CN1053893C - 二甲酰胺的制备方法 - Google Patents

二甲酰胺的制备方法 Download PDF

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CN1053893C
CN1053893C CN95104245A CN95104245A CN1053893C CN 1053893 C CN1053893 C CN 1053893C CN 95104245 A CN95104245 A CN 95104245A CN 95104245 A CN95104245 A CN 95104245A CN 1053893 C CN1053893 C CN 1053893C
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M·索库普
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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Abstract

从相应的N-取代的天冬氨酸和相应的胺G-NHCH(X，Y)开始，通过相应的N-取代的唑烷酮和N，N-取代的天冬氨酸酯制备式1的二甲酰胺的方法，式I中A，G，L，Q，X和Y具有说明书中给出的含意。

Description

二甲酰胺的制备方法
本发明涉及一种新的制备式I的二甲酰胺的方法。
Figure C9510424500041
其中A   是-S(O)2R1，-S(O)2N(R2，R3)或-C(O)R4，R1 是芳基、杂芳基、杂环基、烷基或环烷基，R2和R3是H，低级烷基或芳基低级烷基或R2和R3与N原子一起构
  成可被O或S选择性间断开的-N(CH2)4-9，R4 是R10，-OR40或NHR40，而R40是可被芳基、杂芳基或环烷基选择性取代的低级烷基，或R4 是可被低级烷氧羰基、-O-(芳基、杂芳基或环烷基)或-
S-(芳基、杂芳基或环烷基)取代的低级烷基，G   是H、低级烷基、低级链烯基、芳基、杂芳基、环烷基、芳基
 -低级烷基、杂芳基-低级烷基或环烷基-低级烷基，X    是H、低级烷基、芳基、环烷基、芳基-低级烷基或环烷基-
 低级烷基，或G和X，与所连接的N原子和C原子一起，形成苄氨基或环状基团
 -N(CH2)4-9，后者可被O或S选择性地间隔开并且可被选
 自低级烷基、-C(O)O-低级烷基和-CH2O-苄基的至多
 2个取代基选择性地取代，Y    是H、低级烷基或通过低级亚烷基选择性键合的Y1基，Y1  是COOH、COO-低级烷基、低级烷酰基、低级烷酰氧基、低
 级烷氧基、芳基-低级烷氧基、CONH2、CONHOCH3、CONHO-
 苄基、CONHSO2-低级烷基、CONHCH2CH2-芳基、CONH-
 环烷基、CONHCH2-杂芳基、杂芳基或C(O)N(CH2)4-0，
 后者可被O或S选择性地间隔开并且可被选自低级烷基、
 COO-低级烷基和CH2O-苄基的至多2个取代基选择性地
 取代，Ra和Rb是H、低级烷基或苯基，L    是H、低级烷基或低级烷氧基羰基-低级烷基，Q    是Q1或Q2 T   是CH2或O，该方法包括a)使天冬氨酸与式A-Cl的化合物反应，b)使得到的式II酸二酸
与甲醛反应，
c)使得到的式III的噁唑烷酮
Figure C9510424500062
