JP4442951B2 - Process for producing 5-formylimidazoles - Google Patents
Process for producing 5-formylimidazoles Download PDFInfo
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- JP4442951B2 JP4442951B2 JP17772499A JP17772499A JP4442951B2 JP 4442951 B2 JP4442951 B2 JP 4442951B2 JP 17772499 A JP17772499 A JP 17772499A JP 17772499 A JP17772499 A JP 17772499A JP 4442951 B2 JP4442951 B2 JP 4442951B2
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- formylimidazoles
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- ZQEXIXXJFSQPNA-UHFFFAOYSA-N 1h-imidazole-5-carbaldehyde Chemical class O=CC1=CNC=N1 ZQEXIXXJFSQPNA-UHFFFAOYSA-N 0.000 title claims description 10
- 238000000034 method Methods 0.000 title description 5
- 239000003054 catalyst Substances 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- QDYTUZCWBJRHKK-UHFFFAOYSA-N imidazole-4-methanol Chemical class OCC1=CNC=N1 QDYTUZCWBJRHKK-UHFFFAOYSA-N 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229910000510 noble metal Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000007254 oxidation reaction Methods 0.000 description 12
- 230000003197 catalytic effect Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- JLVIHQCWASNXCK-UHFFFAOYSA-N 2-butyl-5-chloro-1h-imidazole-4-carbaldehyde Chemical compound CCCCC1=NC(C=O)=C(Cl)N1 JLVIHQCWASNXCK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DXSZKDOOHOBZMT-UHFFFAOYSA-N (2-butyl-4-chloro-1h-imidazol-5-yl)methanol Chemical compound CCCCC1=NC(Cl)=C(CO)N1 DXSZKDOOHOBZMT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- AXJZCJSXNZZMDU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol Chemical compound CC=1N=CNC=1CO AXJZCJSXNZZMDU-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- UZKBZGAMRJRWLR-UHFFFAOYSA-N (2-butyl-1H-imidazol-4-yl)methanol Chemical compound CCCCC1=NC=C(CO)N1 UZKBZGAMRJRWLR-UHFFFAOYSA-N 0.000 description 1
- MQRMTENGXFRETM-UHFFFAOYSA-N (2-methyl-1h-imidazol-5-yl)methanol Chemical compound CC1=NC=C(CO)N1 MQRMTENGXFRETM-UHFFFAOYSA-N 0.000 description 1
- TUCQOIQFSKJKPH-UHFFFAOYSA-N (2-propyl-1h-imidazol-5-yl)methanol Chemical compound CCCC1=NC(CO)=CN1 TUCQOIQFSKJKPH-UHFFFAOYSA-N 0.000 description 1
- PTHGVOCFAZSNNA-UHFFFAOYSA-N 2-butyl-1h-imidazole-5-carbaldehyde Chemical compound CCCCC1=NC=C(C=O)N1 PTHGVOCFAZSNNA-UHFFFAOYSA-N 0.000 description 1
- KMWCSNCNHSEXIF-UHFFFAOYSA-N 5-methyl-1h-imidazole-4-carbaldehyde Chemical compound CC=1N=CNC=1C=O KMWCSNCNHSEXIF-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 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
- ZOKDWBDDYVCACM-UHFFFAOYSA-N bismuth platinum Chemical compound [Pt].[Bi] ZOKDWBDDYVCACM-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 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
