CN107033056B - 一种2-甲基-4-苯基-1-吡咯啉的制备方法 - Google Patents
一种2-甲基-4-苯基-1-吡咯啉的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- ZYZBWRYJBZDCIQ-UHFFFAOYSA-N 5-methyl-3-phenyl-3,4-dihydro-2h-pyrrole Chemical compound C1C(C)=NCC1C1=CC=CC=C1 ZYZBWRYJBZDCIQ-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- YMXDOZWKTUBYLU-UHFFFAOYSA-N 1-nitroethenylbenzene Chemical group [O-][N+](=O)C(=C)C1=CC=CC=C1 YMXDOZWKTUBYLU-UHFFFAOYSA-N 0.000 claims abstract description 11
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 8
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 7
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
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- 238000003756 stirring Methods 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 7
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical group [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 229930182821 L-proline Natural products 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
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- 239000000047 product Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 4
- HDACXQXSTHNYRG-UHFFFAOYSA-N 5-nitro-4-phenylpentan-2-one Chemical compound CC(=O)CC(C[N+]([O-])=O)C1=CC=CC=C1 HDACXQXSTHNYRG-UHFFFAOYSA-N 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- ZFOMKMMPBOQKMC-KXUCPTDWSA-N L-pyrrolysine Chemical compound C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H]([NH3+])C([O-])=O ZFOMKMMPBOQKMC-KXUCPTDWSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
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- 229960005370 atorvastatin Drugs 0.000 description 2
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- 150000001875 compounds Chemical class 0.000 description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 2
- 229950005741 rolipram Drugs 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- PIAOLBVUVDXHHL-VOTSOKGWSA-N β-nitrostyrene Chemical compound [O-][N+](=O)\C=C\C1=CC=CC=C1 PIAOLBVUVDXHHL-VOTSOKGWSA-N 0.000 description 2
- UXYYVAAPXNRMDS-UHFFFAOYSA-N 1-phenyl-2,3-dihydropyrrole Chemical compound C1=CCCN1C1=CC=CC=C1 UXYYVAAPXNRMDS-UHFFFAOYSA-N 0.000 description 1
