JP4497572B2 - Process for producing 13C-containing urea - Google Patents

Description

【０００７】
［式中Ｒ¹、Ｒ²、Ｒ³及びＲ⁴はそれぞれ水素原子又は低級アルキル基を示す。Ｃ^*は¹³Ｃを示す。］
で表わされる環状カーボネート誘導体とアンモニアとを反応させることを特徴とする¹³Ｃ含有尿素の製造法に係る。
【０００８】
【発明の実施の形態】
本明細書において、低級アルキル基としては、例えばメチル、エチル、プロピル、イソプロピル、ブチル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル基等の炭素数１〜６の直鎖又は分枝鎖状アルキル基を挙げることができる。
【０００９】
本発明において出発原料として用いられる一般式（１）の化合物は、例えば下記反応式−１の方法に従って製造され得る。
【００１０】
【化７】

【００１１】
［式中Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＣ^*は前記に同じ。］
化合物（２）と化合物（３）との反応は、無溶媒下ルイス酸とオニウム塩又は、ルイス酸とルイス塩基の存在下に行なうことができる。
【００１２】
ルイス酸としては、例えば塩化亜鉛、臭化亜鉛、沃化亜鉛、塩化第二鉄、塩化アルミニウム、沃化アルミニウム、四塩化チタン、三塩化クロム、三塩化モリブデン、五塩化モリブデン、六塩化タングステン、二塩化コバルト、二臭化ニッケル等のハロゲン化金属を挙げることができる。
【００１３】
オニウム塩としては、例えば沃化テトラ−ｎ−ブチルアンモニウム、臭化テトラ−ｎ−ブチルアンモニウム、塩化テトラ−ｎ−ブチルアンモニウム、沃化アセチル，トリメチルアンモニウム、沃化エチル，ジメチル，フェニルアンモニウム、沃化テトラエチルアンモミウム、沃化−ｎ−ブチル，トリエチルアンモニウム、沃化トリ−ｎ−ブチル，メチルアンモニウム、沃化トリ−ｎ−デシル，メチルアンモニウム、沃化（１−フェネチル）トリメチルアンモニウム等のアミノ基上に置換基として炭素数１〜１０の直鎖又は分枝鎖状アルキル基、低級アルカノイル基、フェニル基及びフェニル低級アルキル基なる群より選ばれた基を４個有するハロゲン化アンモニウム類、塩化テトラ−ｎ−ブチルホスホニウム、臭化テトラ−ｎ−ブチルホスホニウム、沃化テトラ−ｎ−ブチルホスホニウム等の同一又は異なった低級アルキル基を４個有するハロゲン化ホスホニウム類、臭化テトラフェニルアンチモニウム等のフェニル基を４個有するハロゲン化アンチモニウム類、沃化トリエチルスルホニウム等の同一又は異なった低級アルキル基を３個有するハロゲン化スルホニウム類等を挙げることができる。
【００１４】
ルイス塩基としては、例えばトリフェニルホスフィン、トリ−ｎ−ブチルホスフィン等のリン化合物、トリエチルアミン等の三級アミン類等を挙げることができる。
【００１５】
化合物（２）と化合物（３）との反応は、通常０℃〜室温付近、二酸化炭素圧が通常常圧〜１０ｋｇ／ｃｍ²、好ましくは常圧〜７ｋｇ／ｃｍ²にて行なわれ、該反応は一般に１〜１０時間程度で終了する。化合物（２）の使用量は、化合物（３）に対して少なくとも当量、好ましくは当量〜１．５当量とするのがよい。ルイス酸の使用量は、化合物（２）に対して通常０．００１〜０．５倍モル、好ましくは０．００１〜０．３倍モル量とするのがよい。またオニウム塩の使用量は、化合物（２）に対して通常０．０１〜０．１倍モル量、好ましくは０．０１〜０．０７倍モル量とするのがよく、ルイス塩基の使用量としては、化合物（２）に対して通常０．０１〜０．５倍モル量、好ましくは０．０１〜０．１倍モル量とするのがよい。
【００１６】
上記反応式−１によれば、高価で貴重な¹³ＣＯ₂を浪費することなく、簡便に且つ高収率、高純度で、¹³Ｃ含有環状カーボネート誘導体（１）を得ることができる。
【００１７】
本発明によれば、上記で得られる¹³Ｃ含有環状カーボネート誘導体（１）にアンモニアと反応させることにより、目的とする¹³Ｃ含有尿素を容易に製造することができる。
【００１８】
本発明の方法は、オートクレーブ中適当な溶媒下、通常１００〜１８０℃、好ましくは１００〜１５０℃付近にて反応が進行し、一般に１〜１５時間程度で該反応は終了する。アンモニアの使用量は、一般式（１）の化合物に対して通常大過剰量、好ましくは１０〜３０倍モル量とするのがよい。この反応で用いられる溶媒としては、例えばメタノール、エタノール、イソプロパノール等のアルコール類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類等を例示できる。
【００１９】
本発明の反応系内には、触媒としてルイス酸や銅等を添加してもよい。ルイル酸としては、例えばｎ−ブチルチンオキシド等のアルキルチンオキシド類、アルミナムイソプロオキシド等のアルミナムアルコキンド類、酢酸銅等の銅化合物、塩化第二錫、蓚酸錫等の錫化合物等を例示できる。
【００２０】
化合物（１）とアンモニアとの反応で、反応系内に中間体として
【００２１】
【化８】

