CN109485601A - 2,6-二卤吡啶-3-羧酸的合成方法 - Google Patents
2,6-二卤吡啶-3-羧酸的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 20
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 6
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 6
- 239000011260 aqueous acid Substances 0.000 claims abstract description 5
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 5
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 claims description 5
- MBTGBRYMJKYYOE-UHFFFAOYSA-N 2,6-difluoropyridine Chemical group FC1=CC=CC(F)=N1 MBTGBRYMJKYYOE-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 24
- 229910002092 carbon dioxide Inorganic materials 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IEVMFAWRTJEFCF-UHFFFAOYSA-N 2,6-difluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(F)N=C1F IEVMFAWRTJEFCF-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- 238000005360 mashing Methods 0.000 description 4
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 3
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- 125000003368 amide group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
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- 150000003222 pyridines Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000000460 chlorine Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SQSYNRCXIZHKAI-UHFFFAOYSA-N 2,6-dichloroisonicotinic acid Chemical compound OC(=O)C1=CC(Cl)=NC(Cl)=C1 SQSYNRCXIZHKAI-UHFFFAOYSA-N 0.000 description 1
- LYBWMGWUDGYKNE-UHFFFAOYSA-N 2,6-diiodopyridine-3-carboxylic acid Chemical compound IC1=C(C(=O)O)C=CC(=N1)I LYBWMGWUDGYKNE-UHFFFAOYSA-N 0.000 description 1
- LLLVHTWJGWNRBD-UHFFFAOYSA-N 2-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1F LLLVHTWJGWNRBD-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- VIWWLVBTPJWYOP-UHFFFAOYSA-N oxolane;n-propan-2-ylpropan-2-amine Chemical compound C1CCOC1.CC(C)NC(C)C VIWWLVBTPJWYOP-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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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
- C07D213/78—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了2,6‑二卤吡啶‑3‑羧酸的合成方法，属于医药中间体合成领域。将2,6‑二卤吡啶和Boc2O溶于有机溶剂中，低温下滴加入LDA或i‑Pr2NMgCl‑LiCl反应，接着加入酸水溶液升温反应，加碱调pH值后得到2,6‑二卤吡啶啶‑3‑羧酸。此外，2,6‑二卤吡啶超低温下加入LDA去质子，接着加入DBU‑CO2反应，淬灭后得到2,6‑二卤吡啶啶‑3‑羧酸。上述两种方法避免了传统采用通入CO2方法放大规模时收率低的问题，批次间操作重现性良好。
Description
技术领域
本发明涉及吡啶类化合物的合成，尤其是涉及2,6-二卤吡啶-3-羧酸的合成方法，属于医药中间体合成技术领域。
背景技术
2,6-二卤吡啶-3-羧酸，包括2,6-二氟吡啶-3-羧酸、2,6-二氯吡啶-3-羧酸、2,6-二碘吡啶-3-羧酸，均为医药化工中间体，用于含有吡啶类药物中酰胺的原料。以2,6-二氟吡啶-3-羧酸和2,6-二氯吡啶-3-羧酸为例，现有公开的文献资料如下：
