JP2018090531A - Method for producing heteroaromatic carboxylic acid - Google Patents
Method for producing heteroaromatic carboxylic acid Download PDFInfo
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- JP2018090531A JP2018090531A JP2016234982A JP2016234982A JP2018090531A JP 2018090531 A JP2018090531 A JP 2018090531A JP 2016234982 A JP2016234982 A JP 2016234982A JP 2016234982 A JP2016234982 A JP 2016234982A JP 2018090531 A JP2018090531 A JP 2018090531A
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- aromatic heterocyclic
- permanganate
- methyl
- carboxylic acid
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- -1 heteroaromatic carboxylic acid Chemical class 0.000 title claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 22
- 150000007514 bases Chemical class 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- 230000003647 oxidation Effects 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 45
- 125000006615 aromatic heterocyclic group Chemical class 0.000 claims description 41
- 238000002156 mixing Methods 0.000 claims description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 239000012286 potassium permanganate Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000002390 heteroarenes Chemical class 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- GCAIEATUVJFSMC-UHFFFAOYSA-N benzene-1,2,3,4-tetracarboxylic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1C(O)=O GCAIEATUVJFSMC-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- LCZUOKDVTBMCMX-UHFFFAOYSA-N 2,5-Dimethylpyrazine Chemical compound CC1=CN=C(C)C=N1 LCZUOKDVTBMCMX-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 229910021642 ultra pure water Inorganic materials 0.000 description 5
- 239000012498 ultrapure water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000001934 2,5-dimethylpyrazine Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- UOHMMEJUHBCKEE-UHFFFAOYSA-N prehnitene Chemical compound CC1=CC=C(C)C(C)=C1C UOHMMEJUHBCKEE-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YSZLFGZFQTTZIQ-UHFFFAOYSA-N 1,2,3,4,5,6,7,8-octahydrophenanthrene Chemical compound C1CCCC2=C1C=CC1=C2CCCC1 YSZLFGZFQTTZIQ-UHFFFAOYSA-N 0.000 description 2
- APQSQLNWAIULLK-UHFFFAOYSA-N 1,4-dimethylnaphthalene Chemical compound C1=CC=C2C(C)=CC=C(C)C2=C1 APQSQLNWAIULLK-UHFFFAOYSA-N 0.000 description 2
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 2
- GWQOOADXMVQEFT-UHFFFAOYSA-N 2,5-Dimethylthiophene Chemical compound CC1=CC=C(C)S1 GWQOOADXMVQEFT-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Natural products OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000002484 inorganic compounds Chemical class 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- GMIOYJQLNFNGPR-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CN=C(C(O)=O)C=N1 GMIOYJQLNFNGPR-UHFFFAOYSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 2
- YCGAZNXXGKTASZ-UHFFFAOYSA-N thiophene-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)S1 YCGAZNXXGKTASZ-UHFFFAOYSA-N 0.000 description 2
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- 239000005967 1,4-Dimethylnaphthalene Substances 0.000 description 1
- SIWNEELMSUHJGO-UHFFFAOYSA-N 2-(4-bromophenyl)-4,5,6,7-tetrahydro-[1,3]oxazolo[4,5-c]pyridine Chemical compound C1=CC(Br)=CC=C1C(O1)=NC2=C1CCNC2 SIWNEELMSUHJGO-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical group N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- ZZCNKSMCIZCVDR-UHFFFAOYSA-N barium(2+);dioxido(dioxo)manganese Chemical compound [Ba+2].[O-][Mn]([O-])(=O)=O ZZCNKSMCIZCVDR-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 244000309464 bull Species 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ABMFBCRYHDZLRD-UHFFFAOYSA-N naphthalene-1,4-dicarboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=C(C(O)=O)C2=C1 ABMFBCRYHDZLRD-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical group N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
本発明は、芳香族複素環カルボン酸の製造方法に関する。 The present invention relates to a method for producing an aromatic heterocyclic carboxylic acid.
従来、カルボン酸の製造法は種々提唱されている。例えば、非特許文献１および非特許文献２では、１，２，３，４−テトラメチルベンゼンを酸化して、１，２，３，４−ベンゼンテトラカルボン酸を合成している。 Conventionally, various methods for producing carboxylic acids have been proposed. For example, in Non-Patent Document 1 and Non-Patent Document 2, 1,2,3,4-tetramethylbenzene is oxidized to synthesize 1,2,3,4-benzenetetracarboxylic acid.
非特許文献３でも、合成により得られた１，２，３，４−テトラメチルベンゼンを過マンガン酸カリウムにより酸化して、１，２，３，４−ベンゼンテトラカルボン酸を合成している。非特許文献４では、１，４−ジメチルナフタレンを４０％濃硝酸で反応温度１７０〜１８０℃、加圧下で酸化して１，２，３，４−ベンゼンテトラカルボン酸を合成している。 Also in Non-Patent Document 3, 1,2,3,4-tetramethylbenzene obtained by synthesis is oxidized with potassium permanganate to synthesize 1,2,3,4-benzenetetracarboxylic acid. In Non-Patent Document 4, 1,4-dimethylnaphthalene is oxidized with 40% concentrated nitric acid at a reaction temperature of 170 to 180 ° C. under pressure to synthesize 1,2,3,4-benzenetetracarboxylic acid.
