JP2004099454A - Method for producing n-substituted imidazolecarboxylic acids - Google Patents
Method for producing n-substituted imidazolecarboxylic acids Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical class OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 title description 2
- -1 N-substituted imidazolecarboxylic acids Chemical class 0.000 claims abstract description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- 239000003513 alkali Substances 0.000 claims abstract description 19
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 22
- 229910052760 oxygen Inorganic materials 0.000 description 22
- 239000001301 oxygen Substances 0.000 description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
- 239000002994 raw material Substances 0.000 description 15
- 238000007254 oxidation reaction Methods 0.000 description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 229910052797 bismuth Inorganic materials 0.000 description 7
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 7
- 229910052697 platinum Inorganic materials 0.000 description 7
- SGIKRGDBBXWNRI-UHFFFAOYSA-N (1-benzylimidazol-2-yl)methanol Chemical compound OCC1=NC=CN1CC1=CC=CC=C1 SGIKRGDBBXWNRI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- QEEBXPXPYKOARL-UHFFFAOYSA-N 1-benzylimidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1CC1=CC=CC=C1 QEEBXPXPYKOARL-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- ZOKDWBDDYVCACM-UHFFFAOYSA-N bismuth platinum Chemical compound [Pt].[Bi] ZOKDWBDDYVCACM-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- PXGQMYCEAWZJJF-UHFFFAOYSA-N (3-methylimidazol-4-yl)methanol Chemical compound CN1C=NC=C1CO PXGQMYCEAWZJJF-UHFFFAOYSA-N 0.000 description 4
- AKFHFMMKMUJLBU-UHFFFAOYSA-N 1-benzylimidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1CC1=CC=CC=C1 AKFHFMMKMUJLBU-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004029 hydroxymethyl group Chemical class [H]OC([H])([H])* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- WKRDOVRQCDLISF-UHFFFAOYSA-N (1-benzylimidazol-4-yl)methanol Chemical compound C1=NC(CO)=CN1CC1=CC=CC=C1 WKRDOVRQCDLISF-UHFFFAOYSA-N 0.000 description 2
- JUKGEFQATJAKDS-UHFFFAOYSA-N (1-propylimidazol-4-yl)methanol Chemical compound CCCN1C=NC(CO)=C1 JUKGEFQATJAKDS-UHFFFAOYSA-N 0.000 description 2
- HUGZJTRIKWMRAL-UHFFFAOYSA-N 1-benzyl-5-methylimidazole-4-carboxylic acid Chemical compound CC1=C(C(O)=O)N=CN1CC1=CC=CC=C1 HUGZJTRIKWMRAL-UHFFFAOYSA-N 0.000 description 2
- KFKAUFNAOVFMPB-UHFFFAOYSA-N 1-benzylimidazole-4-carboxylic acid Chemical compound C1=NC(C(=O)O)=CN1CC1=CC=CC=C1 KFKAUFNAOVFMPB-UHFFFAOYSA-N 0.000 description 2
- YARDQACXPOQDMO-UHFFFAOYSA-N 1-methylimidazole-4,5-dicarboxylic acid Chemical compound CN1C=NC(C(O)=O)=C1C(O)=O YARDQACXPOQDMO-UHFFFAOYSA-N 0.000 description 2
- OUYXIPLZTRNTDL-UHFFFAOYSA-N 1-propylimidazole-4-carboxylic acid Chemical compound CCCN1C=NC(C(O)=O)=C1 OUYXIPLZTRNTDL-UHFFFAOYSA-N 0.000 description 2
- BNYKZFOZWZMEJD-UHFFFAOYSA-N 3-methylimidazole-4-carbaldehyde Chemical compound CN1C=NC=C1C=O BNYKZFOZWZMEJD-UHFFFAOYSA-N 0.000 description 2
