JP4699582B2 - Method for producing 1H-4 (5) -aminoimidazole-5 (4) -carboxamide - Google Patents
Method for producing 1H-4 (5) -aminoimidazole-5 (4) -carboxamide Download PDFInfo
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- JP4699582B2 JP4699582B2 JP33010399A JP33010399A JP4699582B2 JP 4699582 B2 JP4699582 B2 JP 4699582B2 JP 33010399 A JP33010399 A JP 33010399A JP 33010399 A JP33010399 A JP 33010399A JP 4699582 B2 JP4699582 B2 JP 4699582B2
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- aqueous solution
- carboxamide
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Links
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- JOWVYROMILUUHH-UHFFFAOYSA-N n'-(2-amino-1,2-dicyanoethenyl)methanimidamide Chemical compound NC=NC(C#N)=C(N)C#N JOWVYROMILUUHH-UHFFFAOYSA-N 0.000 claims description 3
- 150000007514 bases Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 1
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical compound NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 description 18
- 210000005097 arteria cerebelosa anteroinferior Anatomy 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- DPZSNGJNFHWQDC-ARJAWSKDSA-N (z)-2,3-diaminobut-2-enedinitrile Chemical compound N#CC(/N)=C(/N)C#N DPZSNGJNFHWQDC-ARJAWSKDSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- WAKHKSLIDJTOKC-UHFFFAOYSA-N ethyl n-(2-amino-1,2-dicyanoethenyl)methanimidate Chemical compound CCOC=NC(C#N)=C(N)C#N WAKHKSLIDJTOKC-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- MXCUYSMIELHIQL-UHFFFAOYSA-N (4-carbamoyl-1h-imidazol-5-yl)azanium;chloride Chemical compound Cl.NC(=O)C=1NC=NC=1N MXCUYSMIELHIQL-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 1
- JRWAUKYINYWSTA-UHFFFAOYSA-N 2-amino-2-cyanoacetamide Chemical compound N#CC(N)C(N)=O JRWAUKYINYWSTA-UHFFFAOYSA-N 0.000 description 1