Eur. J. Org. Chem., 2004, 5, 1018 - 1024报道了采用2,6-二氟吡啶与LDA超低温下反应，锂化结束后与二氧化碳反应，处理后得到2,6-二氟吡啶-3-羧酸，反应收率94%。US2009/318412, 2009, A1公开了采用类似的方法制备产品，在锂化结束后，在超低温条件下，将干冰加入反应液中，处理后产品收率为63%。
US2004/142930, 2004, A1公开了采用2,6-二氯吡啶与LDA超低温下反应，锂化结束后倒入固体干冰中，随后加入氢氧化钠调成碱性，乙酸乙酯萃取，分出水层加盐酸调成酸性，得到2,6-二氯吡啶-3-羧酸，反应收率69%。Bioorganic and Medicinal Chemistry,2002, 10, 1793 - 1804报道了采用类似的方法制备产品，主要区别仅在于将锂化反应液倒入了乙醚的二氧化碳溶液中，重结晶后收率为60%。
有趣的是，J. Lab. Cpd. Radiopharm., 2001, 44, 451 - 457报道了将LDA更换为正丁基锂进行锂化，再接着与二氧化碳反应时，得到3位羧酸和4位羧酸的混合物，且以4-位羧酸为主，乙醇和水混合溶剂重结晶后以52%收率获得2,6-二氯吡啶-4-羧酸，核磁纯度97%。
根据已有的公开资料，采用2,6-二卤吡啶与LDA先进行锂化，然后再加入二氧化碳进行羧酸化是最简便有效的方式。然而，该反应在百克规模反应，反应收率相对稳定，原料转化率达到80-90%以上，随着反应规模放大至百公斤时，原料转化率逐渐下降至45-50%，且随着反应时间延长，转化率基本不再增加。推测原因可能为放大时，为了操作方便，仅仅能采用通入二氧化碳的方式进行，超低温下部分二氧化碳固化，或是与2,6-二卤吡啶形成络合形成盐，进一步影响反应的继续进行。
鉴于吡啶类化合物在医药领域的重要性，有必要对现有方法进行重新优化和开发。
发明内容
为了克服上述缺陷，本发明公开了两种方案解决上述问题。一是采用从2,6-二卤吡啶出发，与Boc2O反应后，酸化去掉叔丁基后得到2,6-二卤吡啶啶-3-羧酸；将2,6-二卤吡啶啶和Boc2O 溶于有机溶剂中，低温下滴加入LDA反应，接着加入酸水溶液升温反应，加碱调pH值后得到2,6-二卤吡啶啶-3-羧酸。二是采用DBU-CO2的络合物，替代直接通入CO2的方式。该方法中避免了传统采用通入CO2方法放大规模时收率低的问题，批次间操作重现性良好。
本发明中提供的2,6-二卤吡啶-3-羧酸的合成方法，包括如下步骤：
方案一、将2,6-二卤吡啶与Boc2O溶解在有机溶剂中，低温下滴加LDA溶液，接着加入酸水溶液升温反应，得到2,6-二卤吡啶-3-羧酸。反应方程式如下：
方案二、将2,6-二卤吡啶在有机溶剂中，超低温下与LDA反应后，接着加入DBU-CO2络合物继续保温反应后，加入酸水溶液淬灭，得到2,6-二卤吡啶-3-羧酸。反应方程式如下：
在上述两种方案中，X均选自氟、氯、溴、碘，优选自氟和氯。
进一步地，在上述技术方案中，上述方案中有机溶剂包括四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、环戊基甲基醚、乙二醇二甲醚、二乙氧基甲烷等。
进一步地，在上述技术方案中，LDA采用TEMPLi或HMDSLi替换时，4-位异构体生成量较为明显，需要通过重结晶纯化后处理，收率降低。然而采用二异丙基胺基氯化镁-氯化锂（i-Pr2NMgCl-LiCl）时，效果与LDA基本相当。
进一步地，在上述技术方案中，低温反应温度优选-20℃至0℃。超低温优选反应温度为-75℃至-60℃。
进一步地，在上述技术方案中，2,6-二卤吡啶、Boc2O与LDA当量比为1: 1.05-1.2:1.1-1.5。
进一步地，在上述技术方案中，DBU-CO2络合物采用DBU溶于上述有机溶剂中，接着通入近乎等当量CO2后（最多不超过1.1eq）保温得到。多余的二氧化碳不影响反应。
进一步地，在上述技术方案中，2,6-二卤吡啶、DBU-CO2、LDA当量比为1: 1.1-1.3:1.1-1.5。
进一步地，在上述技术方案中，酸选自盐酸、硫酸、氢溴酸等，优选为盐酸。
本发明的积极效果
本发明采用两种方式来解决现有文献中工艺放大时存在的转化率低的问题，一是利用Boc2O反应成羧酸酯，通过加入酸后将叔丁基去掉，二是采用DBU固定CO2的方式，解决的通入时过快或过慢产生的收率不平行性。该方法中避免了传统采用通入CO2方法放大规模时收率低的问题，批次间操作重现性良好。
具体实施方案
实施例1
氮气保护下，将2,6-二氟吡啶( 11.5克，0.1摩尔)、Boc2O (26.0克，0.12mol) 和四氢呋喃130mL，搅拌至完全溶清后，冰盐浴降至-15℃，开始滴加事先配置好的1M LDA四氢呋喃溶液( 0.13摩尔)，整个滴加过程中控温不超过-10℃。滴加完毕后，保温搅拌2-3小时，随后自然升至室温搅拌反应过夜，TLC检测原料基本无剩余。
再次将反应液降至0℃，滴加15%盐酸水溶液至pH=1-2（注意酸性调节不易过强，在不控制酸性的水解时，检测出少量2-羟基-6-氟-吡啶-3-羧酸）。滴加过程中明显放热，控制温度不超过30℃，滴加完毕升温至35-40℃，继续搅拌反应1-2小时，检测如果仍有少量剩余，可补加15%盐酸继续保温搅拌直至反应完毕，降至室温后，接着加入饱和碳酸钠水溶液，调节pH=4-5，加入乙酸乙酯70mL萃取两次，饱和食盐水洗，无水硫酸钠干燥，旋蒸溶剂后，采用88mL甲基叔丁基醚和正庚烷（体积比1:8）打浆后，得到浅黄色固体13.5克2,6-二氟吡啶-3-羧酸，收率85%，HPLC：98.1%，产品与标准样品在HPLC中出峰一致。HNMR(400MHz, DMSO-d6): 7.29(dd, J= 2.4Hz, 8.2Hz, 1H), 8.59(dd, J= 8.2Hz, 4.2Hz), 13.1(broad s,1H).
