CN104447519B - 一种制备3-取代-2-溴-6-三氟甲基吡啶的方法 - Google Patents
一种制备3-取代-2-溴-6-三氟甲基吡啶的方法 Download PDFInfo
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- DOWNSQADAFSSAR-UHFFFAOYSA-N 2-bromo-6-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC(Br)=N1 DOWNSQADAFSSAR-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- ASPYNUKRQBNFIT-UHFFFAOYSA-N 2-bromo-6-(trifluoromethyl)pyridine-3-carbaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C(Br)=N1 ASPYNUKRQBNFIT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- UTJSAWAOJIQBCB-UHFFFAOYSA-N [2-bromo-6-(trifluoromethyl)pyridin-3-yl]methanol Chemical compound OCC1=CC=C(C(F)(F)F)N=C1Br UTJSAWAOJIQBCB-UHFFFAOYSA-N 0.000 claims abstract description 8
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims abstract description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 7
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910003002 lithium salt Inorganic materials 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 22
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 20
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- JHRPHASLIZOEBJ-UHFFFAOYSA-N 2-methylpyridine-3-carbaldehyde Chemical compound CC1=NC=CC=C1C=O JHRPHASLIZOEBJ-UHFFFAOYSA-N 0.000 claims 1
- 239000004327 boric acid Substances 0.000 claims 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 abstract description 9
- 239000001569 carbon dioxide Substances 0.000 abstract description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 230000002902 bimodal effect Effects 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000002689 soil Substances 0.000 description 3
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 3
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UJJMLGJZQGGQAZ-UHFFFAOYSA-N 2-(fluoromethyl)pyridine Chemical compound FCC1=CC=CC=N1 UJJMLGJZQGGQAZ-UHFFFAOYSA-N 0.000 description 1
- COMFXXABDQGVSV-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-3-carbaldehyde Chemical compound FC(F)(F)C1=NC=CC=C1C=O COMFXXABDQGVSV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- -1 pyridine organic compound Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D213/60—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
- C07D213/61—Halogen atoms or nitro radicals
