CN103351388A - 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法 - Google Patents

手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法 Download PDF

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CN103351388A
CN103351388A CN2013102642361A CN201310264236A CN103351388A CN 103351388 A CN103351388 A CN 103351388A CN 2013102642361 A CN2013102642361 A CN 2013102642361A CN 201310264236 A CN201310264236 A CN 201310264236A CN 103351388 A CN103351388 A CN 103351388A
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沃尔德马.弗兰格尔
索尔斯藤.帕彻
托马斯.尼古拉
阿迪尔.杜兰
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Abstract

本发明是关于制备对映异构体性纯8-(3-氨基-哌啶-1-基)-黄嘌呤的改良方法。

Description

手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法
本申请是中国发明申请(发明名称：手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法；申请日：2005年11月02日；申请号：200580037243.1)的分案申请。
技术领域
本发明涉及制备手性8-(3-氨基哌啶-1-基)-黄嘌呤、其对映异构体及其生理上可耐受盐的改良方法。
背景技术
下列通常结构的8-(3-氨基哌啶-1-基)-黄嘌呤
Figure BDA00003426599300011
其中R1为，例如任选取代的芳基甲基或任选取代的杂芳基甲基，R2为，例如烷基，及R3为，例如任选取代的苄基或直链或支链链烯基或炔基，已从国际专利申请案WO02/068420、WO04/018468、WO04/018467、WO2004/041820及WO2004/046148中得知，其中描述了具有有价值药理性质的化合物，其包括，特别是对酶二肽基肽酶IV(DPP-IV)活性的抑制作用。因此，此类化合物适合用于预防或治疗增加的DPP-IV活性相关的疾病或症状，或其可通过降低DPP-IV活性来预防或减轻疾病或症状，特别是I型或II型糖尿病或葡萄糖耐量的降低。
WO04/018468公开了一种制备方法，其中8-(3-氨基哌啶-1-基)-黄嘌呤是通过将相应的通式(II)的叔丁氧羰基保护的衍生物去保护来制备。
Figure BDA00003426599300021
在该方法中，杂质很难移除，特别是在工业级制备上会发生，这可归因于所用的保护基。因此，此方法不适合用于工业上制备8-(3-氨基哌啶-1-基)-黄嘌呤，特别是对纯度有严格要求的药品制备。再者，此方法在制备对映异构体性的纯的(enantiomerically pure)前体3-(叔丁氧羰基氨基)哌啶上具有复杂且昂贵的缺点。然而，由于副作用的风险及将剂量降至最低的考虑，对映异构体性纯的活性物质对医药的应用是优选的。这些情况对该现知的工业制备对映异构性纯8-(3-氨基哌啶-1-基)-黄嘌呤的适用性为不利的。
考虑了上述该已知制备方法的缺点，本发明的目的是提供一种使用易得的高化学纯及光学纯的起始物质，及无高技术成本及不便性下制备对映异构体性纯的8-(3-氨基哌啶-1-基)-黄嘌呤的方法。该新颖方法亦适用于工业级合成，因此可作为商业应用。
此目的可通过以本发明的方法制备手性8-(3-氨基哌啶-1-基)-黄嘌呤来达到。除了高产率的工业可行性外，绝佳的化学及光学纯度为本发明合成路径的其他的优点。
发明内容
根据本发明的方法，适当的黄嘌呤前体(III)是根据流程1的对映异构体性纯的或外消旋的(3-邻苯二甲酰亚氨基(phthalimido))-哌啶，在适当的溶剂中于20至160℃、优选为80至140℃的温度下反应。所用的溶剂，例如可为四氢呋喃(THF)、二
