JPH0233033B2 - - Google Patents
Info
- Publication number
- JPH0233033B2 JPH0233033B2 JP55126084A JP12608480A JPH0233033B2 JP H0233033 B2 JPH0233033 B2 JP H0233033B2 JP 55126084 A JP55126084 A JP 55126084A JP 12608480 A JP12608480 A JP 12608480A JP H0233033 B2 JPH0233033 B2 JP H0233033B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- compound
- formula
- urea
- temperature
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- 239000004202 carbamide Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229960000458 allantoin Drugs 0.000 claims description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940015043 glyoxal Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 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-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- KFKXSMSQHIOMSO-UHFFFAOYSA-N methyl 2-oxoacetate Chemical compound COC(=O)C=O KFKXSMSQHIOMSO-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 150000005311 thiohalides Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Description
【発明の詳細な説明】
本発明は、次式
で表わされる５―ウレイドヒダントインの新規な
製法に関する。[Detailed Description of the Invention] The present invention is based on the following formula This invention relates to a new method for producing 5-ureidohydantoin represented by
式の化合物及びそのアルミニウム誘導体は顕
著な細胞賦活作用及び細胞増殖作用を有し、副作
用のない潰瘍治療剤及び予防剤として重要な医薬
品である。 The compound of the formula and its aluminum derivatives have remarkable cell activating and cell proliferating effects, and are important pharmaceutical agents as ulcer treatment and prevention agents without side effects.
式の化合物の製法としては、例えばグリオキ
サールを硝酸酸化してグリオキシル酸となし、こ
の酸よりも酸度の強い酸を触媒として温度65〜95
℃で尿素と反応させる方法（特公昭46―2095号公
報参照）、グリオキサールを硫酸酸化して得られ
るグリオキシル酸又はそのアルカリ金属塩水溶液
に鉱酸を加えて予め温度50〜100℃において20〜
120分間加熱処理したのち、尿素と反応させる方
法（特公昭50―11918号公報参照）等が知られて
いる。しかし、これらの方法では、グリオキサー
ルを酸化して得られるグリオキシル酸を工業的に
精製することは不可能に近く、酸化副生物及び未
反応物を含んだまま原料として使用せざるをえな
いため、目的を純品として得ることは極めて困難
である。また、反応条件範囲が非常に狭く、工業
的方法においての調整は至難である。 For example, glyoxal is oxidized with nitric acid to produce glyoxylic acid, and an acid with stronger acidity than this acid is used as a catalyst to produce the compound of the formula at a temperature of 65 to 95%.
A method in which glyoxal is reacted with urea at a temperature of 50 to 100 degrees Celsius (see Japanese Patent Publication No. 46-2095).
A method is known in which the material is heated for 120 minutes and then reacted with urea (see Japanese Patent Publication No. 11918/1983). However, with these methods, it is almost impossible to industrially purify glyoxylic acid obtained by oxidizing glyoxal, and it has to be used as a raw material containing oxidized by-products and unreacted substances. It is extremely difficult to obtain the intended purpose as a pure product. Furthermore, the range of reaction conditions is very narrow, making adjustment in industrial methods extremely difficult.
本発明者は、従来法の欠点を解決し、工業化容
易な製法を開発するため種々研究を重ねた結果、
一般式
OHC―COOR ……
（式中Ｒはアルキル基を示す）で表わされる化
合物を縮合剤の存在下で尿素と反応させることに
より式の目的化合物が高純度で収率よく得られ
ることを見出した。 The inventor of the present invention has conducted various researches in order to solve the drawbacks of conventional methods and develop a manufacturing method that is easy to industrialize.
It has been discovered that by reacting a compound represented by the general formula OHC-COOR (in which R represents an alkyl group) with urea in the presence of a condensing agent, the target compound of the formula can be obtained with high purity and good yield. Ta.