- PBEDVTDUVXFSMW-UHFFFAOYSA-N 3-methylimidazole-4-carboxylic acid Chemical compound CN1C=NC=C1C(O)=O PBEDVTDUVXFSMW-UHFFFAOYSA-N 0.000 description 2
- LKWXOCMGGNTOBW-UHFFFAOYSA-N 3-propylimidazole-4-carboxylic acid Chemical compound CCCN1C=NC=C1C(O)=O LKWXOCMGGNTOBW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JDHVFHMVSHJBDT-UHFFFAOYSA-N CCCCC1=NC(CO)=CN1CC1=CC=CC=C1 Chemical compound CCCCC1=NC(CO)=CN1CC1=CC=CC=C1 JDHVFHMVSHJBDT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003426 co-catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XABUPFKPBDRPAZ-UHFFFAOYSA-N (1-benzyl-5-methylimidazol-4-yl)methanol Chemical compound CC1=C(CO)N=CN1CC1=CC=CC=C1 XABUPFKPBDRPAZ-UHFFFAOYSA-N 0.000 description 1
- JNMJOYZNBDRVDG-UHFFFAOYSA-N (1-propan-2-ylimidazol-4-yl)methanol Chemical compound CC(C)N1C=NC(CO)=C1 JNMJOYZNBDRVDG-UHFFFAOYSA-N 0.000 description 1
- LRLYLIZCQYGYKV-UHFFFAOYSA-N (3-benzyl-5-methylimidazol-4-yl)methanol Chemical compound OCC1=C(C)N=CN1CC1=CC=CC=C1 LRLYLIZCQYGYKV-UHFFFAOYSA-N 0.000 description 1
- ZGRDBHVXJTYPTL-UHFFFAOYSA-N (3-propylimidazol-4-yl)methanol Chemical compound CCCN1C=NC=C1CO ZGRDBHVXJTYPTL-UHFFFAOYSA-N 0.000 description 1
- WHNXSUJWIAAGSF-UHFFFAOYSA-N 1-benzylimidazole-4-carbaldehyde Chemical compound C1=NC(C=O)=CN1CC1=CC=CC=C1 WHNXSUJWIAAGSF-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- NBQKHMVLXOBENG-UHFFFAOYSA-N 1-propan-2-ylimidazole-4-carbaldehyde Chemical compound CC(C)N1C=NC(C=O)=C1 NBQKHMVLXOBENG-UHFFFAOYSA-N 0.000 description 1
- VLWJUYLXFWFDSW-UHFFFAOYSA-N 1-propylimidazole-4-carbaldehyde Chemical compound CCCN1C=NC(C=O)=C1 VLWJUYLXFWFDSW-UHFFFAOYSA-N 0.000 description 1
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical compound OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical class O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XVNIHJYKFTZPEW-UHFFFAOYSA-N 3-benzyl-5-methylimidazole-4-carbaldehyde Chemical compound O=CC1=C(C)N=CN1CC1=CC=CC=C1 XVNIHJYKFTZPEW-UHFFFAOYSA-N 0.000 description 1
- CZNHVLOXIAQFJC-UHFFFAOYSA-N 3-propylimidazole-4-carbaldehyde Chemical compound CCCN1C=NC=C1C=O CZNHVLOXIAQFJC-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XPPVBKJELBDMMR-UHFFFAOYSA-N imidazol-1-ylmethanol Chemical class OCN1C=CN=C1 XPPVBKJELBDMMR-UHFFFAOYSA-N 0.000 description 1
- XBECWGJPSXHFCS-UHFFFAOYSA-N imidazole-1-carbaldehyde Chemical compound O=CN1C=CN=C1 XBECWGJPSXHFCS-UHFFFAOYSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、利尿剤、降圧剤等医薬品の原料として有用性が期待されるＮ−置換イミダゾールカルボン酸類の製造方法に関する。
【０００２】
【従来の技術】
Ｎ−置換イミダゾールカルボン酸類の製造は、１−メチル−４，５−イミダゾールジカルボン酸を脱炭酸している（例えば、非特許文献１参照）。
【０００３】
【非特許文献１】
ジョン エフ オーコーネル、他４名、「シンセシス（Ｓｙｎｔｈｅｓｉｓ）」１９９８年、ｐ．７６７−７７１
【０００４】
【発明が解決しようとする課題】
しかしながら、上記の方法においては、原料の１−メチル−４，５−イミダゾールジカルボン酸がかなり高価で、目的物の収率も７５％程度であり工業的規模での実施には問題が残り、Ｎ−置換イミダゾールカルボン酸類の新規な製造方法の開発が要望されるところである。
【０００５】
【課題を解決するための手段】
しかるに、本発明者は鋭意研究を重ねた結果、Ｎ−置換ホルミルイミダゾール類をアルカリと水の共存下に貴金属触媒を用いて酸化する場合、好ましくは該ホルミルイミダゾール類の原料としてＮ−置換ヒドロキシメチルイミダゾール類を用いて酸化を行う場合、その目的が達成でき、工業的有利にＮ−置換イミダゾールカルボン酸類が製造できることを見いだし本発明を完成するに至った。
【０００６】
【発明の実施の形態】
本発明の製造方法は下記（１）の反応式で示される。
【０００７】
【化１】
