CN1252792A - 制备4'－三氟甲基－联苯基－2－羧酸(1,2,3,4－四氢－异喹啉－6－基)酰胺的方法和中间体 - Google Patents
制备4'－三氟甲基－联苯基－2－羧酸(1,2,3,4－四氢－异喹啉－6－基)酰胺的方法和中间体 Download PDFInfo
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- CN1252792A CN1252792A CN98804206A CN98804206A CN1252792A CN 1252792 A CN1252792 A CN 1252792A CN 98804206 A CN98804206 A CN 98804206A CN 98804206 A CN98804206 A CN 98804206A CN 1252792 A CN1252792 A CN 1252792A
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000000543 intermediate Substances 0.000 title abstract 2
- SAAFIVJVSQVSSW-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-6-amine Chemical compound C1NCCC2=CC(N)=CC=C21 SAAFIVJVSQVSSW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
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- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
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- 239000003795 chemical substances by application Substances 0.000 claims description 23
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 13
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Abstract
本发明涉及制备通式(Ⅰ)的4’－三氟甲基－联苯基－2－羧酸(1,2,3,4－四氢－异喹啉－6－基)酰胺的改进方法和所用中间体。化合物(Ⅰ)可用于制备4’－三氟甲基－联苯基－2－羧酸[2－(1H(1,2,4－三唑－3－基甲基)]－(1,2,3,4－四氢－异喹啉－6－基)酰胺(Ⅱ)化合物,该化合物可用作微粒体甘油三酯转移蛋白和/或载脂蛋白B(ApoB)分泌的抑制剂,并因此可用于预防和治疗动脉粥样硬化及其临床并发症,降低血脂及相关疾病。还涉及通式A－CHR1R2的化合物,其中A是通式(XⅡ)且R1选自H和OR3,其中R3是氢或(C1－C6)烷基;R2选自OR3,－CH2－NH2·(R5H)m,其中m和R5H定义如下,和－CH2－NO2;或R1和R2一起形成=O或=CH－NO2基团;条件是当R1和R2都是OR3基团时,则两个OR3都是(C1－C6)烷基且相同。
Description
