CN104119342A - 一种制备高纯度4-氯-5-甲基-7H-吡咯[2,3-d]嘧啶的方法 - Google Patents
一种制备高纯度4-氯-5-甲基-7H-吡咯[2,3-d]嘧啶的方法 Download PDFInfo
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- CN104119342A CN104119342A CN201310146294.4A CN201310146294A CN104119342A CN 104119342 A CN104119342 A CN 104119342A CN 201310146294 A CN201310146294 A CN 201310146294A CN 104119342 A CN104119342 A CN 104119342A
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- pyrimidine
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- methyl
- pyrroles
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali 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
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开一种制备高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的方法，以4-氯-7H-吡咯[2，3-d]嘧啶为起始原料发生溴代反应，然后甲基化，粗产物经重结晶得到高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶。本方法反应条件温和、简单，成本低，收率高，操作简便，适合于工业生产。
Description
技术领域
本发明涉及一种制备高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的方法，属于医药、化工技术领域。
背景技术
4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶及其衍生物广泛应用于医药领域，具有良好的抗忧郁、抗肿瘤、抗菌等多种生物活性。按照现有的制备方法，难以制得高纯度的产品。
发明内容
本发明目的是优化合成方法来制备高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶，该方法原料易得、价廉，产率高，反应条件温和，适合于工业生产。
反应路线如下：
本发明所述一种制备高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的方法，在合成5-溴-4-氯-7H-吡咯[2，3-d]嘧啶(化合物2)中：所用溴化试剂，包含但不限于NBS和溴等；反应溶剂可以是DMF，也可以是二氯甲烷、氯仿和1，2-二氯乙烷等；反应的温度在0至25℃。
本发明所述一种制备高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的方法，在合成目标化合物4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶中：碘甲烷甲基化所用的碱包含但不限于正丁基锂、异丁基锂和LDA等；反应溶剂可以是四氢呋喃，也可以是乙醚；反应温度在零下78℃。粗产物重结晶所用溶剂可以是DMF，也可以是DMSO、乙酸乙酯、乙醇和甲醇等。
本发明与现有技术相比具有如下的有益效果：
1、甲基化反应快速淬灭，少了氮上甲基化副产物；粗产物未经柱层析或反相制备，直接重结晶，制得高纯度产物。
2、反应路线条件温和，无需硅胶层析分离，缩短了生产过程，适合于工业化生产。
具体实施方式
实施例1：合成5-溴-4-氯-7H-吡咯[2，3-d]嘧啶(化合物2)
4-氯-7H-吡咯[2，3-d]嘧啶(10g，0.06摩尔)溶于DMF(130毫升)，于0℃滴加NBS(11.6g，0.06摩尔)的DMF(70毫升)溶液，约半小时加完。室温搅拌1小时，然后加入甲醇(165毫升)，搅拌1小时。减压蒸馏，残留物用甲醇洗涤，真空干燥得白色固体(2)13.2g，产率：97.8％.
实施例2：合成4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶(化合物3)
化合物2(5g，0.02摩尔)溶于四氢呋喃(100毫升)，于-78℃滴加2.5M正丁基锂(25.8毫升，0.06摩尔)，约半小时加完。继续搅拌半小时后，滴加碘甲烷(4毫升，0.06摩尔)，约半小时加完，然后自然升至室温，20毫升饱和氯化铵水溶液快速淬灭反应。乙酸乙酯萃取，合并有机相，干燥浓缩。粗产物用DMF-甲醇重结晶，得到白色晶体(3)2.3g，产率：64.4％，HPLC纯度：99.8％。
Claims (3)
1.本发明公开一种制备高纯度4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的方法，含以下步骤：(1)4-氯-7H-吡咯[2，3-d]嘧啶为起始原料发生溴代反应得到中间体5-溴-4-氯-7H-吡咯[2，3-d]嘧啶；(2)甲基化得到目标化合物4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶。
2.如权利要求所述4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的合成方法第一步，其特征在于：所用溴化试剂，包含但不限于NBS和溴等；反应溶剂可以是DMF，也可以是二氯甲烷、氯仿和1，2-二氯乙烷等；反应的温度在0至25℃。
3.如权利要求所述4-氯-5-甲基-7H-吡咯[2，3-d]嘧啶的合成方法第二步，其特征在于：碘甲烷甲基化所用的碱包含但不限于正丁基锂、异丁基锂和LDA等；反应溶剂可以是四氢呋喃，也可以是乙醚；反应温度在零下78℃；粗产物重结晶的溶剂包含但不限于DMF、DMSO、乙酸乙酯、乙醇和甲醇等。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310146294.4A CN104119342A (zh) | 2013-04-25 | 2013-04-25 | 一种制备高纯度4-氯-5-甲基-7H-吡咯[2,3-d]嘧啶的方法 |
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| CN201310146294.4A CN104119342A (zh) | 2013-04-25 | 2013-04-25 | 一种制备高纯度4-氯-5-甲基-7H-吡咯[2,3-d]嘧啶的方法 |
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| CN104119342A true CN104119342A (zh) | 2014-10-29 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008075110A1 (en) * | 2006-12-21 | 2008-06-26 | Astex Therapeutics Limited | Substituted piperidines containing a heteroarylamide or heteroarylphenyl moiety |
| WO2011149827A1 (en) * | 2010-05-24 | 2011-12-01 | Glaxosmithkline Llc | Compounds and methods |
| WO2012080735A1 (en) * | 2010-12-16 | 2012-06-21 | Convergence Pharmaceuticals Limited | Ask1 inhibiting pyrrolopyrimidine derivatives |
-
2013
- 2013-04-25 CN CN201310146294.4A patent/CN104119342A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008075110A1 (en) * | 2006-12-21 | 2008-06-26 | Astex Therapeutics Limited | Substituted piperidines containing a heteroarylamide or heteroarylphenyl moiety |
| WO2011149827A1 (en) * | 2010-05-24 | 2011-12-01 | Glaxosmithkline Llc | Compounds and methods |
| WO2012080735A1 (en) * | 2010-12-16 | 2012-06-21 | Convergence Pharmaceuticals Limited | Ask1 inhibiting pyrrolopyrimidine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| FRANK SEELA等: "Synthesis of Certain 5-Substituted 2’-Deoxytubercidin Derivatives", 《HELVETICA CHIMICA ACTA》 * |
| FRANK SEELA等: "Synthesis of Certain 5-Substituted 2’-Deoxytubercidin Derivatives", 《HELVETICA CHIMICA ACTA》, vol. 77, 31 December 1994 (1994-12-31), pages 897 - 903, XP000655155, DOI: doi:10.1002/hlca.19940770403 * |
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