Figure BDA00003426599300022
烷、N,N-二甲基甲酰胺(DMF)、二甲基乙酰胺(DMA)、N-甲基-2-吡咯烷酮(NMP)或二甲基亚砜(DMSO)。优选的是使用NMP。随后以本身已知的方法将邻苯二甲酰基保护基除去。可能的除去方法是描述于，例如T.W.Greene的“Protective Groups in Organic Synthesis”,Wiley1981,第265页(例如溶于乙醇中的肼)。
在上述的化学式中，
X为离去基团，其是选自卤素，例如氟、氯或溴原子，或磺酸酯，例如苯基磺酰基氧基、对甲苯磺酰基氧基、甲基磺酰基氧基或三氟甲基磺酰基氧基的基团。
R1为苯基羰基甲基、苄基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，异喹啉基甲基、喹唑啉基甲基、喹喔啉基甲基、萘啶基甲基或菲啶基甲基，其中上述基团中的芳族或杂芳族基团在各情况下被Ra单或二取代，而该取代基可为相同或不同，及
Ra为氢、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、
甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，
或二个Ra基，当它们与相邻的碳原子键结时，还可为-O-CH2-O-或
-O-CH2-CH2-O-基，
R2为甲基、乙基、丙基、异丙基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苄基、2-氯苄基、2-溴苄基、2-碘苄基、2-甲基苄基、2-(三氟甲基)苄基或2-氰基苄基。
该方法优选的是用于这些化合物，其中
X为氯或溴原子，
R1为苯基羰基甲基、苄基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，异喹啉基甲基、喹唑啉基甲基、喹喔啉基-甲基或萘啶基甲基，其中上述基团中的芳族或杂芳族基团在各情况下被Ra单或二取代，而该取代基可为相同或不同，及
Ra为氢、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，
R2为甲基、乙基、丙基、异丙基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苄基、2-氯苄基、2-溴苄基、2-碘苄基、2-甲基苄基、2-(三氟甲基)苄基或2-氰基苄基基团。
该方法优选的是用于那些化合物，其中
X为氯或溴原子
R1为氰基苄基、(氰基吡啶基)甲基、喹啉基甲基，(甲基喹啉基)甲基、异喹唑啉基甲基、(甲基异喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹喔啉甲基、(甲基喹喔啉基)甲基、(二甲基喹喔啉基)甲基或萘啶基甲基，
R2为甲基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苄基、2-溴苄基或2-氰基苄基，
但特别是对化合物1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤、1-[(3-甲基异喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基哌啶-1-基)-黄嘌呤及1-[(3-氰基哌啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤，其中X为溴。
在各情况下优选的是使用(R)-3-(邻苯二甲酰亚氨基)哌啶作为试剂。式(III)化合物的制备已描述于上述引用的文献中，且可根据已知的方法来进行。
本发明还提供制备光学活性3-(邻苯二甲酰亚氨基)哌啶的方法。在此方法中，先将3-氨基吡啶根据已知的方法氢化。然后将由此得到的外消旋3-氨基哌啶通过邻苯二甲酸酐转变为相应的邻苯二甲酰亚胺。从外消旋、粗邻苯二甲酰亚胺(IV)溶液中通过D-酒石酸可选择性地沉淀出该(R)对映异构体。毋须先将原来存在母液中的过量的D-酒石酸移除，以简单方法通过添加L-酒石酸还可由盐沉淀的母液中得到(IV)的(S)对映异构体。
此极简单的式(IV)化合物的对映异构体的分离，令本领域技术人员非常惊讶。由氢化反应得来的外消旋碱不必预先纯化来达到此目的。该方法本身甚至在工业级制备仍无任何问题。
此外，3-氨基哌啶与邻苯二甲酸酐的出乎意料完全的反应本身令人惊讶，因为根据文献(例如美国专利4,005,208，特别是实施例27)，除了所需的产物外，混合物中预期会含有环上氮原子被酰化的衍生物。