本发明涉及制备下面通式(I)的4’-三氟甲基-联苯基-2-羧酸(1，2，3，4-四氢-异喹啉-6-基)酰胺的改进方法和所用中间体。化合物I可用于制备结构式如下的4’-三氟甲基-联苯基-2-羧酸[2-(1H-[1，2，4-三唑-3-基甲基)]-(1，2，3，4，-四氢-异喹啉-6-基)酰胺，
化合物II可用作微粒体甘油三酯转移蛋白和/或载脂蛋白B(ApoB)分泌的抑制剂，并因此可用于预防和治疗动脉粥样硬化及其临床并发症，降低血脂(lowing serum lipids)及相关疾病。
微粒体甘油三酯转移蛋白(MTP)催化甘油三酯，胆甾醇基酯，和磷脂的转移。有文献指出它可作为装配含Apo B脂蛋白生物分子的试剂，这些脂蛋白和生物分子导致了动脉粥样硬化损害的形成。参见欧洲专利申请公开No.0643057 A1，欧洲专利申请公开No.0584446 A2，和Wetterau等，Science，258，999-1001(1992)。因此，可抑制MTP和/或抑制Apo B分泌的化合物可用于治疗动脉粥样硬化。这些化合物还可用于治疗其它疾病或症状，在这些疾病中，通过抑制MTP和/或ApoB分泌，可降低血浆胆固醇和甘油三酯水平。这些病症包括血胆甾醇过多，血甘油三酯过多(hypertriglyceridemia)，胰腺炎，和肥胖；且血胆甾醇过多，血甘油三酯过多，和高血脂(hyperlipidemia)与胰腺炎，肥胖，和糖尿病有关。
PCT申请序列号No.PCT/IB95/00448(以下称448申请)和美国专利申请序列号60/032307(以下称307申请)，已转让给本申请的受让人，且其全文描述的制备化合物I的方法和其转化为化合物II的方法在此引作参考。其它所涉及的文献在此也全文引作参考。
按照本发明的一个方案，提供了制备下式化合物的改进方法
包括用甲醛源，如福尔马林，多聚甲醛，三噁烷(trioxane)，在第二种酸存在下处理下式化合物，其中
m是0或1，且R5H是第一种酸，其中所述第一种和第二种酸可以相同或不同，且选自无机酸如盐酸，硫酸，硝酸和磷酸，有机酸如磺酸，例如，苯磺酸(besylic)，对甲苯磺酸(PTSA，tosylic)，甲磺酸(MSA，mesylic)和三氟甲磺酸(triflic)；羧酸，例如，甲酸，乙酸，丙酸，苯甲酸，柠檬酸，酒石酸，马来酸，富马酸，琥珀酸和苹果酸。优选的甲醛源是多聚甲醛，第一种酸是HCl或甲酸且第二种酸是甲酸。
按照上述方案的另一方面，提供了一种方法，其中m是1的化合物III，是通过在含有第一种酸的惰性介质中，用选自氢的还原剂在氢化催化剂如Raney Ni，Pd/C和Pd(OH)2；氢化铝；硼烷；硼氢化物存在下处理下式化合物制备的。通式III化合物中，其中m是0的化合物通过R5H中和制备。
按照上述方案的另一方面，提供了一种方法，其中，通式IV化合物是通过用脱水剂，在碱存在下处理通式V化合物制备的。
脱水剂选自(C1-C6)烷基或(C6-C10)芳基磺酰基或羰基卤化物或酸酐。优选的脱水剂是甲磺酰氯。
上述方案的另一方面提供了一种制备方法，其中通式V化合物是通过用硝基甲烷在碱存在下处理通式VI化合物制备的。
按照上述方案的另一方面，提供了一种方法，其中通式VI化合物是通过用含水酸处理通式VII化合物制备的。每个R3分别选自(C1-C6)烷基或两个R3一起形成下式基团其中n是0或1，且R6和R7分别选自氢和(C1-C2)烷基或R6与R7与它们相连的碳原子一起形成(C3-C8)环烷基或(C6-C10)芳环。
上述方案的另一方面提供了一种方法，其中通式VII化合物是通过用下式化合物