ここでＲは水素又は炭素数１〜１５のアルキル基、置換アルキル基（アルキル基中の水素がシアノ基、アミノ基、ハロゲン等のいずれかで置換されたもの）、ベンジル基、アリール基、置換アリール基（アリール基中の水素がアルキル基または、ハロゲンで置換されたもの）、ビニル基、アリル基、イソプロペニル基のいずれかである。
上記のホルミル基はイミダゾール環の２位、４位、５位の炭素のいずれに結合していても良い。更にホルミル基の結合していない炭素にはハロゲン、アルキル基、アリール基、ベンジル基等の置換基が結合していても良い。
【０００９】
Ｎ−置換ホルミルイミダゾール類として具体的には、１−ベンジル−２−ホルミルイミダゾ−ル、１−ベンジル−４−ホルミルイミダゾ−ル、１−メチル−５−ホルミルイミダゾ−ル、１−ベンジル−２−ｎ−ブチル−４−ホルミルイミダゾール、１−ベンジル−４−メチル−５−ホルミルイミダゾ−ル、１−ｎ−プロピル−４−ホルミルイミダゾ−ル、１−ｎ−プロピル−５−ホルミルイミダゾ−ル、１−ｉｓｏ−プロピル−４−ホルミルイミダゾ−ル等が挙げられる。
また、上記Ｎ−置換ホルミルイミダゾール類は塩酸塩、硫酸塩、酢酸塩等の無機あるいは有機酸塩の状態であっても良い。
【００１０】
本発明の製造方法は、上記の如きＮ−置換ホルミルイミダゾール類をアルカリと水の共存下に貴金属触媒を用いて酸化することを特徴とするもので、かかる酸化反応に当たっては、アルカリと水を共存させることが必須条件である。
本発明においてはＮ−置換ホルミルイミダゾール類がその置換基の種類によって水に溶解するものと水に溶解しないものとがある。水に溶解しない原料を使用する時に有機溶媒に溶解して反応が行われる。
【００１１】
かかるアルカリの種類としては、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、ナトリウムメチラートなどのアルコラート類等が挙げられるが、好ましくは水酸化ナトリウム、水酸化カリウムが用いられ、このときのアルカリの共存量は、Ｎ−置換ホルミルイミダゾール類に対して０．５〜１．５倍モルが好ましく、０．５倍モル未満では未反応物が多く残存することがあり、１．５倍モルを超えても収率の向上は見られないことがあり好ましくない。
【００１２】
また、このときの水の共存量はＮ−置換ホルミルイミダゾール類に対して１〜２０倍モルであることが好ましく、更には３〜１０倍モルである。１倍モル未満ではＮ−置換イミダゾールカルボン酸類の生成率が低下することがあり、一方２０倍モルを越えると反応速度が遅くなることがあり好ましくない。
【００１３】
有機溶媒としては、メチルアルコール、エチルアルコール等のアルコール類、酢酸エチル等のエステル類、アセトン等のケトン類、アセトニトリル等のニトリル類等が使用される。
溶媒量は特に制限されないが、通常Ｎ−置換ホルミルイミダゾール類に対して１〜１００重量倍程度使用される。
【００１４】
又、水に溶解性のあるＮ−置換ホルミルイミダゾール類を原料とする時には水媒体が使用される。その量はＮ−置換ホルミルイミダゾール類に対して２〜８０重量倍程度であり、更にアルカリの種類や共存量は有機溶媒系での反応の場合と同様である。
【００１５】
本発明で使用する貴金属触媒は、白金、パラジウム、金やそれらの塩、酸化物等であり、その中でも白金及びパラジウムが実用的である。又かかる貴金属触媒には、助触媒としてビスマス、セリウム、鉛、インジウムやそれらの塩、酸化物等（特にはビスマス）を添加して使用することが好ましい。
貴金属触媒はそのまま、あるいは必要に応じて活性炭、シリカ、アルミナ等の担体に１〜２０重量％程度担持されて用いられる。
またかかる触媒は、発火することがあるので、通常３０〜７０重量％の含水状態で使用される。
【００１６】
貴金属触媒の使用量は原料のＮ−置換ホルミルイミダゾール類に対して０．００１〜５０モル％が好ましく、更には０．０１〜２０モル％である。かかる使用量が０．００１モル％未満では反応時間が長くなることがあり、５０モル％を超えても反応時間の短縮の効果がそれほど発揮できないことがあり好ましくない。上記の助触媒を併用する時は通常貴金属触媒に対して１０〜８０モル％程度使用される。
【００１７】
酸化反応に際しては、反応系内に酸素あるいは空気を導入して酸化したり、あるいは過酸化水素等の過酸化物で酸化してもよいが、取扱いが容易な点で酸素あるいは空気、好ましくは酸素で酸化する方法が好ましい。酸素あるいは空気を導入して酸化する方法では、系は常圧でも加圧でもよい。
酸素を導入する場合の酸素の導入速度は原料のＮ−置換ホルミルイミダゾール類１ｇに対して０．０１〜３．０ミリリットル（標準状態換算）／分〔以下単にミリリットル／分と略記する〕が好ましく、更には０．１〜２．０ミリリットル／分である。かかる導入速度が０．０１ミリリットル／分未満では酸化反応が充分に進まないことがあり、３．０ミリリットル／分を超えても酸化速度の向上が見られないことがあり好ましくない。
なお、空気を導入して酸化する時には、酸素の導入速度が上記の割合になるようにすればよい。
【００１８】
酸化反応を実施するに当たっては、通常反応器に上記のアルカリ、水、触媒、原料のＮ−置換ホルミルイミダゾール類、必要に応じて有機溶媒を仕込み、これに酸素あるいは空気を吹込めばよい。
各成分の仕込は、一括仕込み、分割仕込み、連続仕込み、滴下仕込み等いずれも実施可能であるが、酸素あるいは空気以外は一括仕込みが有利である。
反応温としては０℃〜還流温度が好ましく、更には１０〜８０℃である。０℃未満では反応速度が遅くなることがあり、還流温度を超えると不純物の副生が多くなることがあり好ましくない。
【００１９】
酸化反応時間は特に制限されず、原料のＮ−ホルミルイミダゾール類が消失して酸素の吸収が停止した時点で反応を終了させ、反応終了液から触媒を濾別する。
濾液には生成したＮ−置換イミダゾールカルボン酸類が塩として溶解しているので、塩酸や硫酸等で中和した後適宜抽出を行ったり、系を冷却してＮ−置換イミダゾールカルボン類の結晶を析出させ濾別するなど任意の方法で反応系から単離される。必要であれば更に活性炭処理、再結晶法等の精製が行われる。
本発明の方法によれば、Ｎ−置換イミダゾールカルボン酸類の収率は、Ｎ−置換ホルミルイミダゾール類に対して９０％以上とすることができる。
【００２０】
次に、本発明でＮ−置換イミダゾールカルボン酸類を製造する時に使用するＮ−置換ホルミルイミダゾール類の原料について述べる。かかる原料としては、Ｎ−置換ヒドロキシメチルイミダゾ−ル類、Ｎ−置換イミダゾール類、Ｎ−置換イミダゾールジメチルアセタール類等が例示されるが、Ｎ−置換ヒドロキシメチルイミダゾ−ル類を用いると、Ｎ−置換ホルミルイミダゾール類を酸化する工程と同じ酸化方法でその合成が可能でＮ−置換イミダゾールカルボン類までの一貫生産が可能である点、安価である点、副生物が少ない点で好ましい。
以下にＮ−ヒドロキシメチルイミダゾール類を原料とするＮ−置換イミダゾールカルボン酸類の一貫生産方法について説明する。
【００２１】
かかる方法はＮ−置換ヒドロキシメチルイミダゾール類を酸化して、中間体として生成するＮ−置換ホルミルイミダゾール類を経由してＮ−置換イミダゾールカルボン酸類を製造するもの〔下記（２）式で示す〕であり、中間体を単離したりする必要がないので反応工程の省力、反応時間の短縮が可能となり工業的に有利である。
