CN104870436B - 用于制备(2‑甲基‑1‑(3‑甲基苄基)‑1H‑苯并[d]咪唑‑5‑基)(哌啶‑5‑基)甲酮的方法 - Google Patents
用于制备(2‑甲基‑1‑(3‑甲基苄基)‑1H‑苯并[d]咪唑‑5‑基)(哌啶‑5‑基)甲酮的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 36
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- 229940049706 benzodiazepine Drugs 0.000 title claims abstract description 20
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- 150000002460 imidazoles Chemical class 0.000 title claims abstract description 18
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 title abstract description 5
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- 125000005605 benzo group Chemical group 0.000 title abstract 3
- 239000000126 substance Substances 0.000 claims abstract description 60
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- 150000001412 amines Chemical class 0.000 claims abstract description 13
- 238000000746 purification Methods 0.000 claims abstract description 7
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- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical class CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 claims description 6
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- 239000007864 aqueous solution Substances 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及用于制备具有作为蛋白酶激活受体‑2(PAR‑2)抑制剂活性的(2‑甲基‑1‑(3‑甲基苄基)‑1H‑苯并[d]咪唑‑5‑基)(哌啶‑5‑基)甲酮及其中间体的方法。当使用根据本发明的胺化合物作为新中间体化合物来制备由化学式1表示的(2‑甲基‑1‑(3‑甲基苄基)‑1H‑苯并[d]咪唑‑5‑基)(哌啶‑5‑基)甲酮(其具有作为PAR‑2抑制剂的活性并可用于治疗和预防炎性疾病)时，由于不需要引入保护基和去保护基反应，所以整体上减少了反应步骤，节约了成本，结晶有效并且提高了总产率。此外，关于为最终产物的由化学式1表示的化合物的分离和纯化，可使用适用于工业规模合成的结晶方法、萃取方法等，从而将是非常经济的。
Description
技术领域
本发明涉及用于制备由以下化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮(其已知为具有作为蛋白酶激活受体-2(proteaseactivated receptor-2，PAR-2)抑制剂之活性的化合物)及其中间体的方法：
[化学式1]
背景技术
由以下化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮可用作具有作为蛋白酶激活受体-2(PAR-2)抑制剂的活性并在包括特应性皮炎等的炎性皮肤病中具有抗炎功能的组合物。
[化学式1]
Neopharm Co.，Ltd.和本发明人提交的国际专利申请No.WO12/026766公开了作为PAR-2抑制剂的化合物的效力及其制备方法。相应专利中所公开的化合物的制备方法如以下反应式1所示：
[反应式1]