其中X是任何已知的酰化胺的离去基团，如卤素，例如，F和Cl，和(C2-C6)酰氧基，例如，乙酰氧基；和(C6-C10)芳酰氧基；例如苯甲酰氧；和(C6-C10)芳氧基，如对硝基和对氟苯氧基，优选X是氯，处理下式化合物制备的
其中R3定义如上。
此方案进一步提供了一种方法，其中通式IX的化合物是通过在氢化催化剂存在下用氢处理下面的通式化合物制备的其中R3定义如上。
按照上述方案的另一方面，提供了一种方法，其中通式XI的化合物
与式R3OH的化合物反应，其中R3是(C1-C6)烷基，或与下式化合物其中n是0或1，每个R6和R7选自H和(C1-C3)烷基或R6和R7与它们相连的碳原子一起形成(C3-C10)环烷基或(C6-C10)芳环，在第一种酸如阳离子交换树脂的H+形式或含水无机酸存在下，形成通式X化合物。
按照本发明的第二个方案，提供了下式化合物
A-CHR1R2其中A是下式基团
且R1选自H和OR3，其中R3是氢或(C1-C6)烷基，
R2选自OR3，-CH2-NH2或-CH2-NO2；或
R1和R2一起形成＝O或＝CH-NO2基团；条件是当R1和R2都是OR3基团时，则两个R3都是(C1-C6)烷基且相同。
按照上述方案的另一方面，本发明提供了下式化合物的酸加成盐
A-CHR1R2·R5H其中A和R1定义如上，R2-CH2-NH2和R5H是酸，选自无机酸如盐酸，硫酸，硝酸和磷酸，有机酸如磺酸，例如，苯磺酸(besylic)，对甲苯磺酸(PTSA，tosylic)，甲磺酸(MSA，mesylic)和三氟甲磺酸(triflic)；羧酸，例如，甲酸，乙酸，丙酸，苯甲酸，柠檬酸，酒石酸，马来酸，富马酸，琥珀酸和苹果酸。
一些化合物可显示多晶形。应理解本发明包括任何多晶形式或它们的混合物。
在下面的描述中，使用了常用的化学缩略语和字首组合词：Me(甲基)；Et(乙基)；THF(四氢呋喃)；BOC(叔丁氧羰基，保护基团)；Ms(甲磺酰基，mesyl)；TFA(三氟乙酸)；Ac(乙酰基)；RP(反相)；HPLC(高效液相色谱)；除非另有说明，在反应路线中和下述讨论中的R，R1，R2，R3和R4，以及通式I和通式III至XI定义如上。反应路线1
反应路线1(续)反应路线2
如路线1所示，商业上可得的3-硝基苯甲醛XI与通式R3OH的化合物，其中R3是(C1-C6)烷基，或与下式化合物其中n是0或1，每个R6和R7选自H和(C1-C3)烷基或R6和R7与它们相连的碳原子一起形成(C3-C10)环烷基或(C6-C10)芳环，在第一种酸如阳离子交换树脂的H+形式或含水无机酸存在下反应，形成乙缩醛X化合物。然后将乙缩醛X氢化形成氨基乙缩醛IX，并接着用通式VIII的化合物处理，在碱存在下形成乙缩醛酰胺VII，其中X是酰化胺时的离去基团。酰化胺时的离去基团在本领域是已知的，包括卤素，如F和Cl，和酰基氧，如乙酰氧，和芳酰氧，如苯甲酰氧，和芳基氧，如对硝基和对氟苯基氧。优选X是卤素，且特别优选X是氯。然后将乙酰胺VII用酸处理形成化合物VI。可用于此步骤的酸包括上述第一种和第二种酸。
用于制备乙缩醛X的酸包括无机酸和磺酸和阳离子交换树脂的H+形式。特别优选的酸是H+阳离子交换树脂如Dowex(商标)阳离子交换树脂。
氢化乙缩醛X可使用任何已知方法使之更加有效，包括在氢化催化剂如Pd/C，Pd(OH)2/C和Raney镍存在下用氢气处理。优选的催化剂是Pd/C且氢化的压力可从约100-约510kPA(约14-74 PSI)。优选的氢压为约200-300kPa(约27-44PSI)。