【００２２】
【化２】
上記のＮ−置換ヒドロキシメチルイミダゾール類において置換基Ｒの種類は、前述したＮ−置換ホルミルイミダゾール類の場合と同様であり、ヒドロキシメチル基はイミダゾール環の２位、４位、５位のいずれでも良く、更にヒドロキシメチル基の結合していない炭素にハロゲン基、アルキル基、アリール基、ベンジル基等の置換基が結合していても良い。具体的に例示すれば、１−ベンジル−２−ヒドロキシメチルイミダゾ−ル、１−ベンジル−４−ヒドロキシメチルイミダゾ−ル、１−メチル−５−ヒドロキシメチルイミダゾ−ル、１−ベンジル−２−ｎ−ブチル−４−ヒドロキシメチルイミダゾ−ル、１−ベンジル−４−メチル−５−ヒドロキシメチルイミダゾ−ル、１−ｎ−プロピル−４−ヒドロキシメチルイミダゾ−ル、１−ｎ−プロピル−５−ヒドロキシメチルイミダゾ−ル、１−ｉｓｏ−プロピル−４−ヒドロキシメチルイミダゾ−ル等が挙げられる。
また、上記Ｎ−置換ヒドロキシメチルイミダゾール類は塩酸塩、硫酸塩、酢酸塩等の無機あるいは有機酸塩の状態であっても良い。
【００２４】
上記のＮ−置換ヒドロキシメチルイミダゾール類は例えば、ヒドロキシメチルイミダゾールを、水酸化ナトリウム、炭酸カリウム等の塩基の存在下にベンジルクロライド、ベンジルブロマイド、ｎ−プロピルクロライド、ｉｓｏ−プロピルクロライド、ｎ−プロピルブロマイド、ｉｓｏ−プロピルブロマイド等のアルキル化剤と反応して製造すればよい。
【００２５】
上記（２）式の反応もＮ−置換ヒドロキシメチルイミダゾール類を、アルカリ、水の共存下貴金属触媒を用いて酸化を行うことによって実施される。
Ｎ−置換ヒドロキシメチルイミダゾール類もＮ−置換ホルミルイミダゾール類と同様に水に可溶なものがあるので、〔００１４〕で説明したと同様の操作を行う。
貴金属触媒の種類や担持方法、助触媒の種類、アルカリの種類はいずれも、先にＮ−置換ホルミルイミダゾール類の酸化工程で述べた内容と同様である。
触媒の使用量、アルカリの共存量、水の共存量、溶媒の使用量もその基準をＮ−置換ホルミルイミダゾール類からＮ−置換ヒドロキシイミダゾール類に変更する以外は前記と同様である。
【００２６】
酸化反応に際しては、系は常圧でも加圧でもよく、系内に酸素あるいは空気、好ましくは酸素を導入する。
酸素の場合の導入速度は原料のＮ−置換ヒドロキシメチルイミダゾール類１ｇに対して０．０２〜５．０ミリリットル／分、更には０．２〜３．０ミリリットル／分である。かかる導入速度が０．０２ミリリットル／分未満では、酸化反応が充分に進まないことがあり、５．０ミリリットル／分を超えても酸化速度の向上は見られないことがある。
なお、空気を導入して酸化する時には、酸素の導入速度が上記の割合になるようにすればよい。
【００２７】
酸化反応を実施するに当たっては、通常反応器に上記のアルカリ、水、上記の触媒、原料のＮ−置換ヒドロキシメチルイミダゾール類、必要に応じて有機溶媒を仕込み、これに酸素あるいは空気を吹込めばよい。
各成分の仕込は、一括仕込み、分割仕込み、連続仕込み、滴下仕込み等いずれも実施可能であるが、酸素あるいは空気以外は一括仕込みが有利である。
【００２８】
反応温度は０℃〜還流温度が好ましく、更には１０〜８０℃、特に１５〜６０℃が適当である。反応温度が０℃未満では反応速度が遅くなることがあり、逆に還流温度を超えると不純物の副生が多くなることがある。
又反応時間は特に制限されず、原料のＮ−置換ヒドロキシメチルイミダゾール類や中間体として生成するＮ−置換ホルミルイミダゾール類が消失して酸素の吸収が停止した時点で反応を終了させ、反応終了液から触媒を濾別する。
かかる方法によればＮ−置換イミダゾールカルボン酸類の収率は、Ｎ−置換ヒドロキシメチルイミダゾール類に対して９０％以上とすることができる。
【００２９】
【実施例】
以下、本発明を実施例を挙げて詳述する。「％」は重量基準である。
実施例１
１−ベンジル−２−ヒドロキシメチルイミダゾール９．４ｇ（０．０５モル）をメタノール９０ｇに溶解した溶液、３０％水酸化ナトリウム水溶液７ｇ（０．０５２５モル）、白金−ビスマス系触媒１．８ｇ〔活性炭に白金５％（０．２３ミリモル）およびビスマス２％（０．０９モル）を担持、含水率５０％〕を反応器に仕込み酸素を該イミダゾール１ｇに対して、１．６ミリリットル／分の速度で吹き込んだ。その間反応液の温度を２０℃にして酸化反応を開始した。途中１−ベンジル−２−ホルミルイミダゾールの生成を確認し、２時間反応をつづけ、酸素の吸収が停止したので反応を終了した。反応生成液から触媒を濾別した。濾液を塩酸でｐＨ７にした後、メタノールを留去し析出した結晶を濾過して１−ベンジル−２−イミダゾールカルボン酸を９．８ｇ（ＨＰＬＣによる純度９９．８％、０．０４８４モル）得た〔収率９６．９％〕。
赤外線分析、ＮＭＲ分析の結果、１−ベンジル−２−イミダゾールカルボン酸であることを確認した。
【００３０】
実施例２
１−メチル−５−ヒドロキシメチルイミダゾール５．６ｇ（０．０５モル）を水５０ｇに溶解した溶液、白金−ビスマス系触媒１．１ｇ〔活性炭に白金５％（０．１４ミリモル）およびビスマス２％（０．０５モル）を担持、含水率５０％〕、水酸化ナトリウム２．２ｇ（０．０５５モル）を反応器に仕込み、反応液の温度を３０℃にして酸素を該イミダゾール１ｇに対して１．８ミリリットル／分の速度で吹き込んで反応を開始した。途中１−メチル−５−ホルミルイミダゾールの生成を確認し、５時間反応をつづけ、酸素の吸収が停止したので反応を終了した。反応生成液から触媒を濾別し、濾液を塩酸でｐＨ７にした後、メタノールを留去し析出した結晶を濾過して１−メチル−５−イミダゾールカルボン酸を５．８５ｇ（ＨＰＬＣによる純度９９．３％、０．０４６４モル）得た〔収率９２．７％〕。
赤外線分析、ＮＭＲ分析の結果、１−メチル−５−イミダゾールカルボン酸であることを確認した。
【００３１】
実施例３
実施例１において、１−ベンジル−２−ヒドロキシメチルイミダゾール９．４ｇ（０．０５モル）に替えて、１−ベンジル−４−ヒドロキシメチルイミダゾール９．４ｇ（０．０５モル）を用いた以外は同様して、１−ベンジル−４−イミダゾールカルボン酸を９．５ｇ（ＨＰＬＣによる純度９９．５％、０．０４７２モル）得た〔収率９４．４％〕。
赤外線分析、ＮＭＲ分析の結果、１−ベンジル−４−イミダゾールカルボン酸であることを確認した。
【００３２】
実施例４
実施例１において、１−ベンジル−２−ヒドロキシメチルイミダゾール９．４ｇ（０．０５モル）に替えて、１−ベンジル−４−ヒドロキシメチル−５−メチルイミダゾールを１０．１ｇ（０．０５モル）を用いた以外は同様に実験して、１−ベンジル−５−メチル−４−イミダゾールカルボン酸を１０．３ｇ（ＨＰＬＣによる純度９９．７％、０．０４７４モル）得た〔収率９４．８％〕。
赤外線分析、ＮＭＲ分析の結果、１−ベンジル−５−メチル−４−イミダゾールカルボン酸であることを確認した。
【００３３】
実施例５