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种制备3‑取代‑2‑溴‑6‑三氟甲基吡啶的方法，氮气保护下，以2‑溴‑6‑三氟甲基吡啶为原料，在低温下与二异丙基胺锂反应，生成3‑位的锂盐，再分别加入三甲基硼酸酯，甲酸乙酯，和二氧化碳生成2‑溴‑6‑三氟甲基‑3‑吡啶硼酸，2‑溴‑6‑三氟甲基‑3‑吡啶甲醛和2‑溴‑6‑三氟甲基‑3‑吡啶甲酸。用硼氢化钠还原2‑溴‑6‑三氟甲基‑3‑吡啶甲醛生成2‑溴‑6‑三氟甲基‑3‑吡啶甲醇。所生成的目标化合物，收率高，纯度好，是一类重要的医药中间体，具有广泛的应用前景。本发明操作简便，原料易得，反应选择性好，环境友好，易于放大生产，实现商业化产品。
Description
技术领域
本发明涉及有机化学合成技术领域，具体的说是一种制备3-取代-2-溴-6-三氟甲基吡啶的方法。
背景技术
利用2-溴-6-三氟甲基吡啶为原料，通常是在2-位溴上进行有机化学反应和转化，生成2-取代的吡啶化合物。但是要在此有机化合物的3-位引入官能团却十分困难，本发明巧妙的运用亲核弱的有机碱二异丙基胺锂，利用溴原子的强邻定位效应，在2-溴-6-三氟甲基吡啶的3-位进行攫氢反应生成锂盐，然后与亲电试剂作用生成3-取代的吡啶有机化合物。此类有机小分子中具有三氟甲基结构可以改变分子的物理和化学性质，是合成一些药物的重要中间体，也可以用作有机化工试剂。因此，这类3-取代-2-溴-6-三氟甲基吡啶具有广泛的应用前景。
发明内容
本发明弥补了制备一些3-取代-2-溴-6-三氟甲基吡啶制备上的困难，提供了一类3-取代-2-溴-6-三氟甲基吡啶的制备方法，其性质稳定，容易实现商业化产品。以2-溴-6-三氟甲基吡啶为原料在低温下，与二异丙基胺锂反应，由于溴的强定位效应，生成3-位的锂盐，然后分别与三甲基硼酸酯，甲酸乙酯，和二氧化碳反应，用稀盐酸调节PH＝3-4，用有机溶剂萃取，分离，或过滤，干燥，浓缩溶剂，纯化得到2-溴-6-三氟甲基-3-吡啶硼酸，2-溴-6-三氟甲基-3-吡啶甲醛和2-溴-6-三氟甲基-3-吡啶甲酸，用硼氢化钠在有机溶剂中还原2-溴-6-三氟甲基-3-吡啶甲醛生成2-溴-6-三氟甲基-3-吡啶甲醇。
本发明所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的方法，其制备路线如下：
本发明所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的方法，采用的技术方案是：
以2-溴-6-三氟甲基吡啶为原料，氮气保护下，于低温与二异丙基胺锂反应，生成3-位的锂盐，然后分别与三甲基硼酸酯，甲酸乙酯，和二氧化碳反应，用稀盐酸调节PH＝3-4，用有机溶剂萃取，分离，或过滤，干燥，浓缩溶剂，纯化得到-2-溴-6-三氟甲基-3-吡啶硼酸，2-溴-6-三氟甲基-3-吡啶甲醛和2-溴-6-三氟甲基-3-吡啶甲酸，用硼氢化钠在有机溶剂中还原2-溴-6-三氟甲基-3-吡啶甲醛生成2-溴-6-三氟甲基-3-吡啶甲醇；
所述的低温度为-90℃。
所述的反应时间为12小时。
所述的反应溶剂为四氢呋喃。
所述的二异丙基胺锂是现场通过二异丙基胺与丁基锂反应制备。
所述的萃取有机溶剂为乙醚或乙酸乙酯。
所述的纯化技术为柱层析或重结晶。
所述的稀盐酸为1N浓度。
所述的原料2-溴-6-三氟甲基吡啶与二异丙基胺，丁基锂和三甲基硼酸酯的摩尔比为1:1.2:1.3:1.2。
所述的原料2-溴-6-三氟甲基吡啶与异丙基胺，丁基锂和甲酸乙酯的摩尔比为1:1.2:1.3:1.2。
所述的2-溴-6-三氟甲基吡啶与异丙基胺，丁基锂和二氧化碳的摩尔比为1:1.2:1.3:40。
具体实施方式
下面将结合本发明实施例中的技术方案进行清楚、完整地描述。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
下面结合具体实施对本发明进行进一步的说明。
实施1
2-溴-6-三氟甲基-3-吡啶硼酸的制备：
在5L反应瓶中，加入107.46g二异丙基胺(1.06mol)和1L四氢呋喃，冷至-40℃,缓慢滴加443mL丁基锂(1.15mol，2.6N in hexanes),反应体系冷至-90℃，滴加200g 2-溴-6-三氟甲基吡啶(0.89mol)的1L四氢呋喃溶液，于-90℃反应2小时，再滴加110.35g三甲基硼酸酯(1.06mol),加毕，缓慢升至室温，这一过程需要9小时，滴加1N的洗盐酸，调节PH＝3-4,分离有机相，加入乙酸乙酯萃取水相，合并有机相，水洗，盐洗，干燥，浓缩溶剂，得到的粗产品用正己烷漂洗，生成固体2-溴-6-三氟甲基-3-吡啶硼酸164.8g,产率92％，HPLC>98％,1HNMR((DMSO-d6/D2O)：7.71ppm,双峰(1H)；7.92ppm,双峰(1H)；13CNMR((DMSO-d6/D2O)：119.53ppm,122.35ppm,141.05ppm,141.05ppm,144.59ppm,147.45ppm。
实施2
2-溴-6-三氟甲基-3-吡啶甲醛的制备：