用于将X转化为VII的碱选自无机碱如碱金属或碱土金属氢氧化物，碳酸盐和碳酸氢盐和有机碱如三(C1-C6)烷基胺，吡啶和吗啉。优选的碱是TEA且优选的溶剂是THF。
任何本领域已知的用于水解乙缩醛的含水酸都可用于将VII转化为VI，含水酸包括阳离子交换树脂(其H+形式)，无机酸如盐酸，硫酸，硝酸和磷酸，和有机酸如磺酸，例如，苯磺酸(besylic)，对甲苯磺酸(PTSA，tosylic)，甲磺酸(MSA，mesylic)和三氟甲磺酸(triflic)；和烷基和芳基羧酸，例如，乙酸，丙酸，苯甲酸，柠檬酸，酒石酸，马来酸，富马酸，琥珀酸和苹果酸。优选在此步骤使用HCl(aq)。
通过用硝基甲烷在第一种碱存在下处理化合物VI制备化合物V。将化合物V，如路线2所示，在惰性溶剂中，用选自(C1-C6)烷基或(C6-C10)芳基磺酰基或羰基卤化物或酸酐的脱水剂，在第二种碱存在下处理以形成化合物IV。优选的脱水剂是甲磺酰氯且惰性溶剂包括氯化烃，例如，CH2Cl2。第一种和第二种碱可选自上面涉及将IX转化为VII所描述的碱，且可相同或不同。优选的碱是碱金属碳酸盐和碳酸氢盐，优选Na2CO3。
化合物III可通过还原化合物IV制备。优选的还原剂是氢，在压力约135-555kPA(约20-80PSI)，在氢催化剂如Pd/C，Pd(OH)2/C，Raney镍和Pt/C存在下。其它可用的还原剂有氢化铝，硼烷，和氢硼化物。氢化可在惰性溶剂中如(C1-C6)醇，例如，乙醇或酯，例如，乙酸乙酯，在酸存在下有效地进行，如无机酸如盐酸，硫酸，硝酸和磷酸，有机酸如磺酸，例如，苯磺酸(besylic)，对甲苯磺酸(PTSA，tosylic)，甲磺酸(MSA，mesylic)和三氟甲磺酸(triflic)；和羧酸，例如，甲酸，乙酸，丙酸，苯甲酸，柠檬酸，酒石酸，马来酸，富马酸，琥珀酸和苹果酸，以得到化合物III的酸加成盐，其可直接用于下一步或转化为游离碱。优选的酸是HCl和甲酸。还原优选使用氢压约345kPa(50PSI)，用Pd/C在含浓HCl的乙醇中进行。然后通过用甲醛源，如福尔马林，多聚甲醛和三噁烷和(C1-C6)链烷酸如甲酸在温度约25-100℃处理化合物III，将其转化为化合物I。优选使用游离碱形式的化合物III和多聚甲醛在甲酸中，在约60℃有效地进行反应。
化合物I转化为化合物II的反应在未决专利Attorney Docket号PC9182和PC9687中有描述，也转让给了本申请的受让人，在此全文引作参考。
本领域技术人员已知的纯化和分离的常规方法和/或技术可用于分离本发明的化合物。这些技术包括色谱(HPLC，使用常规吸附剂如硅胶的柱色谱，和薄层色谱)，重结晶，和梯度(例如，液-液)萃取技术。
化合物II，(以下称“活性化合物”)，是可口服给药的，并因此与药学上可接受的适于口服剂量形式的载体或稀释剂结合使用。合适的药学上可接受的载体包括惰性固体填充剂或稀释剂和无菌含水或有机溶液。活性化合物在这样的药物组合物中的存在量应足以满足下述范围所需的量。因此，用于口服给药时，化合物可与合适的固体或液体载体或稀释剂形成胶囊，片剂，粉剂，糖浆，溶液，悬浮液等。药物组合物，如果需要，可含有别的组分如矫味剂，甜味剂，赋形剂等。
片剂，丸剂，胶囊等还可含有粘合剂如西黄蓍胶，阿拉伯胶，玉米淀粉或明胶；赋形剂如磷酸二钙；崩解剂如玉米淀粉，马铃薯淀粉，海藻酸；润滑剂如硬脂酸镁；和甜味剂如蔗糖，乳糖或糖精。当剂量单元形式是胶囊时，除了上述类型的材料外，它还可含有，液体载体如脂肪油。