- 230000001771 impaired effect Effects 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
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
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な２−アルキル−５−ホルミルイミダゾール等の５−ホルミルイミダゾール類の製造方法に関する。
【０００２】
【従来の技術】
アルキルホルミルイミダゾールは上記の如く有用な用途を有し、近年注目されている化学品であるがその製造法に関する公知文献はあまりなく例えば、出発原料として２−アルキル−５−ヒドロキシメチルイミダゾールを用い、重金属類による試薬酸化法、硝酸による酸化法が研究されている。
【０００３】
【発明が解決しようとする課題】
しかしながらかかる技術では、前者の場合は重金属類の取り扱いや廃触媒の処理に多大の労力を必要とすること、後者の場合は目的物の収率面や窒素酸化物の発生の点等において、工業的規模での実施に非常に不利となり満足し得る方法とは言い難い。故に、かかる問題点を避け工業的に安全な方法でかつ高収率で目的物が製造できる、２−アルキル−５−ホルミルイミダゾールの新たな製造方法の開発が当業者間で強く望まれており、本出願人はかかる目的を達成すべく鋭意研究を重ねた結果、先に２−アルキル−５−ヒドロキシメチルイミダゾールを貴金属触媒の存在下で接触酸化させる場合、特にアルカリ水溶媒中での反応においてその目的が有利に達成出来ることを見出し、特許出願を行った。
しかし、かかる反応においては高価な貴金属触媒を使用するので、工業的規模での実施ではその使用量を出来るだけ低減するのが望ましいとの見解から、縷々検討を行ったが、触媒の低減は反応の不安定化を導き、ひいては目的物の収率低下となる難点は容易に解決出来なかった。
【０００４】
【課題を解決するための手段】
しかるに本発明者は、アルカリ水溶媒中で、下記一般式（１）で示される５−ヒドロキシメチルイミダゾール類を貴金属触媒の存在下に、酸素あるいは空気を導入して接触酸化させて下記一般式（２）で示される５−ホルミルイミダゾール類を製造するにあたり、反応液に炭素数１〜３のアルコールを共存させる場合、触媒の使用量を少なくしても、５−ホルミルイミダゾール類を収率良く製造できることを見出し、本発明を完成するに至った。
【化１】
（式中、Ｒは水素又は炭素数１〜５のアルキル基であり、４位の炭素に結合する水素は、ハロゲン、炭素数１〜１２のアルキル基あるいは置換アルキル基で置換されていてもよい。）
【０００５】
【発明の実施の形態】
本発明の反応は下記（３）式で示される。
【化２】
（Ｒは水素又はアルキル基）
【０００６】
ここでＲは水素又は炭素数１〜５のアルキル基であり、好ましくはｎ−ブチル基が有用である。４位の炭素に結合する水素はクロル、ブロム等のハロゲンあるいは炭素数１〜１２のアルキル基あるいは置換アルキル基で置換されていても差し支えない。
具体的に原料を例示すれば、５−ヒドロキシメチルイミダゾール、４−メチル−５−ヒドロキシメチルイミダゾール、２−メチル−５−ヒドロキシメチルイミダゾール、２−プロピル−５−ヒドロキシメチルイミダゾール、２−ブチル−５−ヒドロキシメチルイミダゾール、２−ブチル−４−クロル−５−ヒドロキシメチルイミダゾール等が挙げられる。
【０００７】
本発明では接触酸化反応に当たって、アルカリ水溶媒を使用することが必須条件であり、かかる溶媒の使用により目的物の収率の向上が保持される。
アルカリ水におけるアルカリとしては水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、酢酸ナトリウム等が挙げられる。
アルカリの使用量は原料の５−ヒドロキシメチルイミダゾール類１モルに対して０．９モル以上、好ましくは１．０〜１．５モルが必要である。０．９モル未満では生成する５−ホルミルイミダゾール類が系に溶解しない。一方１．５モルを越えると中和工程での酸量が増大し実用的でない。
【０００８】
本発明で使用する貴金属触媒は白金、パラジウム、金等であり、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第二成分としてビスマス、セリウム、鉛、インジウム等を添加することも可能である。かかる触媒は金属状態ばかりでなく塩、酸化物等の状態であっても良い。本発明で用いる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担持されて用いられる。
接触酸化反応を実施するに当たっては、反応器にアルカリ水溶媒を仕込み、これに上記の触媒、原料の５−ヒドロキシメチルイミダゾール類を供給する。
【０００９】
本発明で使用されるすべての薬剤の仕込み手段は任意であり、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、特に一括仕込みが有利である。
本発明の趣旨を逸脱しない範囲であれば、各種の有機溶媒を併用することもできる。
【００１０】
本発明においてはかかる反応時に反応液に炭素数１〜３のアルコールを共存させることに特徴があり、かかるアルコールの使用により低触媒量にもかかわらず、目的物が収率よく製造出来る。
上記のアルコールとしてはメタノール、エタノール、プロパノールが例示される。
アルコールの使用量は５−ヒドロキシメチルイミダゾール類１モルに対して０．１〜１０．０モル、好ましくは、０．３〜８．０モル、特に好ましくは０．５〜６．０モルである。
０．１モル未満では本発明の効果が得難く、１０．０モルを越えると目的物の収率低下が起こる。
【００１１】
本発明においては反応時に系の撹拌効率を特定化すると更に効果が発揮され、ＰV値を０．３以上、好ましくは０．６以上、特に好ましくは１．０以上とするのが良い。
ここでＰV値とは流体単位体積当たりの撹拌所要動力を意味し、撹拌機の撹拌動力（ｋＷ）／反応液の体積（ｍ3）で定義される。
ＰV値が０．３未満では反応が十分に進行せず、反応に長時間を必要としたり、副生物の生成も増加する。一方ＰV値をあまりに高くしてもそれほど本発明の効果は発揮されず、むしろ大きな撹拌機を必要とする等経済性が損なわれるので、ＰV値の上限は３．０好ましくは２．０で十分である。