- DQBQWWSFRPLIAX-UHFFFAOYSA-N 2-acetyl-1-pyrroline Chemical compound CC(=O)C1=NCCC1 DQBQWWSFRPLIAX-UHFFFAOYSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- VDSBGGXVMPNZNL-UHFFFAOYSA-N N=1CCCC1C(C)=O.C(C)(=O)C1=NCCC1 Chemical compound N=1CCCC1C(C)=O.C(C)(=O)C1=NCCC1 VDSBGGXVMPNZNL-UHFFFAOYSA-N 0.000 description 1
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- 239000002262 Schiff base Substances 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001344 alkene derivatives Chemical class 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- -1 phenyl-substituted 1-pyrroline Chemical class 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明公开了一种2‑甲基‑4‑苯基‑1‑吡咯啉的制备方法，包括如下步骤：步骤S1，苯甲醛和硝基甲烷在碱金属氢氧化物催化下制备苯基硝基乙烯；步骤S2，苯基硝基乙烯和丙酮在L‑脯氨酸的催化下发生加成反应；步骤S3，加成产物经锌粉、铵盐还原关环得目标产物。本发明制备方法的合成原料易得，价格便宜，操作条件温和。路线合成简便易行，每一步反应结束后都不需要使用硅胶柱层析，既适合实验室小量制备做科研，又适合工业化生产放大。有望推动相关药物的工艺改进，为它们的合成提供多种丰富的路线。
Description
技术领域
本发明属于药物化学领域，涉及药物中间体合成工艺的的改进，具体涉及一种2-甲基-4-苯基-1-吡咯啉的制备方法。
背景技术
苯基吡咯类衍生物是一类结构独特应用广泛的有机物，苯环的亲脂性和吡咯的碱性中心的存在使它们具有特定的生物活性，此类结构存在于多种药物分子中，如抗真菌药硝吡咯菌素，降血脂药阿伐他丁(Atorvastatin)，磷酸二酯酶(PDE)抑制剂咯利普兰(Rolipram)等，为人类抵抗疾病的侵袭提供帮助。芳环取代的吡咯杂环的结构成为有机合成的研究重点之一。
硝吡咯菌素、阿伐他丁和咯利普兰化学结构式如下，依次为标号A、B、C：
值得注意的是，在吡咯类衍生物中，1-吡咯啉也被发现具有某些特定的活性，比如2-乙酰基-1-吡咯啉(2-Acetyl-1-pyrroline)具有特殊的气味，在大米、面包，甚至猫科动物尿液中被发现。吡咯赖氨酸(Pyrrolysine)也是一种稀有氨基酸，也是生物体内的关键的信息分子。
2-乙酰基-1-吡咯啉和吡咯赖氨酸化学结构式如下，依次为标号D、E：
对苯基取代的1-吡咯啉的研究是发现药物的有益途径，但其合成方法较少，已经报道的方法第一种是通过对氨基的烯烃衍生物进行催化氧化，使得烯烃发生胺化反应(J.Am.Chem.Soc.2002，124,186-187，Organometallics 2016,35,3452-3460)，分子内关环得到苯基吡咯啉，此类反应往往需要贵重的金属配合物作为催化剂来完成，比如Ru和Ta；第二种方法是分子内羰基对席夫碱的氮原子的缩合反应(Bull.Chem.Soc.Jpn,1986,59,2537-2545)，但该反应原料不易得到，没有普遍性。
发明内容
本发明的目的在于克服现有技术的不足，提供一种2-甲基-4-苯基-1-吡咯啉的制备方法。
本发明的上述目的通过如下技术方案实现：
一种2-甲基-4-苯基-1-吡咯啉的制备方法，包括如下步骤：
步骤S1，苯甲醛和硝基甲烷在碱金属氢氧化物催化下制备苯基硝基乙烯；
步骤S2，苯基硝基乙烯和丙酮在L-脯氨酸的催化下发生加成反应；
步骤S3，加成产物经锌粉、铵盐还原关环得目标产物；
反应式如下，
优选地，步骤S1先使用有机溶剂将原料苯甲醛和硝基甲烷溶解并搅拌均匀，再加入碱金属氢氧化物的水溶液至反应体系进行催化反应。
优选地，所述有机溶剂为甲醇。
优选地，所述碱金属氢氧化物为氢氧化钾。
优选地，步骤S2使用有机溶剂将苯基硝基乙烯、丙酮和L-脯氨酸溶解并搅拌均匀使其充分反应。
优选地，所述有机溶剂为DMSO。
优选地，步骤S3以甲醇为反应溶剂，将步骤S2加成产物与锌粉、铵盐加入反应溶剂中反应。
优选地，所述铵盐为氯化铵或甲酸铵。
本发明的优点：
本发明公开了以苯甲醛为起始物制备2-甲基-4-苯基-1-吡咯啉的新方法，以苯甲醛为原料，和硝基甲烷反应制备苯基硝基乙烯，产物和丙酮反应得到硝基烷烃，然后还原硝基得到目标物。该类苯基吡咯杂环的合成原料易得，价格便宜，操作条件温和。路线合成简便易行，每一步反应结束后都不需要使用硅胶柱层析，既适合实验室小量制备做科研，又适合工业化生产放大。有望推动相关药物的工艺改进，为它们的合成提供多种丰富的路线。
具体实施方式