- DUTJFFGOOSJANZ-UHFFFAOYSA-N 2-phenyldiazenylpropanediimidamide Chemical compound NC(=N)C(C(N)=N)N=NC1=CC=CC=C1 DUTJFFGOOSJANZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JGRWIMRUWDIMOX-DKWTVANSSA-N 4-amino-1h-imidazole-5-carboxamide;(2s)-2-(carbamoylamino)butanedioic acid Chemical compound NC(=O)C=1NC=NC=1N.NC(=O)N[C@H](C(O)=O)CC(O)=O JGRWIMRUWDIMOX-DKWTVANSSA-N 0.000 description 1
- YJHHUXIIKAYKJJ-UHFFFAOYSA-N 4-nitro-1h-imidazole-5-carboxamide Chemical compound NC(=O)C=1NC=NC=1[N+]([O-])=O YJHHUXIIKAYKJJ-UHFFFAOYSA-N 0.000 description 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 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
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬の中間体として有用な１Ｈ−４（５）−アミノイミダゾール−５（４）−カルボキサミドの簡便で効率のよい製造方法に関する。
【０００２】
【従来の技術】
１Ｈ−４（５）−アミノイミダゾール−５（４）−カルボキサミド（以下ＡＩＣＡと略す）及びその塩酸塩は医薬の有用な中間体であり、例えば抗がん剤ダカルバジン（ｄａｃａｒｂａｚｉｎｅ）及びテモゾロミド（ｔｅｍｏｚｏｒｏｍｉｄｅ）、肝臓保護薬ウラザミド（ｕｒａｚａｍｉｄｅ）の原料として知られている。
【０００３】
その合成方法としては、例えば、４−ニトロイミダゾールー５−カルボキサミドを接触還元する方法、フェニルアゾマロンアミジンを蟻酸中で還元閉環する方法、α―アミノーα―シアノアセトアミドを原料とする方法、プリン核を有する化合物を分解する方法があるが原料的、操作的に工業的には不満足なものである。
また、工業原料として利用しうるジアミノマレオニトリル（本文中以下ＤＡＭＮと略す）から４、５-ジシアノイミダゾールを合成(特公昭４６−４３７３)し、水和反応（特公昭４１−２１０２６)して１Ｈ−４（５）−シアノイミダゾール−５（４）−カルボキサミドを合成、ホフマン転移反応を用いて１Ｈ−４（５）−アミノイミダゾール−５（４）−カルボニトリル（本文中以下ＡＩＣＮと略す）に変換(特公昭４６−１０８８９)した後、水和反応でＡＩＣＡを合成する方法があるがホフマン転移反応の収率が低く工程数も多く、目的物の収率が低い問題がある。
【０００４】
更に、Ｂ．Ｌ．Ｂｏｏｔｈ等（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ Ｔｒａｎｓ．Ｉ，１９９０，１７０５）は、Ｎ−(２−アミノ−１，２−ジシアノビニル) ホルムアミジン（本文中以下ＡＭＤと略す）を閉環してＡＩＣＮを合成しているがＡＩＣＡは得ていない。
【０００５】
【発明が解決しようとする課題】
以上述べたように、ＡＭＤからＡＩＣＡの様なイミダゾール体を合成した例は報告されていない。
本発明は、ＡＩＣＡを効率よく製造する新規な製造方法である。
【０００６】
【課題を解決するための手段】
本発明は、ＡＭＤを塩基性水溶液中で環化、加水分解して、ＡＩＣＡを製造する方法である。
【０００７】
即ち、本発明は、ＡＭＤを塩基性水溶液中で環化、加水分解を行うことを特徴とするＡＩＣＡの製造方法であり、更に、塩基性水溶液が、水酸化ナトリウム又は水酸化カリウムの水溶液であることを特徴とするＡＩＣＡの製造方法である。
本発明の反応式を参考のために示すと次の通りである。
【化１】
【発明の実施の形態】
ＡＭＤの環化反応及び加水分解反応は、ＡＭＤ１モルあたり、０．５〜１０ｌの水を加え、１〜１０当量、好ましくは２〜８当量の塩基性化合物を用いて、１〜４８時間反応行う。ＡＭＤは、塩の状態、例えば塩酸塩の状態で反応系に添加することもできる。反応温度は、反応時間とも関係するが、室温〜還流温度の範囲で行われる。この場合、用いる塩基の濃度を低くし、反応時間を短くし、反応温度を低く選択すると、反応が十分完結しないで、ＡＩＣＡの前駆体であるＡＩＣＮが多量に生成する場合がある。反応完了後、水溶液を室温まで冷却し、溶媒で抽出するか反応液を中和した後に水を留去して溶媒で抽出して、充分な純度のＡＩＣＡを得ることができる。反応完結後、室温まで冷却しｐＨを７に調整を行う前、活性炭等を用いて後処理すると、得られる結晶の純度を向上させ、又は着色を防止ができる。
【０００９】