特許文献１では、１，２，３，４，５，６，７，８−オクタヒドロフェナントレンを濃硝酸により、反応温度１５０℃で加圧下、あるいは反応温度１６０〜１６５℃、ジブロモベンゼン溶媒中にて酸化することで１，２，３，４−ベンゼンテトラカルボン酸を合成している。特許文献２では、１，２，３，４，５，６，７，８−オクタヒドロフェナントレンをブチロラクトン溶媒中、反応温度２１０℃、圧力２０キロで酸素酸化して１，２，３，４−ベンゼンテトラカルボン酸を合成している。 In Patent Document 1, 1,2,3,4,5,6,7,8-octahydrophenanthrene is pressurized with concentrated nitric acid at a reaction temperature of 150 ° C. or in a reaction temperature of 160 to 165 ° C. in a dibromobenzene solvent. 1,2,3,4-benzenetetracarboxylic acid is synthesized by oxidation. In Patent Document 2, 1,2,3,4,5,6,7,8-octahydrophenanthrene is oxidized with oxygen in a butyrolactone solvent at a reaction temperature of 210 ° C. and a pressure of 20 kg, and 1,2,3,4- Benzenetetracarboxylic acid is synthesized.
非特許文献５〜８では、１，４−ナフタレンジカルボン酸の過マンガン酸カリウム酸化により１，２，３，４−ベンゼンテトラカルボン酸を合成している。非特許文献９では、１，３−シクロヘキサジエンから、無水マレイン酸とのディールスアルダー反応、液相硝酸酸化、臭素による酸化的脱水素の３段階の反応で１，２，３，４−ベンゼンテトラカルボン酸を合成している。非特許文献１０では、シクロへキセンを出発物質として同様に１，２，３，４−ベンゼンテトラカルボン酸を合成している。 In Non-Patent Documents 5 to 8, 1,2,3,4-benzenetetracarboxylic acid is synthesized by potassium permanganate oxidation of 1,4-naphthalenedicarboxylic acid. In Non-Patent Document 9, 1,3-cyclohexadiene is converted into 1,2,3,4-benzenetetraleth by a three-stage reaction of Diels-Alder reaction with maleic anhydride, liquid phase nitric acid oxidation, and oxidative dehydrogenation with bromine. Carboxylic acid is synthesized. In Non-Patent Document 10, 1,2,3,4-benzenetetracarboxylic acid is synthesized similarly using cyclohexene as a starting material.
しかしながら、メチル置換芳香族複素環化合物（芳香族複素環にメチル基が置換した芳香族複素環式化合物）を過マンガン酸カリウムで酸化して、芳香族複素環カルボン酸を合成する場合、得られる芳香族複素環カルボン酸の収率が低いという問題点があった。 However, it can be obtained by synthesizing an aromatic heterocyclic carboxylic acid by oxidizing a methyl-substituted aromatic heterocyclic compound (aromatic heterocyclic compound having an aromatic heterocyclic ring substituted with a methyl group) with potassium permanganate. There was a problem that the yield of aromatic heterocyclic carboxylic acid was low.
上記の事情に鑑み、本発明の目的は、芳香族複素環カルボン酸を収率良く製造する方法を提供することである。 In view of the above circumstances, an object of the present invention is to provide a method for producing an aromatic heterocyclic carboxylic acid with high yield.
本発明者らは、上記のようなメチル置換芳香族複素環化合物を過マンガン酸カリウムで酸化して得られる芳香族複素環カルボン酸の低収率の一因が、原料のメチル置換芳香族複素環化合物が酸化に不安定で分解してしまうためと推察し、鋭意検討の結果、本課題を解決する方法を見出した。 The inventors of the present invention contributed to the low yield of the aromatic heterocyclic carboxylic acid obtained by oxidizing the above methyl-substituted aromatic heterocyclic compound with potassium permanganate. Assuming that the ring compound is unstable to oxidation and decomposes, as a result of intensive studies, a method for solving this problem has been found.
すなわち、本発明は下記の芳香族複素環カルボン酸の製造方法を提供するものである。
［１］１つ以上のメチル基を芳香族複素環上に有するメチル置換芳香族複素環化合物を、塩基性化合物と過マンガン酸塩を用いて酸化することを含む、芳香族複素環カルボン酸の製造方法。
That is, this invention provides the manufacturing method of the following aromatic heterocyclic carboxylic acid.
[1] An aromatic heterocyclic carboxylic acid comprising oxidizing a methyl-substituted aromatic heterocyclic compound having one or more methyl groups on an aromatic heterocyclic ring with a basic compound and a permanganate. Production method.
［２］前記塩基性化合物が、水酸化ナトリウム又は水酸化カリウムである、［１］に記載の芳香族複素環カルボン酸の製造方法。 [2] The method for producing an aromatic heterocyclic carboxylic acid according to [1], wherein the basic compound is sodium hydroxide or potassium hydroxide.
［３］前記過マンガン酸塩が、過マンガン酸カリウムである、［１］又は［２］に記載の芳香族複素環カルボン酸の製造方法。 [3] The method for producing an aromatic heterocyclic carboxylic acid according to [1] or [2], wherein the permanganate is potassium permanganate.
［４］前記メチル置換芳香族複素環化合物の酸化を、前記塩基性化合物及び溶媒を含有する塩基性溶媒中で行う、［１］〜［３］のいずれかに記載の芳香族複素環カルボン酸の製造方法。 [4] The aromatic heterocyclic carboxylic acid according to any one of [1] to [3], wherein the methyl-substituted aromatic heterocyclic compound is oxidized in a basic solvent containing the basic compound and a solvent. Manufacturing method.