与式IV的胺反应
Figure C9510424500063
其中Y是H，低级烷基或可通过低级亚烷基选择性键合的Y1
基，而G，X和Y1如上，限制性条件是Y1不是COOH，d)使得到的式V的酸
Figure C9510424500071
与式H2NCH2-Q的胺反应，和e)若需要式I的酸(其中Y是可通过低级亚烷基选择性键合的COOH基)，则使得到的式I的低级烷基酯水解。
式I的化合物是EP 0468231 A3和EP 0559046 A1中记载的已知化合物。它们具有有价值的药理学特性，能够用于防治疾病。
本说明书中所用的术语“低级”是指含有1～6个，优选1～4个C原子的基团。因此，低级烷基(单元或结合)表示含有1-6个，优选1-4个C原子的直链或支链基团如甲基、乙基、丙基、异丙基、丁基、叔丁基、2-丁基和戊基。优选的低级烷基是烷基R1。链烯基的实例是烯丙基。“芳基”表示选择性地具有1个或多个取代基如卤素，例如氯，或低级烷基或烷氧基，例如CH3，叔丁基，OCH3，苯基，CF3，OCF3，环戊基，COOCH3，COOC2H5，CONH2或四唑基的基团如苯基和1-或2-萘基。“杂芳基”是由1或2个环构成的并且含有1个或多个N和/或O原子的5元或10元芳基。其实例是2-，3-或4-吡啶基，也可以其N-氧化物、四唑基、噁唑基、吡嗪基和喹啉基的形式存在。它们可被例如低级烷基如CH3或卤素如氯所取代。“环烷基”含有3-8个C原子。其实例是环丙基、环戊基和环己基。可被O选择性间隔开的四至五亚甲基亚氨基N(CH2)4-9的实例是六氢氮杂草代和吗啉代。
在步骤a)中，在对甲苯磺酸存在下，使天冬氨酸，优选L-天冬氨酸的水溶液(在碱如碱金属氢氧化物，优选NaOH中)与磺酰氯或式A-Cl的酰氯反应，方便的是在水和非极性溶剂如乙酸乙酯、己烷或甲苯中，在至60℃的温度下进行。
磺酰胺或甲酰胺II环化为噁唑烷酮III的步骤b)方便的是在酸，优选对甲苯磺酸存在下，在非极性溶剂如甲苯中，在低于回流的温度下用仲甲醛进行的，随后进行H2O分离。
步骤c)中所用的胺IV可通过使胺G-NH2与溴化物BrCH(X，Y)反应来制备。方便的是在碱如三乙胺存在下，在非质子传递溶剂如己烷中，在低于回流的温度下进行制备。
步骤c)可在非质子传递溶剂如乙酸乙酯中，在不高于80℃的温度下，优选在60℃下进行。
步骤d)中所用的胺H2NCH2-Q可按照EP 0468 231 A3中所述的方法进行制备。其中Q是N-脒基哌啶基Q1(T＝CH2)的胺也可通过3-氨基甲基-哌啶由3-吡啶甲基胺如下制备：
例如在水中，用铑/氧化铝催化剂可催化氢化3-吡啶甲基胺。可将得到的3-氨基甲基-哌啶溶于水和低级链烷醇如2-丙醇(含有(L)-O，O-二苯甲酰酒石酸)。然后使生成的3-氨基甲基-哌啶-(L)-O，O-二苯甲酰酒石酸酯转化成二盐酸盐(例如加入盐酸)。为了选择性保护伯氨基，可在三丁胺存在下，在甲醇中使得到的3-氨基甲基-哌啶-二盐酸盐与乙酰乙酸甲酯反应。生成的3-(3-哌啶基-甲基氨基)-2-丁烯酸甲酯然后可在三丁基胺存在下，在非质子传递或质子传递溶剂中，优选的是在低级链烷醇，例如甲醇或乙醇中，或在DMF或DMSO中，在不高于回流温度的温度下，优选的是在室温下与1-脒基-1，2，4-***盐酸盐进行N-脒化反应。脒化中所用的脒基***盐可通过在盐酸存在下在非极性溶剂如二噁烷中使1，2，4-***与氨基氰反应而制得。
