CN110028435A - 一种合成3-甲酸酯-2-吡咯啉类化合物的方法 - Google Patents
一种合成3-甲酸酯-2-吡咯啉类化合物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 17
- -1 4-aminobutyric acid compound Chemical class 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract 2
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001503 aryl iodides Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
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- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
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- 239000007788 liquid Substances 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
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- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutanoic acid Natural products NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- 229960003692 gamma aminobutyric acid Drugs 0.000 abstract description 5
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- 229910052740 iodine Inorganic materials 0.000 abstract 2
- 239000011630 iodine Substances 0.000 abstract 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 150000004065 2-pyrrolines Chemical class 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical compound CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical class CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
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- 238000010523 cascade reaction Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
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- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 1
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- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
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- 238000006356 dehydrogenation reaction Methods 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
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- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical class COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
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
- C07D207/22—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
Abstract
一种合成3‑甲酸酯‑2‑吡咯啉类化合物的方法,所述方法为:将4‑氨基丁酸类化合物(I)、N,N‑二甲基甲酰胺二甲基缩醛混合,在60~70℃下搅拌2~4h,随后加入芳基碘(II)、DMEDA、DBU、CuI、DMF,在140~160℃下反应10~14h,之后反应液经后处理,得到产物3‑甲酸酯‑2‑吡咯啉类化合物(III);本发明原料廉价易得,收率较高,无复杂操作,本发明的创新点在于使用4‑氨基丁酸为原料,两步一锅合成得到3‑甲酸甲酯‑2‑吡咯啉类化合物,本发明所得的3‑甲酸甲酯‑2‑吡咯啉类化合物收率最高为81%;
Description
(一)技术领域
本发明涉及一种合成2-吡咯啉类化合物的方法,即通过4-氨基丁酸类化合物与N,N’-二甲基甲酰胺二甲基缩醛反应,高效地合成2-吡咯啉类化合物的方法。