Figure BDA00003426599300051
下列实施例将更详细的说明本发明：
实施例1：
3-(邻苯二甲酰亚氨基)哌啶的R对映异构体的D-酒石酸盐
a.氢化作用：
Figure BDA00003426599300052
将10.00kg(106.25mol)的3-氨基吡啶、500g工业级的活性炭及65升醋酸先装入氢化反应器中。将50g的Nishimura催化剂(市售的铑/铂混合催化剂)加入2.5升的醋酸中形成浆液并冲入（flush in）2.5升的醋酸。于50℃及100bar的氢气压下进行氢化，直到停止吸收氢气，及随后于50℃进行后氢化(post-hydrogenation)反应30分钟。将催化剂及活性炭滤出并以10升的醋酸洗涤。毋须纯化将产物溶液进行进一步的反应。
反应亦可在较不严格的压力下进行。
b.酰化作用
Figure BDA00003426599300061
先将15.74kg(106.25mol)的邻苯二甲酸酐装入反应器中。并与由氢化反应得来的滤液混合。将其冲入7.5升的醋酸并随后将反应混合物加热回流，在此期间一小时内，蒸馏出约30%所用的醋酸。将反应溶液冷却至90℃。毋须纯化将产物溶液进行进一步的反应。
c.旋光拆开
Figure BDA00003426599300062
将加热至50℃的11.16kg D(-)-酒石酸(74.38mol)的50升的无水乙醇溶液于90℃计量加入酰化反应溶液中。将其中冲入10升的无水乙醇并于90℃搅拌30分钟，在此期间产物结晶出。冷却至5℃后，将产物离心及以无水乙醇洗涤。毋须纯化将产物溶液进行进一步的反应。
d.重结晶
将湿的粗产物置于50升丙酮及90升水的混合物中加热回流直到溶液形成。随后，溶液冷却至5℃，在此期间有产物结晶出。将悬浮液于5℃搅拌30分钟，并将产物离心，最后用20升丙酮和10升水的混合物洗涤。将混合物在45℃在惰性条件下在干燥箱中干燥。
产率：11.7-12.5kg(理论值的29-31%)
实施例2
合成1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤
a.2-氯甲基-4-甲基喹唑啉
Figure BDA00003426599300071
先装入10.00kg(73.98mol)的2-氨基苯乙酮并加入24.5升的1,4-二
Figure BDA00003426599300073
烷。将溶液冷却至10℃，与引入的16.72kg(458.68mol)的氯化氢混合。将反应混合物加温至22-25℃。于此温度下再引入氯化氢。约至总引入量的一半时，混合物冷却至-10℃并继续引入。随后，将形成的悬浮液放置于-10℃下过夜。于-10℃，一小时内加入6.70kg(88.78mol)氯乙腈的2.5升1,4-二
Figure BDA00003426599300074
烷溶液。向原料容器(feed vessel)冲入2升的1,4-二
Figure BDA00003426599300075
烷。之后，将反应器的内容物加温至6℃并再搅拌约2小时。
先向另一反应器中装入122升水及62.04kg(775.31mol)氢氧化钠溶液(50%)的混合物并冷却至6℃。分次加入第一反应器的反应混合物。内部的温度不超过11℃。随后，首先将第一反应器用6升1,4-二
Figure BDA00003426599300076
烷冲洗，然后用6升的水冲洗。将生成的悬浮液于5℃再搅拌30分钟。将产物离心，以41升的水洗涤并于35℃在惰性条件下在干燥箱中干燥。
产率：10.5-12.1kg(理论值的74-85%)
b.1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤
Figure BDA00003426599300072
将10.00kg(33.66mol)的3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、7.13kg(37.02mol)2-氯甲基-4-甲基喹唑啉、3.92kg(37.02mol)无水碳酸钠及30升N-甲基-2-吡咯烷酮先装入反应器中。将反应器内容物加热至140℃并于140℃搅拌2小时。反应结束后，将反应混合物冷却至80℃并用60升的96%乙醇稀释，随后于70℃用55升的水稀释。于60℃，计量加入4.04kg(67.32mol)醋酸并冲入5升的水。将生成的悬浮液于60℃搅拌30分钟，然后冷却至23℃并再搅拌30分钟。随后将产物离心并先以20升96%乙醇及20升水的混合物洗涤，然后以40升96%乙醇及40升水的混合物洗涤。于45℃在惰性条件下(under inertization)在干燥箱中干燥。