実施例１において、１−ベンジル−２−ヒドロキシメチルイミダゾール９．４ｇ（０．０５モル）に替えて、１−ベンジル−２−ｎ−ブチル−４−ヒドロキシメチルイミダゾールを１２．２ｇ（０．０５モル）を用い、更に、白金−ビスマス系触媒を２．４ｇ〔活性炭に白金５％（０．３１ミリモル）およびビスマス２％（０．１１ミリモル）を担持、含水率５０％〕に変更した以外は同様にして、１−ベンジル−２−ｎ−ブチル−４−イミダゾールカルボン酸を１２．３ｇ（ＨＰＬＣによる純度９９．８％０．４７８モル）得た〔収率９５．６％〕。
赤外線分析、ＮＭＲ分析の結果、１−ベンジル−２−ｎ−ブチル−４−イミダゾールカルボン酸であることを確認した。
【００３４】
実施例６
実施例２において、１−メチル−５−ヒドロキシメチルイミダゾール５．６ｇ（０．０５モル）を１−ｎ−プロピル−４−ヒドロキシメチルイミダゾール７．０ｇ（０．０５モル）に変更し、水の量を７０ｇ、白金−ビスマス系触媒の量を１．４ｇ〔活性炭に白金５％（０．１８ミリモル）およびビスマス２％（０．０７ミリモル）を担持、含水率５０％〕、水酸化ナトリウムを２．４ｇ（０．０６モル）に変更した以外は実施例２と同様にして、１−ｎ−プロピル−４−イミダゾールカルボン酸を７．５ｇ（ＨＰＬＣによる純度９９．６％、０．０４８８モル）得た〔収率９７．５％〕。
赤外線分析、ＮＭＲ分析の結果、１−ｎ−プロピル−４−イミダゾールカルボン酸であることを確認した。
【００３５】
実施例７
実施例２において、１−メチル−５−ヒドロキシメチルイミダゾール５．６ｇ（０．０５モル）を１−ｎ−プロピル−５−ヒドロキシメチルイミダゾール７．０ｇ（０．０５モル）に変更し、水を７０ｇ、白金−ビスマス系触媒の量を１．４ｇ〔活性炭に白金５％（０．１８ミリモル）およびビスマス２％（０．０７ミリモル）を担持、含水率５０％〕に、水酸化ナトリウムの量を２．４ｇ（０．０６モル）に変更した以外は実施例２と同様にして、１−ｎ−プロピル−５−イミダゾールカルボン酸を７．４ｇ（ＨＰＬＣによる純度９９．５％、０．０４８５モル）得た〔収率９７．１％〕。
赤外線分析、ＮＭＲ分析の結果、１−ｎ−プロピル−５−イミダゾールカルボン酸であることを確認した。
【００３６】
実施例８
実施例１において、１−ベンジル−２−ヒドロキシメチルイミダゾール９．４ｇ（０．０５モル）を１−ベンジル−２−ホルミルイミダゾール９．３ｇ（０．０５モル）に、及び酸素の導入速度を該イミダゾール１ｇに対して１．０ミリリットル／分に変更した以外は、実施例１と同様にして１−ベンジル−２−イミダゾールカルボン酸を９．９ｇ（ＨＰＬＣによる純度９９．８％、０．０４９０モル）得た〔収率９８．１％〕。
赤外線分析、ＮＭＲ分析の結果、１−ベンジル−２−イミダゾールカルボン酸であることを確認した。
【００３７】
対照例１
実施例１で水酸化ナトリウム水溶液７ｇの替わりに水酸化ナトリウム２．２ｇ（０．０５５モル）を用いて反応を行ったが、１−ベンジル−２−イミダゾールカルボン酸は全く進行せず、系中には１−ベンジル−２−ホルミルイミダゾールのみが生成していた。
【００３８】
対照例２
実施例１で３０％水酸化ナトリウム水溶液７ｇの代わりに水７ｇを用いて２０℃で９時間反応を行ったが、反応は全く進まなかった。
【００３９】
【発明の効果】
本発明では、Ｎ−置換ホルミルイミダゾール類をアルカリと水の共存下に貴金属触媒を用いて酸化し、好ましくはＮ−置換ヒドロキシメチルイミダゾール類を、アルカリと水の共存下に貴金属触媒を用いて酸化させて製造されるＮ−置換ホルミルイミダゾール類を工業的有利に純度の高いＮ−置換イミダゾールカルボン酸類を収率良く得ることができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing N-substituted imidazole carboxylic acids which are expected to be useful as raw materials for pharmaceuticals such as diuretics and antihypertensives.
[0002]
[Prior art]
In the production of N-substituted imidazole carboxylic acids, 1-methyl-4,5-imidazole dicarboxylic acid is decarboxylated (for example, see Non-Patent Document 1).
[0003]
[Non-patent document 1]
John F. O'Connell, et al., "Synthesis", 1998, p. 767-771
[0004]
[Problems to be solved by the invention]
However, in the above-mentioned method, the raw material 1-methyl-4,5-imidazole dicarboxylic acid is considerably expensive, the yield of the target substance is about 75%, and there remains a problem in practice on an industrial scale. -There is a need for the development of new processes for the production of substituted imidazole carboxylic acids.
[0005]
[Means for Solving the Problems]
However, as a result of intensive studies, the present inventors have found that when N-substituted formylimidazoles are oxidized using a noble metal catalyst in the presence of alkali and water, N-substituted hydroxymethyl is preferably used as a raw material for the formylimidazoles. When the oxidation is carried out using imidazoles, the object can be achieved, and it has been found that N-substituted imidazolecarboxylic acids can be produced industrially advantageously, and the present invention has been completed.
[0006]
BEST MODE FOR CARRYING OUT THE INVENTION
The production method of the present invention is represented by the following reaction formula (1).