实施例2
氮气保护下，将2,6-二氯吡啶( 14.8克，0.1摩尔)、Boc2O (26.0克，0.12mol) 和四氢呋喃130mL，搅拌至完全溶清后，冰盐浴降至-15℃，开始滴加事先由异丙基氯化镁-氯化锂溶液滴加入二异丙胺四氢呋喃溶液中，配置好1M 二异丙基胺基氯化镁-氯化锂四氢呋喃溶液( 0.15摩尔)，整个滴加过程中控温不超过-10℃。滴加完毕后，保温搅拌2-3小时，随后自然升至室温搅拌反应过夜，TLC检测原料基本无剩余。
再次将反应液降至0℃，滴加36%盐酸水溶液至pH=1。滴加过程中明显放热，控制温度不超过30℃，滴加完毕升温至35-40℃，继续搅拌反应1-2小时，降至室温后，接着加入1M氢氧化钠水溶液，调节pH=4-5，加入乙酸乙酯70mL萃取两次，饱和食盐水洗，无水硫酸钠干燥，旋蒸溶剂后，采用75mL甲基叔丁基醚和正庚烷（体积比1:10）打浆后，得到类白色固体15.9克2,6-二氯吡啶-3-羧酸，收率83%，HPLC：98.8%，产品与标准样品在HPLC中出峰一致。HNMR(400MHz, DMSO-d6): 7.33(dd, J= 2.4Hz, 8.4Hz, 1H), 8.48(dd, J= 8.4Hz,4.2Hz), 13.0(broad s, 1H).
实施例3
氮气保护下，将2,6-二氟吡啶( 11.5克，0.1摩尔)和四氢呋喃120mL，搅拌至完全溶清后，干冰/丙酮体系降温至-75℃，开始滴加事先配置好的1M LDA四氢呋喃溶液( 0.12摩尔)，整个滴加过程中控温不超过-60℃。滴加完毕后，保温搅拌1.5小时，随后将DBU-CO2络合物(0.11mol)溶解在65mL四氢呋喃溶液中，控温不超过-60℃滴加进入反应液，保温搅拌2小时，自然升至室温搅拌反应过夜，TLC检测原料基本无剩余。
再次将反应液降至0℃，滴加15%盐酸水溶液至pH=3-5。滴加过程中明显放热，控制温度不超过20℃，滴加完毕继续搅拌反应1-2小时，加入乙酸乙酯70mL萃取两次，饱和食盐水洗，无水硫酸钠干燥，旋蒸溶剂后，采用80mL甲基叔丁基醚和正庚烷（体积比1:8）打浆后，得到浅黄色固体12.9克2,6-二氟吡啶-3-羧酸，收率81%，HPLC：97.2%。
实施例4
氮气保护下，将2,6-二氯吡啶( 14.8克，0.1摩尔)和四氢呋喃120mL，搅拌至完全溶清后，干冰/丙酮体系降温至-75℃，开始滴加事先由异丙基氯化镁-氯化锂滴加入二异丙胺四氢呋喃溶液中，配置好1M 二异丙基胺基氯化镁-氯化锂四氢呋喃溶液( 0.15摩尔)，整个滴加过程中控温不超过-60℃。滴加完毕后，保温搅拌1.5小时，随后将DBU-CO2络合物(0.12mol)溶解在65mL四氢呋喃溶液中，控温不超过-60℃滴加进入反应液，保温搅拌2小时，自然升至室温搅拌反应过夜，TLC检测原料基本无剩余。
再次将反应液降至0℃，滴加40%氢溴酸水溶液至pH=3-5。滴加过程中明显放热，控制温度不超过20℃，滴加完毕继续搅拌反应1-2小时，加入乙酸乙酯70mL萃取两次，饱和食盐水洗，无水硫酸钠干燥，旋蒸溶剂后，采用85mL甲基叔丁基醚和正庚烷（体积比1:10）打浆后，得到类白色固体17.1克2,6-二氯吡啶-3-羧酸，收率89%，HPLC：97.4%。
实施例5
氮气保护下，将2,6-二氯吡啶(145kg，1Kmol)和四氢呋喃850L加入2000L不锈钢超低温反应釜内，搅拌下采用液氮将反应釜降温至-75℃至-70℃，开始滴加配置好1M LDA四氢呋喃溶液( 0.13摩尔)，整个滴加过程中控温不超过-65℃。滴加完毕后，保温搅拌3.5小时，随后将DBU-CO2络合物(1.1Kmol)溶解在350L四氢呋喃溶液中，控温不超过-65℃缓慢加入上述反应体系，继续保温搅拌4-5小时，取样检测反应完毕，TLC检测原料基本无剩余，HPLC检测原料剩余1.7%。
将上述反应液加入水淬灭至反应温度为-20℃至-10℃，转移至搪瓷反应釜后，开始滴加15%盐酸水溶液至pH=3-4。滴加过程中明显放热，控制温度不超过0℃，滴加完毕继续搅拌反应1-2小时，加入乙酸乙酯450L萃取，饱和食盐水洗，分出有机层减压蒸馏，加入330L甲基叔丁基醚和正庚烷（体积比1:10）打浆后，得到浅黄色固体161kg 2,6-二氯吡啶-3-羧酸，收率84%，HPLC：97.7%。产品再次采用上述混合溶剂打浆后，得到类白色纯度99.4%产品，回收率93%。
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (10)
