JP4841053B2 - Method for producing formylimidazoles - Google Patents
Method for producing formylimidazoles Download PDFInfo
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- JP4841053B2 JP4841053B2 JP2001108036A JP2001108036A JP4841053B2 JP 4841053 B2 JP4841053 B2 JP 4841053B2 JP 2001108036 A JP2001108036 A JP 2001108036A JP 2001108036 A JP2001108036 A JP 2001108036A JP 4841053 B2 JP4841053 B2 JP 4841053B2
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- Prior art keywords
- formylimidazole
- manganese dioxide
- producing
- reaction
- formylimidazoles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000004519 manufacturing process Methods 0.000 title claims description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 235000019441 ethanol Nutrition 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical compound OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 claims description 15
- 239000013078 crystal Substances 0.000 claims description 14
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 11
- 238000007254 oxidation reaction Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 10
- ZQEXIXXJFSQPNA-UHFFFAOYSA-N 1h-imidazole-5-carbaldehyde Chemical compound O=CC1=CNC=N1 ZQEXIXXJFSQPNA-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- QDYTUZCWBJRHKK-UHFFFAOYSA-N imidazole-4-methanol Chemical compound OCC1=CNC=N1 QDYTUZCWBJRHKK-UHFFFAOYSA-N 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 230000000903 blocking effect Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- PXGQMYCEAWZJJF-UHFFFAOYSA-N (3-methylimidazol-4-yl)methanol Chemical compound CN1C=NC=C1CO PXGQMYCEAWZJJF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- BNYKZFOZWZMEJD-UHFFFAOYSA-N 3-methylimidazole-4-carbaldehyde Chemical compound CN1C=NC=C1C=O BNYKZFOZWZMEJD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000001994 activation Methods 0.000 description 2
- -1 alicyclic hydrocarbons Chemical class 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000006227 byproduct Substances 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
- 230000000694 effects Effects 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940099596 manganese sulfate Drugs 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
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】
ホルミルイミダゾール類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り、その製造方法としてはヒドロキシメチルイミダゾール類を金属酸化物、硝酸あるいは空気や酸素等の各種酸化剤を用いて酸化する方法が知られている。
