CN102838609B - 一种氮杂双环[3.3.0]辛烷衍生物及其制备方法和应用 - Google Patents
一种氮杂双环[3.3.0]辛烷衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种新结构的氮杂双环[3.3.0]辛烷衍生物,其结构如式(I),式中R1是CH3、CH3CH2、(CH2)2、(CH2CH2CH2)或(CH2C(CH2)2CH2)。本发明还公开了所述氮杂双环[3.3.0]辛烷衍生物的制备方法。本发明制备方法操作简单,产率较高,能广泛适用于工业化规模生产。本发明所制备的氮杂双环[3.3.0]辛烷衍生物是一种潜在治疗糖尿病的中间体,可用于治疗糖尿病药物及其中间体的制备。
Description
技术领域
本发明属于医药技术领域,尤其涉及一种氮杂双环[3.3.0]辛烷衍生物及其制备方法和应用。
背景技术
糖尿病是一种因体内胰岛素绝对或者相对不足所导致的一系列临床综合症。世界卫生组织2011年的报告指出全世界有3.46亿人患有糖尿病,2004年估计有340万人死于高血糖引起的后果,超过80%的糖尿病死亡发生在低收入和中等收入国家。目前,1型和2型糖尿病是不能完全根治的。因此,研究和开发新型的治疗糖尿病的药物成为现在国内外公司及科研院所的一项重要课题。
现有技术中,氮杂双环[3.3.0]辛烷衍生物(aza-bicyclo octane[3.3.0]derivatives)是一类非常重要的化工中间体,具有非常高的医药应用价值,例如,治疗糖尿病用的丝氨酸蛋白酶二肽肽酶(DDP-4)抑制剂(结构见式1)(Bioorganic and Medicinal Chemistry Letters,2010,20,3565-3568),其具有氮杂双环[3.3.0]辛烷结构。
现有技术中氮杂双环[3.3.0]辛烷衍生物的合成方法的主要包括:方法之一如方程式(a)所示,是将(7S,8R)-1,4-二氧杂螺[4.4]-7.8-二甲酸甲酯((7S,8R)-1,4-dioxaspiro[4.4]nonane-7,8-dicarboxylic acid dimethyl ester)与二级胺于190℃下封管反应16小时得到(J.Org.Chem.1989,54,5115-5122和WO2004/087142)。该方法的不足之处在于反应条件苛刻,在工业放大规模化生产中难以实现。另一种方法是以带Pg保护的N,N’-丙炔,丙烯-胺(N-(prop-2-ynyl)prop-2-en-1-amine)在金属催化下通过葆森-侃德(Pauson-Khand)反应成环,然后还原烯键得到,如方程式(b)所示(Organic Letters,2002,4,3983-3988,J. Org.Chem.2002,67,1233-246和US2004/44029),该方法的不足之处在于是以剧毒的金属试剂Co2(CO)8为原料。
发明内容
本发明针对上述现有技术存在的缺陷,提供一种新结构的氮杂双环[3.3.0]辛烷衍生物,可以用于制备治疗糖尿病的药物及其中间体。本发明提供的制备方法操作简单,产率较高。
本发明提供一种式(I)化合物氮杂双环[3.3.0]辛烷衍生物,其结构如式(I)所示:
其中,R1是CH3、CH3CH2;或两个R1共同构成(CH2)2、两个R1共同构成(CH2CH2CH2)、或两个R1共同构成(CH2C(CH3)2CH2)。
上述式(I)化合物氮杂双环[3.3.0]辛烷衍生物采用的反应路线如下式(A)所示:
本发明提供了上述式(I)化合物氮杂双环[3.3.0]辛烷衍生物的制备方法,以式(VII)所示的1,2,3,6-四氢邻苯二甲酰亚胺为原料,依次经过N原子上保护基反应、氧化反应、环化脱羧反应、羰基缩酮保护反应、还原反应、脱去取代苄基反应,得到所述如式(I)所示的氮杂双 环[3.3.0]辛烷衍生物。
本发明氮杂双环[3.3.0]辛烷衍生物的制备方法,具体包括如下步骤:
第一步:1,2,3,6-四氢邻苯二甲酰亚胺与氯化苄,在碱性条件下极性溶剂中,于30~60℃反应,分离纯化后得到式(VI)所示的化合物。
第二步:式(VI)所示的化合物与KMnO4在丙酮/水的混合溶剂中,于室温下发生氧化反应,分离纯化后得到式(V)所示的化合物。
第三步:式(V)所示的化合物与NaOAc在酸性溶剂中,于100~130℃条件下反应,分离纯化后得到式(IV)所示的化合物。
第四步:式(1V)所示的化合物与R1OH或HOR1R1OH二元醇,在酸的催化,苯或甲苯中回流的条件下反应,分离纯化后得到式(III)所示的化合物。
其中,R1为CH3、CH3CH2;或两个R1共同构成(CH2)2、两个R1共同构成(CH2CH2CH2)或两个R1共同构成(CH2C(CH3)2CH2)。
第五步:式(III)所示的化合物与LiAlH4,在非质子溶剂中回流的条件下反应,分离纯化后得到式(11)所示的化合物。