本発明に使用される、塩基性水溶液は、塩基性を呈する化合物の水溶液であれば特に制限されず、具体的には水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム、水酸化アルミニウム等のアルカリ金属、又はアルカリ土類金属水酸化物、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸マグネシウム等の炭酸塩等の水溶液を例示することができるが、特に水酸化ナトリウム、水酸化カリウムの水溶液が好ましい。
塩基性水溶液の量は用いられるＡＭＤの量に対して当量を超えているのが望ましく、当量以下であると毒性ガスが発生する場合があり、溶媒として用いる場合は大過剰用いる。反応は通常０℃〜２００℃の範囲で行われ、特に室温から還流温度の範囲で行うのが好ましい。
【００１０】
多くの場合、反応生成物は系中に溶解しており、溶媒で抽出するか反応液を中和した後に水を留去して溶媒で抽出してＡＩＣＡが得られる。必要に応じて、これを非水溶媒に溶解し塩酸ガス或いは濃塩酸を加えればＡＩＣＡの塩酸塩が析出し濾過によりこの塩酸塩を単離する事ができる。
生成するＡＩＣＡの塩は、用いる酸で一義的に決まるが、塩を中和後、別の酸を加え、また直接塩交換を行い様々の塩を合成することができる。ＡＩＣＡは、結晶として得られた塩を中和することによっても得ることができる。
【００１１】
一方、原料化合物として本発明に用いられるＡＭＤは、公知の方法で、ＤＡＭＮから容易に合成することができる。例えばＤＡＭＮとホルムアミジン酢酸塩との反応による方法、ＤＡＭＮとオルト蟻酸エステルから合成されるＮ−(２−アミノ−１，２−ジシアノビニル) ホルムイミデートとアンモニアとの反応による方法がある（Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ Ｔｒａｎｓ．Ｉ，１９９０，１７０５）。
【化２】
以下、実施例により本発明を詳細に説明するが、本発明の範囲は実施例に限定されるものではない。
【００１３】
【実施例】
実施例1 （ＡＤＭからＡＩＣＡの合成）
ＡＭＤ８．０ｇに水５０ｍｌと２５％ＮａＯＨ水溶液４３．０ｇを加え、２時間還流下反応した。この水溶液を室温下まで冷却し、３５％塩酸を加えてｐＨを7に調製した。反応液を減圧下で濃縮乾固した後エタノールを加え不溶物の食塩を濾別した。濾液を活性炭処理後濃縮し、ＡＩＣＡのエタノール溶液を得た。これに３５％塩酸を加えてｐＨを３以下にして１０℃以下まで冷却しここで生成した結晶を濾別した。この結晶を乾燥して８．１ｇのＡＩＣＡ塩酸塩を得た。(収率８４％)
融点：２５０〜２５２℃（分解）
【００１４】
参考例１ （ＤＡＭＮから原料ＡＭＤの合成）
ジオキサン３００ｍｌにＤＡＭＮ２０．０ｇ、オルト蟻酸トリエチル３０．２ｇを加え、還流温度で９０分間加熱した。蒸留により、ジオキサンとエタノールの混合物を２３０ｍｌ留出させた後、反応液を室温まで冷却しｎ−ヘキサン２００ｍｌを加えて３℃まで冷却した。析出した結晶を濾別しｎ−ヘキサンで洗浄した。結晶をジエチルエーテルから再結晶、乾燥して２４．５ｇのエチルＮ−(２−アミノ−１，２−ジシアノビニル) ホルムイミデートを得た。(収率８１％) 融点：１３４〜１３５℃
【００１５】
クロロホルム３００ｍｌに、エチルＮ−(２−アミノ−１，２−ジシアノビニル) ホルムイミデート１３．０ｇ、アニリン塩酸塩０．０３３ｇを加え４℃まで冷却した。温度を４〜５℃を維持しながら攪拌下に３時間でアンモニア２４．０ｇを吹き込んだ。温度を室温まで上げ、６６時間攪拌した。析出した結晶を濾別、クロロホルムで洗浄後、乾燥してＡＭＤを９．１ｇ得た。(収率８５％)
融点：３００℃以上
【００１６】
【発明の効果】
以上、述べたように本発明の方法を用いれば、（１）ＤＡＭＮ（ジアミノマレオニトリル）から工業的に容易に合成可能なＡＭＤ（Ｎ−(２−アミノ−１，２−ジシアノビニル) ホルムアミジン）を原料として使用することができ、（２）短工程でしかも簡便な後処理操作で収率よくＡＩＣＡ（１Ｈ−４（５）−アミノイミダゾール−５（４）−カルボキサミド）を充分な純度をもって合成することができる。従って、本発明の方法は、工業的な生産方法として好適である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a simple and efficient method for producing 1H-4 (5) -aminoimidazole-5 (4) -carboxamide useful as a pharmaceutical intermediate.