产率：11.6-12.6kg(理论值的76-83%)
c.1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤
Figure BDA00003426599300081
将10.00kg(22.06mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、12.59kg(33.09mol)的3-(邻苯二甲酰亚氨基)哌啶D-酒石酸盐及17.5升的N-甲基-2-吡咯烷酮先装入反应器中。将反应器内容物加热至140℃。达到此温度后，于20分钟内计量加入11.41kg(88.24mol)的二异丙基乙胺。向原料容器中冲入2.5升的N-甲基-2-吡咯烷酮及随后将反应混合物于140℃搅拌2小时。反应结束后，将反应混合物冷却至60℃并以80升的甲醇稀释。将生成的悬浮液于50℃搅拌30分钟，然后冷却至23℃并再搅拌30分钟。随后将产物离心并各以20升的甲醇洗涤3次。于45℃在惰性条件下在干燥箱中干燥。
产率：12.0-12.5kg(理论值的90-94%)
d.1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤
Figure BDA00003426599300091
将1800kg(3mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤于18升的甲苯中加热至80-85℃。随后，于75-80℃将1.815升(30mol)的乙醇胺加到悬浮液中。将混合物于80-85℃搅拌2小时使反应完全，在此期间有固体进入溶液中。随后进行相分离。用温热的甲苯洗涤乙醇胺层二次(每次4升)。将合并的甲苯层每次各以8升的水于75-80℃洗涤二次。将22升的甲苯于减压下由甲苯层中蒸馏出。于40-50℃计量4升的叔丁基甲醚加至生成的悬浮液中并随后冷却至0-5℃。经过滤分离出产物，用叔丁基甲醚洗涤并抽真空干燥(suction dry)。之后将湿的粗物质与5倍量的无水乙醇加热回流并将该热溶液经活性炭过滤净化。将滤液冷却至20℃后，开始结晶，将其用叔丁基甲基醚稀释成二倍体积。将悬浮液冷却至2℃，另再搅拌2小时，抽滤并于45℃在真空干燥箱中干燥。
产率：1174g(理论值的83.2%)
步骤d的另一种方法：
将1400kg(2.32mol)的1-[(4-甲基喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤先置入4.9升的四氢呋喃中，随后加热至55-65℃。之后，将350ml的水及1433g(2.32mol)的乙醇胺加到悬浮液中。将混合物于60-63℃再搅拌3小时使反应完全。之后，加入619ml的45%的氢氧化钠溶液及3.85升的水，并将混合物于55-65℃搅拌30分钟，然后向反应混合物中加入5.6升的甲苯，将混合物搅拌15分钟，之后进行相分离。以2.8升的水于55-65℃洗涤有机层，随后分离。减压下从有机层蒸馏出4.2升。之后，于65-75℃加入1.4升的甲基环己烷，在此期间产物结晶。将悬浮液在15-25℃搅拌8-16小时，然后冷却至0-5℃。将产物过滤分离，用4.2升的甲基环己烷洗涤，抽真空干燥并于35℃减压干燥。随后将干燥的粗物质(991g)与5倍量的甲醇加热回流，加入活性炭并过滤混合物。将甲醇蒸馏出使滤液体积降至1.5升。将滤液冷却至45-55℃后，以叔丁基甲醚稀释成四倍体积。悬浮液冷却至0-5℃，搅拌2小时，抽滤、用叔丁基甲醚洗涤并于35℃在真空干燥箱中干燥。
产率：899g(81.9%的理论值)
实施例3
1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基-哌啶-1-基)-黄嘌呤
a.3-氰基-2-(氯甲基)-吡啶
将165.5g(0.98mol)的2-羟基甲基-3-吡啶甲酰胺(pyridinecarboxamide)与270ml的三氯氧化磷(phosphorus oxychloride)共同于90-100℃加热1小时。将反应混合物冷却至室温及随后于50-60℃逐滴加入约800ml的水。待三氯氧化磷水解后，冷却下以氢氧化钠溶液中和，在此期间沉淀出产物。将其过滤，以300ml的水洗涤及随后于35-40℃下干燥。