各種酸化剤の中でも、安価であること、取り扱いに不都合がなく環境問題にも対応できること、加圧反応器等の特別の装置も必要でないこと等の利点を有しているものとして、二酸化マンガンが工業的規模での実施で注目されるところである。かかる二酸化マンガンを使用する方法として、例えば▲1▼4−ヒドロキシメチルイミダゾールを50重量倍のジオキサン溶媒中で酸化する方法[特開平3−24083号公報]や▲2▼1−メチル−5−ヒドロキシメチルイミダゾールを30重量倍のクロロホルム溶媒中で酸化する方法[J.Org.Chem.,58,1159(1993)]等があるが、いずれも大量の有機溶媒の使用が必要である点で工業的には実施し難い方法と言わざるを得ない。
【0003】
【発明が解決しようとする課題】
上記公知の方法で大量の有機溶媒を使用しなければならないのは、原料のヒドロキシメチルイミダゾール類の溶解度が小さいことが原因であり、必然的に反応時の装置効率の低下を招き、更に反応生成液を濾別して得られる目的物の結晶から未反応の原料ヒドロキシメチルイミダゾール類を洗浄除去する際にも大量の溶媒が必要となる。
かかる難点を回避するために上記▲2▼では濾別した結晶を減圧下で昇華させて精製するという工業的製法としてはあまり有利とは言えない手法を実施しているが、この場合ホルミルイミダゾール類がブロッキングしたり、固化したりする恐れがある。
従って、上記のような欠点がなく工業的に有利に実施でき、しかも最終製品はブロッキングや固化等の発生のない、二酸化マンガン酸化法によるホルミルイミダゾール類の製造方法の開発が要望されるところである。
【0004】
【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メチルアルコール又はエチルアルコール中で、下記一般式(a)で示されるヒドロキシメチルイミダゾール類を二酸化マンガンを用いて酸化する場合、下記一般式(b)で示されるホルミルイミダゾール類を有利に製造できることを見出し、本発明を完成するに至った。
つまり、本発明ではアルコール溶媒としてメチルアルコール又はエチルアルコールの使用に特徴があり、ヒドロキシメチルイミダゾール類をアルコールの一種との見方をすると、該ヒドロキシメチル基の酸化を行う反応に、アルコール溶媒を用いれば酸化を受け溶媒としての機能を発揮できないのではないかという予想に反して、優先的にヒドロキシメチル基の酸化が起こり、目的物を有利に製造できるという顕著な事実に基づいて本発明はなされたものである。
【0005】
【発明の実施の形態】
本発明の反応は下記(1)式で示される。
【化1】
【0006】
ここでRは水素又は炭素数1〜5のアルキル基であり、ヒドロキシメチル基は2位、4位、5位の炭素のいずれに結合していても良い。
本発明で使用する原料を具体的に例示すれば、4−ヒドロキシメチルイミダゾ−ル、2−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−ル等が挙げられる。
【0007】
本発明では酸化反応に当たって、アルコール溶媒としてメチルアルコール又はエチルアルコール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及び純度、品質を高く維持できると共に、特別の反応装置も不要である等の顕著な効果が発揮できる。
又本発明の趣旨から逸脱しない範囲で酢酸エチル等のエステル類、エチレンジクロライド等のハロゲン化炭化水素、トルエン等の芳香族炭化水素、シクロヘキサン等の脂環式炭化水素、アセトニトリル等のニトリル類等の他の有機溶媒の併用も差し支えない。
【0008】
アルコール溶媒の使用量はヒドロキシメチルイミダゾール類の5〜30重量倍、好ましくは8〜20重量倍であることが望ましく、5重量倍未満では目的物のホルミルイミダゾール類が反応系に析出しやすくなり、反応終了後の二酸化マンガンとの分離に多大の手間がかかり、一方30重量倍を越えると生産性等の点で経済的に不利となり実用的でなくなる。
【0009】
本発明で使用する二酸化マンガンは特に限定はなく、通常市販されている過酸化マンガンにAttenburrow法やMancera−Sondheimer法等の慣用の活性化処理を施して活性化二酸化マンガンや、硫酸マンガン溶液を電解して得られる電解二酸化マンガン等がいずれも用いられる。活性化処理の手間が省けるという意味では、電解二酸化マンガンが有利に使用される。二酸化マンガンの粒径分布としては粒子径が100μm以下のものが90重量%以上が好ましく、更には45μm以下のものが90重量%以上である。
二酸化マンガンの使用量は原料のヒドロキシメチルイミダゾール類1モルに対して2〜10倍モル、好ましくは4〜8倍モルが適当であり、2倍モル未満では反応性に乏しく目的物の収率が低下し、10倍モルを越えるとメチルエステル体等の副生物の生成が顕著となり収率及び品質の低下が問題となる。
【0010】
酸化反応を実施するに当たっては、反応器に反応溶媒、二酸化マンガン、原料のヒドロキシメチルイミダゾール類を供給する。
反応器へ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。
【0011】
反応温度は20℃〜還流温度のいずれでも良いが、通常は30〜50℃が適当であり、又、反応時間は1〜20時間、好ましくは2〜10時間が有利である。反応温度が低すぎると反応速度が遅く、逆に高すぎると不純物の副生が多くなる。
【0012】
酸化反応が終了した後に、反応生成液中に分散している二酸化マンガンを濾別する。