［５］ 前記塩基性化合物を溶媒に混合し、塩基性溶媒を得る工程；
前記塩基性溶媒に前記メチル置換芳香族複素環化合物を混合する工程；
及び、
前記塩基性溶媒に前記過マンガン酸塩を混合する工程；
を含む［１］〜［４］のいずれかに記載の芳香族複素環カルボン酸の製造方法。
[5] A step of mixing the basic compound with a solvent to obtain a basic solvent;
Mixing the methyl-substituted aromatic heterocyclic compound with the basic solvent;
as well as,
Mixing the permanganate with the basic solvent;
The process for producing an aromatic heterocyclic carboxylic acid according to any one of [1] to [4].
［６］ 前記塩基性溶媒に前記メチル置換芳香族複素環化合物を混合する工程の後に、前記塩基性溶媒に前記過マンガン酸塩を混合する工程を行う［５］に記載の芳香族複素環カルボン酸の製造方法。 [6] The aromatic heterocyclic carboxylic acid according to [5], wherein the step of mixing the permanganate with the basic solvent is performed after the step of mixing the methyl-substituted aromatic heterocyclic compound with the basic solvent. Acid production method.
本発明の芳香族複素環カルボン酸の製造方法によれば、芳香族複素環カルボン酸を収率良く製造することができる。 According to the method for producing an aromatic heterocyclic carboxylic acid of the present invention, an aromatic heterocyclic carboxylic acid can be produced with high yield.
以下、本発明を実施するための一実施形態を説明するが、本発明は下記実施の形態に限定されるものではない。 Hereinafter, although one embodiment for carrying out the present invention is described, the present invention is not limited to the following embodiment.
本実施の形態の芳香族複素環カルボン酸の製造方法は、１つ以上のメチル基を芳香族複素環上に有するメチル置換芳香族複素環化合物を、塩基性化合物と過マンガン酸塩を用いて酸化することを含む。 In the method for producing an aromatic heterocyclic carboxylic acid according to the present embodiment, a methyl-substituted aromatic heterocyclic compound having one or more methyl groups on an aromatic heterocyclic ring is obtained by using a basic compound and a permanganate. Including oxidizing.
＜原料＞
本実施の形態に用いられるメチル置換芳香族複素環化合物及び本実施の形態で製造される芳香族複素環カルボン酸における芳香族複素環としては、環構造に不飽和結合を有し、環の構成原子として、炭素原子と炭素原子以外の少なくとも１種類の原子とを含む３員環以上、好ましくは３員環〜４員環、より好ましくは５員環〜６員環の環構造であれば、特に限定されず、単環であっても縮合環であってもよい。炭素原子以外の環の構成原子としては、例えば、窒素原子、硫黄原子及び酸素原子が好ましい。環の構成原子としての炭素原子以外の原子の数は特に制限はないが、窒素原子を含む場合、窒素原子の数は、好ましくは１〜２個である。環の構成原子として硫黄原子を含む場合、硫黄原子の数は、好ましくは１〜２個である。環の構成原子として酸素原子を含む場合、酸素原子の数は、好ましくは１〜２個である。炭素原子以外に含まれる環構成原子は、１種のみであってもよく、２種以上であってもよく、例えば、炭素原子以外に、窒素原子及び／又は硫黄原子を、合計で１〜２個有することが好ましい。好ましい芳香族複素環の具体例としては、例えば、ピリジン環、イミダゾール環、チオフェン環、ピラジン環、ピロール環、アゼピン環、チエピン環、ピラゾール環、オキサゾール環、チアゾール環、イミダゾリン環、チアジン環、インドール環、イソインドール環、ベンゾイミダゾール環、プリン環、キノリン環、イソキノリン環、キノキサリン環、シンノリン環、プテリジン環等が挙げられる。なかでも、材料入手のしやすさの観点から、例えば、ピラジン環、チオフェン環、ピリジン環、イミダゾール環が好ましい。
<Raw material>
As the aromatic heterocyclic ring in the methyl-substituted aromatic heterocyclic compound used in the present embodiment and the aromatic heterocyclic carboxylic acid produced in the present embodiment, the ring structure has an unsaturated bond, and the ring structure If the ring structure is a 3-membered ring or more, preferably a 3-membered ring to 4-membered ring, more preferably a 5-membered ring to 6-membered ring containing a carbon atom and at least one kind of atom other than carbon atoms, There is no particular limitation, and it may be a single ring or a condensed ring. As the constituent atoms of the ring other than the carbon atom, for example, a nitrogen atom, a sulfur atom and an oxygen atom are preferable. The number of atoms other than carbon atoms as a constituent atom of the ring is not particularly limited, but when a nitrogen atom is included, the number of nitrogen atoms is preferably 1 to 2. When a sulfur atom is included as a constituent atom of the ring, the number of sulfur atoms is preferably 1 to 2. When an oxygen atom is included as a ring-constituting atom, the number of oxygen atoms is preferably 1 to 2. The ring-constituting atoms contained other than carbon atoms may be only one kind or two or more kinds. For example, in addition to carbon atoms, nitrogen atoms and / or sulfur atoms may be added in a total of 1-2. It is preferable to have one. Specific examples of preferred aromatic heterocycle include, for example, pyridine ring, imidazole ring, thiophene ring, pyrazine ring, pyrrole ring, azepine ring, thiepin ring, pyrazole ring, oxazole ring, thiazole ring, imidazoline ring, thiazine ring, indole. Ring, isoindole ring, benzimidazole ring, purine ring, quinoline ring, isoquinoline ring, quinoxaline ring, cinnoline ring, pteridine ring and the like. Among these, from the viewpoint of easy availability of materials, for example, a pyrazine ring, a thiophene ring, a pyridine ring, and an imidazole ring are preferable.