产率：122.6g(理论值的82%)
步骤a的另一种方法：3-氰基-2-(氯甲基)吡啶
将20.0g(131.45mmol)的2-羟基甲基-3-吡啶甲酰胺悬浮于110ml的乙腈中并加热至78℃。于15分钟内，计量加入60.65g(395.52mmol)的三氯氧化磷至混合物中并将混合物于81℃加热2小时。于22℃冷却后，将反应混合物置于200ml的水中于40℃下搅拌。加入100ml的甲苯后，以氢氧化钠溶液冷却下中和。进行相分离后，以100ml的水洗涤有机层。移出有机层并减压蒸发溶剂得到起初生成的油状残留物，将其静置使其结晶。
产率：16.66g(理论值的83%)
b.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤
Figure BDA00003426599300101
将202g(0.68mol)的3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、188.5g(1.36mol)的无水碳酸钾及1.68升的N-甲基-2-吡咯烷酮(pyrrolidone)先装入反应器中并加热至70℃。随后，逐滴加入119g(0.75mol)的2-氯甲基-3-氰基吡啶的240ml的N-甲基-2-吡咯烷酮(pyrrolidine)(NMP)溶液。将反应器内容物于70℃下搅拌19小时。待反应结束后，将2.8升的水加到反应混合物中并冷却至25℃。将产物过滤出，以2升的水洗涤并于70℃在惰性条件下在干燥箱中干燥。
产率：257.5g(理论值的91%)
c.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤
Figure BDA00003426599300111
将230g(0.557mol)的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-溴黄嘌呤、318g(0.835mol)的3-(邻苯二甲酰亚氨基)哌啶D-酒石酸盐及1.15升的N-甲基-2-吡咯烷酮先装入反应器中。将反应器内容物加热至140℃。待达到此温度后，在20分钟内计量加入478ml(2.78mol)的二异丙基乙胺，随后将反应混合物于140℃搅拌2小时。之后，将反应混合物冷却至75℃并以720ml的甲醇稀释，之后，于68-60℃加入2.7升水并将混合物冷却至25℃。将产物过滤出并以2升的水洗涤。于70℃在惰性条件下在干燥箱中进行干燥。
之后将得到的粗产物置于1升的甲醇中煮沸搅拌，热过滤，以200ml的甲醇冲洗，随后于70℃惰性条件下干燥。
产率：275g(理论值的88%)
d.1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-氨基哌啶-1-基)-黄嘌呤
Figure BDA00003426599300121
将412.5g(0.733mol)的1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-邻苯二甲酰亚氨基哌啶-1-基)-黄嘌呤于4125ml的甲苯中加热至80℃。随后于75-80℃将445ml的乙醇胺(7.33mol)加到悬浮液中。将混合物于80-85℃再搅拌2小时，使反应完全，在此期间有固体进入溶液中。之后，进行相分离。将乙醇胺相用温甲苯萃取二次(每次1升)。将合并的甲苯相于75-80℃以每次2升的水洗涤二次。用硫酸钠干燥甲苯相，过滤并随后于减压下蒸馏将体积降至约430ml。之后于50-55℃计量加入1升的叔丁基甲醚，然后将混合物冷却至0-5℃。将产物过滤分离，用叔丁基甲醚洗涤并于60℃在干燥箱中干燥。
产率：273g(理论值的86%)
熔点：188±3℃
类似实施例2及3，还制备出1-[(3-甲基异喹啉-1-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-氨基-哌啶-1-基)-黄嘌呤。

Claims (14)

1.一种制备通式(I)化合物或其对映异构体或其盐的方法
Figure FDA00003426599200011
其中R1为苯基羰基甲基、苄基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，异喹啉基甲基、喹唑啉基甲基、喹喔啉基甲基、萘啶基甲基或菲啶基甲基，其中上述基团中的芳族或杂芳族基团在各情况下被Ra单或双取代，而该取代基可为相同或不同，及