[0002]
[Prior art]
1H-4 (5) -aminoimidazole-5 (4) -carboxamide (hereinafter abbreviated as AICA) and its hydrochloride are useful intermediates in medicine, for example, the anticancer drugs dacarbazine and temozolomide. It is known as a raw material for the hepatoprotective drug urazamide.
[0003]
The synthesis method includes, for example, a method of catalytic reduction of 4-nitroimidazole-5-carboxamide, a method of reductive ring closure of phenylazomalonamidine in formic acid, a method using α-amino-α-cyanoacetamide as a raw material, a purine nucleus Although there is a method for decomposing a compound having a chemical compound, it is unsatisfactory industrially in terms of raw materials and operation.
In addition, 4,5-dicyanoimidazole was synthesized from diaminomaleonitrile (hereinafter abbreviated as DAMN), which can be used as an industrial raw material (Japanese Examined Patent Publication No. Sho 46-4373), and hydrated (Japanese Examined Publication No. Sho 41-21026) to produce 1H. -4 (5) -Cyanoimidazole-5 (4) -carboxamide was synthesized into 1H-4 (5) -aminoimidazole-5 (4) -carbonitrile (hereinafter abbreviated as AICN) using the Hofmann rearrangement reaction. After conversion (Japanese Examined Patent Publication No. 46-10889), there is a method of synthesizing AICA by a hydration reaction, but there are problems that the yield of the Hoffmann rearrangement reaction is low and the number of steps is large, and the yield of the target product is low.
[0004]
Further, B.I. L. Booth et al. (J. Chem. Soc. Perkin Trans. I, 1990, 1705) closed N- (2-amino-1,2-dicyanovinyl) formamidine (hereinafter abbreviated as AMD) to form AICN. Synthesized but not AICA.
[0005]
[Problems to be solved by the invention]
As described above, no example of synthesizing an imidazole form such as AICA from AMD has been reported.
The present invention is a novel production method for efficiently producing AICA.
[0006]
[Means for Solving the Problems]
The present invention is a method for producing AICA by cyclizing and hydrolyzing AMD in a basic aqueous solution.
[0007]
That is, the present invention is an AICA production method characterized in that AMD is cyclized and hydrolyzed in a basic aqueous solution, and the basic aqueous solution is an aqueous solution of sodium hydroxide or potassium hydroxide. An AICA manufacturing method characterized by the above.
The reaction formula of the present invention is shown for reference as follows.
[Chemical 1]
DETAILED DESCRIPTION OF THE INVENTION
The cyclization reaction and hydrolysis reaction of AMD are carried out for 1 to 48 hours by adding 0.5 to 10 l of water per 1 mol of AMD and using 1 to 10 equivalents, preferably 2 to 8 equivalents of a basic compound. . AMD can also be added to the reaction system in the form of a salt, such as the hydrochloride. Although reaction temperature is related also with reaction time, it is performed in the range of room temperature-reflux temperature. In this case, if the concentration of the base used is lowered, the reaction time is shortened, and the reaction temperature is selected to be low, the reaction may not be completed sufficiently, and AICA, which is a precursor of AICA, may be produced in a large amount. After completion of the reaction, the aqueous solution is cooled to room temperature and extracted with a solvent or the reaction solution is neutralized, and then water is distilled off and extracted with a solvent to obtain AICA with sufficient purity. After the completion of the reaction, before cooling to room temperature and adjusting the pH to 7, post-treatment using activated carbon or the like can improve the purity of the crystals obtained or prevent coloring.
[0009]
The basic aqueous solution used in the present invention is not particularly limited as long as it is an aqueous solution of a compound exhibiting basicity. Specifically, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, aluminum hydroxide Examples of the alkali metal such as alkali metal or alkaline earth metal hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, magnesium carbonate and the like aqueous solution, particularly sodium hydroxide, An aqueous solution of potassium hydroxide is preferred.
