CN107325045A - 一种2‑溴‑5‑碘吡啶‑3‑胺的合成方法 - Google Patents
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 title abstract 3
- 150000001412 amines Chemical class 0.000 title abstract 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 title abstract 3
- 229910052794 bromium Inorganic materials 0.000 title abstract 3
- ZFTKWAVDJBKFCS-UHFFFAOYSA-N iodine;pyridine Chemical compound [I].C1=CC=NC=C1 ZFTKWAVDJBKFCS-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940125782 compound 2 Drugs 0.000 claims abstract description 12
- 229940125904 compound 1 Drugs 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 239000011630 iodine Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 4
- 229940126214 compound 3 Drugs 0.000 claims abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 3
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims abstract description 3
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims abstract 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- BPYHGTCRXDWOIQ-UHFFFAOYSA-N 3-nitropyridin-2-amine Chemical compound NC1=NC=CC=C1[N+]([O-])=O BPYHGTCRXDWOIQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 abstract 1
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- -1 nitro Amino Chemical group 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- GOPBSKKOGHDCEH-UHFFFAOYSA-N periodic acid;sodium Chemical compound [Na].OI(=O)(=O)=O GOPBSKKOGHDCEH-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
Classifications
-
- 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
- C07D213/60—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 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及一种2‑溴‑5‑碘吡啶‑3‑胺的合成方法。主要解决其有效合成方法缺乏的技术问题。本发明合成方法包括以下步骤：2‑氨基‑3‑硝基吡啶在水和醋酸的混合液中，在浓硫酸的催化作用下，和高碘酸钠、碘生成化合物1；化合物1在重氮化反应条件下，和氢溴酸、亚硝酸钠、溴化亚铜反应，生成化合物2；化合物2在乙醇和水的混合液中和氯化铵，铁粉反应，硝基被还原成氨基，生成目标化合物3；反应式如下：
Description
技术领域
本发明涉及到2-溴-5-碘吡啶-3-胺的合成。
背景技术
2-溴-5-碘吡啶-3-胺（CAS：1138444-06-0）作为非常重要的医药中间体，在制药行业中得到广泛应用。迄今为止，其相关的合成方法未见公开报道。
2003年至今，只有F.I.Carroll以专利的形式发表了化合物1 和2 的合成方法（US6,538,010 B1）； 但是产率较低，化合物1的产率只有79%，化合物2的产率只有23%。
发明内容
本发明的目的是提供一种2-溴-5-碘吡啶-3-胺的合成方法，主要解决其有效合成方法缺乏的技术问题。
本发明技术方案为：一种2-溴-5-碘吡啶-3-胺的合成方法，其特征是包括以下步骤：第一步，2-氨基-3-硝基吡啶在水和醋酸的混合液中，在浓硫酸的催化作用下，和高碘酸钠、碘反应，生成化合物1；第二步，化合物1在重氮化反应条件下，和氢溴酸、亚硝酸钠、溴化亚铜反应，生成化合物2；第三步，化合物2在乙醇和水的混合液中和氯化铵，铁粉反应，硝基被还原成氨基，生成目标化合物3。
合成线路如下：
。
第一步反应温度为60-120℃，优选90℃，反应时间为30-90分钟，优选60分钟；碘的用量为0.4-0.6当量，优选0.5当量；第二步反应在0℃时加入亚硝酸钠水溶液，第三步反应为室温过夜。
本发明的有益效果是：本发明在原有方法的基础上，增加了碘的用量和改变后处理方法以后，得到高纯度的化合物1，产率提高了19%； 在重氮化条件下，Carroll室温下加入了亚硝酸钠水溶液，得到23%的化合物2，考虑到重氮盐对温度的敏感性，加入亚硝酸钠溶液的温度被控制在0℃，同时大大减少了亚硝酸钠的用量，化合物2的产率提高到45%。
具体实施方式
实施例1：
步骤1：
向250毫升三口烧瓶中加入2-氨基-3-硝基吡啶（10.0 g, 72.0 mmol），醋酸（44 mL）和水（10 mL）。90℃时加入高碘酸（3.28 g, 14.4 mmol）和质量百分浓度为98%的浓硫酸（1.3mL）；搅拌10分钟后，加入碘（9.1 g, 36.0 mmol），此温度下继续搅拌60分钟。冷却至室温后，反应液加入饱和硫代硫酸钠水溶液（100 mL）；过滤分离，固体用饱和食盐水（50 mL x2）和石油醚（50 mL x 2）洗涤。粗产物在石油醚和乙酸乙酯混合液（体积比：5:1）中重结晶，得到黄色固体，高纯度的化合物1（17.57 g, 69.1 mmol, 96%）。1H NMR (400 MHz, DMSO-d6): 8.58 (s, 1H), 8.54 (s, 1H), 8.05 (br s, 2H) ppm。 LC-MS (ESI): m/z 265.6[M+H]+；