濾液にはホルミルイミダゾール類が溶解しているので、アルコール溶媒を留去してホルミルイミダゾール類の結晶を析出させる。この際濾液の固形分濃度が25〜45重量%好ましくは30〜40重量%となるまでアルコール溶媒を留去させると、ホルミルイミダゾール類のみが選択的に析出され未反応の原料ヒドロキシメチルイミダゾール類はアルコール溶媒中に溶解したままの状態に止めることができるので、目的物の単離と精製とが同時に可能となる。析出した結晶を濾別して目的物である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。
【0013】
【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
4−ヒドロキシメチルイミダゾール25.1g(0.254モル)をメチルアルコール250gに溶解させ、この溶液を容量500mlの反応容器に仕込み、更に二酸化マンガン(東ソー社製電解二酸化マンガン「HMH」、粒径分布は45μm以下の粒子が94%)125g(1.43モル)を添加して40℃で6時間酸化反応を行った。
【0014】
反応終了後、系を25℃まで冷却し反応生成液から二酸化マンガンを濾別した。該濾別した二酸化マンガンを室温のメチルアルコール50gで2回洗浄し、洗浄液と濾液を混合した後、250mmHgの減圧下、45℃にてメチルアルコールを311g留去して固形分濃度34.6%のスラリー液とした。スラリー液を20℃に冷却後、析出した結晶を濾別、乾燥し4−ホルミルイミダゾールの結晶22.2gを得た。ブロッキング等は全くないサラサラした粉末であった。
4−ヒドロキシメチルイミダゾールに対する収率は91%であり、純度は99.8%(HPLC、260nmにて測定、以下同様)であった。
赤外線分析、NMR分析の結果、4−ホルミルイミダゾールと確認できた。
【0015】
実施例2
実施例1において4−ヒドロキシメチルイミダゾールに変えて2−ヒドロキシメチルイミダゾールを原料とした以外は同例に従って実験をした。収率90.5%で2−ホルミルイミダゾール(純度99.7%)を得た。ブロッキングも全くなかった。
赤外線分析、NMR分析の結果、2−ホルミルイミダゾールと確認できた。
【0016】
実施例3
実施例1において、メチルアルコールに変えてエチルアルコールを使用し同例に準じて実験を行った。4−ホルミルイミダゾールの結晶22.0gを得た。ブロッキング等は全くないサラサラした粉末であった。4−ヒドロキシメチルイミダゾールに対する収率は90.1%であり、純度は99.8%であった。
赤外線分析、NMR分析の結果、4−ホルミルイミダゾールと確認できた。
【0017】
実施例4
実施例1においてメチルアルコール溶媒の使用量を500gに変更した以外は同例に準じて実験を行ない、4−ホルミルイミダゾールの結晶22.3gを得た。ブロッキング等は全くないサラサラした粉末であった。4−ヒドロキシメチルイミダゾールに対する収率は91.3%であり、純度は99.8%であった。
赤外線分析、NMR分析の結果、4−ホルミルイミダゾールと確認できた。
【0018】
実施例5
1−メチル−5−ヒドロキシメチルイミダゾール28.3g(0.25モル)をメチルアルコール280gに溶解させ、この溶液を容量500mlの反応容器に仕込み、更に二酸化マンガン(東ソー社製電解二酸化マンガン「HMH」、粒径分布は45μm以下の粒子が94%)109g(1.25モル)を添加して40℃で8時間酸化反応を行った。
反応終了後、実施例1と同様に処理して固形分濃度35%のスラリー液とした。スラリー液を20℃に冷却後、析出した結晶を濾別、乾燥し1−メチル−5−ホルミルイミダゾールの結晶25.2gを得た。ブロッキング等は全くないサラサラした粉末であった。1−メチル−5−ヒドロキシメチルイミダゾールに対する収率は91.6%であり、純度は99.7%であった。
赤外線分析、NMR分析の結果、1−メチル−5−ホルミルイミダゾールと確認できた。
【0019】
対照例1
4−ヒドロキシメチルイミダゾール25.1g(0.254モル)をジオキサン1250gに溶解させ、この溶液を容量2000mlの反応容器に仕込み、更に二酸化マンガン(東ソー社製電解二酸化マンガン「HMH」、粒径分布45μm以下の粒子が94%)66.4g(0.76モル)を添加して40℃で8時間酸化反応を行った。
【0020】
反応終了後、系を25℃まで冷却し反応生成液から二酸化マンガンを濾別した。該濾別した二酸化マンガンを55℃のジオキサン200gで5回洗浄し、洗浄液と濾液を混合した後、140mmHgの減圧下、50℃にてジオキサンを留去し、次いで酢酸エチル200mlに懸濁して20℃に冷却後、析出した結晶を濾別した。濾別した4−ホルミルイミダゾールを90mlの酢酸エチルで洗浄し19.6gの目的物を得た。4−ヒドロキシメチルイミダゾールに対する収率は80.5%であり、純度は98.9%であった。
赤外線分析、NMR分析の結果、4−ホルミルイミダゾールと確認できた。
【0021】
【発明の効果】
本発明では、利尿剤や降圧剤等医薬品の原料として有用な4−ホルミルイミダゾールを初めとするホルミルイミダゾール類を、ヒドロキシメチルイミダゾール類の二酸化マンガンによる酸化法で製造するに際して、アルコール溶媒として、メチルアルコール又はエチルアルコールを使用することによって、ブロッキングや固化等の発生のない、しかも純度の高いホルミルイミダゾール類を収率良く工業的有利に製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing formylimidazoles useful as raw materials for pharmaceuticals such as diuretics and antihypertensives.