第六步:分离纯化后得到式(III)所示的化合物与氢气,在金属催化条件下,在醇溶剂中发生还原反应,分离纯化后得到式(I)所示的化合物。
其中,
上述的碱为K2CO3,Na2CO3,NaH,吡啶,三乙胺或二异丙基乙基胺。
上述的酸为HCl,HBr,H2SO4,H3PO4,AcOH,CH3COOH,CF3COOH,TsOH或草酸。
上述的酸性溶剂为乙酸,乙酸酐或丙酸。
上述的极性溶剂为甲醇,乙醇或N,N-二甲基甲酰胺(DMF)。
上述的非质子溶剂为四氢呋喃,甲基四氢呋喃,***,甲基叔丁基醚,苯,甲苯或乙苯。
上述金属催化中,采用的催化剂为Pd/C或Pd(OH)2/C。
上述的KMnO4的用量为式(VI)所示化合物摩尔量的三倍。
上述的LiAlH4的用量为式(III)所示化合物摩尔量的二倍。
本发明创新提出了一种新结构的氮杂双环[3.3.0]辛烷衍生物。本发明提出的制备方法的条件温和,原料易得价廉,不涉及有毒有害危险品试剂,反应路线简单,产率较高,适用于大规模工业化生产。本发明制备得到的氮杂双环[3.3.0]辛烷衍生物是一种潜在治疗糖尿病的中间体,可用于治疗糖尿病药物及其中间体的制备。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特 别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
实施例1
称取1,2,3,6-四氢邻苯二甲酰亚胺VII(4540.0mg,30.0mmo1),K2CO3(12440.0mg,90.0mmo1),四丁基溴化铵(TBAB)(970.0mg,3.0mmo1)于250mL圆底烧瓶内,加入50.0mL DMF溶解。称取氯化苄(4940.0mg,39.0mmo1),搅拌下缓慢的滴加到反应瓶内。于30℃下5h后反应完毕,加入50.0mL水淬灭反应。然后加入100.0mL乙酸乙酯萃取,分液后有机相用饱和食盐水洗涤(40.0mL×5),用无水硫酸钠干燥过夜。过滤除去硫酸钠,旋转蒸发除去乙酸乙酯,得到白色固体粗产品。用乙酸乙酯/正己烷重结晶得到5740.0mg目标化合物(VI),收率79.3%。质谱分析MS(ESI,m/s):241。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.30~7.27(m,5H),5.88~5.87(t,2H),4.62(s,2H),3.10~3.08(t,2H),2.63~2.58(m,2H),2.25~2.19(m,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)179.8,135.8,128.5,128.3,127.8,127.7,42.5,39.1,23.5。
本实施例中采用的碱为K2CO3,其它适用的碱还可以是Na2CO3,NaH,吡啶,三乙胺或二异丙基乙基胺。本实施例中采用DMF作为极性溶剂,其它适用的极性溶剂还可以是甲醇、乙醇。
实施例2
将120.0mL化合物VI(8542.7mg,35.4mmo1)的丙酮溶液缓慢滴加到200.0mL的KMnO4(16780.0mg,106.2mmo1)水溶液中,于室温下搅拌反应3小时,TLC监测原料消失。加入亚硫酸钠和浓盐酸,将反应液中得二氯甲烷旋转蒸发后,用乙酸乙酯萃取4次。合并乙酸乙酯,用无水硫酸钠干燥,得到9393.0mg白色泡沫状固体粗产品即化合物(V)。直接投入下步反应。
称取醋酸钠(3.788.0mg)于上述化合物(V)的粗产品内,加入50.0mL醋酸酐,然后再加热到120℃反应3小时反应结束。抽干醋酸酐,冷却到室温,加入50.0mL水,分多次加入固体碳酸钠使pH值为9左右。用乙酸乙酯萃取,合并有机层,用无水硫酸钠干燥,柱层析得到4453.0mg目标化合物。产率:51.7%,产物为白色固体即化合物(IV)。质谱分析MS(ESI,m/s):243(M+H)。以上采用的酸性溶剂是醋酸酐,此处所适用的酸性溶剂还可以是乙酸或丙酸。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.37~7.31(m,5H),4.66(s,2H),3.56~3.52(m,2H),2.82~2.74(m,2H),2.59~2.53(m,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)212.7,177.7,135.3,128.8,128.7,128.2,42.8,40.7,39.1。
实施例3