本実施の形態の製造方法の原料に用いられる、メチル置換芳香族複素環化合物は、上述の「芳香族複素環」に少なくとも１つのメチル基が置換基として結合している化合物である。芳香族複素環上のメチル基の結合部位は特に制限はないが、芳香族複素環の構成原子のうち、炭素原子に結合していることが好ましい。原料のメチル置換芳香族複素環化合物は、メチル基以外の置換基を１つ以上有していてもよい。このような置換基としては、例えば、ハロゲン、ヒドロキシ基等が挙げられる。 The methyl-substituted aromatic heterocyclic compound used as a raw material for the production method of the present embodiment is a compound in which at least one methyl group is bonded as a substituent to the “aromatic heterocyclic ring” described above. The bonding site of the methyl group on the aromatic heterocyclic ring is not particularly limited, but is preferably bonded to a carbon atom among the constituent atoms of the aromatic heterocyclic ring. The raw material methyl-substituted aromatic heterocyclic compound may have one or more substituents other than the methyl group. Examples of such a substituent include a halogen and a hydroxy group.
＜塩基性化合物＞
本実施の形態に用いられる塩基性化合物としては、特に限定されるものではなく、塩基性無機化合物又は塩基性有機化合物のいずれであってもよい。好適に用いられる塩基性無機化合物としては、例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化ルビジウム、水酸化セシウム等が挙げられる。使用可能な塩基性有機化合物としては、例えば、ピリジン、トリエチルアミン等が挙げられる。これらは１種を単独で用いても、２種以上を併用してもよい。これらの中でも、入手のし易さから、水酸化ナトリウム及び水酸化カリウムが好ましい。
<Basic compound>
The basic compound used in the present embodiment is not particularly limited, and may be either a basic inorganic compound or a basic organic compound. Suitable basic inorganic compounds include sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, cesium hydroxide, and the like. Examples of the basic organic compound that can be used include pyridine and triethylamine. These may be used alone or in combination of two or more. Among these, sodium hydroxide and potassium hydroxide are preferable because they are easily available.
＜過マンガン酸塩＞
本実施の形態に用いられる過マンガン酸塩としては、特に限定されるものではなく、例えば、過マンガン酸カリウム、過マンガン酸ナトリウム、過マンガン酸アンモニウム、過マンガン酸マグネシウム、過マンガン酸カルシウム、過マンガン酸バリウム等が挙げられる。これらは１種を単独で用いても、２種以上を併用してもよい。これらの中でも、入手のし易さから、過マンガン酸カリウムが好ましい。
<Permanganate>
The permanganate used in the present embodiment is not particularly limited. For example, potassium permanganate, sodium permanganate, ammonium permanganate, magnesium permanganate, calcium permanganate, permanganate, Examples thereof include barium manganate. These may be used alone or in combination of two or more. Among these, potassium permanganate is preferable because it is easily available.
＜反応＞
本実施の形態の芳香族複素環カルボン酸の製造方法は、塩基性化合物と過マンガン酸塩を用いてメチル置換芳香族複素環化合物を酸化することにより、芳香族複素環カルボン酸を製造するものである。
<Reaction>
The method for producing an aromatic heterocyclic carboxylic acid according to the present embodiment produces an aromatic heterocyclic carboxylic acid by oxidizing a methyl-substituted aromatic heterocyclic compound using a basic compound and a permanganate. It is.
本実施の形態の芳香族複素環カルボン酸の製造方法において、塩基性化合物と過マンガン酸塩とを用いてメチル置換芳香族複素環化合物を酸化する具体的操作としては特に制限はない。例えば、塩基性化合物を溶媒に混合して塩基性溶媒を調製し、この塩基性溶媒中でメチル置換芳香族複素環化合物の過マンガン酸塩との反応を行う方法が挙げられる。 In the method for producing an aromatic heterocyclic carboxylic acid of the present embodiment, the specific operation for oxidizing a methyl-substituted aromatic heterocyclic compound using a basic compound and a permanganate is not particularly limited. For example, there is a method in which a basic compound is mixed with a solvent to prepare a basic solvent, and a reaction with a permanganate of a methyl-substituted aromatic heterocyclic compound is performed in this basic solvent.
このような塩基性溶媒を用いる実施の形態としては、例えば、塩基性化合物を溶媒に混合し、塩基性溶媒を得る工程（以下、塩基性溶媒調整工程ともいう）と、得られた塩基性溶媒にメチル置換芳香族複素環化合物を混合する工程（以下、メチル置換芳香族複素環化合物混合工程ともいう）と、過マンガン酸塩を混合する工程（以下、過マンガン酸塩混合工程ともいう）と、を有する実施の形態が挙げられる。以下、この実施の形態について、説明する。 As an embodiment using such a basic solvent, for example, a step of mixing a basic compound with a solvent to obtain a basic solvent (hereinafter also referred to as a basic solvent adjustment step), and the obtained basic solvent A step of mixing a methyl-substituted aromatic heterocyclic compound (hereinafter also referred to as a methyl-substituted aromatic heterocyclic compound mixing step), a step of mixing a permanganate (hereinafter also referred to as a permanganate mixing step), And an embodiment having Hereinafter, this embodiment will be described.