酰胺形成步骤d)可用肽合成中已知的偶联试剂，特别是二环己基碳化二亚胺(单独或在催化量的例如N-羟基琥珀酰亚胺存在下)进行。
选择性水解步骤e)可在质子传递溶剂，例如乙醇中，用碱，例如NaOH进行。实施例A)起始材料的制备A′)1.a)在0.51高压釜中加入100g 3-吡啶甲基胺，100ml水和5g5％铑/氧化铝。脱气并建立40巴的内部氢压之后，在50℃下加热并搅拌反应混合物4小时。冷却至室温并用惰性气氛冲洗之后，将反应液转入21烧瓶中并用水冲洗高压釜。在减压下将得到的3-氨基甲基-哌啶水溶液蒸发至525g的重量，用198.9g(L)-O，O-二苯甲酰酒石酸处理后冷却至28℃。A)1.b)为了结晶得到的(L)-O，O-二苯甲酰酒石酸酯，在搅拌下慢慢加入112-丙醇。搅拌18小时后，滤集结晶，用2-丙醇洗涤，最后在高真空、45℃下干燥。在75℃、搅拌下将残余物溶于400ml水。将此溶液冷却至28℃，然后用112-丙醇在搅拌下处理3小时。在室温下搅拌过夜后，滤集结晶，用2-丙醇洗涤，最后在高真空、45℃下干燥，得到193.9g(44.4％)(S)-3-氨基甲基-哌啶-(L)-O，O-二苯甲酰酒石酸酯，m.p.146-148℃(分解)，[α]D 25＝-86.2℃(C＝1，水)。A)2.在1.51烧瓶中加入41.4g 1，2，4-***，25.3g氨基氰和600ml二噁烷。搅拌所得溶液并加热至回流。在1小时内加入150ml4.15N HCl二噁烷溶液之后，将反应混合物在回流下进一步搅拌1.5小时。将悬浮液缓慢冷却至室温，然后搅拌1小时。将产物过滤，用二恶烷洗涤并在40℃、高真空下干燥，得到85.9g 1-脒基-1，2，3-***盐酸盐，m.p.198-199℃。A)3.a)在2.51烧瓶中加入100g A)1.b)的L-O，O-二苯甲酰酒石酸酯产物，500ml水和11乙酸乙酯。在室温下搅拌反应混合物并用80ml 25％HCl处理。搅拌15分钟后，分离有机相并用水萃取。合并水相，用乙酸乙酯反萃取，然后减压蒸发。将残余物溶于乙醇和甲苯的混合物并在减压下再次蒸发。为了除去剩余的痕量水，重复此溶解和蒸发步骤，得到36.6g(92.4％)(S)-3-氨基甲基-哌啶二盐酸盐。[α]D 25＝-3.6℃(C＝1，水)。A)3.b)在1.51烧瓶中加入36.6g A)3.a)的二盐酸盐，300ml甲醇，93.3ml三丁基胺和23.2ml乙酰乙酸甲酯。将悬浮液在室温下搅拌5小时。随着反应的进行，二盐酸盐缓慢溶解，得到清澈的溶液。加入46.7ml三丁基胺和28.9gl-脒基-1，2，4-***盐酸盐之后，将反应溶液在室温下搅拌18小时，然后在室温下，在15分钟内用65.2ml浓盐酸处理，随后再搅拌45分钟。减压蒸发反应混合物。向残余物中加入300ml乙醇，将悬浮液在回流下搅拌30分钟，在室温下搅拌过夜。将悬浮液冷却至0℃，搅拌2小时后，滤集结晶，用乙醇洗涤并在室温下真空干燥。将粗物料悬溶于乙醇中，将混合物回流并搅拌30分钟，然后冷却至室温并搅拌1小时。滤集结晶，用乙醇洗涤，在室温下真空干燥，得到31.94g(70％)(S)-1-脒基-3-氨基甲基-哌啶二盐酸盐的无色结晶，m.p.245-247℃，[α]D 25＝-17.4℃(C＝1，水)。A)4.在室温下向137ml环丙基胺和456ml三乙胺的21己烷混合物中慢慢加入180ml溴代乙酸乙酯。在回流下加热所得悬浮液2小时。冷却至室温后，过滤沉淀物(三乙胺盐酸盐)用己烷洗涤结晶并蒸发滤液。随后蒸馏油状残余物，得到191.3gN-环丙基-乙基甘氨酸酯(81％，纯度96.GC)。