP3194370A4 (en) | 2018-01-24 |
US10493062B2 (en) | 2019-12-03 |
IL250846A0 (en) | 2017-04-30 |
CA2959387A1 (en) | 2016-03-10 |
AU2015312159A1 (en) | 2017-03-16 |
US20170273950A1 (en) | 2017-09-28 |
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