出発物質である式の化合物は、近年修酸エス
テル類を還元することにより容易に製造でき、再
結晶などの精製方法により高純度のものを得るこ
とができる。式の化合物の置換基Ｒのためのア
ルキル基としては、メチル基、エチル基、プロピ
ル基、ブチル基等があげられる。縮合剤として
は、酸好ましくは鉱酸例えば塩酸、硫酸、硝酸等
チオハライド例えばクロルスルフオン酸、メタン
スルフオン酸クロリド、ベンゼンスルフオン酸ク
ロリド、塩化チオニル、塩化スルフリル等、無機
アルカリ例えば苛性カリ、苛性ソーダ、炭酸カリ
ウム、炭酸水素ナトリウム等、アルコラート例え
ばナトリウムメチラート、ナトリウムエチラート
等を用いることができる。 The compound of the formula, which is a starting material, can be easily produced by reducing oxalate esters in recent years, and can be obtained with high purity by purification methods such as recrystallization. Examples of the alkyl group for the substituent R in the compound of formula include methyl group, ethyl group, propyl group, butyl group, and the like. Condensing agents include acids, preferably mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, thiohalides such as chlorosulfonic acid, methanesulfonic acid chloride, benzenesulfonic acid chloride, thionyl chloride, sulfuryl chloride, inorganic alkalis such as caustic potash, caustic soda, Potassium carbonate, sodium hydrogen carbonate, etc., alcoholates such as sodium methylate, sodium ethylate, etc. can be used.
これらの縮合剤の使用量は、式の化合物１当
量に対して0.5〜4.0当量の範囲が好ましい。 The amount of these condensing agents used is preferably in the range of 0.5 to 4.0 equivalents per equivalent of the compound of the formula.
本発明を実施するに際しては、好ましくは溶媒
の存在下に式の化合物と尿素を反応させる。 In practicing the invention, a compound of formula and urea are reacted, preferably in the presence of a solvent.
溶媒としては、水又はアルコール類、グリコー
ル類、アセトニトリル、ジメチルホルムアミド等
の極性溶媒が好ましい。 As the solvent, water or polar solvents such as alcohols, glycols, acetonitrile, and dimethylformamide are preferred.
反応温度は反応混合物の沸騰温度以下、好まし
くは、55〜85℃であり、数十分ないし十数時間で
反応が終了する。反応の進行は、目的物が析出
し、白濁することにより確認できる。 The reaction temperature is below the boiling temperature of the reaction mixture, preferably 55 to 85°C, and the reaction is completed in several tens of minutes to more than ten hours. Progress of the reaction can be confirmed by precipitation of the target product and cloudiness.
実施例 １
グリオキシル酸メチルエステル8.8g及び尿素
18.0gを水―エタノール（２：１）60mlに溶解し、
次いで35％純塩酸20mlを加えて水浴上でゆるやか
に還流する。１時間を経過するころより内液が白
濁しはじめ、次第に結晶が増大していく。Example 1 8.8g glyoxylic acid methyl ester and urea
Dissolve 18.0g in 60ml of water-ethanol (2:1),
Next, add 20 ml of 35% pure hydrochloric acid and gently reflux on a water bath. After 1 hour, the internal fluid begins to become cloudy and the crystals gradually increase.
約４時間反応させたのち、内温を室温まで冷却
し、析出した結晶を取する。この結晶を再結晶
することなくそのまま乾燥すると、目的物11.8g
（収率約74.7％）が得られる。 After reacting for about 4 hours, the internal temperature was cooled to room temperature and the precipitated crystals were collected. When these crystals are dried as they are without recrystallization, 11.8g of the target product is obtained.
(yield about 74.7%).
融点：224℃（分解）
元素分析値：C4H6O3N4＝158.1として
Ｃ Ｈ Ｎ
実測値（％） 30.28 3.77 35.39
理論値（％） 30.39 3.82 35.43
純度（Ｎ定量法）：99.8％
赤外部吸収スペクトル
νKBr naxcm-1：3450、3350、3050、1780、1660、
1540、1180
実施 ２
尿素15gを水80mlに溶解し、水浴上で75〜80℃
に加温する。次いでグリオキシル酸エチルエステ
ル10g及び微粉末炭酸カリウム14gを加え、約６
時間、同温度に加温し、撹拌する。以下実施例１
と同様に処理すると、同一化合物12g（収率約76
％）が得られる。 Melting point: 224℃ (decomposition) Elemental analysis value: C 4 H 6 O 3 N 4 = 158.1 C H N Actual value (%) 30.28 3.77 35.39 Theoretical value (%) 30.39 3.82 35.43 Purity (N quantitative method): 99.8% Infrared absorption spectrum ν KBr nax cm -1 : 3450, 3350, 3050, 1780, 1660,
1540, 1180 Implementation 2 Dissolve 15g of urea in 80ml of water and heat at 75-80℃ on a water bath.
Warm to. Next, 10 g of glyoxylic acid ethyl ester and 14 g of finely powdered potassium carbonate were added, and about 6
Heat to the same temperature for an hour and stir. Example 1 below
When treated in the same manner as above, 12g of the same compound (yield approx. 76
%) is obtained.