撹拌機の種類は特定されず、例えば三枚後退翼、フルゾーン翼、タービン翼、マックスブレンド翼等任意のものが挙げられる。
【００１２】
触媒の使用量は原料の５−ヒドロキシメチルイミダゾール類に対して０．０１〜５０モル％、好ましくは０．０５〜２０モル％が適当であるが、本発明の効果が顕著に発揮されるのは、上記範囲でも触媒使用量の少ない範囲すなわち０．１〜１０モル％である。
溶媒は原料の３〜５０重量倍で使用する。
反応温度は０℃〜還流温度のいずれでも良いが、通常は室温以上、好ましくは１０〜８０℃、特に望ましくは１５〜６０℃が適当であり、又反応時間は１〜２４時間、好ましくは２〜１５時間が有利である。
【００１３】
接触酸化反応に際しては、上記の系内に酸素あるいは空気を導入することが必要である。系は常圧でも加圧でもよく、酸素あるいは空気の導入速度は５−ヒドロキシメチルイミダゾール類１ｇに対して０．０１〜１．０ミリリットル（標準状態換算）／分程度である。反応は懸濁系で進行し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５−ホルミルイミダゾール類が塩の形で溶解しているので、硫酸、塩酸等の鉱酸で中和して目的物である５−ホルミルイミダゾール類の結晶を得る。必要であれば更に精製が行われる。目的物の収率は、原料５−ヒドロキシメチルイミダゾール類に対して９０％以上である。
【００１４】
【実施例】
以下、本発明を実例を挙げて詳述する。「％」は重量基準である。
実施例１
内径１００ｍｍφのセパラブルフラスコにタービン翼（翼径６０ｍｍφ）と、酸素ガス吹き込み管及び温度計を取り付けた反応装置に、２−ｎ−ブチル−４−クロロ−５−ヒドロキシメチルイミダゾール１００ｇ（０．５３モル）、水酸化ナトリウム２５．４ｇ（０．６４モル）、水９３０ｍｌ、メタノ−ル９．３ｇ（０．２９モル）更に、白金−ビスマス系触媒（活性炭に白金５％及びビスマス２％を担持、含水率５０％）６．７ｇをそれぞれ仕込んだ。
ＰV値が１．３となるように撹拌し、反応液の温度を２０℃にコントロールしながら、酸素を２０ｍｌ／分の割合で７時間吹き込み接触酸化反応を行った。
【００１５】
反応終了後、反応液から触媒を濾別し濾液を３０％硫酸水で中和し２−ｎ−ブチル−４−クロロ−５−ホルミルイミダゾールを結晶として析出させ濾取、乾燥して９５．３ｇの白色結晶を得た。
２−ｎ−ブチル−４−クロロ−５−ヒドロキシメチルイミダゾールに対する収率は９６．４％であり、純度は１００％であった。
赤外線分析、ＮＭＲ分析の結果、２−ｎ−ブチル−４−クロロ−５−ホルミルイミダゾールと確認できた。
【００１６】
実施例２
実施例１においてメタノールに変えてエタノールを１３．１ｇ（０．２９モル）使用し、撹拌翼をフルゾ−ン翼に、ＰV値を１．８にそれぞれ変更した以外は同例に従って実験をした。
収率９５．５％で２−ｎ−ブチル−４−クロロ−５−ホルミルイミダゾール（純度１００％）を得た。
【００１７】
実施例３
実施例１において撹拌翼としてマックスブレンド翼を使用し、ＰV値を１．５に変更した以外は同例に従って実験をした。
収率９６．０％で２−ｎ−ブチル−４−クロロ−５−ホルミルイミダゾール（純度１００％）を得た。
【００１８】
実施例４
実施例１において触媒を白金黒３．３ｇに変えて、接触酸化反応を行った。
赤外線分析、ＮＭＲ分析の結果、２−ｎ−ブチル−４−クロロ−５−ホルミルイミダゾールと確認できた。純度１００％、収率は９４．１％であった。
【００１９】
実施例５
実施例１に準じて、２−ｎ−ブチル−５−ヒドロキシメチルイミダゾールを接触酸化した。
赤外線分析、ＮＭＲ分析の結果、２−ｎ−ブチル−５−ホルミルイミダゾールと確認できた。純度１００％、収率は９３．１％であった。
【００２０】
実施例６
実施例１に準じて、４−メチル−５−ヒドロキシメチルイミダゾールの接触酸化反応を行った。
赤外線分析、ＮＭＲ分析の結果、４−メチル−５−ホルミルイミダゾールと確認できた。純度１００％、収率は９２．２％であった。
【００２１】
実施例７
実施例１に準じて、５−ヒドロキシメチルイミダゾールの接触酸化反応を行った。
赤外線分析、ＮＭＲ分析の結果、５−ホルミルイミダゾールと確認できた。
純度１００％、収率は９１．７％であった。
【００２２】
対照例１
実施例１において、メタノールの使用を省略した以外は同様の実験を行った。純度７７．３％の２−ｎ−ブチル−４−クロロ−５−ホルミルイミダゾールが収率８２．６％で得られたに過ぎなかった。
【００２３】
【発明の効果】
本発明は、利尿剤や降圧剤等医薬品の原料として有用な２−アルキル−５−ホルミルイミダゾールを初めとする５−ホルミルイミダゾール類を接触酸化法によって製造するに際して、アルカリ水溶媒を使用し、反応液に炭素数１〜３のアルコ−ルを共存させると、貴金属触媒の使用量を低減しても、高収率で目的物が得られるので経済面、製造面において非常に有利である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 5-formylimidazoles such as 2-alkyl-5-formylimidazole useful as a raw material for pharmaceuticals such as diuretics and antihypertensives.
[0002]
[Prior art]
Alkylformylimidazole has a useful use as described above, and is a chemical product that has been attracting attention in recent years, but there are not many known literatures regarding its production method. For example, 2-alkyl-5-hydroxymethylimidazole is used as a starting material, Reagent oxidation methods using heavy metals and oxidation methods using nitric acid have been studied.