各种其它材料可用于包衣或修饰剂量单元的物理形式。例如，片剂可用虫胶，糖或两者包衣。糖浆或酏剂除了活性组分，还可含有蔗糖作为甜味剂，对羟基苯甲酸甲酯或丙酯作为防腐剂，染料和矫味剂如樱桃或桔子调味剂。
活性化合物可经非肠道给药。用于非肠道给药时，化合物可与无菌含水的或有机介质形成可注射溶液或悬浮液。溶液或悬浮液可使活性化合物在水中适当地与表面活性剂如羟丙基纤维素混合制备。分散液也可在芝麻或花生油，乙醇，水，多元醇(例如，丙二醇和液体聚乙二醇)以及合适的它们的混合物；植物油；N-甲基葡糖胺；聚乙烯基吡咯烷酮和它们的混合物在化合物的药用盐的油以及水溶液中制备。在常规贮存和使用条件下，这些制剂含有抑制微生物生长的防腐剂。以同样方法制备的可注射溶液可通过静脉内、腹膜内、皮下或肌内给药。
适用于注射给药的药物形式包括无菌水溶液或分散液和用于当时制备无菌可注射溶液或分散液的无菌粉末。在所有情况下，制剂必须是无菌的且必须达到容易在注射管中存在的流动程度。它在制造和贮存条件下必须是稳定的且必须防止微生物如细菌或真菌的污染。
活性化合物的给药剂量一般按照本领域已知的原则根据被治疗疾病的严重程度和给药途径而变化。通常，活性化合物对温血动物(如人)给药达到的有效剂量为，一般公认的日剂量一次或分次给药量为约0.1-15mg/公斤体重。优选约1-5mg/公斤体重。一天中总的接受剂量在1-1000mg，优选5-350mg。
活性化合物可与其它药物结合使用，包括其它降脂试剂。这类试剂包括胆固醇生物合成抑制剂，特别是HMG CoA还原酶抑制剂和角鲨烯合成酶抑制剂；胆汁酸螯合剂；纤维剂(fibrates)；胆固醇吸收抑制剂；和烟酸。
下面用实施例举例说明本发明。但应理解本发明并不限于这些实施例的具体细节。
实施例1
4’-三氟甲基-联苯基-2-甲酸(3-甲酰基-苯基)酰胺
在250mL圆底烧瓶中放入用两份5mL甲醇洗涤过的，并以在5mL甲醇中的浆液形式的3-硝基苯甲醛(5.20g，34.4mmol)，100mL甲醇，和Dowex磺酸树脂(例如，Dowex 50WX4400，Aldrich商品目录号21-784-4)的H+形式(0.57g)。将所得浆液加热回流90分钟，然后在室温搅拌过夜(等分试样的1HNMR分析显示二甲基乙缩醛与起始醛的比为95∶5)。过滤除去树脂，并浓缩滤液得到浅黄色油。将乙缩醛溶于100mL THF并加入10％ Pd/C(0.52g)。将混合物置于Parr氢化器中，氢气压为276kPa(40psi)。三次填充氢气，氢气压保持稳定，90分钟后，反应器中混合物用氮气净化。通过Celite过滤除去催化剂，并用50mL的THF冲洗。滤液用三乙胺处理(10.6mL，76mmol)，然后用15分钟滴加入4’-三氟甲基-联苯基-2-甲酸氯化物(9.8g，34mmol)的10mLTHF溶液。将所得浆液在室温搅拌20小时。加入1N HCl(含水)(100mL)，然后将混合物剧烈搅拌2小时。旋转蒸发除去大部分THF。含水层用每次50mL异丙醚/乙酸乙酯(3∶1 v/v)萃取三次。合并有机萃取物用1NHCl[aq]洗涤两次，饱和NaHCO3水溶液洗涤两次，然后用MgSO4干燥，过滤，然后浓缩得到白色固体。用4∶1的己烷乙酸乙酯(250mL)重结晶，得到标题化合物为粉末状白色固体(10.5g，83％)。1HNMR：(CDCl3)：δ9.92(s，1H)，7.76(d，J＝7.5Hz，1H)，7.69-7.67(m，3H)，7.62-7.52(m，5H)，7.46-7.42(m，3H)，7.06(br s，1H)。MS(电子碰撞)：369(M+，20)，249(100).
