CN107033058A - 氮杂环高选择性醛的合成工艺 - Google Patents
氮杂环高选择性醛的合成工艺 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 25
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 24
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 title abstract 5
- 150000003053 piperidines Chemical class 0.000 claims abstract description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 12
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 12
- 150000003217 pyrazoles Chemical class 0.000 claims abstract description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 57
- 150000001299 aldehydes Chemical class 0.000 claims description 20
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 19
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 18
- -1 1- benzyl pyrroles Azoles Chemical class 0.000 claims description 17
- FNEQHKCQXDKYEO-UHFFFAOYSA-N 1-benzylpyrrole Chemical class C1=CC=CN1CC1=CC=CC=C1 FNEQHKCQXDKYEO-UHFFFAOYSA-N 0.000 claims description 13
- AKQAJYLKBCWJBV-UHFFFAOYSA-N 1-benzylpyrazole Chemical class C1=CC=NN1CC1=CC=CC=C1 AKQAJYLKBCWJBV-UHFFFAOYSA-N 0.000 claims description 12
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 12
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- JNHZZTKKFSPICX-UHFFFAOYSA-N 1-benzylpyrrole-2-carbaldehyde Chemical compound O=CC1=CC=CN1CC1=CC=CC=C1 JNHZZTKKFSPICX-UHFFFAOYSA-N 0.000 claims description 7
- CCOXWRVWKFVFDG-UHFFFAOYSA-N pyrimidine-2-carbaldehyde Chemical compound O=CC1=NC=CC=N1 CCOXWRVWKFVFDG-UHFFFAOYSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 2
- BOGSOFADOWIECK-UHFFFAOYSA-N [N].C=1C=NNC=1 Chemical group [N].C=1C=NNC=1 BOGSOFADOWIECK-UHFFFAOYSA-N 0.000 claims description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 2
- 238000007867 post-reaction treatment Methods 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 6
- 206010011224 Cough Diseases 0.000 claims 3
- KTFGWHSLIOZEKH-UHFFFAOYSA-N 5-benzyl-1h-pyrazole Chemical compound C=1C=CC=CC=1CC1=CC=NN1 KTFGWHSLIOZEKH-UHFFFAOYSA-N 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 10
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 5
- 230000000977 initiatory effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 abstract 2
- 238000003756 stirring Methods 0.000 description 45
- 238000010791 quenching Methods 0.000 description 24
- 230000000171 quenching effect Effects 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000010410 layer Substances 0.000 description 10
- 238000010792 warming Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 150000005525 1-benzylpiperazines Chemical class 0.000 description 1