称取化合物IV(973.2mg),乙二醇(744.0mg)和对甲基苯磺酸(76.1mg)于50.0mL带分水器的单口反应瓶内,加入30.0mL苯。加热到60℃分水,大约6小时反应基本结束。抽干剩余的溶剂,加入30.0mL乙酸乙酯稀释,用10.0mL饱和碳酸氢钠水溶液洗涤有机层,然后用10.0mL饱和食盐水洗涤有机层。用无水硫酸钠干燥,柱层析得到1103.2mg目标化合物III(a)。产率:96.0%,白色固体。质谱分析MS(ESI,m/s):287。以上采用的酸为TsOH,此处适用的酸还可以是HCl,HBr,H2SO4,H3PO4,AcOH,CH3COOH,CF3COOH或草酸。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.33~7.31(d,2H),7.24~7.18(m,3H),4.58(s,2H),3.78~3.75(t,2H),3.61~3.58(t,2H),3.14~3.12(m,2H),2.10~2.03(m,4H)。
13C-NMR(CDCl3,75MHz):δ(ppm)179.5,135.6,128.8,128.2,127.6,65.4,64.1,42.7,41.6,37.5。
实施例4
操作同实施例3。产率95.0%,产物为白色固体即化合物III(b)。质谱分析MS(ESI,m/s):288(M-H)。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.37~7.35(d,2H),7.28~7.17(m,3H),4.54(s,2H),3.11(s,3H),3.09~3.06(q,2H),2.54(s,3H),2.36~2.33(m,2H),1.89~1.83(m,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)179.5,135.7,129.2,128.4,127.7,108.5,50.8,48.1,42.6,41.7.35.8。
实施例5
操作同实施例3。产率95.0%,产物为白色固体即化合物III(c)。质谱分析MS(ESI,m/s):317(M+H)。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.42~7.40(d,2H),7.32~7.27(m,3H),4.60(s,2H),3.51~3.45(q,2H),3.22~3.12(m,4H),2.49~2.42(m,2H),2.03~1.93(m,2H),1.17~1.14(t,2H),0.85~0.81(t,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)179.7,135.8,129.0,128.6,127.8,106.1,58.7,56.6,42.5,41.9,36.7,15.3,14.9。
实施例6
操作同实施例3。产率94.0%,产物为白色固体即化合物III(d)。质谱分析MS(ESI,m/s):301。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.43~7.41(d,2H),7.33~7.24(m,3H),4.61(s,2H),3.82~3.79(t,2H),3.30~3.27(t,2H),3.21~3.15(m,2H),2.67~2.64(d,2H),1.99~1.93(m,2H),1.60~1.55(m,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)179.6,135.7,129.1,128.4,127.6,106.0,62.8,60.0,42.6,41.5,36.3,24.9。
实施例7
操作同实施例3。产率96.0%,产物为白色固体即化合物III(e)。质谱分析MS(ESI,m/s):329。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.41~7.39(d,2H),7.32~7.24(m,3H),4.60(s,2H),3.40(s,2H),3.20~3.15(m,2H),2.90(s,2H),2.66~2.62(d,2H),0.84(s,6H)。
13C-NMR(CDCl3,75MHz):δ(ppm)179.7,135.7,129.0,128.3,127.6,105.7,73.2,70.5,42.6,41.5,35.9,29.8,22.3。
实施例8
称取LiAlH4(304.0mg)于100mL带回流冷凝管的双口瓶内,抽空换氮气,加入20.0mL四氢呋喃(THF)。称取化合物III(a)(1149.2mg)用20.0mL THF溶解,缓慢滴加到双口瓶内。滴加完毕后,加热回流,TLC检测原料基本消失。冷却到室温,用20%NaOH水溶液淬灭反应,然后再加入THF稀释,用无水硫酸钠干燥。得到无色油状粗产品即化合物II(a)。产率99.0%,产物足够纯,无需纯化直接投入下步反应。质谱分析MS(ESI,m/s):260(M+H)。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.34~7.29(m,4H),7.24~7.21(q,1H),3.91(s,4H),3.58(s,2H),2.67~2.58(m,2H),2.49~2.42(m,4H),1.98~1.93(m,2H),1.74~1.69(q,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)139.5,128.6,128.1,126.7,118.8,64.7,63.9,60.6,59.6,40.7,39.1。