[0007]
Embedded image
Here, R is hydrogen or an alkyl group having 1 to 15 carbon atoms, a substituted alkyl group (the hydrogen in the alkyl group is substituted with any of a cyano group, an amino group, a halogen, etc.), a benzyl group, an aryl group, An aryl group (where hydrogen in the aryl group is substituted with an alkyl group or a halogen), a vinyl group, an allyl group, or an isopropenyl group.
The above-mentioned formyl group may be bonded to any of the 2-, 4- and 5-position carbons of the imidazole ring. Further, a substituent such as a halogen, an alkyl group, an aryl group, or a benzyl group may be bonded to the carbon to which the formyl group is not bonded.
[0009]
Specific examples of the N-substituted formyl imidazoles include 1-benzyl-2-formyl imidazole, 1-benzyl-4-formyl imidazole, 1-methyl-5-formyl imidazole, and 1-benzyl-2. -N-butyl-4-formylimidazole, 1-benzyl-4-methyl-5-formylimidazole, 1-n-propyl-4-formylimidazole, 1-n-propyl-5-formylimidazole And 1-iso-propyl-4-formylimidazole.
The N-substituted formyl imidazoles may be in the form of inorganic or organic acid salts such as hydrochloride, sulfate, acetate and the like.
[0010]
The production method of the present invention is characterized by oxidizing an N-substituted formyl imidazole as described above using a noble metal catalyst in the presence of an alkali and water. Is an essential condition.
In the present invention, N-substituted formyl imidazoles may be soluble in water or insoluble in water depending on the type of the substituent. When a raw material that does not dissolve in water is used, the reaction is performed by dissolving it in an organic solvent.
[0011]
Examples of the type of the alkali include alcoholates such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and sodium methylate, and preferably, sodium hydroxide and potassium hydroxide are used. In this case, the coexistence amount of the alkali is preferably 0.5 to 1.5 times mol with respect to the N-substituted formyl imidazoles, and if less than 0.5 times mol, a large amount of unreacted substances may remain and 1 If the molar amount exceeds 0.5 times, no improvement in yield may be observed, which is not preferable.
[0012]
Further, the coexisting amount of water at this time is preferably 1 to 20 times mol, more preferably 3 to 10 times mol, based on N-substituted formyl imidazoles. If it is less than 1 mole, the yield of N-substituted imidazole carboxylic acids may decrease, while if it exceeds 20 moles, the reaction rate may decrease, which is not preferable.
[0013]
Examples of the organic solvent include alcohols such as methyl alcohol and ethyl alcohol, esters such as ethyl acetate, ketones such as acetone, and nitriles such as acetonitrile.
Although the amount of the solvent is not particularly limited, it is usually used in an amount of about 1 to 100 times by weight based on the N-substituted formyl imidazoles.
[0014]
When using water-soluble N-substituted formylimidazoles as raw materials, an aqueous medium is used. The amount is about 2 to 80 times by weight based on the N-substituted formyl imidazoles, and the kind and coexistence amount of the alkali are the same as in the case of the reaction in the organic solvent system.
[0015]
The noble metal catalyst used in the present invention is platinum, palladium, gold, salts or oxides thereof, among which platinum and palladium are practical. It is preferable that bismuth, cerium, lead, indium and their salts and oxides (particularly bismuth) are added to such a noble metal catalyst as a promoter.
The noble metal catalyst is used as it is or, if necessary, supported on a carrier such as activated carbon, silica or alumina at about 1 to 20% by weight.
Since such a catalyst may ignite, it is usually used in a water-containing state of 30 to 70% by weight.
[0016]
The amount of the noble metal catalyst used is preferably from 0.001 to 50 mol%, more preferably from 0.01 to 20 mol%, based on the N-substituted formyl imidazoles as the raw material. If the amount is less than 0.001 mol%, the reaction time may be prolonged, and if it exceeds 50 mol%, the effect of shortening the reaction time may not be sufficiently exhibited, which is not preferable. When the above co-catalyst is used in combination, it is usually used in an amount of about 10 to 80 mol% based on the noble metal catalyst.
[0017]
In the oxidation reaction, oxidation may be performed by introducing oxygen or air into the reaction system, or oxidation may be performed with a peroxide such as hydrogen peroxide.However, oxygen or air, preferably oxygen Is preferred. In the method of oxidizing by introducing oxygen or air, the system may be normal pressure or pressurized.
When oxygen is introduced, the rate of oxygen introduction is preferably 0.01 to 3.0 milliliters (converted to a standard state) / min (hereinafter simply abbreviated as milliliter / min) per gram of N-substituted formyl imidazoles as a raw material. And 0.1 to 2.0 ml / min. If the introduction rate is less than 0.01 ml / min, the oxidation reaction may not proceed sufficiently. If the introduction rate exceeds 3.0 ml / min, the oxidation rate may not be improved, which is not preferable.
When oxidizing by introducing air, the rate of introducing oxygen may be set to the above-described ratio.
[0018]
In carrying out the oxidation reaction, generally, the above-mentioned alkali, water, catalyst, N-substituted formyl imidazoles as raw materials, and an organic solvent as required are charged into a reactor, and oxygen or air may be blown into the charged organic solvent.
The charging of each component can be carried out in any of batch charging, divided charging, continuous charging, dropping charging, etc., but collective charging is advantageous except for oxygen or air.
The reaction temperature is preferably from 0 ° C to reflux temperature, more preferably from 10 ° C to 80 ° C. If the temperature is lower than 0 ° C., the reaction rate may be low, and if the temperature is higher than the reflux temperature, impurities may be increased as by-products, which is not preferable.
[0019]
The oxidation reaction time is not particularly limited, and the reaction is terminated when N-formylimidazole as a raw material disappears and the absorption of oxygen stops, and the catalyst is filtered from the reaction-terminated liquid.
Since the N-substituted imidazole carboxylic acids formed are dissolved in the filtrate as salts, neutralize with hydrochloric acid, sulfuric acid, etc. and perform extraction as appropriate, or cool the system to precipitate crystals of N-substituted imidazole carboxylic acids. And isolated from the reaction system by any method such as filtration. If necessary, purification such as activated carbon treatment and recrystallization is further performed.