[0002]
[Prior art]
Formylimidazoles have useful applications as described above, and are recently attracting attention as chemicals. As a method for producing them, hydroxymethylimidazoles are prepared using metal oxides, nitric acid, various oxidizing agents such as air and oxygen. There is a known method of oxidizing.
Among various oxidants, manganese dioxide has the advantages that it is inexpensive, can handle environmental problems without inconvenience, and does not require special equipment such as a pressurized reactor. Attention is being paid to implementation on an industrial scale. As a method of using such manganese dioxide, for example, (1) a method of oxidizing 4-hydroxymethylimidazole in a 50 times weight dioxane solvent [JP-A-3-24083] or (2) 1-methyl-5-hydroxy Method of oxidizing methylimidazole in 30 times by weight chloroform solvent [J. Org. Chem. , 58 , 1159 (1993)], etc., all of which are industrially difficult to implement because a large amount of organic solvent is required.
[0003]
[Problems to be solved by the invention]
The reason why a large amount of organic solvent must be used in the above-mentioned known method is that the solubility of the raw material hydroxymethylimidazoles is low, which inevitably decreases the efficiency of the apparatus during the reaction, and further generates a reaction. A large amount of solvent is also required when washing and removing unreacted raw material hydroxymethylimidazoles from the target crystals obtained by filtering the liquid.
In order to avoid such difficulties, in the above (2), a method which is not very advantageous as an industrial production method in which the crystals separated by filtration are purified by sublimation under reduced pressure is used. May block or solidify.
Accordingly, there is a demand for development of a method for producing formylimidazoles by the manganese dioxide oxidation method, which can be carried out industrially advantageously without the above-mentioned drawbacks, and in which the final product does not cause blocking or solidification.
[0004]
[Means for Solving the Problems]
However, the present inventors have conducted intensive and extensive research results methyl alcohol or ethyl alcohol, hydroxymethyl imidazoles of the following general formula (a) if oxidation with manganese dioxide, by the following general formula (b) The inventors have found that the formylimidazoles shown can be produced advantageously, and have completed the present invention.
In other words, the present invention is characterized by the use of methyl alcohol or ethyl alcohol as the alcohol solvent. When the hydroxymethylimidazole is regarded as a kind of alcohol, the alcohol solvent is used for the reaction for oxidizing the hydroxymethyl group. Contrary to the expectation that the function as a solvent cannot be exhibited by oxidation, the present invention was made on the basis of the remarkable fact that the oxidation of the hydroxymethyl group occurs preferentially and the target product can be produced advantageously. Is.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The reaction of the present invention is represented by the following formula (1).
[Chemical 1]
[0006]
Here, R is hydrogen or an alkyl group having 1 to 5 carbon atoms, and the hydroxymethyl group may be bonded to any of the carbons at the 2nd, 4th and 5th positions.
Specific examples of the raw material used in the present invention include 4-hydroxymethyl imidazole, 2-hydroxymethyl imidazole, 1-methyl-5-hydroxymethyl imidazole and the like.
[0007]
In the present invention, in the oxidation reaction, it is essential to use methyl alcohol or ethyl alcohol as an alcohol solvent. By using such a solvent, the yield, purity and quality of the target product can be maintained high, and a special reaction apparatus is also used. Significant effects such as unnecessary are exhibited .
In addition , esters such as ethyl acetate, halogenated hydrocarbons such as ethylene dichloride, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane, nitriles such as acetonitrile, etc. within the scope of the present invention. Other organic solvents can be used in combination.
[0008]
The amount of alcohol solvent used is 5 to 30 times by weight, preferably 8 to 20 times by weight of hydroxymethylimidazoles, and if it is less than 5 times by weight, the desired formylimidazoles are likely to precipitate in the reaction system, Separation from manganese dioxide after completion of the reaction takes a great deal of labor. On the other hand, if it exceeds 30 times by weight, it becomes economically disadvantageous in terms of productivity and becomes impractical.