B)方法C)1.将140g(L)-天冬氨酸和14g对甲苯磺酸溶于525m14N NaOH并将溶液冷却至室温。在室温下将227g 2-萘磺酰氯的500ml乙酸乙酯溶液滴加到反应混合物中。将此混合物温热至33-44℃并搅拌过夜，通过加入410ml 4N NaOH维持PH10。冷却至室温后，进行相分离，用4N NaOH洗涤有机相。合并水相，用乙酸乙酯洗涤，然后用230ml浓HCl酸化至PH1并用乙酸乙酯萃取产物。乙酸乙酯相用1/10饱和NaCl溶液洗涤，然后干燥并过滤。减压蒸发滤液，在40℃、高真空下干燥残余物，得到达352.7g(S)-N-(2-萘磺酰)-天冬氨酸粘稠的油状物。此物料直接用于下一步骤。为了分析的目的，用二氯甲烷结晶粗物料，m.p.94-96℃，无色结晶。B)2.将330gB)1.的磺酰胺产物，60g仲甲醛和10.9g对甲苯磺酸溶于51甲苯。回流加热反应混合物并分离水，历时80分钟。冷却至室温后，搅拌悬浮液2小时，滤集沉淀物，用甲苯和己烷洗涤。在40℃、高真空下干燥产物，得到287mg(91％，由L-天冬氨酸)(R)-4-羧甲基-3-(2-萘磺酰)-5-噁唑烷酮无色结晶，m.p.143-144℃。此物料直接用于下一步骤。B)3.将50g B)2.的噁唑烷酮产物，107.5g A)4.的N-环丙基-乙基甘氨酸酯和200ml乙酸乙酯在60℃搅拌7.5小时，然后冷却至室温并倒入200m饱和NaHCO3溶液中。使两相分开，用乙酸乙酯萃取水相。合并有机相，用饱和NaHCO3溶液洗涤，干燥，然后进行蒸馏以回收过量的N-环丙基-乙基甘氨酸酯。合并水相，用浓HCl使之酸化至PH1，搅拌15分钟并用乙酸乙酯萃取。有机相用饱和NaCl溶液洗涤，干燥并过滤。减压蒸发滤液。在40℃、高真空下干燥残余物，得到55.8g(S)-N-环丙基-N-乙氧羰基甲基-3-(2-萘磺酰氨基)-琥珀酸(83％，白色泡沫)，根据HPLC的纯度：96.2％，[α]D 25＝-26.9°(C＝1，甲醇)。
为了分析的目的，将粗产物溶于丙酮并用1当量二环己胺处理。所得二环己基铵盐用***/己烷结晶，m.p.142.5-143.5℃。B)4.将54.94g(S)-1-脒基-3-氨基甲基-哌啶二盐酸盐(A)3.b)溶于239.8ml 1N NaOH溶液，向此搅拌溶液中，缓慢地加入溶于450ml THF的102.5g B)3的天冬酰胺产物。加入期间，反应温度升至30℃并且溶液的PH变为7.4。加入2.63gN-羟基琥珀酰亚胺并冷却至14℃(PH＝6.92)之后，在保持同样的温度下缓慢地加入65.9g二环己基碳化二亚胺(PH＝7.3)。加毕，将反应混合物搅拌1小时，温热至室温，并继续搅拌过夜。滤出沉淀的脲，用含水THF洗涤，然后用THF洗涤。滤液用水稀释并用乙酸乙酯萃取。合并有机相，用水洗涤并弃去。将二氯甲烷加入到合并的水相中，形成三相。分离下面的两相，用二氯甲烷萃取水相。减压蒸发合并的有机相，得到140.6g(98％产率)粗产物N-[N4-[[(S)-1-脒基-3-哌啶基]甲基]-N2-(2-萘磺酰)-L-天冬氨酰]-N-环丙基甘氨酸乙酯，其不必纯化用于下一步骤。NMR(DMSO-d6)：0.82(m，4H)，1.41(t，3H)，1.1-1.78(m，6H)，2.16(d×d，1H)，2.50(s，1H)，2.50-2.80(m，1H)，2.75-2.90(m，4H)，3.50-4.05(m，6H)，5.26(q，1H)，7.38(bs，4H)，7.65-8.43(m，9H)。