以上采用的非质子溶剂为四氢呋喃,此处适用的非质子溶剂还可以是甲基四氢呋喃,***,甲基叔丁基醚,苯,甲苯或乙苯。
实施例9
操作同实施例8。产率99.0%,产物II(b)呈无色油状。质谱分析MS(ESI,m/s):262(M+H)。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.27~7.22(m,4H),7.18~7.13(m,1H),3.51(s,2H),3.15(s,3H),3.10(s,3H),2.53~2.43(m,2H),2.41~2.38(m,2H),2.32~2.28(m,2H),2.07~2.02(m,2H),1.54~1.49(q,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)139.3,128.6,128.1,126.7,111.9,60.2,59.5,50.2,48.6,39.2,39.0。
实施例10
操作同实施例8。产率99.0%,产物II(c)呈无色油状。质谱分析MS(ESI,m/s):290(M+H)。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.34~7.28(m,4H),7.25~7.21(m,1H),3.58(s,2H),3.54~3.42(m,4H),2.62~2.54(m,2H),2.47~2.45(q,2H),2.39~2.35(m,2H),2.16~2.11(t,2H),1.63~1.58(m,2H),1.21~1.15(q,6H)。
13C-NMR(CDCl3,75MHz):δ(ppm)139.4,128.6,128.1,126.7,111.4,60.2,59.7,57.9,56.3,40.0,39.3,15.6,15.5。
实施例11
操作同实施例8。产率99.0%,产物II(d)呈无色油状。质谱分析MS(ESI,m/s):273。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.35~7.30(m,4H),7.25~7.21(m,1H),3.90~3.86(q,4H),3.59(s,2H),2.63~2.54(m,2H),2.48~2.39(m,4H),2.33~2.27(m,2H),1.74~1.63(m,4H)。
13C-NMR(CDCl3,75MHz):δ(ppm)139.3,128.6,128.1,126.8,109.9,62.2,60.8,60.3,59.5,39.7,39.0,25.7。
实施例12
操作同实施例8。产率99.0%,产物II(e)呈白色固体。质谱分析MS(ESI,m/s):301。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.31~7.21(m,4H),7.19~7.15(m,1H),3.53(s,2H),3.42~3.40(d,4H),2.58~2.48(m,2H),2.45~2.36(m,4H),2.24~2.19(m,2H),1.61~1.57(m,2H),0.89(s,6H)。
13C-NMR(CDCl3,75MHz):δ(ppm)128.7,128.2,126.9,109.7,72.7,71.5,60.3,59.5,39.2,
39.0,30.3,30.1,22.5。
实施例13
将Pd/C(21.0mg)加入到5.0mL含化合物II(a)(107.7mg)的甲醇溶液中,置于氢气球下于45℃下反应24小时后,GC监测原料消失。过滤除去Pd/C,旋转蒸发除去甲醇溶剂,即得到 目标化合物I(a)。产率:97%,产物为无色液体。质谱分析MS(ESI,m/s):168(M-H)。
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)3.88(s,4H),2.91~2.86(m,2H),2.74~2.68(m,2H),2.66~2.58(m,2H),2.04~1.99(m,2H),1.57~1.53(q,2H)。
13C-NMR(CDCl3,75MHz):δ(ppm)118.6,64.6,64.2,54.6,41.3,41.0。
以上金属催化采用的催化剂为Pd/C,此处适用的非质子溶剂还可以是Pd(OH)2/C。
实施例14
将所制备的化合物I(a)经过以上反应路线制备得到能够作为治疗糖尿病药物的前体原料,详细合成步骤及治疗糖尿病药物药物活性数据可参考文献Bioorganic andMedicinal Chemistry Letters,2010,20,3565-3568。