所述制备方法包括引入保护基、通过亲核取代反应引入苄基胺基、硝基的还原反应、苯并咪唑的环化反应、去保护反应和脱水缩合反应，其中4-氟-硝基苯甲酸用作原料。然而，该方法的缺点在于该过程由多个反应步骤组成，总产率不高而且每个步骤中均需要进行柱色谱，从而不适合于大批量生产。
发明内容
技术问题
本发明人已进行了努力来克服上述的制备方法存在的问题，并因此发现了与现有制备方法相比能够减少反应步骤、降低成本并且通过除去保护基之引入和去保护反应而进行有效结晶的新中间体，从而完成了本发明。
本发明的一个目的是提供用于制备(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮的方法，与相关领域技术相比，所述方法不但能够减少反应步骤的总数量并提高总产率，而且能够通过在分离和纯化方法中使用适用于工业规模合成的结晶方法、萃取方法等而更为简单和经济并具有高纯度。
本发明的另一个目的是提供用于制备(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮的中间体以及制备所述中间体的方法。
技术方案
在一个一般方面中，提供了用于制备由化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮及其中间体的方法，所述(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮可用作具有作为蛋白酶激活受体-2(PAR-2)抑制剂的活性并且在包括特应性皮炎等的炎性皮肤病中具有抗炎功能的组合物。
此外，各种形式的盐能够从由以下化学式1表示的化合物来制备，并且本发明还包括其可药用盐。根据本发明的方法可以以工业规模应用。特别地，根据本发明，使用新中间体使得不需要现有制备方法中必须进行的引入保护基和去保护反应，可减少反应步骤的总数量，可降低成本并且可进行有效结晶。此外，本发明包括可用作中间体的新的胺化合物、其加成盐和其制备方法，所述胺化合物能够降低成本并进行有效结晶，以便进行工业规模的化学制备方法。
[化学式1]
下文中，将更详细地描述本发明。
如反应式2所示，本发明提供了用于制备由化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮或其可药用盐的方法，所述方法包括：
使由以下化学式4表示的4-氯-3-硝基苯甲酸与哌啶进行脱水缩合反应以制备由以下化学式3表示的化合物；以及
使由以下化学式3表示的化合物与3-甲基苄胺反应以制备由以下化学式2-1表示的化合物；
还原由以下化学式2-1表示的化合物的硝基以制备由以下化学式2-2表示的胺化合物；以及
使由以下化学式2-2表示的胺化合物进行环化反应以制备(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮：
[反应式2]
下文中，将更详细地描述所述方法中的每个步骤。
[步骤a]制备由化学式3表示的化合物
由化学式3表示的化合物通过由化学式4表示的4-氯-3-硝基苯甲酸作为原料与哌啶的脱水缩合反应来获得。脱水缩合反应在有机合成领域中是众所周知的，并且可通过多种方法来进行。原料4-氯-3-硝基苯甲酸可以是市售的或者可根据本领域已知的简单方法(例如，美国专利No.4,036,838)通过4-氯-苯甲酸的硝化反应容易地获得。
该反应可通过将亚硫酰氯添加至二氯甲烷溶剂中以获得作为中间体的4-氯-3-硝基-苯甲酰氯并添加哌啶，随后在室温下搅拌来进行；或者更优选地，通过与激活剂如1，1’-羰基二咪唑(CDI)或1-[3-(二甲基氨基)丙基]-3-乙基-碳二亚胺(EDC)反应，并添加哌啶，随后在室温下搅拌来进行。
在本发明的一个特定实施方案中，化合物通过以下过程来制备：根据已知方法(美国专利No.6,313,115B1)使由化学式4表示的4-氯-3-硝基苯甲酸与1，1′-羰基二咪唑在乙酸乙酯溶剂中反应，添加哌啶，随后在室温下搅拌。后处理时，添加蒸馏水以萃取有机层，并移除溶剂以获得黄色固体。如果需要的话，则可通过从乙醇中重结晶进行纯化而获得高纯度的期望的由化学式3表示的化合物。
[步骤b]制备由化学式2-1表示的化合物
由化学式2-1表示的化合物通过在回流下搅拌有机溶剂中由化学式3表示的化合物和3-甲基苄胺的混合物以进行亲核取代反应来获得。
这里，可用的溶剂包括：腈类，如乙腈；醇类，如乙醇、异丙醇等；醚类，如四氢呋喃、二异丙醚、二氧六环、1，2-二甲氧基乙烷等；芳香烃类，如苯、甲苯等；以及酰胺类，如二甲基乙酰胺、二甲基甲酰胺、n-甲基吡咯烷酮等。然而，本发明不限于这些惰性溶剂，并且这些溶剂可单独使用或组合使用。优选地，所述溶剂可为二甲基乙酰胺、n-甲基吡咯烷酮等，更优选地为n-甲基吡咯烷酮。反应温度的范围可为60℃至130℃，优选100℃至120℃。