B)5.a)在室温下，用5分钟将564ml 1N NaOH溶液加入到140.5gB)4.的乙酯产物的700ml乙醇溶液中。在室温下搅拌反应混合物90分钟。用1N HCl酸化至PH＝7.0后，减压蒸发溶液。B)5.b)在回流下将B)5.a)的产物悬浮于21乙醇和10ml水中。加热悬浮液，滤集固体沉淀物(NaCl)并用乙醇洗涤。减压蒸发滤液。将粗产物溶于1.41乙醇，在回流下搅拌溶液，然后使之慢慢地冷却至室温。向此悬浮液中加入11乙酸乙酯。搅拌悬浮液2小时，滤集所得结晶，用乙酸乙酯洗涤，最后在40℃下真空干燥，再于室温、高真空下干燥，得到109.7gN-[N4-[[(S)-1-脒基-3-吡啶基]甲基]-N2-(2-萘磺酰)-L-天冬氨酰]-N-环丙基甘氨酸(纯度88.6％，HPLC)。B)5.c)将108.7g B)5.b)的产物悬浮于3l乙醇和42ml水中。在回流下搅拌30分钟，并进行热过滤。用乙醇洗涤滤器，使滤液冷却至室温并搅拌过夜。滤集结晶，用乙醇洗涤并在40℃、高真空下干燥，得到72.5g无色结晶，纯度(HPLC)为98.7％；m.p.220-221℃。B)5.d)真空蒸发母液。将残余物悬浮于500ml乙醇和8ml水中并回流悬浮液30分钟。过滤热溶液并用乙醇洗涤后，使滤液冷却至室温并搅拌16小时。过滤沉淀物并用乙醇洗涤。得到的结晶在40℃、高真空下干燥，得到14.9g无色结晶，纯度(HPLC)为94.8％；m.p.220-223℃。B)5.e)将得自B)5.b)和B)5.d)的母液的蒸发残余物合并，溶于90ml乙醇和10ml水。通过硅胶过滤溶液。用90％(体积)含水乙醇洗脱后，将级分3～5合并，在40℃、减压下蒸发。将残余物溶于煮沸的乙醇。过滤混浊的热溶液，冷却至室温并搅拌过夜。过滤沉淀物，用乙醇洗涤并在40℃、高真空下干燥。用200ml煮沸的乙醇和3ml水重结晶产物，得到4.27g产物(纯度：99％，HPLC)；m.p.220-223℃。

Claims (3)

1.一种制备式I的二甲酰胺的方法，其中Q是
Figure C9510424500022
T是CH2或O，A是-SO2-芳基；G是环烷基；L和X是H；Y是COOH或COO-低级烷基该方法包括a)使天冬氨酸与芳基磺酰氯A-Cl反应，其中A如上，b)在酸的存在下使得到的式II的二酸
Figure C9510424500023
与仲甲醛反应，c)使得到的式III的噁唑烷酮
Figure C9510424500031
与式IV的N-环烷基-低级烷基甘氨酸酯反应
         G-NHCH2COO-低级烷基    IVd)在偶合剂的存在下使得到的式V的酸
Figure C9510424500032
其中A，G，L，X和Y如上，与胺H2NCH2-Q反应和e)若需要式I的酸，其中Y是COOH，则使得到的式I的低级烷基酯水解，术语“低级”表示具有1-4个碳原子的基团，“芳基”表示选择性取代的苯基或1-或2-萘基。
2.根据权利要求1的方法，其中A是2-萘磺酰；G是环丙基；L和X是H；Y是COOH或COOC2H5；Q是1-脒基-3-哌啶基。
3.根据权利要求2的方法，其中制备N-[N4-[[(S)-1-脒基-3-哌啶基]甲基]-N2-(2-萘磺酰)-L-天冬氨酰]-N-环丙基甘氨酸。
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