[0009]
Manganese dioxide used in the present invention is not particularly limited, and usually activated manganese dioxide or manganese sulfate solution is electrolyzed by subjecting commercially available manganese peroxide to a conventional activation treatment such as the Attenburrow method or the Mancera-Sondaheimer method. Any of the electrolytic manganese dioxide obtained in the above manner is used. Electrolytic manganese dioxide is advantageously used in the sense that the activation process can be saved. The particle size distribution of manganese dioxide is preferably 90% by weight or more with a particle size of 100 μm or less, and more preferably 90% by weight or more with 45 μm or less.
The amount of manganese dioxide to be used is 2 to 10 times mol, preferably 4 to 8 times mol, per mol of hydroxymethylimidazole as a raw material, and less than 2 times mol results in poor reactivity and yield of the desired product. When the amount exceeds 10 moles, by-products such as methyl ester are markedly produced, and the yield and quality are problematic.
[0010]
In carrying out the oxidation reaction, a reaction solvent, manganese dioxide, and raw material hydroxymethylimidazoles are supplied to the reactor.
The charging means to the reactor is arbitrary, and batch charging, split charging, continuous charging, dropping charging, etc. can be carried out, but batch charging is particularly advantageous.
[0011]
The reaction temperature may be any of 20 ° C. to reflux temperature, but usually 30 to 50 ° C. is appropriate, and the reaction time is 1 to 20 hours, preferably 2 to 10 hours. If the reaction temperature is too low, the reaction rate is slow, whereas if it is too high, by-products of impurities increase.
[0012]
After the oxidation reaction is completed, manganese dioxide dispersed in the reaction product solution is filtered off.
Since the formylimidazoles are dissolved in the filtrate, the alcohol solvent is distilled off to precipitate formylimidazole crystals. At this time, when the alcohol solvent is distilled off until the solids concentration of the filtrate is 25 to 45% by weight, preferably 30 to 40% by weight, only formylimidazoles are selectively precipitated and the unreacted raw material hydroxymethylimidazoles are Since the solution can be kept dissolved in the alcohol solvent, the target product can be isolated and purified at the same time. The precipitated crystals are separated by filtration to obtain crystals of the desired formylimidazoles. Further purification is performed if necessary.
The yield of the target product is 90% or more based on the raw material hydroxymethylimidazoles.
[0013]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples. “%” Is based on weight.
Example 1
4-Hydroxymethylimidazole (25.1 g, 0.254 mol) was dissolved in methyl alcohol (250 g), and this solution was charged into a 500 ml reaction vessel. Further, manganese dioxide (electrolytic manganese dioxide “HMH” manufactured by Tosoh Corporation), particle size distribution (94% of particles of 45 μm or less) was added and 125 g (1.43 mol) was added, and the oxidation reaction was carried out at 40 ° C. for 6 hours.
[0014]
After completion of the reaction, the system was cooled to 25 ° C., and manganese dioxide was filtered off from the reaction product solution. The manganese dioxide separated by filtration was washed twice with 50 g of methyl alcohol at room temperature, and the washing liquid and the filtrate were mixed. Then, 311 g of methyl alcohol was distilled off at 45 ° C. under a reduced pressure of 250 mmHg to obtain a solid concentration of 34.6%. A slurry liquid was prepared. After cooling the slurry to 20 ° C., the precipitated crystals were separated by filtration and dried to obtain 22.2 g of 4-formylimidazole crystals. It was a smooth powder with no blocking or the like.
The yield based on 4-hydroxymethylimidazole was 91%, and the purity was 99.8% (HPLC, measured at 260 nm, the same applies hereinafter).
As a result of infrared analysis and NMR analysis, 4-formylimidazole was confirmed.
[0015]
Example 2
The experiment was conducted according to the same example except that instead of 4-hydroxymethylimidazole in Example 1, 2-hydroxymethylimidazole was used as a raw material. 2-Formylimidazole (purity 99.7%) was obtained with a yield of 90.5%. There was no blocking at all.