It is desirable that the amount of the basic aqueous solution exceeds the equivalent with respect to the amount of AMD to be used, and if it is less than the equivalent, toxic gas may be generated. The reaction is usually carried out in the range of 0 ° C. to 200 ° C., particularly preferably in the range of room temperature to reflux temperature.
[0010]
In many cases, the reaction product is dissolved in the system, and after extracting with a solvent or neutralizing the reaction solution, water is distilled off and extraction with a solvent is performed to obtain AICA. If necessary, if this is dissolved in a non-aqueous solvent and hydrochloric acid gas or concentrated hydrochloric acid is added, the hydrochloride of AICA precipitates, and this hydrochloride can be isolated by filtration.
The salt of AICA to be produced is uniquely determined by the acid used, but after neutralizing the salt, another acid can be added and direct salt exchange can be performed to synthesize various salts. AICA can also be obtained by neutralizing the salt obtained as crystals.
[0011]
On the other hand, AMD used in the present invention as a raw material compound can be easily synthesized from DAMN by a known method. For example, there is a method by a reaction of DAMN and formamidine acetate, and a method by a reaction of N- (2-amino-1,2-dicyanovinyl) formimidate synthesized from DAMN and orthoformate ester (J Chem. Soc. Perkin Trans. I, 1990, 1705).
[Chemical 2]
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, the scope of the present invention is not limited to an Example.
[0013]
【Example】
Example 1 (Synthesis of AICA from ADM)
To 8.0 g of AMD, 50 ml of water and 43.0 g of 25% NaOH aqueous solution were added and reacted under reflux for 2 hours. The aqueous solution was cooled to room temperature, and 35% hydrochloric acid was added to adjust the pH to 7. The reaction solution was concentrated to dryness under reduced pressure, ethanol was added, and insoluble sodium chloride was filtered off. The filtrate was treated with activated carbon and concentrated to obtain an ethanol solution of AICA. 35% hydrochloric acid was added thereto to adjust the pH to 3 or less, and the solution was cooled to 10 ° C. or less, and the produced crystals were separated by filtration. The crystals were dried to obtain 8.1 g of AICA hydrochloride. (Yield 84%)
Melting point: 250-252 ° C. (decomposition)
[0014]
Reference Example 1 (Synthesis of raw material AMD from DAMN)
To 300 ml of dioxane, 20.0 g of DAMN and 30.2 g of triethyl orthoformate were added and heated at reflux temperature for 90 minutes. After distilling 230 ml of a mixture of dioxane and ethanol by distillation, the reaction solution was cooled to room temperature, 200 ml of n-hexane was added, and the mixture was cooled to 3 ° C. The precipitated crystals were separated by filtration and washed with n-hexane. The crystals were recrystallized from diethyl ether and dried to obtain 24.5 g of ethyl N- (2-amino-1,2-dicyanovinyl) formimidate. (Yield 81%) Melting point: 134-135 ° C
[0015]
Ethyl N- (2-amino-1,2-dicyanovinyl) formimidate (13.0 g) and aniline hydrochloride (0.033 g) were added to 300 ml of chloroform, and the mixture was cooled to 4 ° C. While maintaining the temperature at 4 to 5 ° C., 24.0 g of ammonia was blown in with stirring for 3 hours. The temperature was raised to room temperature and stirred for 66 hours. The precipitated crystals were separated by filtration, washed with chloroform, and dried to obtain 9.1 g of AMD. (Yield 85%)
Melting point: 300 ° C or higher
【The invention's effect】
As described above, by using the method of the present invention, (1) AMD (N- (2-amino-1,2-dicyanovinyl) formamidine which can be easily synthesized industrially from DAMN (diaminomaleonitrile) ) Can be used as a raw material, and (2) AICA (1H-4 (5) -aminoimidazole-5 (4) -carboxamide) is sufficiently purified in a short process and in a simple post-treatment operation with a high yield. Can be synthesized. Therefore, the method of the present invention is suitable as an industrial production method.