[0003]
[Problems to be solved by the invention]
However, in such a technique, in the former case, a great deal of labor is required for handling heavy metals and processing of the waste catalyst, and in the latter case, in terms of yield of the target product and generation of nitrogen oxides, etc. It is difficult to say that it is very disadvantageous and satisfactory for implementation on a scale. Therefore, development of a new method for producing 2-alkyl-5-formylimidazole, which avoids such problems and can produce the target product in an industrially safe manner and in a high yield, is strongly desired among those skilled in the art. As a result of intensive researches to achieve such an object, the present applicant has previously conducted catalytic oxidation of 2-alkyl-5-hydroxymethylimidazole in the presence of a noble metal catalyst, particularly in a reaction in an alkaline water solvent. We found that the object can be achieved advantageously, and filed a patent application.
However, since an expensive precious metal catalyst is used in such a reaction, it has been frequently studied from the view that it is desirable to reduce the amount used in an industrial scale as much as possible. The problem of leading to destabilization of the product and thus reducing the yield of the target product could not be easily solved.
[0004]
[Means for Solving the Problems]
The present inventors have however, in alkaline water solvent, the 5-hydroxymethyl imidazoles shown in the presence of a noble metal catalyst by the following general formula (1), oxygen or an air is catalytic oxidation by introducing the general formula ( In producing 5-formylimidazoles represented by 2), when alcohols having 1 to 3 carbon atoms are allowed to coexist in the reaction solution, 5-formylimidazoles are produced with good yield even if the amount of catalyst used is reduced. The present inventors have found that this can be done and have completed the present invention.
[Chemical 1]
(In the formula, R is hydrogen or an alkyl group having 1 to 5 carbon atoms, and the hydrogen bonded to the 4-position carbon may be substituted with halogen, an alkyl group having 1 to 12 carbon atoms or a substituted alkyl group. .)
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The reaction of the present invention is represented by the following formula ( 3 ).
[Chemical 2 ]
(R is hydrogen or an alkyl group)
[0006]
Here, R is hydrogen or an alkyl group having 1 to 5 carbon atoms, preferably an n-butyl group. Hydrogen bonded to carbon at the 4-position may be substituted with halogen such as chloro and bromo, alkyl groups having 1 to 12 carbon atoms or substituted alkyl groups.