根据所使用的3-甲基苄胺的量，该反应可在碱存在或碱不存在两种情况下进行，即，当基于由化学式3表示的化合物使用2.5当量或更多的过量3-甲基苄胺时，可不使用碱；但是优选使用1.2当量的3-甲基苄胺和0.6当量至1.2当量的碱。适当的碱的实例可包括：碱金属碳酸盐和碱土金属碳酸盐，如碳酸钠、碳酸钾和碳酸钙；碱金属氢氧化物和碱土金属氢氧化物，如氢氧化钠、氢氧化钾和氢氧化钙；乙酸盐，如乙酸钠、乙酸钾和乙酸铵；有机碱，如三乙胺、二乙基异丙胺、甲基吡啶或吡啶；以及磷酸盐，如磷酸钾。
用于进行重结晶的溶剂的实例可包括：C1-C4醇类，如甲醇、乙醇、正丙醇、异丙醇、正丁醇和异丁醇；C4-C8酯类，如乙酸乙酯；C4-C8醚类，如甲基叔丁基醚和异丙醚；或者上述溶剂混合物；或者上述溶剂和水的混合物。用于进一步纯化由化学式2-1表示的化合物的重结晶的最适当实例是从乙醇中重结晶。
在本发明的一个特定实施方案中，所述反应通过在120℃下使作为溶剂的n-甲基吡咯烷酮中由化学式3表示的化合物与1.2当量的3-甲基苄基胺和1.2当量的碳酸氢钠的混合物搅拌2小时来进行。后处理时，将反应混合物冷却至室温，并用乙酸乙酯稀释，用氢氧化钠水溶液和蒸馏水洗涤。然后，除去有机溶剂以获得固体残留物，随后从乙醇中进行重结晶。
[步骤c]制备由化学式2-2表示的化合物
由化学式2-2表示的胺化合物通过在惰性溶剂中还原获得自上述反应的由化学式2-1表示的化合物的硝基来获得。
本发明中可使用任何溶剂而无限制，只要其不显著抑制本反应的进展即可。溶剂的实例可包括：醇类，如甲醇、乙醇、丙醇等；醚类，如四氢呋喃、二异丙醚、二氧六环、1，2-二甲氧基乙烷等；有机酸，如乙酸等；无机酸，如盐酸等；水；等等。硝基的还原可通过使用还原剂或通过氢化方法来进行。可用于本反应的还原剂的实例可包括金属还原剂，如硼烷络合物、二硼烷、硼氢化钠、硼氢化锂、硼氢化钠-氯化锂、氢化铝锂或二异丁基氢化铝，并且在酸性条件下可使用金属如锌、铁、锡、氯化锡等，并且只有锌还可用于中性或碱性条件下。此外，氢化方法可在标准压力或大气压下进行。过渡金属如雷尼镍、钯-碳、钯氧化物、铂、铂黑、铂氧化物、硫化碳载铂、铑、钌、氧化铝等用作催化剂。当进行催化还原时，甲酸铵、磷酸二氢钠或肼可用作氢源。当在酸性条件下进行还原时，可使用化学计算量或过量的还原剂。一般来说，使用过量的还原剂。在氢化方法中，雷尼镍可以以基于由化学式2-1表示的化合物的5重量％至30重量％来使用，并且贵金属催化剂如铂、钯等可以以基于由化学式2-1表示的化合物的0.02重量％至30重量％来使用。
反应温度可选自0℃至150℃，优选10℃至110℃的范围。反应时间根据反应规模、反应温度等可变；然而，其可选自数分钟至48小时的范围。
[步骤d]制备由化学式1表示的化合物
由化学式1表示的化合物通过在乙酸中使由化学式2-2表示的胺化合物与原乙酸酯反应以形成苯并咪唑环来获得。这里，优选地通过使用乙酸作为溶剂，在回流下搅拌胺化合物和过量原甲酸三甲酯的混合物来进行环化反应以获得苯并咪唑。
用于进行结晶的溶剂的实例包括：烃类，如甲苯和二甲苯；C4-C8酯类，如乙酸乙酯；C4-C8醚类，如甲基叔丁基醚和异丙醚；或者如上所述的溶剂的混合物。用于进一步纯化由化学式1表示的化合物的最适当的方法是从乙酸乙酯中重结晶。
由化学式1表示的化合物可以以各种盐的形式来制备，其中所述盐包括可用作药剂的所有可能的盐。根据本发明的可药用盐包括通过添加可药用游离酸所形成的酸盐。有机酸和无机酸二者均可用作游离酸，其中待使用的无机酸包括盐酸、溴酸、硫酸、磷酸等，并且待使用的有机酸包括柠檬酸、乙酸、乳酸、马来酸、富马酸、葡萄糖酸、甲磺酸、葡萄糖酸、琥珀酸、4-甲苯磺酸、三氟乙酸、葡萄糖醛酸、帕莫酸、谷氨酸、天冬氨酸等。此外，本发明包括由化学式1表示的化合物的盐的水合物，并且特别地，当所述盐具有吸湿性时，根据本发明的化合物可作为具有结晶度的水合物使用。
本发明所使用的溶剂和试剂可用本领域已知的功能性替代物或其衍生物来代替，并且可调整反应条件如反应时间、反应温度等以优化反应。与本发明类似地，可从所述反应中分离产物，并且在一些情况中，其可通过本领域的一般方法如萃取、结晶和研磨进行进一步纯化。
此外，本发明提供了由以下化学式2表示的新的胺化合物，其作为用于制备由化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮的中间体：
[化学式2]
在化学式2中，R表示硝基(NO2)或氨基(NH2)。
有利效果