According to the method of the present invention, the yield of N-substituted imidazole carboxylic acids can be 90% or more based on N-substituted formyl imidazoles.
[0020]
Next, the raw materials of the N-substituted formyl imidazoles used in producing the N-substituted imidazole carboxylic acids in the present invention will be described. Examples of such a raw material include N-substituted hydroxymethylimidazoles, N-substituted imidazoles, N-substituted imidazole dimethylacetals and the like. It is preferable in that it can be synthesized by the same oxidation method as in the step of oxidizing substituted formyl imidazoles, can be integratedly produced up to N-substituted imidazole carboxylic acids, is inexpensive, and has few by-products.
Hereinafter, an integrated production method of N-substituted imidazolecarboxylic acids using N-hydroxymethylimidazoles as a raw material will be described.
[0021]
Such a method involves oxidizing N-substituted hydroxymethylimidazoles to produce N-substituted imidazolecarboxylic acids via N-substituted formylimidazoles produced as intermediates (shown by the following formula (2)). In addition, there is no need to isolate an intermediate, so that it is possible to save the labor of the reaction step and shorten the reaction time, which is industrially advantageous.
[0022]
Embedded image
In the above-mentioned N-substituted hydroxymethylimidazoles, the type of the substituent R is the same as in the case of the above-mentioned N-substituted formylimidazoles, and the hydroxymethyl group may be at any of the 2-, 4-, and 5-positions of the imidazole ring. Further, a substituent such as a halogen group, an alkyl group, an aryl group, or a benzyl group may be bonded to the carbon to which the hydroxymethyl group is not bonded. Specific examples include 1-benzyl-2-hydroxymethylimidazole, 1-benzyl-4-hydroxymethylimidazole, 1-methyl-5-hydroxymethylimidazole, and 1-benzyl-2-n -Butyl-4-hydroxymethylimidazole, 1-benzyl-4-methyl-5-hydroxymethylimidazole, 1-n-propyl-4-hydroxymethylimidazole, 1-n-propyl-5-hydroxy Methyl imidazole, 1-iso-propyl-4-hydroxymethyl imidazole and the like can be mentioned.
The N-substituted hydroxymethylimidazoles may be in the form of an inorganic or organic acid salt such as hydrochloride, sulfate, acetate and the like.
[0024]
The above-mentioned N-substituted hydroxymethylimidazoles are obtained, for example, by converting hydroxymethylimidazole into benzyl chloride, benzyl bromide, n-propyl chloride, iso-propyl chloride, n-propyl bromide in the presence of a base such as sodium hydroxide and potassium carbonate. And an alkylating agent such as iso-propyl bromide.
[0025]
The reaction of the above formula (2) is also carried out by oxidizing N-substituted hydroxymethylimidazoles using a noble metal catalyst in the presence of alkali and water.
Since some N-substituted hydroxymethylimidazoles are soluble in water similarly to N-substituted formylimidazoles, the same operation as described in [0014] is performed.
The type of the noble metal catalyst, the supporting method, the type of the co-catalyst, and the type of the alkali are all the same as those described above in the step of oxidizing N-substituted formyl imidazoles.
The amount of catalyst used, the amount of coexisting alkali, the amount of coexisting water, and the amount of solvent used are the same as described above, except that the standards are changed from N-substituted formyl imidazoles to N-substituted hydroxyimidazoles.
[0026]
In the oxidation reaction, the system may be at normal pressure or under pressure, and oxygen or air, preferably oxygen is introduced into the system.
The rate of introduction of oxygen is 0.02 to 5.0 ml / min, and more preferably 0.2 to 3.0 ml / min, based on 1 g of the raw material N-substituted hydroxymethylimidazole. If the introduction rate is less than 0.02 ml / min, the oxidation reaction may not proceed sufficiently, and if it exceeds 5.0 ml / min, the oxidation rate may not be improved.
When oxidizing by introducing air, the rate of introducing oxygen may be set to the above-described ratio.
[0027]
In carrying out the oxidation reaction, usually, the above-mentioned alkali, water, the above-mentioned catalyst, the raw material N-substituted hydroxymethylimidazoles and an organic solvent are charged into a reactor, and oxygen or air is blown into this. Good.
The charging of each component can be carried out in any of batch charging, divided charging, continuous charging, dropping charging, etc., but collective charging is advantageous except for oxygen or air.
[0028]
The reaction temperature is preferably from 0C to reflux temperature, more preferably from 10C to 80C, especially from 15C to 60C. If the reaction temperature is lower than 0 ° C., the reaction rate may be slow. On the contrary, if the reaction temperature is higher than the reflux temperature, by-products of impurities may increase.
The reaction time is not particularly limited, and the reaction is terminated when the N-substituted hydroxymethylimidazole as a raw material and the N-substituted formylimidazole produced as an intermediate disappear and the absorption of oxygen is stopped, and the reaction is terminated. From which the catalyst is filtered off.
According to such a method, the yield of N-substituted imidazole carboxylic acids can be 90% or more based on N-substituted hydroxymethylimidazoles.
[0029]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples. “%” Is based on weight.
Example 1
A solution of 9.4 g (0.05 mol) of 1-benzyl-2-hydroxymethylimidazole in 90 g of methanol, 7 g (0.0525 mol) of a 30% aqueous sodium hydroxide solution, 1.8 g of a platinum-bismuth catalyst [activated carbon , 5% (0.23 mmol) of platinum and 2% (0.09 mol) of bismuth, and a water content of 50%] were charged to the reactor, and oxygen was supplied at a rate of 1.6 ml / min to 1 g of the imidazole. I blew it. During that time, the temperature of the reaction solution was set at 20 ° C. to start the oxidation reaction. On the way, the formation of 1-benzyl-2-formylimidazole was confirmed, the reaction was continued for 2 hours, and the reaction was terminated because the absorption of oxygen was stopped. The catalyst was separated from the reaction product by filtration. After the filtrate was adjusted to pH 7 with hydrochloric acid, methanol was distilled off, and the precipitated crystals were filtered to obtain 9.8 g of 1-benzyl-2-imidazolecarboxylic acid (99.8% purity by HPLC, 0.0484 mol). [Yield 96.9%].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-benzyl-2-imidazolecarboxylic acid.