实施例2
4’-三氟甲基-联苯基-2-甲酸[3-(2-硝基-乙烯基)-苯基]酰胺
向实施例1的标题产物(3.0g，8.1mmol)在50％含水乙醇(15mL)中的溶液中，加入硝基甲烷(1.8mL，32mmol)和Na2CO3(86mg，0.81mmol)。将所得溶液在室温搅拌4小时，然后在旋转蒸发仪上浓缩。所得产物在乙酸乙酯和水(ca.各25mL)之间分配。分出有机层，用MgSO4干燥，过滤，并浓缩，得到中间体硝基醇为棕色油状物(3.73g)。
将粗品硝基醇(3.4g，7.9mmol)溶于CH2Cl2(90mL)，冷却至0℃，并用甲磺酰氯(1.5mL，19mmol)处理。在0℃ 30分钟后，TLC分析(10％甲醇-CH2Cl2)显示完成转化至较小极性的产物。将溶液用1N HCl[aq]洗涤，MgSO4干燥，过滤，浓缩得到暗黄色固体(3.3g)。用硅胶色谱纯化(100g硅胶，用3％甲醇-CH2Cl2洗脱)，得到标题化合物为无色固体(3.2g，98％)1HNMR：(CDCl3)：δ7.89(d，J＝13.9Hz，1H)，7.79(d，J＝7.5Hz，1H)，7.66-7.43 9(m，11H)，7.29(d，J＝7.7Hz，1H)，7.07(brs，1H).MS(化学电离)：413(M+H，100)。
实施例3
4’-三氟甲基-联苯基-2-甲酸[3-(2-氨基乙基)-苯基]酰胺盐酸盐
在一Parr氢化烧瓶中放入实施例2的标题产物(1.90g，4.61mmol)，10％ Pd/C(0.58g)，95％乙醇(20ml)，和浓HCl(0.96mL，12mmol)。将混合物氢化，在276kPa(40psi)氢压下氢化19小时。用Clite过滤除去催化剂，浓缩滤液得到一油性，黄白色固体，用HPLC分析为85％纯度。将一部分此材料以其游离碱形式用硅胶色谱纯化(即，将HCl盐溶于甲醇，用1摩尔当量的K2CO3处理，过滤并浓缩)，用500∶50∶1的CH2Cl2-甲醇-NH4OH洗脱，得到标题化合物为白色固体，将其用HPLC分析。1HNMR(CDCl3)：δ7.64-7.61(m，4H)，7.50-7.47(m，2H)，7.41-7.34(m，2H)，7.13(brs，1H)，7.09-7.05(m，1H)，6.99(d，J＝8.1Hz，1H)，6.84(d，J＝7.5Hz，1H)，4.78(br s，2H)，2.97(t，J＝7.3Hz，2H)，2.80(t，J＝7.3Hz，2H).MS(化学电离)：385(M＝H，100)。
实施例4
4’-三氟甲基-联苯基-2-甲酸(1，2，3，4-四氢异喹啉-6-基)酰胺
在25ml圆底烧瓶中放入游离碱形式的实施例3标题化合物(512mg，1.33mmol)，多聚甲醛(41mg，1.35mmol)和甲酸(7mL)。所得浆液在60℃油浴加热17小时。冷却至室温后向其中滴加入冰和饱和[aq]NH4OH(12ml，190mmol)的混合物中和浆液。所得溶液用4份CH2Cl2萃取。合并有机萃取物，用盐水洗涤，K2CO3干燥，过滤，浓缩得到441mg(理论值的84％)标题化合物为灰白色固体。1H NMR和MS分析显示此材料与上述按照307和448申请中描述的路线制备的化合物相同。
Claims (10)
1、制备下式化合物的方法包括用甲醛源在第二种酸存在下处理下式化合物
其中m是0或1，且R5H是第一种酸，其中所述第一种和第二种酸可以相同或不同。
2、按照权利要求1的方法，其中m是1的通式III化合物，通过在含有第一种酸的惰性介质中，用选自氢的还原剂在氢化催化剂，氢化铝，硼烷，硼氢化物存在下处理下式化合物制备。
3、按照权利要求2的方法，其中通式IV化合物通过用脱水剂，在碱存在下处理下式化合物制备的
脱水剂选自(C1-C6)烷基或(C6-C10)芳基磺酰基或羰基卤化物或酸酐。
4、按照权利要求3的方法，其中通式V化合物是通过用硝基甲烷在碱存在下处理下式化合物制备的。
5、按照权利要求4的方法，其中通式VI化合物是通过用含水酸处理下式化合物制备的
其中，每个R3分别选自(C1-C6)烷基或两个R3一起形成下式基团
其中n是0或1，且R6和R7分别选自氢和(C1-C2)烷基或R6与R7与它们相连的碳原子一起形成(C3-C8)环烷基或(C6-C10)芳环。
6、按照权利要求5的方法，其中通式VII化合物是通过用下式化合物
其中每个R3定义如上，处理下式化合物
其中X是酰化胺的离去基团，选自卤素，(C2-C6)酰氧基，(C6-C10)芳酰氧基，和(C6-C10)芳氧基。
7、按照权利要求6的方法，其中通式IX的化合物是通过用还原剂处理下面的通式化合物制备的
其中R3定义如上。
8、按照权利要求7的方法，其中通式X的化合物是通过用通式R3OH的化合物，其中，R3是(C1-C6)烷基，或下式化合物
其中n，R6和R7定义如上，处理下式化合物制备的。
9、下式化合物
A-CHR1R2
其中A是下式基团
且R1选自H和OR3，其中R3是氢或(C1-C6)烷基，
R2选自OR3，-CH2-NH2·(R5H)n，其中n是0或1且R5定义如上，或-CH2-NO2；或