如上所述，当使用根据本发明的新中间体化合物来制备由化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮(其具有作为PAR-2抑制剂的活性并且可用于治疗和预防炎性疾病)时，不需要引入保护基和去保护反应，使得可减少反应步骤的总数量，可降低成本，可进行有效结晶并且可提高总产率。此外，与相关领域技术相比，通过在分离和纯化方法中使用适用于工业规模合成的结晶方法、萃取方法等，可以以工业规模经济地合成具有高纯度的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮。
最佳实施方式
下文中，将对本发明的优选实施方案和实验实施例进行描述以帮助理解本发明。然而，提供以下实施方案和实验实施例仅为了更容易地理解本发明，因此，本发明不限于此。
[实施例1]由化学式2-1表示的化合物的制备
制备由化学式3表示的化合物
将1，1’-羰基二咪唑(4.22g，26.04mmol)溶解于50mL乙酸乙酯中，并且在室温下向其中缓慢添加4-氯-3-硝基苯甲酸(式4，5.00g，24.80mmol)并搅拌1小时。向其中缓慢添加哌啶(2.7mL，27.3mmol)并在室温下搅拌1小时，然后，所得混合物依次用6N盐酸溶液(30mL，两次)、碳酸氢钠饱和水溶液(50mL)、蒸馏水(50mL)和盐水(50mL)洗涤。有机层经无水硫酸钠(20g)干燥并在减压下浓缩以获得作为黄色结晶固体的由化学式3表示的化合物(6.39g，95％)。
1H NMR(600MHz，氯仿-d1)δ＝7.92(d，J＝2.4Hz，1H)，7.60(d，J＝8.4Hz，1H)，7.56(dd，J1＝8.1Hz，J2＝2.1Hz，1H)，3.71(br，2H)，3.35(br，2H)，1.71-1.54(br，6H).
C12H13ClN2O3的LCMS测定值：269(M+H+)
制备由化学式2-1表示的化合物
将由化学式3表示的化合物(5.00g，18.61mmol)溶解在n-甲基吡咯烷酮(15mL)中，向其中添加碳酸氢钠(1.88g，22.38mmol)，并且在室温下缓慢地添加3-甲基苄胺(2.8mL，22.3mmol)。将反应混合物在120℃下搅拌2小时，用60mL乙酸乙酯稀释并用蒸馏水(50mL)洗涤，然后，依次用2N氢氧化钠水溶液(40mL，两次)、蒸馏水(40mL，两次)和盐水(40mL)洗涤有机层。所得有机层经无水硫酸钠(20g)干燥并在减压下过滤以获得橙色固体，随后在无水乙醇中重结晶以获得作为橙色结晶固体的由化学式2-1表示的化合物(6.13g，93％)。
1H NMR(600MHz，氯仿-d1)δ＝8.55(t，J＝5.4Hz，1H)，8.30(d，J＝1.8Hz，1H)，7.51(dd，J1＝8.7Hz，J2＝2.1Hz，1H)，7.14(m，3H)，6.85(d，J＝9.0Hz，1H)，4.54(d，J＝5.4Hz，2H)，3.55(br，4H)，2.36(s，3H)，1.67-1.61(br m，6H)
C20H23N3O3的LCMS测定值：354(M+H+)
[实施例2]由化学式2-2表示的胺化合物的制备
将铁(2.85g，51.0mmol)和1.5mL乙酸添加至乙醇和水的混合溶剂(5∶2，28mL)中并在120℃下搅拌2小时。冷却至室温之后，向其中添加由化学式2-1表示的化合物(3.00g，8.49mmol)，并向其中再次添加乙醇和水的混合溶剂(5∶2，14mL)。将反应混合物在110℃下搅拌1小时，并在其仍然是热的时使用硅藻土在减压下进行过滤，并用热乙醇洗涤。浓缩滤液并添加2N氢氧化钠水溶液直到pH为8或更大。然后，用乙酸乙酯(50mL，两次)萃取所得反应混合物。收集有机层，用饱和碳酸钠溶液(20mL，两次)、蒸馏水(30mL，两次)和盐水(30mL)洗涤并且经无水硫酸钠干燥，随后在减压下浓缩以获得作为米黄色固体的由化学式2-2表示的化合物(2.74g，99％)。由化学式2-2表示的胺化合物可直接用于下一步合成而无需进行进一步的纯化过程。
1H NMR(600MHz，氯仿-d1)δ＝7.24(t，J＝7.8Hz，1H)，7.18(d，J＝7.8Hz，2H)，7.10(d，J＝7.2Hz，1H)，6.87-6.84(m，2H)，6.59(d，J＝7.8Hz，1H)，4.29(s，2H)，3.54(br s，7H)，2.35(s，3H)，1.65(m，2H)，1.57(br，4H)
C20H25N3O的LCMS测定值：324(M+H+)
[实施例3]由化学式1表示的化合物的制备