［塩基性溶媒調整工程］
塩基性溶媒調整工程は、塩基性化合物を溶媒に混合し、塩基性溶媒を得る工程である。塩基性化合物としては、前述の塩基性化合物を用いることができる。溶媒としては、例えば、水、が挙げられる。塩基性化合物と溶媒との混合方法は、特に限定されるものではなく、公知の方法を用いることができる。
[Basic solvent adjustment step]
The basic solvent adjustment step is a step of obtaining a basic solvent by mixing a basic compound with a solvent. As the basic compound, the above-mentioned basic compounds can be used. Examples of the solvent include water. The mixing method of a basic compound and a solvent is not specifically limited, A well-known method can be used.
溶媒に対する塩基性化合物の配合量は、例えば、０．１〜１０規定であることが好ましく、０．５〜５規定であることがより好ましく、１〜２規定であることが特に好ましい。 The compounding amount of the basic compound with respect to the solvent is, for example, preferably 0.1 to 10 N, more preferably 0.5 to 5 N, and particularly preferably 1 to 2 N.
［メチル置換芳香族複素環化合物混合工程］
メチル置換芳香族複素環化合物混合工程は、塩基性溶媒調整工程で得られた塩基性溶媒に、メチル置換芳香族複素環化合物を混合する工程である。
混合方法は、特に限定されるものではなく、公知の方法を用いることができる。仕込みやすさの観点から、塩基性溶媒にメチル置換芳香族複素環化合物を混合し、加熱撹拌することが好ましい。この際の、混合溶液の温度としては、特に限定されるものではないが、５０〜１００℃が好ましく、５０〜８０℃がより好ましく、５０〜６０℃が特に好ましい。塩基性溶媒に対するメチル置換芳香族複素環化合物の混合比（質量比）としては、特に限定されるものではなく、過マンガン酸カリウムの溶解性の観点からは、例えば、塩基性溶媒：メチル置換芳香族複素環化合物=６０:１〜１:１が好ましく、塩基性溶媒：メチル置換芳香族複素環化合物=３０:１〜５:１がより好ましく、塩基性溶媒：メチル置換芳香族複素環化合物=１５:１〜１０:１が特に好ましい。
[Methyl-substituted aromatic heterocyclic compound mixing step]
The methyl-substituted aromatic heterocyclic compound mixing step is a step of mixing the methyl-substituted aromatic heterocyclic compound with the basic solvent obtained in the basic solvent adjusting step.
The mixing method is not particularly limited, and a known method can be used. From the viewpoint of ease of preparation, it is preferable to mix a methyl-substituted aromatic heterocyclic compound in a basic solvent and stir with heating. The temperature of the mixed solution at this time is not particularly limited, but is preferably 50 to 100 ° C, more preferably 50 to 80 ° C, and particularly preferably 50 to 60 ° C. The mixing ratio (mass ratio) of the methyl-substituted aromatic heterocyclic compound with respect to the basic solvent is not particularly limited. From the viewpoint of the solubility of potassium permanganate, for example, the basic solvent: methyl-substituted aromatic Group heterocyclic compound = 60: 1 to 1: 1 is preferable, basic solvent: methyl-substituted aromatic heterocyclic compound = 30: 1 to 5: 1 is more preferable, basic solvent: methyl-substituted aromatic heterocyclic compound = 15: 1 to 10: 1 are particularly preferred.
［過マンガン酸塩混合工程］
過マンガン酸塩混合工程は、過マンガン酸塩を混合する工程である。過マンガン酸塩混合工程は、前述のメチル置換芳香族複素環化合物混合工程に次いで行うことが好ましい。
過マンガン酸塩の混合方法は、特に限定されるものではなく、粉体の状態で混合してもよく、粒状で混合してもよい。また、水等の溶媒に溶解させて溶液の状態で混合してもよい。仕込みやすさの観点からは、粒状で混合することが好ましい。また、過マンガン酸塩は、一度に投入し、混合してもよく、複数回に分割して投入してもよい。歩留まりの観点からは、複数回に分割して投入することが好ましい。より好ましくは、粒状の過マンガン酸塩を複数回に分割して投入する。こうすることで、溶媒量を大幅に低減することができ、歩留まりを向上させることができる。
[Permanganate mixing process]
The permanganate mixing step is a step of mixing permanganate. The permanganate mixing step is preferably performed after the above-described methyl-substituted aromatic heterocyclic compound mixing step.
The method for mixing the permanganate is not particularly limited, and may be mixed in a powder state or in a granular form. Alternatively, it may be dissolved in a solvent such as water and mixed in the form of a solution. From the viewpoint of ease of preparation, it is preferable to mix in a granular form. In addition, the permanganate may be added at a time and mixed, or may be added dividedly a plurality of times. From the viewpoint of yield, it is preferable to divide and input a plurality of times. More preferably, the granular permanganate is added divided into a plurality of times. By doing so, the amount of solvent can be greatly reduced, and the yield can be improved.
メチル置換芳香族複素環化合物と過マンガン酸塩の仕込みモル比は、反応率の観点から、メチル置換芳香族複素環化合物：過マンガン酸塩＝１：１．５〜１２であることが好ましく、芳香族複素和メチル：過マンガン酸塩=１：２〜８であることがより好ましく、メチル置換芳香族複素環化合物：過マンガン酸塩＝１：３〜４であることが特に好ましい。 The charged molar ratio of the methyl-substituted aromatic heterocyclic compound and the permanganate is preferably methyl-substituted aromatic heterocyclic compound: permanganate = 1: 1.5 to 12 from the viewpoint of the reaction rate. Aromatic heteromethyl: permanganate = 1: 2 to 8 is more preferable, and methyl-substituted aromatic heterocyclic compound: permanganate = 1: 3 to 4 is particularly preferable.