Specific examples of raw materials include 5-hydroxymethylimidazole, 4-methyl-5-hydroxymethylimidazole, 2-methyl-5-hydroxymethylimidazole, 2-propyl-5-hydroxymethylimidazole, 2-butyl-5. -Hydroxymethylimidazole, 2-butyl-4-chloro-5-hydroxymethylimidazole and the like.
[0007]
In the present invention, it is an essential condition to use an alkaline water solvent in the catalytic oxidation reaction, and the use of such a solvent maintains the improvement in the yield of the target product.
Examples of the alkali in the alkaline water include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate and the like.
The amount of alkali used is 0.9 mol or more, preferably 1.0 to 1.5 mol, per mol of 5-hydroxymethylimidazole as a raw material. If it is less than 0.9 mol, the resulting 5-formylimidazoles will not dissolve in the system. On the other hand, when the amount exceeds 1.5 mol, the acid amount in the neutralization step increases, which is not practical.
[0008]
The noble metal catalyst used in the present invention is platinum, palladium, gold or the like, and platinum and palladium are practical. It is also possible to add bismuth, cerium, lead, indium or the like as the second component to such noble metal catalyst. Such a catalyst may be in the form of not only a metal state but also a salt, an oxide or the like. The noble metal catalyst used in the present invention is used as it is or supported on a carrier such as activated carbon, silica, alumina or the like as necessary.
In carrying out the catalytic oxidation reaction, an alkaline water solvent is charged into the reactor, and the above-mentioned catalyst and raw material 5-hydroxymethylimidazoles are supplied thereto.
[0009]
The means for charging all the chemicals used in the present invention is arbitrary, and batch charging, split charging, continuous charging, dropping charging, etc. can be carried out, but batch charging is particularly advantageous.
Various organic solvents can be used in combination as long as they do not depart from the spirit of the present invention.
[0010]
The present invention is characterized in that an alcohol having 1 to 3 carbon atoms is allowed to coexist in the reaction solution during the reaction, and the use of such an alcohol makes it possible to produce the target product in a high yield despite the low catalyst amount.
The above Examples alcohol methanol, ethanol, propanol and the like.
The amount of alcohol used is 0.1 to 10.0 mol, preferably 0.3 to 8.0 mol, particularly preferably 0.5 to 6.0 mol, per 1 mol of 5-hydroxymethylimidazoles. .
If the amount is less than 0.1 mol, the effect of the present invention is difficult to obtain. If the amount exceeds 10.0 mol, the yield of the target product is reduced.
[0011]
In the present invention, if the stirring efficiency of the system is specified during the reaction, the effect is further exerted, and the P V value is 0.3 or more, preferably 0.6 or more, particularly preferably 1.0 or more.
Here, the P V value means the power required for stirring per unit volume of fluid, and is defined as stirring power (kW) of the stirrer / volume of reaction liquid (m 3 ).
If the P V value is less than 0.3, the reaction does not proceed sufficiently, requiring a long time for the reaction, and increasing the production of by-products. On the other hand, even if the P V value is too high, the effect of the present invention is not exhibited so much. Rather, the economic efficiency such as the need for a large stirrer is impaired, so the upper limit of the P V value is 3.0, preferably 2.0. Is enough.
The type of the stirrer is not specified, and examples thereof include arbitrary ones such as a three-blade swept blade, a full zone blade, a turbine blade, and a max blend blade.
[0012]
The catalyst is used in an amount of 0.01 to 50 mol%, preferably 0.05 to 20 mol%, based on the starting 5-hydroxymethylimidazoles, but the effects of the present invention are remarkably exhibited. Is a range where the amount of catalyst used is small, that is, 0.1 to 10 mol%.
The solvent is used 3 to 50 times by weight of the raw material.
The reaction temperature may be any of 0 ° C. to reflux temperature, but is usually room temperature or higher, preferably 10 to 80 ° C., particularly preferably 15 to 60 ° C., and the reaction time is 1 to 24 hours, preferably 2 ~ 15 hours is advantageous.
[0013]
In the catalytic oxidation reaction, it is necessary to introduce oxygen or air into the above system. The system may be normal pressure or pressurized, and the introduction rate of oxygen or air is about 0.01 to 1.0 milliliter (standard state conversion) / minute with respect to 1 g of 5-hydroxymethylimidazole. The reaction proceeds in a suspension system and is terminated when the absorption of oxygen is stopped, and the catalyst is filtered off from the reaction completed solution. Since 5-formylimidazoles are dissolved in the filtrate in the form of a salt, they are neutralized with a mineral acid such as sulfuric acid or hydrochloric acid to obtain crystals of the desired 5-formylimidazoles. Further purification is performed if necessary. The yield of the target product is 90% or more based on the starting 5-hydroxymethylimidazoles.