Claims (2)
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33010399A JP4699582B2 (en) | 1999-11-19 | 1999-11-19 | Method for producing 1H-4 (5) -aminoimidazole-5 (4) -carboxamide |
| CNB2003101214353A CN1238338C (en) | 1999-09-20 | 2000-09-20 | Process for the preparation of 4(5)-amino-5(4)carboxamidoimidoimidazoles and intermediates thereof |
| DE60029803T DE60029803T2 (en) | 1999-09-20 | 2000-09-20 | PROCESS FOR THE PREPARATION OF 4 (5) -AMINO-5 (4) -CARBOXAMIDOIMIDAZOLENES AND THEIR INTERMEDIATE PRODUCTS |
| CNB008131155A CN1150169C (en) | 1999-09-20 | 2000-09-20 | Process for the preparation of 4(5)-amino-5(4) carboxamidoimidazoles and intermediates thereof |
| KR10-2002-7003643A KR100538958B1 (en) | 1999-09-20 | 2000-09-20 | Processes for the preparation of 4(5)-amino-5(4)-carboxamidoimidazoles and intermediates thereof |
| AT00961096T ATE334972T1 (en) | 1999-09-20 | 2000-09-20 | METHOD FOR THE PRODUCTION OF 4(5)-AMINO-5(4)-CARBOXAMIDOIMIDAZOLE AND THEIR INTERMEDIATE PRODUCTS |
| US10/088,425 US6797828B1 (en) | 1999-09-20 | 2000-09-20 | Processes for the preparation of 4(5)-amino-5(4)-carboxamidoimidazoles and intermediates thereof |
| PCT/JP2000/006397 WO2001021592A1 (en) | 1999-09-20 | 2000-09-20 | Processes for the preparation of 4(5)-amino-5(4)-carboxamidoimidazoles and intermediates thereof |
| EP00961096A EP1215206B1 (en) | 1999-09-20 | 2000-09-20 | Processes for the preparation of 4(5)-amino-5(4)-carboxamidoimidazoles and intermediates thereof |
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|---|---|---|---|
| JP33010399A JP4699582B2 (en) | 1999-11-19 | 1999-11-19 | Method for producing 1H-4 (5) -aminoimidazole-5 (4) -carboxamide |
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| JP2001151760A JP2001151760A (en) | 2001-06-05 |
| JP4699582B2 true JP4699582B2 (en) | 2011-06-15 |
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| KR101161602B1 (en) | 2007-04-19 | 2012-07-03 | 닛뽕소다 가부시키가이샤 | Method for production of n-(2-amino-1,2-dicyanovinyl)formamidine |
| JP5112737B2 (en) * | 2007-04-19 | 2013-01-09 | 日本曹達株式会社 | Method for producing aminoimidazole derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS511467A (en) * | 1974-06-19 | 1976-01-08 | Kyowa Gas Chem Ind Co Ltd | 44 aminoimidazooru 55 karuhonitoriruto 44 aminoimidazooru 55 karubokishiamidono bunrihoho |
| JPS5283750A (en) * | 1976-01-01 | 1977-07-12 | Ajinomoto Co Inc | Crystals of 5-amino-4-imidazol-carboxyamide |
-
1999
- 1999-11-19 JP JP33010399A patent/JP4699582B2/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS511467A (en) * | 1974-06-19 | 1976-01-08 | Kyowa Gas Chem Ind Co Ltd | 44 aminoimidazooru 55 karuhonitoriruto 44 aminoimidazooru 55 karubokishiamidono bunrihoho |
| JPS5283750A (en) * | 1976-01-01 | 1977-07-12 | Ajinomoto Co Inc | Crystals of 5-amino-4-imidazol-carboxyamide |
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