(二)背景技术
含氮杂环骨架在很多具有生物活性或生理活性的结构中都很常见。其中,2-吡咯啉类化合物具有明显的生物活性和药用价值,在医药、农药等领域都有广泛的运用(Chem.Commun.,1999,651-652;J.Am.Chem.Soc.,1968,90(20),pp 5584–5587;J.Nat.Prod.,2004,67,2141)。在合成化学领域也是一种应用广泛的反应中间体。尤其是3-甲酸酯-2-吡咯啉类化合物,不仅有明显的生物活性,同时也是很多天然产物和活性化合物的合成中关键的中间体(J.Org.Chem.1999,64,3122-3131;Tetrahedron Lett.2011,52,2162-2164;M.Bioorg.Med;Chem.2008,16,1613-1631;Chem.Rev.,2011,111,2815;Bioorg.Med.Chem.Lett.,2008,18,1392;J.Med.Chem.,2010,53,2927;ACSMed.Chem.Lett.,2010,1,427.)。
但是目前为止,高效构建3-甲酸酯-2-吡咯啉类化合物的方法还比较少,目前的方法主要有:1)[3+2]的环加成(J.Org.Chem.1984,49,3314-3322);2)取代环丙烷与伯胺的反应(Tetrahedron Lett.1987,28,6597-6600;Angew.Chem.,Int.Ed.2015,54,227-230);3)烯基取代的β-烯氨基酯的碘代环化(J.Org.Chem.1995,60,7357-7359;Synthesis 2009,2009,3963-3966);4)Ce(IV)介导的烯丙基三甲基硅烷氧化加成β-羰基亚胺(J.Org.Chem.2004,69,6267-6272)等等。近年来,也有很多新的合成方法不断被提出,如四氢吡咯在一氧化碳和乙醇的脱氢酯化的串联反应(Chem.Commun.,2017,53,4002);2-(2,3-烯丙基)酰基乙酸酯与芳基卤化物和胺在钯催化下发生的三组分串联反应(Adv.Synth.Catal.2011,353,1676–1682)等等。虽然这些方法均能有效构筑2-吡咯啉结构,但反应中仍不可避免地存在各种各样的问题。比如氧化或还原方法需要高压,催化剂昂贵,条件苛刻,原料获取困难,底物限制等等。因此,开发以廉价易得的原料出发,通过简单的条件获得2-吡咯啉类化合物具有重要的应用价值。
(三)发明内容
本发明的目的是通过4-氨基丁酸类化合物合成3-甲酸酯-2-吡咯啉类化合物,解决以往合成3-甲酸酯-2-吡咯啉类化合物原料价格昂贵、反应条件苛刻等问题。
本发明的技术方案如下:
一种合成3-甲酸酯-2-吡咯啉类化合物的方法,所述方法为:
将4-氨基丁酸类化合物(I)、N,N-二甲基甲酰胺二甲基缩醛混合,在60~70℃下搅拌2~4h,随后加入芳基碘(II)、DMEDA(N,N'-二甲基乙二胺)、DBU(1,8-二氮杂二环十一碳-7-烯)、CuI、DMF(N,N-二甲基甲酰胺),在140~160℃下反应10~14h,之后反应液经后处理,得到产物3-甲酸酯-2-吡咯啉类化合物(III);
所述4-氨基丁酸类化合物(I)、N,N’-二甲基甲酰胺二甲基缩醛、芳基碘(II)、DMEDA、DBU、CuI的物质的量之比为1:6~8:2:0.2:2:0.1;
所述DMF的体积用量以4-氨基丁酸类化合物(I)的物质的量计为4~6mL/mmol;
所述后处理的方法为:反应结束后,反应液用乙酸乙酯萃取,萃取液经水洗,饱和NaCl水溶液洗,无水硫酸钠干燥后,浓缩,进行柱层析分离,以石油醚与乙酸乙酯体积比20~10:1的混合液作为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到产物3-甲酸酯-2-吡咯啉类化合物(III);
反应式如下:
式(I)、(II)或(III)中,
R1为:氢、苯基、C3~C5烷基或者与所连接的C形成C6~C10环烷基,优选氢、叔丁基或者与所连接的C形成环己烷基;
R2为:氢、C1~C3烷基、C1~C3烷氧基、三氟甲基、甲氧基羰基或卤素,优选氢、甲基、甲氧基、三氟甲基、甲氧基羰基或溴。
本发明具有以下优点:原料廉价易得,收率较高,无复杂操作。本发明的创新点在于使用4-氨基丁酸为原料,两步一锅合成得到3-甲酸甲酯-2-吡咯啉类化合物。本发明所得的3-甲酸甲酯-2-吡咯啉类化合物收率最高为81%。
(四)具体实施方式
下面通过具体实施例对本发明作进一步的说明,但本发明的保护范围并不仅限于此。
实施例1
1-苯基-3-甲酸甲酯-2-吡咯啉的合成
将4-氨基丁酸(51.5mg,0.5mmol),N,N’-二甲基甲酰胺二甲基缩醛(0.5ml,3.3mmol)混合后,65℃下搅拌3h。然后加入碘苯(204mg,1mmol),碘化亚铜(9.5mg,0.05mmol),DMEDA(23μL,0.1mmol),DBU(150μL,1mmol),DMF(2ml),150℃下反应12h。反应完成后,乙酸乙酯萃取,水洗,饱和食盐水洗,浓缩干燥,柱层析,得到白色粉末状产物76mg,收率为75%。
1H NMR(500MHz,CDCl3)δ7.75(t,J=1.4Hz,1H),7.34–7.29(m,2H),6.99–6.93(m,1H),6.92–6.87(m,2H),3.96(dd,J=10.7,9.3Hz,2H),3.75(s,3H),2.97(ddd,J=11.1,9.2,1.5Hz,2H).13C NMR(126MHz,CDCl3)δ142.21,141.50,129.53,120.93,113.82,106.51,50.86,49.61,27.05.HRMS calcd for C12H13NO2:204.1019[M+H]+,found:204.1022.