将通过实施例2获得的由化学式2-2表示的胺化合物(2.74g，8.48mmol)添加至乙酸(16mL)和原乙酸三乙酯(4.6mL，25.1mol)中并在回流下搅拌2小时。在减压下浓缩反应混合物并用乙酸乙酯(50mL)稀释。然后，向其中添加饱和碳酸钠溶液直到pH为8或更大，并通过分液漏斗分离有机层。有机层用蒸馏水(40mL)和盐水(40mL)洗涤，经无水硫酸钠干燥，随后过滤并在减压下浓缩以获得黄色固体(2.75g)。用3mL乙酸乙酯对固体进行重结晶以获得作为白色固体的由化学式1表示的化合物(2.23g，76％)。
1H NMR(600MHz，氯仿-d1)δ＝7.74(t，J＝0.6Hz，1H)，7.30(dd，J1＝8.1Hz，J2＝0.5Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.20(d，J＝7.8Hz，1H)，7.09(d，J＝7.8Hz，1H)，6.84-6.83(m，2H)，5.29(s，2H)，3.72(br s，2H)，3.54(br s，7H)，3.42(br s，2H)，2.58(s，3H)，2.29(s，3H)，1.67(m，2H)，1.57(br，4H)
C22H25N3O的LCMS测定值：347(M+H+)
工业适用性
如上所述，当使用根据本发明的新中间体化合物来制备由化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮(其具有作为PAR-2抑制剂的活性并且可用于治疗和预防炎性疾病)时，不需要引入保护基和去保护反应，使得可减少反应步骤的总数量，可降低成本，可进行有效结晶并且可提高总产率。此外，与相关领域技术相比，通过在分离和纯化方法中使用适用于工业规模合成的结晶方法、萃取方法等，可以以工业规模经济地合成具有高纯度的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮。
Claims (2)
1.一种用于制备由以下化学式1表示的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮或其可药用盐的方法，所述方法包括：
使由以下化学式4表示的4-氯-3-硝基苯甲酸与哌啶进行脱水缩合反应以制备由化学式3表示的化合物，
使所述由化学式3表示的化合物与3-甲基苄胺反应以制备由化学式2-1表示的化合物，
通过还原由化学式2-1表示的化合物的硝基来制备由化学式2-2表示的胺化合物，
使由以下化学式2-2表示的所述胺化合物进行环化反应以制备(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮，并且
通过从乙酸乙酯中重结晶来纯化所制备的(2-甲基-1-(3-甲基苄基)-1H-苯并[d]咪唑-5-基)(哌啶-5-基)甲酮：
[化学式1]
[化学式2-2]
[化学式2-1]
[化学式3]
[化学式4]
2.一种由以下化学式2表示的胺化合物：[化学式2]
在化学式2中，R表示硝基或氨基。
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| CN1305464A (zh) * | 1998-05-22 | 2001-07-25 | 西奥斯股份有限公司 | 杂环化合物和治疗心力衰竭及其它疾病的方法 |
| WO2012026766A2 (ko) * | 2010-08-25 | 2012-03-01 | (주)네오팜 | 신규한 헤테로고리 화합물 및 이를 이용한 염증성 질환 치료용 조성물 |
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| US20040063938A1 (en) * | 2002-09-30 | 2004-04-01 | Pfizer Inc | Process for preparing haloalkyl pyrimidines |
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| CN1247534A (zh) * | 1997-02-13 | 2000-03-15 | 加利福尼亚大学董事会 | 可以增强ampa受体活性的苯并呋喃化合物 |
| CN1305464A (zh) * | 1998-05-22 | 2001-07-25 | 西奥斯股份有限公司 | 杂环化合物和治疗心力衰竭及其它疾病的方法 |
| WO2012026766A2 (ko) * | 2010-08-25 | 2012-03-01 | (주)네오팜 | 신규한 헤테로고리 화합물 및 이를 이용한 염증성 질환 치료용 조성물 |
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