酸化反応の反応条件は、特に限定されるものではないが、反応温度としては、例えば、５０〜１００℃であることが好ましく、５０〜８０℃であることがより好ましく、５０〜６０℃であることが特に好ましい。また、反応時間としては、１〜２４時間であることが好ましく、３〜２０時間であることがより好ましく、５〜１０時間であることが特に好ましい。 Although the reaction conditions for the oxidation reaction are not particularly limited, the reaction temperature is, for example, preferably 50 to 100 ° C, more preferably 50 to 80 ° C, and 50 to 60 ° C. It is particularly preferred. The reaction time is preferably 1 to 24 hours, more preferably 3 to 20 hours, and particularly preferably 5 to 10 hours.
過マンガン酸塩混合工程後は、好ましくは、得られた反応混合物をろ過、洗浄、晶析、乾燥することにより、酸化生成物を目的の芳香族複素環カルボン酸として得ることができる。ただし、過マンガン酸塩混合工程後の反応混合物の処理は、上記の処理に特に限定されるものではない。上記例示のろ過、洗浄、晶析及び乾燥の各工程について説明する。 After the permanganate mixing step, preferably, the obtained reaction mixture is filtered, washed, crystallized and dried to obtain the oxidized product as the desired aromatic heterocyclic carboxylic acid. However, the treatment of the reaction mixture after the permanganate mixing step is not particularly limited to the above treatment. Each process of the filtration of the said illustration, washing | cleaning, crystallization, and drying is demonstrated.
［ろ過工程］
ろ過工程は、反応系内の副生物である二酸化マンガンを、反応混合物から過ケーキとして除去する工程である。ろ過方法は、特に限定されるものではなく、公知の方法を用いることができる。ろ過助剤としては、例えば、ラジオライト、濾過板等が挙げられる。
[Filtration process]
The filtration step is a step of removing manganese dioxide, which is a by-product in the reaction system, from the reaction mixture as an overcake. The filtration method is not particularly limited, and a known method can be used. Examples of filter aids include radiolites and filter plates.
［晶析工程］
晶析工程は、上記ろ化にて得られたろ液に酸物質を添加し、カルボン酸の塩として存在している目的物をカルボン酸へと変換する工程である。晶析工程は、前述のろ過工程に次いで行うことが好ましい。晶析方法は、特に限定されるものではなく、公知の方法を用いることができる。使用する酸物質としては、例えば、塩酸、硫酸、硝酸等が挙げられる。酸物質をそのまま使用してもよいが、それらの酸物質を水で希釈して使用してもよい。酸物質の使用量は特に制限は無いが、反応系内がｐＨ４以下が好ましく、ｐＨ２以下であることがより好ましく、ｐＨ＜１であることが特に好ましい。
[Crystalling process]
The crystallization step is a step of adding an acid substance to the filtrate obtained by the above filtration to convert the target product existing as a carboxylic acid salt into a carboxylic acid. The crystallization step is preferably performed after the filtration step described above. The crystallization method is not particularly limited, and a known method can be used. Examples of the acid substance to be used include hydrochloric acid, sulfuric acid, nitric acid and the like. The acid substances may be used as they are, but those acid substances may be diluted with water. The amount of the acid substance used is not particularly limited, but the inside of the reaction system is preferably pH 4 or less, more preferably pH 2 or less, and particularly preferably pH <1.
［洗浄工程］
洗浄工程は、晶析工程で得られた析出物から、未反応原料及び酸物質を除去する工程である。洗浄工程は、前述の晶析工程に次いで行うことが好ましい。洗浄方法は、特に限定されるものではなく、公知の方法を用いることができる。使用する洗浄溶媒としては、例えば水、アセトン等の有機溶媒が挙げられる。これら洗浄溶媒は、１種単独で用いてもよいし、２種以上を併用してもよい。
[Washing process]
The washing step is a step of removing unreacted raw materials and acid substances from the precipitate obtained in the crystallization step. The washing step is preferably performed after the crystallization step described above. The cleaning method is not particularly limited, and a known method can be used. Examples of the cleaning solvent used include organic solvents such as water and acetone. These washing solvents may be used alone or in combination of two or more.
［乾燥工程］
乾燥工程は、得られた目的物質中の溶媒を除去する工程である。乾燥工程は、先述の洗浄工程に次いで行なうことが好ましい。乾燥方法は、例えば箱型乾燥機やエバポレーター等での加熱、真空条件が挙げられる。乾燥方法は、特に限定されるものではないが、加熱温度としては、例えば、５０〜１５０℃であることが好ましく、７０〜１２０℃であることがより好ましく、１００〜１２０℃であることが特に好ましい。また、乾燥時間としては、１０〜５０時間であることが好ましく、２０〜４８時間であることがより好ましく、２４〜３６時間であることがさらに好ましい。真空度としては、２ｋＰａであることが好ましく、０．５ｋＰａであることがより好ましく、０．１ｋＰａ未満であることがさらに好ましい。
[Drying process]
A drying process is a process of removing the solvent in the obtained target substance. The drying step is preferably performed after the above-described washing step. Examples of the drying method include heating with a box-type dryer or an evaporator, and vacuum conditions. Although a drying method is not specifically limited, As heating temperature, it is preferable that it is 50-150 degreeC, for example, it is more preferable that it is 70-120 degreeC, and it is especially that it is 100-120 degreeC. preferable. Moreover, as drying time, it is preferable that it is 10 to 50 hours, It is more preferable that it is 20 to 48 hours, It is further more preferable that it is 24 to 36 hours. The degree of vacuum is preferably 2 kPa, more preferably 0.5 kPa, and even more preferably less than 0.1 kPa.