实施例2
1-(4-甲基苯基)-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用芳基碘为对甲基碘苯(218mg,1mmol),得到白色粉末状产物88mg,收率为81%。
1H NMR(500MHz,DMSO-d6)δ7.95(t,J=1.4Hz,1H),7.11–7.07(m,2H),7.02–6.97(m,2H),3.90(dd,J=10.8,9.4Hz,2H),3.62(s,3H),2.86–2.74(m,2H),2.23(s,3H).13C NMR(126MHz,DMSO-d6)δ142.87,129.73,114.08,104.83,50.29,49.19,39.69,39.52,39.35,26.64,20.10.HRMS calcd for C13H16NO2:218.1176[M+H]+,found:218.1178.
实施例3
1-(4-甲氧基苯基)-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用芳基碘为对碘苯甲醚(234mg,1mmol),得到白色粉末状产物93mg,收率为80%。
1H NMR(500MHz,CDCl3)δ7.66(t,J=1.4Hz,1H),6.86(d,J=7.3Hz,4H),3.94(dd,J=10.8,9.4Hz,2H),3.79(s,3H),3.74(s,3H),2.96(ddd,J=11.0,9.3,1.4Hz,2H).13C NMR(126MHz,DMSO-d6)δ165.43,153.85,143.32,135.11,115.37,114.65,104.05,55.24,50.19,49.53,26.66.HRMS calcd for C13H16NO3:234.1125[M+H]+,found:234.1126.
实施例4
1-(4-溴基苯基)-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用芳基碘为对溴碘苯(283mg,1mmol),得到白色粉末状产物98.7mg,收率为81%。
1H NMR(500MHz,DMSO-d6)δ8.02–7.96(m,1H),7.45–7.39(m,2H),7.09–7.04(m,2H),3.95–3.83(m,2H),3.63(s,3H),2.82(ddd,J=11.0,9.1,1.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ165.33,142.27,140.63,131.84,116.12,111.89,106.74,50.46,49.12,26.72.HRMS calcd for C12H13BrNO2:282.0124[M+H]+,found:282.0124.
实施例5
1-(3-三氟甲基苯基)-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用芳基碘为3-碘三氟甲苯(272mg,1mmol),得到白色粉末状产物110mg,收率为81%。
1H NMR(500MHz,DMSO-d6)δ8.17(d,J=1.6Hz,1H),7.49(t,J=7.9Hz,1H),7.42–7.36(m,2H),7.21(d,J=7.6Hz,1H),3.98(dd,J=10.6,9.3Hz,2H),3.65(s,3H),2.84(ddd,J=10.8,9.0,1.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ165.29,142.25,141.98,130.27,117.76,116.35,110.32,110.29,107.51,50.48,49.08,26.69.HRMS calcd forC13H13F3NO2:272.0893[M+H]+,found:272.0897.
实施例6
1-(2-甲氧基苯基)-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用芳基碘为2-碘苯甲醚(234mg,1mmol),得到白色粉末状产物80mg,收率为69%。
1H NMR(500MHz,DMSO-d6)δ7.89(t,J=1.3Hz,1H),7.07(dd,J=8.2,1.5Hz,1H),7.01(td,J=8.1,7.6,1.8Hz,1H),6.97(dd,J=8.0,1.8Hz,1H),6.93(ddd,J=8.1,7.0,1.5Hz,1H),3.96(dd,J=10.6,9.2Hz,2H),3.83(s,3H),3.60(s,3H),2.73(ddd,J=10.8,9.2,1.4Hz,2H).13C NMR(126MHz,DMSO-d6)δ165.51,150.11,147.31,131.01,123.11,121.09,118.39,112.49,103.88,55.82,51.79,50.25,26.00.HRMS calcd for C13H16NO3:234.1125[M+H]+,found:234.1127.