将本发明氮杂双环[3.3.0]辛烷衍生物用于制备得到治疗糖尿病药物的应用实例如下表:
Claims (8)
1.式(I)所示氮杂双环[3.3.0]辛烷衍生物的制备方法,其特征在于,以式(VII)所示的1,2,3,6-四氢邻苯二甲酰亚胺为原料,根据以下式(A)所示路线进行反应,制备得到所述氮杂双环[3.3.0]辛烷衍生物;
其中,R1为CH3、CH3CH2;或两个R1共同构成(CH2)2、两个R1共同构成(CH2CH2CH2)或两个R1共同构成(CH2C(CH3)2CH2);
其中,将1,2,3,6-四氢邻苯二甲酰亚胺与氯化苄,在四丁基溴化铵催化的碱性条件下,在极性溶剂中,于30~60℃反应,分离纯化后得到式(VI)所示的化合物
其中,将式(VI)所示的化合物与KMnO4在丙酮/水的混合溶剂中,于室温下发生氧化反应,分离纯化后得到式(V)所示的化合物
其中,将式(V)所示的化合物与NaOAc在酸性溶剂中,于100~130℃条件下反应,分离纯化后得到式(IV)所示的化合物
其中,将式(IV)所示的化合物与R1OH或HOR1R1OH二元醇,在酸的催化,苯或甲苯中回流的条件下反应,分离纯化后得到式(III)所示的化合物
其中,R1为CH3、CH3CH2;或两个R1共同构成(CH2)2、两个R1共同构成(CH2CH2CH2)或两个R1共同构成(CH2C(CH3)2CH2)
其中,将式(III)所示的化合物与LiAlH4,在非质子溶剂中回流的条件下反应,分离纯化后得到式(II)所示的化合物
其中,将式(II)所示的化合物与氢气,在金属催化条件下,在醇溶剂中发生还原反应,分离纯化后得到式(I)所示的化合物
2.如权利要求1所述的制备方法,其特征在于,所述碱为K2CO3,Na2CO3,NaH,吡啶,三乙胺或二异丙基乙基胺;所述极性溶剂为甲醇,乙醇或DMF。
3.如权利要求1所述的制备方法,其特征在于,所述酸性溶剂为乙酸,乙酸酐或丙酸。
4.如权利要求1所述的制备方法,其特征在于,所述酸为HCl,HBr,H2SO4,H3PO4,AcOH,CH3COOH,CF3COOH,TsOH或草酸。
5.如权利要求1所述的制备方法,其特征在于,所述非质子溶剂为四氢呋喃,甲基四氢呋喃,***,甲基叔丁基醚,苯,甲苯或乙苯。
6.如权利要求1所述的制备方法,其特征在于,所述金属催化采用的催化剂为Pd/C或Pd(OH)2/C。
7.如权利要求1所述的制备方法,其特征在于,所述KMnO4的用量为式(VI)所示化合物摩尔量的三倍。
8.如权利要求1所述的制备方法,其特征在于,所述LiAlH4的用量为式(III)所示化合物摩尔量的二倍。
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US5736550A (en) * | 1994-05-18 | 1998-04-07 | Nisshin Flour Milling Co., Ltd. | Pyrimidine derivatives |
US20040044029A1 (en) * | 2002-08-14 | 2004-03-04 | Dart Michael J. | Azabicyclic compounds are central nervous system active agents |
WO2006012396A1 (en) * | 2004-07-22 | 2006-02-02 | Glaxo Group Limited | Antibacterial agents |
CN1798559A (zh) * | 2003-04-04 | 2006-07-05 | 诺瓦提斯公司 | 用于治疗气管疾病的喹啉-2-酮衍生物 |
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US5736550A (en) * | 1994-05-18 | 1998-04-07 | Nisshin Flour Milling Co., Ltd. | Pyrimidine derivatives |
US20040044029A1 (en) * | 2002-08-14 | 2004-03-04 | Dart Michael J. | Azabicyclic compounds are central nervous system active agents |
CN1798559A (zh) * | 2003-04-04 | 2006-07-05 | 诺瓦提斯公司 | 用于治疗气管疾病的喹啉-2-酮衍生物 |
WO2006012396A1 (en) * | 2004-07-22 | 2006-02-02 | Glaxo Group Limited | Antibacterial agents |
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