在5L反应瓶中，加入107.46g异丙基胺(1.06mol)和1L四氢呋喃，冷至-40℃,缓慢滴加443mL丁基锂(1.11mol，2.6N in hexanes),反应体系冷至-90℃，滴加200g 2-溴-6-三氟甲基吡啶(0.89mol)的1L四氢呋喃溶液，于-90℃反应2小时，再滴加78.67g甲酸乙酯(1.06mol),加毕，缓慢升至室温，这一过程需要9小时，滴加1N的洗盐酸，调节PH＝3-4,分离有机相，加入乙醚萃取水相，合并有机相，水洗，盐洗，干燥，浓缩溶剂，得到的粗产品通过柱层析纯化，生成油状液体2-溴-6-三氟甲基-3-吡啶甲醛162g,产率72％，GC>98％,1HNMR(CDCl3)：7.78ppm,双峰(1H)；8.26ppm,双峰(1H)；10.26ppm,单峰(1H)；13CNMR(CDCl3)：118.65ppm,121.39ppm,132.59ppm,139.79ppm,151.07ppm,151.80ppm,189.65ppm；19FNMR(CDCl3)：-68.32ppm。
实施3
2-溴-6-三氟甲基-3-吡啶甲醇的制备：
在2L反应瓶中，加入50g 2-溴-6-三氟甲基-3-吡啶甲醛(0.20mol),和500mL四氢呋喃,冷至0℃,加入9g硼氢化钠(0.24mol),升至室温反应12小时，加入1N氢氧化钠，分离有机相，加入乙酸乙酯萃取水相，合并有机相，水洗，盐洗，干燥，浓缩溶剂，粗产品用正己烷重结晶，即得2-溴-6-三氟甲基-3-吡啶甲醇26g,产率52％，GC>98％,1HNMR(CDCl3)：3.90ppm,单峰(1H),4.86ppm,单峰(2H),7.82pp,双峰(1H)；8.06ppm,双峰(1H)；13CNMR(CDCl3)：62.68ppm,120.03ppm,137.46ppm,141.00ppm,141.61ppm,146.59；19FNMR(CDCl3)：-67.48ppm。
实施4
2-溴-6-三氟甲基-3-吡啶甲酸的制备：
在3L反应瓶中，加53.73g异丙基胺(0.53mol)和1L四氢呋喃，冷至-40℃,缓慢滴加220mL丁基锂(0.57mol，2.6N in hexanes),反应体系冷至-90℃，滴加100g 2-溴-6-三氟甲基吡啶(0.44mol)的500mL四氢呋喃溶液，于-90℃反应2小时后，倒入775g固体二氧化碳中，搅拌，缓慢升至室温，这一过程需要9小时，滴加1N的洗盐酸，调节PH＝3-4,分离有机相，加入乙酸乙酯萃取水相，合并有机相，水洗，盐洗，干燥，浓缩溶剂，得到的粗产品用正己烷漂洗，生成固体2-溴-6-三氟甲基-3-吡啶甲酸93g,产率78％，HPLC>98％,1HNMR((DMSO-d6/D2O)：7.92ppm,双峰(1H)；8.26ppm,双峰(1H)；13CNMR((DMSO-d6/D2O)：119.34ppm,120.68ppm,122.07ppm,139.65ppm,141.64ppm,148.31ppm,165.98,19FNMR((DMSO-d6/D2O)：-66.93ppm。
Claims (9)
1.一种制备3-取代-2-溴-6-三氟甲基吡啶方法，包括2-溴-6-三氟甲基-3-吡啶硼酸的制备，2-溴-6-三氟甲基-3-吡啶甲醛的制备，2-溴-6-三氟甲基-3-吡啶甲醇的制备；其特征在于：
①3-取代-2-溴-6-三氟甲基吡啶的结构如下：
②2-溴-6-三氟甲基-3-吡啶硼酸的制备：氮气保护下，以2-溴-6-三氟甲基吡啶为原料，在低温下与二异丙基胺锂反应，生成3-位的锂盐，再与三甲基硼酸酯反应，稀盐酸调节pH＝3-4,用有机溶剂萃取，分离，或过滤，干燥，浓缩溶剂，纯化生成2-溴-6-三氟甲基-3-吡啶硼酸；
③2-溴-6-三氟甲基-3-吡啶甲醛的制备：氮气保护下，以2-溴-6-三氟甲基吡啶为原料，在低温下与二异丙基胺锂反应，生成3-位的锂盐，再与甲酸乙酯反应，稀盐酸调节pH＝3-4,用有机溶剂萃取，分离，或过滤，干燥，浓缩溶剂，纯化生成2-溴-6-三氟甲基-3-吡啶甲醛；
④2-溴-6-三氟甲基-3-吡啶甲醇的制备：用硼氢化钠在有机溶剂中还原2-溴-6-三氟甲基-3-吡啶甲醛生成2-溴-6-三氟甲基-3-吡啶甲醇。
2.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的方法，其特征在于：所述步骤②，③中低温度为-90℃。
3.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②，③，④中反应时间为12小时。
4.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②，③，④中反应溶剂为四氢呋喃。
5.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②，③中二异丙基胺锂是现场通过二异丙基胺与丁基锂反应制备。
6.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②，③中萃取有机溶剂为乙醚或乙酸乙酯。
7.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②，③中纯化技术为柱层析或重结晶。
8.根据权利要求1所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②，③稀盐酸为1N浓度。
9.根据权利要求5所述的一种制备3-取代-2-溴-6-三氟甲基吡啶的制备方法，其特征在于：所述步骤②中原料2-溴-6-三氟甲基吡啶与二异丙基胺，丁基锂和三甲基硼酸酯的摩尔比为1:1.2:1.3:1.2，所述步骤③中原料2-溴-6-三氟甲基吡啶与二异丙基胺，丁基锂和甲酸乙酯的摩尔比为1:1.2:1.3:1.2。
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