实施例7
1-(4-甲酸甲酯基苯基)-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用芳基碘为4-碘苯甲酸甲酯(262mg,1mmol),得到白色粉末状产物99mg,收率为76%。
1H NMR(500MHz,DMSO-d6)δ8.08(t,J=1.6Hz,1H),7.88–7.82(m,2H),7.20–7.16(m,2H),3.97(dd,J=10.6,9.1Hz,2H),3.80(s,3H),3.65(s,3H),2.85(td,J=9.8,9.2,1.5Hz,2H).13C NMR(126MHz,DMSO-d6)δ165.88,165.21,145.11,141.51,130.74,120.68,113.62,108.90,51.67,50.64,48.98,26.72.HRMS calcd for C14H16NO4:262.1074[M+H]+,found:262.1075.
实施例8
1-(2-甲苯基)-3-甲酸甲酯-2-吡咯啉
按实施例1所述的方法,不同的所用芳基碘为2-碘甲苯(218mg,1mmol),得到白色粉末状产物55mg,收率为51%。
1H NMR(500MHz,DMSO-d6)δ7.44–7.42(m,1H),7.25–7.16(m,2H),7.10–7.05(m,2H),3.88(dd,J=10.5,9.4Hz,2H),3.60(s,3H),2.79(ddd,J=10.8,9.4,1.3Hz,2H),2.28(s,3H).13C NMR(126MHz,DMSO-d6)δ148.65,131.50,130.76,126.80,124.78,121.89,53.21,50.19,39.69,39.52,39.35,18.65.HRMS calcd for C13H16NO2:218.1176[M+H]+,found:218.1176.
实施例9
2-苯基-2-氮杂螺[4.5]癸-3-烯-4-甲酸甲酯吡咯的合成
按实施例1所述的方法,不同的所用氨基丁酸为加吧喷丁(85.5mg,0.5mmol),得到白色粉末状产物56mg,收率为41%。
1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.33–7.26(m,2H),7.19–7.13(m,2H),6.93(tt,J=7.3,1.0Hz,1H),3.76(s,2H),3.61(s,3H),2.05(td,J=13.4,3.8Hz,2H),1.69–1.56(m,3H),1.49–1.32(m,4H),1.18(dddd,J=22.3,13.0,11.2,2.6Hz,1H).13C NMR(126MHz,DMSO-d6)δ164.86,141.87,141.10,129.27,120.71,114.21,113.21,59.15,49.97,45.50,34.09,24.94,22.00.HRMS calcd for C17H22NO2:272.1645[M+H]+,found:272.1640.
实施例10
1-苯基-4-异丁基-3-甲酸甲酯-2-吡咯啉的合成
按实施例1所述的方法,不同的所用氨基丁酸为普瑞巴林(79.5mg,0.5mmol),得到白色粉末状产物66mg,收率为51%。1H NMR(500MHz,DMSO-d6)δ7.96(d,J=1.0Hz,1H),7.32–7.24(m,2H),7.12(dt,J=7.1,1.1Hz,2H),6.91(tt,J=7.3,1.1Hz,1H),4.01(t,J=10.8Hz,1H),3.62(s,4H),3.20(tt,J=10.6,3.9Hz,1H),1.76–1.59(m,2H),1.24(ddd,J=12.8,10.4,4.0Hz,1H),0.91(dd,J=6.4,1.9Hz,6H).13C NMR(126MHz,DMSO-d6)δ165.21,142.15,141.20,129.28,120.62,114.15,109.99,54.96,50.21,43.44,37.39,25.13,23.74,21.45.HRMS calcd for C16H22NO2:260.1645[M+H]+,found:260.1647
对比例
目前,最新的3-甲酸酯-2-吡咯啉类化合物的合成方法在2017年由范学森课题组报道(Chem.Commun.,2017,53,4002—4005;CN106748953A)。该方法同样采用多组分串联法反应,以吡咯烷、一氧化碳和醇为原料,以氯化钯为催化剂,醋酸铜为氧化剂,在碘化钾存在下,在乙腈中80℃反应12小时。
与该方法相比,本文所介绍的方法具有以下优势:(1)无需在反应中使用额外的过渡金属钯作为催化剂,成本较低;(2)反应中无需使用易燃易爆或有毒气体,操作更简便,更安全;(3)反应以4-氨基丁酸为原料出发,廉价易得;(4)本文反应收率更高,优势更大。