R1和R3一起形成＝O或＝CH-NO3基团；
条件是当R1和R3都是OR3基团时，则两个R3都是(C1-C6)烷基且相同。
10、制备下式化合物的方法
包括下列步骤
a)用通式R3OH的化合物，其中，R3是(C1-C6)烷基，或下式化合物
其中n，R6和R7定义如上，在酸存在下处理下式化合物。
以形成下式化合物
其中每个R3分别是，选自(C1-C3)烷基或两个R3一起形成下式基团
其中n，R3和R7定义如上；
b)用还原剂处理通式X化合物以形成下式化合物
c)用下式化合物处理通式IX化合物
其中X是酰化胺的离去基团，以形成下式化合物
其中R3定义如上；
d)用含水酸处理通式VII的化合物以形成下式化合物
e)用硝基甲烷在碱存在下处理通式VI化合物，以形成下式化合物
f)在碱存在下，用脱水剂处理通式V化合物，脱水剂选自(C1-C6)烷基或(C6-C10)芳基磺酰基或羰基卤化物或酸酐，以形成下式化合物
g)在含有第一种酸的惰性介质中，用选自氢化铝，硼烷，氢硼化物，和在氢化催化剂存在下的氢还原剂处理通式IV化合物，以形成下式化合物
其中m是1，且R5H选自无机酸，该无机酸选自盐酸，硫酸，硝酸和磷酸；有机酸选自磺酸，该磺酸选自苯磺酸，对甲苯磺酸，甲磺酸和三氟甲磺酸；和羧酸，选自甲酸，乙酸，丙酸，苯甲酸，柠檬酸，酒石酸，马来酸，富马酸，琥珀酸和苹果酸；和任何中和R5H形成其中m是0的通式III化合物；和
h)用甲醛源在第二种酸存在下处理通式III化合物，其中R3H定义如上，且m是0或1。
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| CN105418514A (zh) * | 2015-11-18 | 2016-03-23 | 上海应用技术学院 | 一种(e)-叔丁基-5-(2-硝基乙烯基)-1h-咪唑-1-甲酸叔丁酯及其制备方法 |
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| WO2004011427A2 (en) * | 2002-07-31 | 2004-02-05 | Smithkline Beecham Corporation | Substituted benzanilides as modulators of the ccr5 receptor |
| WO2004039795A2 (en) * | 2002-10-29 | 2004-05-13 | Fujisawa Pharmaceutical Co., Ltd. | Amide compounds for the treatment of hyperlipidemia |
| EP1669345A4 (en) | 2003-08-29 | 2008-02-20 | Japan Tobacco Inc | ESTER DERIVATIVE AND MEDICAL USE THEREOF |
| US8101774B2 (en) | 2004-10-18 | 2012-01-24 | Japan Tobacco Inc. | Ester derivatives and medicinal use thereof |
| RU2008100543A (ru) * | 2005-06-17 | 2009-07-27 | БАСФ Акциенгезельшафт (DE) | Способ получения усилителей эффекта отбеливания |
| JP4854253B2 (ja) | 2005-09-30 | 2012-01-18 | 国立大学法人佐賀大学 | 脂質代謝改善用組成物 |
| EP3563842A1 (en) | 2009-04-29 | 2019-11-06 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
| CN104725265B (zh) * | 2015-04-13 | 2016-11-30 | 江苏海阳化纤有限公司 | 一种硝基酰胺类化合物的合成方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0832069B1 (en) * | 1995-06-07 | 2003-03-05 | Pfizer Inc. | BIPHENYL-2-CARBOXYLIC ACID-TETRAHYDRO-ISOQUINOLIN-6-YL AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND/OR APOLIPOPROTEIN B (Apo B) SECRETION |
-
1998
- 1998-04-06 CN CN98804206A patent/CN1252792A/zh active Pending
- 1998-04-06 HU HU0001910A patent/HUP0001910A2/hu unknown