1.2,6-二卤吡啶-3-羧酸的合成方法，其特征在于，包括如下步骤：
将2,6-二卤吡啶与Boc2O溶解在有机溶剂中，低温下滴加LDA或i-Pr2NMgCl-LiCl溶液，接着加入酸水溶液升温反应，得到2,6-二卤吡啶啶-3-羧酸。
2.根据权利要求1所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：有机溶剂选自四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、环戊基甲基醚、乙二醇二甲醚或二乙氧基甲烷。
3.根据权利要求1所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：低温反应温度优选-20℃至0℃。
4.根据权利要求1所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：2,6-二卤吡啶、Boc2O、LDA或i-Pr2NMgCl当量比为1: 1.05-1.2: 1.1-1.5。
5.2,6-二卤吡啶-3-羧酸的合成方法，其特征在于，包括如下步骤：
将2,6-二卤吡啶在有机溶剂中，超低温下与LDA或i-Pr2NMgCl-LiCl反应后，接着加入DBU-CO2络合物继续保温反应后，加入酸水溶液淬灭，得到2,6-二卤吡啶啶-3-羧酸。
6.根据权利要求5所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：超低温反应温度为-75℃至-60℃。
7.根据权利要求5所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：采用DBU溶于有机溶剂中，接着通入CO2后保温得到DBU-CO2络合物。
8.根据权利要求6所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：2,6-二卤吡啶、DBU-CO2、LDA或i-Pr2NMgCl-LiCl当量比为1: 1.1-1.3: 1.1-1.5。
9.根据权利要求1或5所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：2,6-二卤吡啶选自2,6-二氟吡啶或2,6-二氯吡啶。
10.根据权利要求1或5所述2,6-二卤吡啶-3-羧酸的合成方法，其特征在于：酸选自盐酸、硫酸、氢溴酸。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006105063A1 (en) * | 2005-03-25 | 2006-10-05 | Scios Inc. | Heterobicylic inhibitors of tgfbeta |
| CN103889224A (zh) * | 2011-08-29 | 2014-06-25 | Ptc医疗公司 | 抗细菌化合物及使用方法 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006105063A1 (en) * | 2005-03-25 | 2006-10-05 | Scios Inc. | Heterobicylic inhibitors of tgfbeta |
| CN103889224A (zh) * | 2011-08-29 | 2014-06-25 | Ptc医疗公司 | 抗细菌化合物及使用方法 |
Non-Patent Citations (3)
| Title |
|---|
| MANFRED SCHLOSSER ET AL.: ""The Structural Proliferation of 2,6-Difluoropyridine through Organometallic Intermediates"", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| 柳思: ""DBU促进C02羧化邻羟基／乙酰胺基苯乙酮研究"", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
| 赵建茹主编: "《基础化学教程（第2版）》", 28 February 2014, 西安交通大学出版社 * |
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