As a result of infrared analysis and NMR analysis, it was confirmed to be 2-formylimidazole.
[0016]
Example 3
In Example 1, instead of methyl alcohol, ethyl alcohol was used and an experiment was conducted according to the same example. There were obtained 22.0 g of 4-formylimidazole crystals. It was a smooth powder with no blocking or the like. The yield based on 4-hydroxymethylimidazole was 90.1%, and the purity was 99.8%.
As a result of infrared analysis and NMR analysis, 4-formylimidazole was confirmed.
[0017]
Example 4
An experiment was conducted in the same manner as in Example 1 except that the amount of the methyl alcohol solvent was changed to 500 g, to obtain 22.3 g of 4-formylimidazole crystals. It was a smooth powder with no blocking or the like. The yield based on 4-hydroxymethylimidazole was 91.3%, and the purity was 99.8%.
As a result of infrared analysis and NMR analysis, 4-formylimidazole was confirmed.
[0018]
Example 5
28.3 g (0.25 mol) of 1-methyl-5-hydroxymethylimidazole was dissolved in 280 g of methyl alcohol, and this solution was charged into a reaction vessel having a capacity of 500 ml, and further manganese dioxide (electrolytic manganese dioxide “HMH” manufactured by Tosoh Corporation). The particle size distribution was 94% of particles having a particle size of 45 μm or less), 109 g (1.25 mol) was added, and an oxidation reaction was carried out at 40 ° C. for 8 hours.
After completion of the reaction, the same treatment as in Example 1 was performed to obtain a slurry liquid having a solid content concentration of 35%. After cooling the slurry to 20 ° C., the precipitated crystals were separated by filtration and dried to obtain 25.2 g of 1-methyl-5-formylimidazole crystals. It was a smooth powder with no blocking or the like. The yield based on 1-methyl-5 -hydroxymethylimidazole was 91.6%, and the purity was 99.7%.
As a result of infrared analysis and NMR analysis, it was confirmed to be 1-methyl-5-formylimidazole.
[0019]
Control Example 1
4-Hydroxymethylimidazole (25.1 g, 0.254 mol) was dissolved in 1250 g of dioxane, and this solution was charged into a reaction vessel having a capacity of 2000 ml. Further, manganese dioxide (electrolytic manganese dioxide “HMH” manufactured by Tosoh Corporation), particle size distribution: 45 μm The following particles were 94%) 66.4 g (0.76 mol) was added, and an oxidation reaction was carried out at 40 ° C. for 8 hours.
[0020]
After completion of the reaction, the system was cooled to 25 ° C., and manganese dioxide was filtered off from the reaction product solution. The filtered manganese dioxide was washed 5 times with 200 g of dioxane at 55 ° C., and the washing solution and the filtrate were mixed. Then, dioxane was distilled off at 50 ° C. under a reduced pressure of 140 mmHg, and then suspended in 200 ml of ethyl acetate. After cooling to ° C., the precipitated crystals were separated by filtration. The filtered 4-formylimidazole was washed with 90 ml of ethyl acetate to obtain 19.6 g of the desired product. The yield based on 4-hydroxymethylimidazole was 80.5%, and the purity was 98.9%.
As a result of infrared analysis and NMR analysis, 4-formylimidazole was confirmed.
[0021]
【The invention's effect】
In the present invention, when producing formylimidazoles such as 4-formylimidazole useful as a raw material for pharmaceuticals such as diuretics and antihypertensive agents by the oxidation method of hydroxymethylimidazoles with manganese dioxide , methyl alcohol is used as an alcohol solvent. Alternatively, by using ethyl alcohol , it is possible to produce formylimidazoles having high purity and high industrial yield without causing blocking or solidification.
Claims (3)
上記一般式(a)中のヒドロキシメチル基、一般式(b)中のホルミル基は、2位、4位、5位の炭素いずれに結合していてもよい。A method for producing a formylimidazole represented by the following general formula (b) in which a hydroxymethylimidazole represented by the following general formula (a) is oxidized using manganese dioxide in an alcohol solvent. Alternatively, a method for producing formylimidazoles using ethyl alcohol.
The hydroxymethyl group in the general formula (a) and the formyl group in the general formula (b) may be bonded to any of the carbons at the 2-position, 4-position, and 5-position.
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