- SGIBOXBBPQRZDM-UHFFFAOYSA-N 1-benzylpiperidine-4-carbaldehyde Chemical class C1CC(C=O)CCN1CC1=CC=CC=C1 SGIBOXBBPQRZDM-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/48—Aldehydo radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及氮杂环高选择性醛的合成工艺，公开了氮杂环氮原子上存在氢原子，以吡咯、哌啶、吡唑为起始原料，经氮原子保护，然后与哌啶‑1‑甲醛反应，即得到所需的氮原子邻位醛的合成工艺。氮杂环氮原子上无氢原子，以吡啶、嘧啶与哌啶‑1‑甲醛反应，即得到所需的氮原子邻位醛的合成工艺。此工艺操作简单，步骤少，选择性高，是氮杂环合成氮邻位醛通用方法。
Description
技术领域
本发明属于有机合成技术药物化学领域，具体涉及氮杂环高选择性醛的合成工艺。
背景技术
氮杂环是有机化学中的重要组成部分，氮杂环高选择性的醛的合成是精细化学不可缺少的部分，氮邻位醛的合成是医药、农药、染料和其他精细化工产品的中间体的重要合成步骤，所以对其合成方法的研究开展具有重要意义。
目前国内外制备氮杂环醛的方法有许多，多数存在很多缺点，没有一通用简洁的办法直接合成其高选择性醛。比如专利CN10435604A中报道的5-(2-氟苯基)-1H-吡咯-3-甲醛和 CN103086979A中报道的咪唑醛以及CN102079720A中报道的1-苄基-4-哌啶甲醛的合成方法中，都是通过先引入醇羟基然后再氧化得到醛，步骤多，而且不易控制氧化程度，必然影响收率，增加杂质生成。
专利CN101548974A中公布的1,3-二苯基-4-吡唑甲醛缩异烟腈的合成方法中，1,3-二苯基-4-吡唑甲醛是通过DMF和POCl3的Vilsmeier反应合成而得。但无法在氮邻位引入醛基。
氮杂环氮邻位醛的合成在精细化工领域是有很重要的意义，研究其合成的通用方法对氮杂环化学研究具有重要意义。
发明内容
本发明目的在于针对研究吡咯、哌啶、吡唑氮原子上含氢以及吡啶、嘧啶氮原子无氢的邻位醛基合成，研究氮杂环高选择性醛的合成工艺。研究现有技术工艺的中合成氮杂环醛缺点和不足，提供一条新颖而高选择性通用方法。
本发明是通过以下技术方案实现的：一：氮杂环氮原子上存在氢原子，以吡咯、哌啶、吡唑为起始原料，经氮原子保护，然后与哌啶-1-甲醛反应，即得到所需的氮原子邻位醛。二：氮杂环氮原子上无氢原子，吡啶、嘧啶与哌啶-1-甲醛反应，即得到所需的氮原子邻位醛。此工艺操作简单，步骤少，选择性高，是氮杂环合成氮邻位醛通用方法。
本发明的具体技术方案如下：
本发明所述氮杂环高选择性醛的合成工艺中，工艺路线是：吡咯、哌啶、吡唑氮原子上含氢，分别以吡咯、哌啶、吡唑为原料，与苄基溴反应，分别生成1-苄基吡咯，1-苄基哌啶， 1-苄基吡唑，氮原子无氢的吡啶、嘧啶即可直接生成醛基。1-苄基吡咯、1-苄基哌啶、1-苄基吡唑、吡啶、嘧啶，在正丁基锂存在下，分别与哌啶-1-甲醛反应，生成1-苄基吡咯-2-甲醛、 1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛。
本发明所述1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的合成工艺中，吡咯、哌啶、吡唑溶于DMF中，DMF溶剂量优选于5～6倍，碱性试剂优选于NaH、CH3ONa，摩尔当量优选于1.1eq，溴苄的摩尔当量优选于1.05～1.1eq，反应温度优先于60-75℃。
本发明所述1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的合成工艺中，反应后处理萃取溶剂优选于PE、MTBE，更优选于MTBE。
本发明所述1-苄基吡咯-2-甲醛、1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛的制备方法中，原料使用哌啶-1-甲醛，碱性试剂优选于正丁基锂，反应溶剂优选于THF、DCM，更优选于DCM。
本发明所述的合成工艺选择性高，步骤少，收率高，处理简便，纯度不低于99.5％(HPLC)。
附图说明
附图1为氮杂环高选择性醛的合成工艺路线的示意图。
具体实施方式
下面对本发明的实施例作详细说明：本实施例在以本发明技术方案为前提下进行实施，给出了详细地实施方式和过程，但本发明的保护范围不限于下述的实施例。
实施例1
1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的制备
取10g吡咯于三口瓶中，加入50mlDMF，搅拌降温至-10℃，缓慢投入NaH3.94g，搅拌30min，滴加溴苄26.77g，升温至60℃反应4h。反应完加水猝灭，MTBE萃取三遍，浓缩得 1-苄基吡咯，收率95％。
同理：
取10g哌啶于三口瓶中，加入50mlDMF，搅拌降温至-10℃，缓慢投入NaH2.96g，搅拌30min，滴加溴苄21.09g，升温至60℃反应4h。反应完加水猝灭，MTBE萃取三遍，浓缩得 1-苄基哌啶，收率94％。
取10g吡唑于三口瓶中，加入50mlDMF，搅拌降温至-10℃，缓慢投入NaH3.70g，搅拌30min，滴加溴苄26.38g，升温至60℃反应4h。反应完加水猝灭，MTBE萃取三遍，浓缩得 1-苄基哌啶，收率92％。
1-苄基吡咯-2-甲醛、1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛的制备
取10g 1-苄基吡咯溶于100mlDCM中，降温至-75℃，投入正丁基锂，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品1-苄基吡咯-2-甲醛。
同理：
取10g 1-苄基哌啶溶于100mlDCM中，降温至-75℃，投入正丁基锂，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品1-苄基哌啶-2-甲醛。
取10g 1-苄基吡唑溶于100mlDCM中，降温至-75℃，投入正丁基锂，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品1-苄基吡唑-2-甲醛。
取10g吡啶溶于100mlDCM中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品吡啶-2-甲醛。
取10g嘧啶溶于100mlDCM中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品嘧啶-2-甲醛。