Claims (6)
1.一种合成3-甲酸酯-2-吡咯啉类化合物的方法,其特征在于,所述方法为:
将4-氨基丁酸类化合物(I)、N,N-二甲基甲酰胺二甲基缩醛混合,在60~70℃下搅拌2~4h,随后加入芳基碘(II)、DMEDA、DBU、CuI、DMF,在140~160℃下反应10~14h,之后反应液经后处理,得到产物3-甲酸酯-2-吡咯啉类化合物(III);
式(I)、(II)或(III)中,
R1为:氢、苯基、C3~C5烷基或者与所连接的C形成C6~C10环烷基;
R2为:氢、C1~C3烷基、C1~C3烷氧基、三氟甲基、甲氧基羰基或卤素。
2.如权利要求1所述合成3-甲酸酯-2-吡咯啉类化合物的方法,其特征在于,所述4-氨基丁酸类化合物(I)、N,N’-二甲基甲酰胺二甲基缩醛、芳基碘(II)、DMEDA、DBU、CuI的物质的量之比为1:6~8:2:0.2:2:0.1。
3.如权利要求1所述合成3-甲酸酯-2-吡咯啉类化合物的方法,其特征在于,所述DMF的体积用量以4-氨基丁酸类化合物(I)的物质的量计为4~6mL/mmol。
4.如权利要求1所述合成3-甲酸酯-2-吡咯啉类化合物的方法,其特征在于,所述后处理的方法为:反应结束后,反应液用乙酸乙酯萃取,萃取液经水洗,饱和NaCl水溶液洗,无水硫酸钠干燥后,浓缩,进行柱层析分离,以石油醚与乙酸乙酯体积比20~10:1的混合液作为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到产物3-甲酸酯-2-吡咯啉类化合物(III)。
5.如权利要求1所述合成3-甲酸酯-2-吡咯啉类化合物的方法,其特征在于,R1为:氢、叔丁基或者与所连接的C形成环己烷基。
6.如权利要求1所述合成3-甲酸酯-2-吡咯啉类化合物的方法,其特征在于,R2为:氢、甲基、甲氧基、三氟甲基、甲氧基羰基或溴。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4333878A (en) * | 1980-04-04 | 1982-06-08 | Ethyl Corporation | Process for producing substituted pyrroles |
JPH02135718A (ja) * | 1988-11-16 | 1990-05-24 | Nippon Soda Co Ltd | 電気二重層コンデンサー |
WO2007037303A1 (ja) * | 2005-09-28 | 2007-04-05 | Daiichi Sankyo Company, Limited | テトラ置換-5-アザスピロ[2.4]へプタン誘導体の製法およびその光学活性中間体 |
CN104829493A (zh) * | 2015-04-20 | 2015-08-12 | 华南理工大学 | 一种合成氨基甲酸芳香酯的方法 |
CN106543065A (zh) * | 2016-10-13 | 2017-03-29 | 华东师范大学 | 一种4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯衍生物及其制备方法和应用 |
-
2019
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4333878A (en) * | 1980-04-04 | 1982-06-08 | Ethyl Corporation | Process for producing substituted pyrroles |
JPH02135718A (ja) * | 1988-11-16 | 1990-05-24 | Nippon Soda Co Ltd | 電気二重層コンデンサー |
WO2007037303A1 (ja) * | 2005-09-28 | 2007-04-05 | Daiichi Sankyo Company, Limited | テトラ置換-5-アザスピロ[2.4]へプタン誘導体の製法およびその光学活性中間体 |
CN104829493A (zh) * | 2015-04-20 | 2015-08-12 | 华南理工大学 | 一种合成氨基甲酸芳香酯的方法 |
CN106543065A (zh) * | 2016-10-13 | 2017-03-29 | 华东师范大学 | 一种4‑三氟甲基‑2,4‑二取代‑2,5‑二氢吡咯衍生物及其制备方法和应用 |
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