[0030]
Example 2
A solution prepared by dissolving 5.6 g (0.05 mol) of 1-methyl-5-hydroxymethylimidazole in 50 g of water, 1.1 g of a platinum-bismuth catalyst [5% of platinum (0.14 mmol) on activated carbon and 2% of bismuth] (0.05 mol), water content 50%], 2.2 g (0.055 mol) of sodium hydroxide were charged into the reactor, the temperature of the reaction solution was set to 30 ° C., and oxygen was added to 1 g of the imidazole. The reaction was started by blowing at a rate of 1.8 ml / min. On the way, the formation of 1-methyl-5-formylimidazole was confirmed, the reaction was continued for 5 hours, and the reaction was terminated because the absorption of oxygen was stopped. The catalyst was filtered off from the reaction product, the filtrate was adjusted to pH 7 with hydrochloric acid, methanol was distilled off, and the precipitated crystals were filtered to give 5.85 g of 1-methyl-5-imidazolecarboxylic acid (purity of 99.99 by HPLC). 3%, 0.0464 mol) [yield 92.7%].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-methyl-5-imidazolecarboxylic acid.
[0031]
Example 3
In Example 1, except that 9.4 g (0.05 mol) of 1-benzyl-4-hydroxymethylimidazole was used instead of 9.4 g (0.05 mol) of 1-benzyl-2-hydroxymethylimidazole. Similarly, 1-benzyl-4-imidazolecarboxylic acid was obtained in an amount of 9.5 g (purity by HPLC: 99.5%, 0.0472 mol) [yield: 94.4%].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-benzyl-4-imidazolecarboxylic acid.
[0032]
Example 4
In Example 1, 10.1 g (0.05 mol) of 1-benzyl-4-hydroxymethyl-5-methylimidazole was used instead of 9.4 g (0.05 mol) of 1-benzyl-2-hydroxymethylimidazole. In the same manner as above, 10.3 g (purity 99.7% by HPLC, 0.0474 mol) of 1-benzyl-5-methyl-4-imidazolecarboxylic acid was obtained [yield 94.8]. %].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-benzyl-5-methyl-4-imidazolecarboxylic acid.
[0033]
Example 5
In Example 1, 12.2 g (0.05 mol) of 1-benzyl-2-n-butyl-4-hydroxymethylimidazole was used instead of 9.4 g (0.05 mol) of 1-benzyl-2-hydroxymethylimidazole. Mol), and the platinum-bismuth catalyst was changed to 2.4 g [5% (0.31 mmol) of platinum and 2% (0.11 mmol) of bismuth were loaded on activated carbon and the water content was 50%]. In the same manner, 12.3 g of 1-benzyl-2-n-butyl-4-imidazolecarboxylic acid was obtained (purity 99.8% by HPLC, 0.478 mol) [yield 95.6%].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-benzyl-2-n-butyl-4-imidazolecarboxylic acid.
[0034]
Example 6
In Example 2, 5.6 g (0.05 mol) of 1-methyl-5-hydroxymethylimidazole was changed to 7.0 g (0.05 mol) of 1-n-propyl-4-hydroxymethylimidazole, and water was added. The amount was 70 g, the amount of a platinum-bismuth-based catalyst was 1.4 g [5% (0.18 mmol) of platinum and 2% (0.07 mmol) of bismuth were loaded on activated carbon, and the water content was 50%]. 7.5 g of 1-n-propyl-4-imidazolecarboxylic acid (99.6% purity by HPLC, 0.0488 mol) in the same manner as in Example 2 except that the amount was changed to 2.4 g (0.06 mol). ) Obtained [yield 97.5%].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-n-propyl-4-imidazolecarboxylic acid.
[0035]
Example 7
In Example 2, 5.6 g (0.05 mol) of 1-methyl-5-hydroxymethylimidazole was changed to 7.0 g (0.05 mol) of 1-n-propyl-5-hydroxymethylimidazole, and water was added. The amount of sodium hydroxide was 70 g, the amount of platinum-bismuth-based catalyst was 1.4 g [5% (0.18 mmol) of platinum and 2% (0.07 mmol) of bismuth supported on activated carbon, and the water content was 50%]. Was changed to 2.4 g (0.06 mol) in the same manner as in Example 2 to obtain 7.4 g of 1-n-propyl-5-imidazolecarboxylic acid (purity 99.5% by HPLC, 0.0485). Mol) obtained [97.1% yield].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-n-propyl-5-imidazolecarboxylic acid.
[0036]
Example 8
In Example 1, 9.4 g (0.05 mol) of 1-benzyl-2-hydroxymethylimidazole was added to 9.3 g (0.05 mol) of 1-benzyl-2-formylimidazole, and the introduction rate of oxygen was changed. 9.9 g of 1-benzyl-2-imidazolecarboxylic acid (purity 99.8% by HPLC, 0.0490 mol) in the same manner as in Example 1 except that the amount was changed to 1.0 ml / min per 1 g of imidazole. ) Obtained [yield 98.1%].
As a result of infrared analysis and NMR analysis, it was confirmed that the substance was 1-benzyl-2-imidazolecarboxylic acid.
[0037]
Comparative Example 1
In Example 1, the reaction was carried out using 2.2 g (0.055 mol) of sodium hydroxide instead of 7 g of the aqueous sodium hydroxide solution, but 1-benzyl-2-imidazolecarboxylic acid did not proceed at all, and the reaction was carried out in the system. Produced only 1-benzyl-2-formylimidazole.
[0038]
Comparative Example 2
In Example 1, the reaction was carried out at 20 ° C. for 9 hours using 7 g of water instead of 7 g of a 30% aqueous sodium hydroxide solution, but the reaction did not proceed at all.
[0039]
【The invention's effect】
In the present invention, N-substituted formyl imidazoles are oxidized using a noble metal catalyst in the presence of an alkali and water. Preferably, N-substituted hydroxymethyl imidazoles are oxidized using a noble metal catalyst in the presence of an alkali and water. An N-substituted imidazole carboxylic acid having high purity can be obtained with good yield in an industrially advantageous manner from the N-substituted formyl imidazoles produced by the production.
Claims (9)
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