Ra为氢、氟、氯或溴原子或氰基、甲基、三氟甲基、乙基、苯基、甲氧基、二氟甲氧基、三氟甲氧基或乙氧基，
或二个Ra基，当与相邻的碳原子连接时，还可为-O-CH2-O-或-O-CH2-CH2-O-基，
R2为甲基、乙基、丙基、异丙基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苄基、2-氯苄基、2-溴苄基、2-碘苄基、2-甲基苄基、2-(三氟甲基)苄基或2-氰基苄基，
所述方法包括下列合成步骤：
a)将通式(III)的化合物与3-(邻苯二甲酰亚氨基)哌啶或其对映异构体反应，
Figure FDA00003426599200012
其中X为离去基团，其选自卤素或磺酸酯，及
R1至R3各如上述的定义，
b)将得到的通式(II)化合物去保护
Figure FDA00003426599200021
其中R1至R3各如上述定义，及
c)任选转变为生理上可耐受的盐。
2.根据权利要求1所述的方法，其中
X为氯或溴原子
R1为苯基羰基甲基、苄基、萘基甲基、吡啶基甲基、嘧啶基甲基、喹啉基甲基，异喹啉基甲基、喹唑啉基甲基、喹喔啉基甲基或萘啶基甲基，其中上述基团中的芳族或杂芳族基团在各情况下被Ra单或双取代，而该取代基可为相同或不同，及
Ra为氢、氟或氯原子或氰基、甲基、乙基、甲氧基或乙氧基，
R2为甲基、乙基、丙基、异丙基、环丙基或苯基及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氟苄基、2-氯苄基、2-溴苄基、2-碘苄基、2-甲基苄基、2-(三氟甲基)苄基或2-氰基苄基。
3.根据权利要求2所述的方法，其中
X为氯或溴原子
R1为氰基苄基、(氰基吡啶基)甲基、喹啉基甲基，(甲基喹啉基)甲基、异喹啉基甲基、(甲基异喹啉基)甲基、喹唑啉基甲基、(甲基喹唑啉基)甲基、喹喔啉甲基、(甲基喹喔啉基)甲基、(二甲基喹喔啉基)甲基或萘啶基甲基，
R2为甲基、环丙基或苯基，及
R3为2-丁烯-1-基、3-甲基-2-丁烯-1-基、2-丁炔-1-基、2-氯苄基、2-溴苄基或2-氰基苄基。
4.根据权利要求3所述的方法，其中
X为溴原子，
R1为(4-甲基喹唑啉-2-基)甲基，(3-甲基异喹啉-1-基)甲基或(3-氰基吡啶-2-基)甲基，
R2为甲基，及
R3为2-丁炔-1-基。
5.根据权利要求1至4中任一项所述的方法，其中用于步骤a)的反应物为(R)-3-(邻苯二甲酰亚氨基)哌啶。
6.一种制备(R)-3-(邻苯二甲酰亚氨基)哌啶的方法，其包括下列合成步骤：
a)将外消旋-3-氨基哌啶于适当的溶剂中与邻苯二甲酸酐反应，及
b)通过加入D-酒石酸并分离沉淀的酒石酸盐，从得到的外消旋-3-(邻苯二甲酰亚氨基)哌啶的溶液中分离出(R)-3-(邻苯二甲酰亚氨基)哌啶。
7.一种制备(S)-3-(邻苯二甲酰亚氨基)哌啶的方法，其包括下列合成步骤：
a)将外消旋-3-氨基哌啶于适当的溶剂中与邻苯二甲酸酐反应，及
b)通过加入L-酒石酸及分离沉淀的酒石酸盐，从得到的外消旋-3-(邻苯二甲酰亚氨基)哌啶的溶液中分离出(S)-3-(邻苯二甲酰亚氨基)哌啶。
8.一种制备(S)-3-(邻苯二甲酰亚氨基)哌啶的方法，其包括下列合成步骤：
a)将外消旋-3-氨基哌啶于适当的溶剂中与邻苯二甲酸酐反应，及
b)通过加入D-酒石酸并分离沉淀的酒石酸盐，从得到的外消旋-3-(邻苯二甲酰亚氨基)哌啶的溶液中分离出(R)-3-(邻苯二甲酰亚氨基)哌啶，及
c)将L-酒石酸加至由第一次盐沉淀所得到的母液中并分离出沉淀的(S)-3-(邻苯二甲酰亚氨基)哌啶酒石酸盐。
9.根据权利要求6至8中任一项所述的方法，其中用于步骤b)中的溶剂为乙醇。
10.(R)-3-(邻苯二甲酰亚氨基)哌啶。
11.(S)-3-(邻苯二甲酰亚氨基)哌啶。
12.下列通式的化合物，或其对映异构体，或其一种盐，
Figure FDA00003426599200041
其中R1至R3各如权利要求1至4定义，其可通过根据权利要求1至5中任一项所述的方法得到。
13.药物，其包含如权利要求12所述的化合物及任选一或多种惰性载体及/或稀释剂。
14.如权利要求12所述的化合物在制备适合治疗I型及II型糖尿病、糖尿病前期或葡萄糖耐量降低、关节炎、肥胖症、同种异体移植及降钙素引起的骨质疏松症的药物中的用途。
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