[0014]
【Example】
Hereinafter, the present invention will be described in detail with examples. “%” Is based on weight.
Example 1
To a reactor equipped with a turbine blade (blade diameter 60 mmφ), an oxygen gas blowing tube and a thermometer on a separable flask having an inner diameter of 100 mmφ, 100 g of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (0.53 Mol), sodium hydroxide 25.4 g (0.64 mol), water 930 ml, methanol 9.3 g (0.29 mol), and platinum-bismuth catalyst (activated carbon loaded with 5% platinum and 2% bismuth) And 6.7 g of water content 50%).
Stirring was performed so that the P V value was 1.3, and the temperature of the reaction solution was controlled at 20 ° C., and oxygen was blown in at a rate of 20 ml / min for 7 hours to perform a catalytic oxidation reaction.
[0015]
After completion of the reaction, the catalyst was filtered off from the reaction solution, and the filtrate was neutralized with 30% aqueous sulfuric acid to precipitate 2-n-butyl-4-chloro-5-formylimidazole as crystals, collected by filtration and dried to obtain 95.3 g. Of white crystals were obtained.
The yield based on 2-n-butyl-4-chloro-5-hydroxymethylimidazole was 96.4%, and the purity was 100%.
As a result of infrared analysis and NMR analysis, it could be confirmed as 2-n-butyl-4-chloro-5-formylimidazole.
[0016]
Example 2
In Example 1, 13.1 g (0.29 mol) of ethanol was used instead of methanol, and the experiment was performed according to the same example except that the stirring blade was changed to a full-zone blade and the P V value was changed to 1.8. .
2-n-butyl-4-chloro-5-formylimidazole (purity 100%) was obtained with a yield of 95.5%.
[0017]
Example 3
The experiment was conducted according to the same example except that a Max blend blade was used as a stirring blade in Example 1 and the P V value was changed to 1.5.
2-n-butyl-4-chloro-5-formylimidazole (purity 100%) was obtained in a yield of 96.0%.
[0018]
Example 4
In Example 1, the catalytic oxidation reaction was carried out by changing the catalyst to 3.3 g of platinum black.
As a result of infrared analysis and NMR analysis, it could be confirmed as 2-n-butyl-4-chloro-5-formylimidazole. The purity was 100% and the yield was 94.1%.
[0019]
Example 5
According to Example 1, 2-n-butyl-5-hydroxymethylimidazole was catalytically oxidized.
As a result of infrared analysis and NMR analysis, it could be confirmed as 2-n-butyl-5-formylimidazole. The purity was 100% and the yield was 93.1%.
[0020]
Example 6
According to Example 1, the catalytic oxidation reaction of 4-methyl-5-hydroxymethylimidazole was performed.
As a result of infrared analysis and NMR analysis, 4-methyl-5-formylimidazole was confirmed. The purity was 100% and the yield was 92.2%.
[0021]
Example 7
According to Example 1, the catalytic oxidation reaction of 5-hydroxymethylimidazole was performed.
As a result of infrared analysis and NMR analysis, it was confirmed as 5-formylimidazole.
The purity was 100% and the yield was 91.7%.
[0022]
Control Example 1
In Example 1, the same experiment was conducted except that the use of methanol was omitted. Only 77.3% pure 2-n-butyl-4-chloro-5-formylimidazole was obtained with a yield of 82.6%.
[0023]
【The invention's effect】
The present invention uses an alkaline water solvent to produce 5-formylimidazoles such as 2-alkyl-5-formylimidazole useful as a raw material for pharmaceuticals such as diuretics and antihypertensive agents by a catalytic oxidation method. When an alcohol having 1 to 3 carbon atoms is allowed to coexist in the liquid, the target product can be obtained in a high yield even if the amount of noble metal catalyst used is reduced, which is very advantageous in terms of economy and production.
Claims (2)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17772499A JP4442951B2 (en) | 1999-06-24 | 1999-06-24 | Process for producing 5-formylimidazoles |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17772499A JP4442951B2 (en) | 1999-06-24 | 1999-06-24 | Process for producing 5-formylimidazoles |
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| Publication Number | Publication Date |
|---|---|
| JP2001002653A JP2001002653A (en) | 2001-01-09 |
| JP4442951B2 true JP4442951B2 (en) | 2010-03-31 |
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| Country | Link |
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