实施例2
1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的制备
取10g吡咯于三口瓶中，加入60mlDMF，搅拌降温至-10℃，缓慢投入CH3ONa8.87g，搅拌30min，滴加溴苄28.04g，升温至75℃反应4h。反应完加水猝灭，MTBE萃取三遍，浓缩得1-苄基吡咯，收率96％。
同理：
取10g哌啶于三口瓶中，加入60mlDMF，搅拌降温至-10℃，缓慢投入CH3ONa6.66g，搅拌30min，滴加溴苄22.09g，升温至75℃反应4h。反应完加水猝灭，MTBE萃取三遍，浓缩得1-苄基哌啶，收率95％。
取10g吡唑于三口瓶中，加入60mlDMF，搅拌降温至-10℃，缓慢投入CH3ONa8.33g，搅拌30min，滴加溴苄27.64g，升温至75℃反应4h。反应完加水猝灭，MTBE萃取三遍，浓缩得1-苄基哌啶，收率94％。
1-苄基吡咯-2-甲醛、1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛的制备
取10g 1-苄基吡咯溶于100mlTHF中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌6h，反应结束。加水猝灭反应。加入DCM萃取反应，浓缩有机层，得产品1-苄基吡咯-2-甲醛。
同理：
取10g 1-苄基哌啶溶于100mlTHF中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌6h，反应结束。加水猝灭反应。加入DCM萃取反应，浓缩有机层，得产品1-苄基哌啶-2-甲醛。
取10g 1-苄基吡唑溶于100mlTHF中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌6h，反应结束。加水猝灭反应。加入DCM萃取反应，浓缩有机层，得产品1-苄基吡唑-2-甲醛。
取10g吡啶溶于100mlTHF中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌6h，反应结束。加水猝灭反应。加入DCM萃取反应，浓缩有机层，得产品吡啶-2-甲醛。
取10g嘧啶溶于100mlTHF中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌6h，反应结束。加水猝灭反应。加入DCM萃取反应，浓缩有机层，得产品嘧啶-2-甲醛。
实施例3
1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的制备
取10g吡咯于三口瓶中，加入50mlDMF，搅拌降温至-10℃，缓慢投入NaH3.94g，搅拌30min，滴加溴苄26.77g，升温至60℃反应4h。反应完加水猝灭，PE萃取三遍，浓缩得1- 苄基吡咯，收率83％。
同理：
取10g哌啶于三口瓶中，加入50mlDMF，搅拌降温至-10℃，缓慢投入NaH2.96g，搅拌30min，滴加溴苄21.09g，升温至60℃反应4h。反应完加水猝灭，PE萃取三遍，浓缩得1- 苄基哌啶，收率81％。
取10g吡唑于三口瓶中，加入50mlDMF，搅拌降温至-10℃，缓慢投入NaH3.70g，搅拌30min，滴加溴苄26.38g，升温至60℃反应4h。反应完加水猝灭，PE萃取三遍，浓缩得1- 苄基哌啶，收率79％。
1-苄基吡咯-2-甲醛、1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛的制备
取10g 1-苄基吡咯溶于100mlDCM中，降温至-75℃，投入正丁基锂，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品1-苄基吡咯-2-甲醛。
同理：
取10g 1-苄基哌啶溶于100mlDCM中，降温至-75℃，投入正丁基锂，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品1-苄基哌啶-2-甲醛。
取10g 1-苄基吡唑溶于100mlDCM中，降温至-75℃，投入正丁基锂，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品1-苄基吡唑-2-甲醛。
取10g吡啶溶于100mlDCM中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品吡啶-2-甲醛。
取10g嘧啶溶于100mlDCM中，降温至-75℃，投入正丁基锂1.1摩尔量，搅拌1h，滴入哌啶-1-甲醛，滴加完缓慢升温至-30℃，搅拌5h，反应结束。加水猝灭反应。分层萃取反应，浓缩DCM层，得产品嘧啶-2-甲醛。
Claims (4)
1.氮杂环高选择性醛的合成工艺，其特征在于：工艺路线是：吡咯、哌啶、吡唑氮原子上含氢，分别以吡咯、哌啶、吡唑为原料，与苄基溴反应，分别生成1-苄基吡咯，1-苄基哌啶，1-苄基吡唑，氮原子无氢的吡啶、嘧啶即可直接生成醛基。1-苄基吡咯、1-苄基哌啶、1-苄基吡唑、吡啶、嘧啶，在正丁基锂存在下，分别与哌啶-1-甲醛反应，生成1-苄基吡咯-2-甲醛、1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛。
2.根据权利要求1所述的氮杂环高选择性醛的合成工艺，其特征在于：所述1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的合成工艺，反应溶剂选择DMF，溶剂量选择5至6倍，碱性试剂选择NaH、CH3ONa中的任一种，摩尔当量选择1.1eq，溴苄的摩尔当量优选择1.05～1.1eq，反应温度选择60-75℃之间任一温度。
3.根据权利要求1所述的氮杂环高选择性醛的合成工艺，其特征在于：所述1-苄基吡咯、1-苄基哌啶、1-苄基吡唑的合成工艺，反应后处理萃取溶剂选择PE、MTBE中任一种。
4.根据权利要求1所述的氮杂环高选择性醛的合成工艺，其特征在于：所述1-苄基吡咯-2-甲醛、1-苄基哌啶-2-甲醛、1-苄基吡唑-2-甲醛、吡啶-2-甲醛、嘧啶-2-甲醛的合成工艺，原料选择哌啶-1-甲醛，碱性试剂选择正丁基锂，反应溶剂选择THF、DCM中任一种。
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