以下、本発明を実施例用いて詳細に説明する。なお、当然のことであるが、以下の実施例は本発明の一例を示すものであって、本発明はこの実施例にのみ限定されるものではない。 Hereinafter, the present invention will be described in detail using examples. Of course, the following examples show examples of the present invention, and the present invention is not limited to these examples.
［実施例１］
スリーワンモーター、温度計、冷却管、を備えた２００ｍｌの四口フラスコに、２，５−ジメチルピラジン（１０ｇ、０．０９３ｍｏｌ）と、１規定の水酸化カリウム水溶液（１５４ｇ）を秤り取り、オイルバスで加熱撹拌を行い、内温を６０℃まで温めた。この水酸化カリウム水溶液中に、過マンガン酸カリウム（５８．５ｇ、０．３７ｍｏｌ）を１２回に分け６時間かけて分割投入した。分割投入終了後、１時間熟成した。反応終了後、ラヂオライトを用いてセライトろ過を行った。ろ液をスリーワンモーター、等圧滴下ロート、温度計を備えた１Ｌの四つ口フラスコに仕込み、氷浴で冷却しながら撹拌を行い、内温を５℃以下とした後、３６質量％ＨＣｌａｑ（５０ｇ）を滴下し、室温で１時間撹拌した。１晩静置した後、ｐＨ試験紙にてｐＨが1以下であることを確認した。次いで、結晶をろ過し、超純水、アセトンで洗浄後、エバポレーターで１００℃、０．２ｋＰａで４８時間乾燥を行い、２，５−ピラジン−ジ−カルボン酸（１４．３５ｇ）として白色結晶を収率９２％で得た。
[Example 1]
Weigh 2,5-dimethylpyrazine (10 g, 0.093 mol) and 1 N aqueous potassium hydroxide solution (154 g) in a 200 ml four-necked flask equipped with a three-one motor, thermometer and condenser. The bath was heated and stirred to warm the internal temperature to 60 ° C. In this aqueous potassium hydroxide solution, potassium permanganate (58.5 g, 0.37 mol) was dividedly added in 12 portions over 6 hours. After completion of divided charging, the mixture was aged for 1 hour. After completion of the reaction, Celite filtration was performed using radiolite. The filtrate was charged into a 1 L four-necked flask equipped with a three-one motor, an isobaric dropping funnel, and a thermometer, stirred while cooling in an ice bath to bring the internal temperature to 5 ° C. or lower, and then 36 mass% HClaq ( 50 g) was added dropwise and stirred at room temperature for 1 hour. After allowing to stand overnight, it was confirmed that the pH was 1 or less using a pH test paper. Next, the crystals are filtered, washed with ultrapure water and acetone, and then dried with an evaporator at 100 ° C. and 0.2 kPa for 48 hours to obtain white crystals as 2,5-pyrazine-di-carboxylic acid (14.35 g). The yield was 92%.
［比較例１］
水酸化カリウム水溶液の代わりに、超純水（１５４ｇ）を用いた他は、実施例1と同様な操作を行い、２，５−ピラジン−ジ−カルボン酸（３．５３ｇ）として白色結晶を収率２２％で得た。
[Comparative Example 1]
The same procedure as in Example 1 was performed, except that ultrapure water (154 g) was used instead of the potassium hydroxide aqueous solution, and white crystals were collected as 2,5-pyrazine-dicarboxylic acid (3.53 g). Obtained at a rate of 22%.
［実施例２］
２，５−ジメチルピラジンの代わりに、２，５−ジメチルチオフェン（１ｇ、８．９１ｍｍｏｌ）を用い、過マンガン酸カリウム（５．６３ｇ、３５．６４ｍｍｏｌ）と、１規定の水酸化カリウム溶液（１５．４ｇ）を用いた他は、実施例１と同様な操作を行い、２，５−チオフェン−ジ−カルボン酸（０．４１ｇ）として収率２７％で得た。
[Example 2]
Instead of 2,5-dimethylpyrazine, 2,5-dimethylthiophene (1 g, 8.91 mmol) was used, and potassium permanganate (5.63 g, 35.64 mmol) and a 1 N potassium hydroxide solution (15 The same procedure as in Example 1 was performed, except that .4 g) was used, and 2,5-thiophene-di-carboxylic acid (0.41 g) was obtained in a yield of 27%.
［比較例２］
１規定の水酸化カリウム水溶液の代わりに、超純水（１５．４ｇ）を用いた他は、実施例２と同様な操作を行い、２，５−チオフェン−ジ−カルボン酸（０．０３ｇ）として収率２％で得た。
[Comparative Example 2]
2,5-thiophene-di-carboxylic acid (0.03 g) was prepared in the same manner as in Example 2 except that ultrapure water (15.4 g) was used instead of the 1 N aqueous potassium hydroxide solution. As a yield of 2%.