下面结合实施例具体介绍本发明的实质性内容，但并不以此限定本发明的保护范围。实验中未详述的试验操作均为本领域技术人员所熟知的常规试验操作。
反应实例1 1-苯基-2-硝基乙烯的制备
冰水浴中，向100ml的单口瓶中加入苯甲醛(5.3g，50mmol)，10ml甲醇和硝基甲烷(3.05g，50mmol)搅拌反应，然后将含2.17gNaOH的5ml水溶液缓慢加入到反应液中，并使温度保持在15℃以下。有白色沉淀产生，TLC跟踪(Rf＝0.75，展开剂：1：3＝乙酸乙酯：石油醚v/v)，反应完全后，加入50ml冰水到装有反应液的单口瓶中搅拌，之后将产物缓慢滴加到25ml的4M稀盐酸中，过程中会慢慢析出固体。加完之后继续搅拌15分钟，将固体抽滤，静置，风干得到淡黄色固体，5g，67％，熔点54-58℃。1H NMR(400MHz,CDCl3)δ7.93(1H)，7.39–7.30(5H)，7.48(1H)。确定为1-苯基-2-硝基乙烯。
反应实例2 4-苯基-5-硝基-2-戊酮
向100ml单口瓶中加入15mLDMSO，苯基硝基乙烯(0.63g，4.2mmol)，丙酮(3.1ml，42mmol)，L-脯氨酸(0.19g，1.66mmol)，磁力搅拌，r，t.下反应24h，利用TLC跟踪(Rf＝0.68，展开剂：1：3＝乙酸乙酯：石油醚v/v)，直到其显示反应完全。将单口瓶中的反应液倒入分液漏斗，加入30ml水，搅拌分液。然后用乙酸乙酯(3*20ml)萃取，用30ml饱和食盐水洗涤有机相，无水硫酸镁干燥，过滤除去MgSO4，旋蒸除去溶剂，得粗产物为油状物，室温放置固化，0.79g，产率90％。1H NMR(400MHz,CDCl3)δ7.20-7.38(m,5H,H-Ar),4.72(dd,1H,J＝9Hz、4Hz，-CH2-NO2)，4.63(dd,1H,J＝9Hz、8Hz，-CH2-NO2)，4.03(m,1H,-CH-)，2.95(d,2H,J＝8Hz，H-3)，2.15(s,3H,H-1)。确定为4-苯基-5-硝基-2-戊酮。
反应实例3 2-甲基-4-苯基-1-吡咯啉的制备
取4-苯基-5-硝基-2-戊酮0.5g(2.43mmol)加入100ml单口瓶中，加入0.28g(36.4mmol)甲酸铵、2.37g(36.4mmol)锌粉，加入15ml甲醇搅拌，室温反应25min，TLC点板(Rf＝0.45，展开剂为乙酸乙酯：石油醚＝1：3)发现反应完全。将反应液倒入15ml乙酸乙酯中，搅拌，抽滤，滤饼以乙酸乙酯洗涤，滤液以30ml水和30ml饱和食盐水洗涤，硫酸钠干燥，蒸干得到油状物，0.29g，硅胶柱层析得到纯品0.213g，产率55％。1HNMR(400MHz,CDCl3)δ7.12-7.32(m,5H,H-Ar),4.25(m,1H,-CH2-N-)，3.85(m,1H,-CH2-N-)，3.53(m,1H,H-4)，3.00(dd,1H,J＝8Hz，16Hz，H-3b)，2.62(dd,1H,J＝12Hz，8Hz，H-3a)，2.10(s,3H,CH3-)。和文献(Bull.Chem.Soc.Jpn,1986,59,2537-2545)一致。LC-MS：calculated C11H13N1，159.10，found160.0(M+H+)。确定为2-甲基-4-苯基-1-吡咯啉。
本发明公开了以苯甲醛为起始物制备2-甲基-4-苯基-1-吡咯啉的新方法，以苯甲醛为原料，和硝基甲烷反应制备苯基硝基乙烯，产物和丙酮反应得到硝基烷烃，然后还原硝基得到目标物。该类苯基吡咯杂环的合成原料易得，价格便宜，操作条件温和。路线合成简便易行，每一步反应结束后都不需要使用硅胶柱层析，既适合实验室小量制备做科研，又适合工业化生产放大。有望推动相关药物的工艺改进，为它们的合成提供多种丰富的路线。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。
Claims (8)
1.一种2-甲基-4-苯基-1-吡咯啉的制备方法，其特征在于，包括如下步骤：
步骤S1，苯甲醛和硝基甲烷在碱金属氢氧化物催化下制备苯基硝基乙烯；
步骤S2，苯基硝基乙烯和丙酮在L-脯氨酸的催化下发生加成反应；
步骤S3，加成产物经锌粉、铵盐还原关环得目标产物；
反应式如下，
2.根据权利要求1所述的制备方法，其特征在于：步骤S1先使用有机溶剂将原料苯甲醛和硝基甲烷溶解并搅拌均匀，再加入碱金属氢氧化物的水溶液至反应体系进行催化反应。
3.根据权利要求1或2所述的制备方法，其特征在于：所述有机溶剂为甲醇。
4.根据权利要求1或2所述的制备方法，其特征在于：所述碱金属氢氧化物为氢氧化钾。
5.根据权利要求1所述的制备方法，其特征在于：步骤S2使用有机溶剂将苯基硝基乙烯、丙酮和L-脯氨酸溶解并搅拌均匀使其充分反应。
6.根据权利要求1或5所述的制备方法，其特征在于：所述有机溶剂为DMSO。
7.根据权利要求1所述的制备方法，其特征在于：步骤S3以甲醇为反应溶剂，将步骤S2加成产物与锌粉、铵盐加入反应溶剂中反应。
8.根据权利要求1或7所述的制备方法，其特征在于：所述铵盐为氯化铵或甲酸铵。
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