步骤2：
向250毫升三口烧瓶中加入化合物1（4.00 g, 15.0 mmol）和氢溴酸（48%. 40 mL）。0℃时滴加亚硝酸钠溶液（溶于 20 mL 水, 2.07 g, 30.0 mmol），并搅拌10 分钟，然后室温时分别加入溴化亚铜（2.74 g, 19.5 mol）和水（20 mL）；室温搅拌过夜。反应液中加入水（40mL）和氨水（40 mL），乙酸乙酯萃取（50 mL x 3）；有机相合并，饱和食盐水（50 mL）洗涤，无水硫酸钠干燥。滤液旋干，粗产物用硅胶柱色谱分离（石油醚:乙酸乙酯体积比 = 20:1），得到黄色固体，化合物2(2.25 g, 6.98 mmol, 45%)。 1H NMR (400 MHz, CDCl3): δH 8.79(d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H) ppm。LC-MS (ESI): m/z 329.02 [M+H]+；
步骤3：
向100 毫升三口烧瓶中加入化合物2（1.40 g, 4.3 mmol），铁粉（0.718 g, 12.8mmol），氯化铵（0.28 g, 5.3 mmol）乙醇（7 mL）和水（14 mL）；反应液室温搅拌过夜。乙酸乙酯萃取（30 mL x 3）；有机相合并，饱和食盐水（30 mL）洗涤，无水硫酸钠干燥。滤液旋干，粗产物用硅胶柱色谱分离（石油醚:乙酸乙酯体积比 = 20:1），得到黄色固体，目标化合物3(1.13 g, 3.9 mmol, 85%)。1H NMR (400 MHz, DMSO-d6): 7.74 (d, J = 2.0 Hz, 1H),7.41 (d, J = 2.0 Hz, 1H), 5.74 (br s, 2H) ppm。 LC-MS (ESI): m/z 299.1 [M+H]+。
实施例2：第一步反应温度60℃，反应时间为90分钟，碘用量为0.6当量；其余同实施例1。
实施例3：第一步反应温度120℃，反应时间为30分钟，碘用量为0.4当量；其余同实施例1。
Claims (6)
1.一种2-溴-5-碘吡啶-3-胺的合成方法, 其特征是包括以下步骤：第一步，2-氨基-3-硝基吡啶在水和醋酸的混合液中，在浓硫酸的催化作用下，和高碘酸钠、碘生成化合物1；第二步，化合物1在重氮化反应条件下，和氢溴酸、亚硝酸钠、溴化亚铜反应，生成化合物2；第三步，化合物2在乙醇和水的混合液中和氯化铵，铁粉反应，硝基被还原成氨基，生成目标化合物3；合成线路如下：
。
2.根据权利要求1所述的一种2-溴-5-碘吡啶-3-胺的合成方法， 其特征是第一步碘的加入量为0.4-0.6当量。
3. 根据权利要求1所述的一种2-溴-5-碘吡啶-3-胺的合成方法， 其特征是第一步在60-120℃下反应。
4. 根据权利要求1所述的一种2-溴-5-碘吡啶-3-胺的合成方法， 其特征是第一步反应30-90分钟。
5. 根据权利要求1所述的一种2-溴-5-碘吡啶-3-胺的合成方法， 其特征是第二步在0℃下加入亚硝酸钠水溶液。
6. 根据权利要求1所述的一种2-溴-5-碘吡啶-3-胺的合成方法， 其特征是第三步室温反应过夜。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1199306A1 (en) * | 1999-07-26 | 2002-04-24 | Banyu Pharmaceutical Co., Ltd. | Biarylurea derivatives |
| EP2494975A1 (en) * | 2000-11-08 | 2012-09-05 | Research Triangle Institute | Compounds and methods for promoting smoking cessation |
| CN104262242A (zh) * | 2014-09-22 | 2015-01-07 | 西华大学 | 原位生成碘代试剂法合成3,5-二碘-4-氨基吡啶 |
| US20170050980A1 (en) * | 2015-08-18 | 2017-02-23 | Forum Pharmaceuticals Inc. | Oxadiazine compounds and methods of use thereof |
-
2017
- 2017-07-07 CN CN201710549711.8A patent/CN107325045A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1199306A1 (en) * | 1999-07-26 | 2002-04-24 | Banyu Pharmaceutical Co., Ltd. | Biarylurea derivatives |
| EP2494975A1 (en) * | 2000-11-08 | 2012-09-05 | Research Triangle Institute | Compounds and methods for promoting smoking cessation |
| CN104262242A (zh) * | 2014-09-22 | 2015-01-07 | 西华大学 | 原位生成碘代试剂法合成3,5-二碘-4-氨基吡啶 |
| US20170050980A1 (en) * | 2015-08-18 | 2017-02-23 | Forum Pharmaceuticals Inc. | Oxadiazine compounds and methods of use thereof |
Non-Patent Citations (3)
| Title |
|---|
| ACS: "RN 1138444-06-0", 《STN-REG》 * |
| F. IVY CARROLL ET AL.: "Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2-exo-2-(2’,3’-Disubstituted 5’-pyridinyl)-7-azabicyclo[2.2.1]heptanes: Epibatidine Analogues", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 陈金龙、陈群编著: "《精细化工清洁生产工艺技术》", 30 April 1999, 中国石化出版社 * |
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