実施例 ３
グリオキシル酸エチルエステル10g中に、クロ
ルスルホン酸23.2gを極めてゆつくりと滴下する。
滴下終了後、尿素18gを粉末状態のまま加えたの
ち、約30分間60〜70℃に加温し、撹拌する。以下
実施例１と同様に処理すると、同一化合物11.3g
（収率約71.5％）が得られる。Example 3 23.2 g of chlorosulfonic acid is added dropwise very slowly into 10 g of glyoxylic acid ethyl ester.
After dropping, add 18 g of urea in powder form, then heat to 60-70°C for about 30 minutes and stir. When treated in the same manner as in Example 1, 11.3g of the same compound was obtained.
(yield about 71.5%).
Claims (1)
合物を縮合剤の存在下で尿素と反応させることを
特徴とする、次式 で表わされる５―ウレイドヒダントインの製法。[Claims] 1. A compound represented by the general formula OHC-COOR (in the formula, R represents an alkyl group), which is characterized by reacting with urea in the presence of a condensing agent, A method for producing 5-ureidohydantoin represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12608480A JPS5750970A (en) | 1980-09-12 | 1980-09-12 | Preparation of 5-ureidohydantoin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12608480A JPS5750970A (en) | 1980-09-12 | 1980-09-12 | Preparation of 5-ureidohydantoin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5750970A JPS5750970A (en) | 1982-03-25 |
| JPH0233033B2 true JPH0233033B2 (en) | 1990-07-25 |
Family
ID=14926201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12608480A Granted JPS5750970A (en) | 1980-09-12 | 1980-09-12 | Preparation of 5-ureidohydantoin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5750970A (en) |
-
1980
- 1980-09-12 JP JP12608480A patent/JPS5750970A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5750970A (en) | 1982-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102266680B1 (en) | Polymorphic Forms of Belinostet and Methods of Making It | |
| JPH05208978A (en) | Method for aroylating 5-position of 1,2-dihydro-3h-pyrrolo(1,2-alpha)pyrrole-1-carboxyic ester | |
| EP0000200B1 (en) | New n-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same | |
| US5498711A (en) | Synthesis of 4,10-dinitro-2,6,8,12-tetraoxa-4,10-diazatetracyclo[5.5.0.05,903,11]dodecane | |
| JPH0233033B2 (en) | ||
| JPS61293963A (en) | 1-cycloalkene-1-carboxyamide derivative,sulfoxide thereof, manufacture and use | |
| US20060142595A1 (en) | Process for preparing 5,6-dihydro-4-(S)-(ethylamino)-6-(S) methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide HCI | |
| JPH0233034B2 (en) | ||
| Caldwell et al. | The synthesis of some trifluoromethyl derivatives of p-aminobenzoic acid, sulfanilamide and p, p'-diamino diphenyl sulfone | |
| JP3259206B2 (en) | Method for producing 2-substituted benzo [b] thiophene | |
| US4080505A (en) | α-Chlorocarboxylic acids | |
| JPH0522709B2 (en) | ||
| KR910002282B1 (en) | Process for the preparation of inden acetic acid | |
| EP0713865A1 (en) | 2-Aminobenzenesulphonic acid and 2-aminobenzenesulphonyl chloride derivatives, their preparation and their use as synthetic intermediates | |
| JPS6210500B2 (en) | ||
| JPS584698B2 (en) | Method for producing 2-(3-benzoylphenyl)propionic acid | |
| US4402875A (en) | Substituted teraselenafulvalenes and high pressure synthesis thereof | |
| KR810000802B1 (en) | Preparing process for 4-benzoyl pyrazol derivatives and its aluminum salts | |
| RU2039046C1 (en) | Process for preparing 5-bromonicotinic acid | |
| JPS6051180A (en) | Preparation of 1,2,4-triazolin-5-one | |
| CN115093399A (en) | Preparation method of anti-gout drug topiroxostat | |
| JPS6026395B2 (en) | Synthesis method of N-trialkylsilylmethylurea | |
| SU497766A3 (en) | Method for producing amino derivatives of 1,2-diphenyl-1,1,2.2-tetrafluoroethane | |
| JPS6117822B2 (en) | ||
| JPS6344552A (en) | 2,6-dichloro-3,4-dinitroethylbenzene and production thereof |