- 1998-04-06 IL IL13185098A patent/IL131850A0/xx unknown
- 1998-04-06 KR KR1019997009569A patent/KR20010006479A/ko not_active Application Discontinuation
- 1998-04-06 BR BR9809577-3A patent/BR9809577A/pt not_active IP Right Cessation
- 1998-04-06 TR TR1999/02579T patent/TR199902579T2/xx unknown
- 1998-04-06 WO PCT/IB1998/000493 patent/WO1998047875A1/en not_active Application Discontinuation
- 1998-04-06 CA CA002286108A patent/CA2286108A1/en not_active Abandoned
- 1998-04-06 US US09/403,266 patent/US6147214A/en not_active Expired - Fee Related
- 1998-04-06 JP JP10545338A patent/JP2000510483A/ja not_active Ceased
- 1998-04-06 EP EP98909696A patent/EP0975598A1/en not_active Withdrawn
- 1998-04-06 AU AU64159/98A patent/AU6415998A/en not_active Abandoned
- 1998-04-06 PL PL98336481A patent/PL336481A1/xx unknown
- 1998-04-15 TW TW087105745A patent/TW413676B/zh active
- 1998-04-16 AR ARP980101764A patent/AR012452A1/es unknown
- 1998-04-17 ZA ZA9803244A patent/ZA983244B/xx unknown
- 1998-06-04 ID IDW991213A patent/ID23387A/id unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100366252C (zh) * | 2002-08-12 | 2008-02-06 | 詹森药业有限公司 | 作为载脂蛋白b分泌抑制剂的n-芳基六氢吡啶取代的联苯基羧酰胺 |
| CN105418513A (zh) * | 2015-11-13 | 2016-03-23 | 上海应用技术学院 | 一种5-(1,3-二硝基丙-2-基)-1h-咪唑化合物及制备方法 |
| CN105418514A (zh) * | 2015-11-18 | 2016-03-23 | 上海应用技术学院 | 一种(e)-叔丁基-5-(2-硝基乙烯基)-1h-咪唑-1-甲酸叔丁酯及其制备方法 |
| CN105418514B (zh) * | 2015-11-18 | 2018-07-31 | 上海应用技术学院 | 一种(e)-叔丁基-5-(2-硝基乙烯基)-1h-咪唑-1-甲酸叔丁酯及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| PL336481A1 (en) | 2000-06-19 |
| AR012452A1 (es) | 2000-10-18 |
| WO1998047875A1 (en) | 1998-10-29 |
| ID23387A (id) | 2000-04-20 |
| BR9809577A (pt) | 2000-07-04 |
| ZA983244B (en) | 1999-10-18 |
| IL131850A0 (en) | 2001-03-19 |
| US6147214A (en) | 2000-11-14 |
| TR199902579T2 (xx) | 2000-01-21 |
| JP2000510483A (ja) | 2000-08-15 |
| KR20010006479A (ko) | 2001-01-26 |
| AU6415998A (en) | 1998-11-13 |
| CA2286108A1 (en) | 1998-10-29 |
| EP0975598A1 (en) | 2000-02-02 |
| HUP0001910A2 (hu) | 2000-10-28 |
| TW413676B (en) | 2000-12-01 |
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