［実施例３］
２，５−ジメチルピラジンの代わりに、２−メチルピリジン（１ｇ、１０．７ｍｍｏｌ）を用い、過マンガン酸カリウム（３．３８ｇ、２１．４ｍｍｏｌ）、１規定の水酸化カリウム溶液(１５．４ｇ)を用いた他は、実施例１と同様な操作を行い２−ピリジンカルボン酸（０．２２ｇ）として収率１７％で得た。
[Example 3]
Instead of 2,5-dimethylpyrazine, 2-methylpyridine (1 g, 10.7 mmol) was used, potassium permanganate (3.38 g, 21.4 mmol), 1 N potassium hydroxide solution (15.4 g) In the same manner as in Example 1 except that was used, 2-pyridinecarboxylic acid (0.22 g) was obtained in a yield of 17%.
［比較例３］
１規定の水酸化カリウム水溶液の代わりに、超純水（１５．４ｇ）を用いた他は、実施例３と同様な操作を行い、２−ピリジンカルボン酸（０．０６ｇ）として収率５％で得た。
[Comparative Example 3]
The same procedure as in Example 3 was performed, except that ultrapure water (15.4 g) was used instead of the 1 N aqueous potassium hydroxide solution, yielding 5% as 2-pyridinecarboxylic acid (0.06 g). I got it.
［実施例４］
２，５−ジメチルピラジンの代わりに、４−メチルイミダゾール（１ｇ、１２．１ｍｍｏｌ）を用い、過マンガン酸カリウム（３．８２ｇ、２４．２ｍｍｏｌ）、１規定の水酸化カリウム溶液(１５．４ｇ)を用いた他は、実施例1と同様な操作を行い、４−イミダゾールカルボン酸（０．３ｇ）として収率２２％で得た。
[Example 4]
4-methylimidazole (1 g, 12.1 mmol) was used instead of 2,5-dimethylpyrazine, potassium permanganate (3.82 g, 24.2 mmol), 1 N potassium hydroxide solution (15.4 g) The procedure was the same as in Example 1 except that 4-imidazolecarboxylic acid (0.3 g) was obtained in a yield of 22%.
［比較例４］
１規定の水酸化カリウム水溶液の代わりに、超純水（１５．４ｇ）を用いた他は、実施例３と同様な操作を行い、４−イミダゾールカルボン酸（０．０４ｇ）として収率３％で得た。
[Comparative Example 4]
The same procedure as in Example 3 was performed, except that ultrapure water (15.4 g) was used instead of the 1 N aqueous potassium hydroxide solution, yielding 3% as 4-imidazolecarboxylic acid (0.04 g). I got it.
比較例１〜４のように、中性水溶液中でのメチル置換芳香族複素環化合物と過マンガン酸塩の反応では、芳香族複素環の分解が起こり、目的物の収率は低い。これに対して、本発明によれば、実施例１〜４からも明かなとおり、収率良く芳香族複素環カルボン酸を製造できる。 As in Comparative Examples 1 to 4, in the reaction of a methyl-substituted aromatic heterocyclic compound and a permanganate in a neutral aqueous solution, the aromatic heterocyclic ring is decomposed and the yield of the target product is low. On the other hand, according to the present invention, as is clear from Examples 1 to 4, aromatic heterocyclic carboxylic acids can be produced with good yield.
Claims (6)
前記塩基性溶媒に前記メチル置換芳香族複素環化合物を混合する工程；
及び、
前記塩基性溶媒に前記過マンガン酸塩を混合する工程；
を含む請求項１〜４のいずれかに記載の芳香族複素環カルボン酸の製造方法。 Mixing the basic compound with a solvent to obtain a basic solvent;
Mixing the methyl-substituted aromatic heterocyclic compound with the basic solvent;
as well as,
Mixing the permanganate with the basic solvent;
The manufacturing method of the aromatic heterocyclic carboxylic acid in any one of Claims 1-4 containing this.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134389A (en) * | 2018-09-21 | 2019-01-04 | 江苏铁锚玻璃股份有限公司 | The purification process of 2,5- pyrazine dicarboxylic acids and obtained 2,5- pyrazine dicarboxylic acids |
| CN110563728A (en) * | 2019-09-23 | 2019-12-13 | 南京奇可药业有限公司 | Preparation method of linagliptin intermediate |
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| CN115403529A (en) * | 2022-09-26 | 2022-11-29 | 济南悟通生物科技有限公司 | Purification method of 2, 5-pyrazine dicarboxylic acid by-product |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134389A (en) * | 2018-09-21 | 2019-01-04 | 江苏铁锚玻璃股份有限公司 | The purification process of 2,5- pyrazine dicarboxylic acids and obtained 2,5- pyrazine dicarboxylic acids |
| CN110563728A (en) * | 2019-09-23 | 2019-12-13 | 南京奇可药业有限公司 | Preparation method of linagliptin intermediate |
| CN110563728B (en) * | 2019-09-23 | 2020-09-25 | 安庆奇创药业有限公司 | Preparation method of linagliptin intermediate |
| CN112358442A (en) * | 2020-11-20 | 2021-02-12 | 内蒙古佳瑞米精细化工有限公司 | Preparation method of 2-fluoro-5-formyl chloropyridine |
| CN115403529A (en) * | 2022-09-26 | 2022-11-29 | 济南悟通生物科技有限公司 | Purification method of 2, 5-pyrazine dicarboxylic acid by-product |
| CN115403529B (en) * | 2022-09-26 | 2023-06-13 | 济南悟通生物科技有限公司 | Purification method of 2, 5-pyrazine dicarboxylic acid byproduct |
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