【００２２】
が生成するが、これらは単離することなく、最終化合物である¹³Ｃ含有尿素に誘導され得る。
【００２３】
また上記中間体の化合物（４）又は（５）を単離して、これらとアンモニアとを、前記化合物（１）とアンモニアとの反応と同様の条件下に反応させても、¹³Ｃ含有尿素を簡便に、且つ高収率、高純度で製造することができる。
【００２４】
更に下記反応式−２に示す如く、上記中間体の化合物（４）又は（５）をカーバメイト誘導体に変換後、前記化合物（１）とアンモニアとの反応と同様の条件下に反応させても、¹³Ｃ含有尿素を製造することができる。
【００２５】
【化９】

【００２６】
［式中Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＣ^*は前記に同じ。Ｒ⁵は低級アルキル基を示す。］
化合物（４）又は化合物（５）と化合物（６）との反応及び化合物（７）とアンモニア（８）との反応は、いずれも前記化合物（１）とアンモニアとの反応と同様の条件下に行なわれる。¹³Ｃ含有カーバメイト誘導体（７）は従来の種々の方法で合成され得るが、本発明の方法によれば¹³Ｃ含有カーバメイト誘導体（７）を高収率、高純度で製造でき、また¹³Ｃ含有カーバメイト誘導体（７）とアンモニア（８）とを反応させることにより¹³Ｃ含有尿素を簡便に、且つ高収率、高純度で製造できる。
【００２７】
【発明の効果】
本発明によれば、¹³Ｃ含有尿素を、上記一般式（１）の化合物から、簡便且つ高収率、高純度で、しかも安全性よく製造し得る。
【００２８】
【実施例】
以下に参考例及び実施例を掲げて本発明をより一層明らかにする。
【００２９】
参考例１
氷冷下、窒素気流を行ないながら、沃化テトラ−ｎ−ブチルアンモニウム１６．９ｇ及び塩化亜鉛１．５６ｇに、プロピレンオキシド２００ｍｌを加える。系内を減圧にし脱気を行なう。そこに、¹³Ｃ−二酸化炭素を１．５〜４．５ｋｇ／ｃｍ²で流入する。吸収が止まったら、リークし、再び系内を減圧にしてから¹³Ｃ−二酸化炭素を流入する。この操作を繰り返し、プロピレンオキシドに対して約０．９当量の¹³Ｃ−二酸化炭素を吸収させる。反応終了後、未反応のプロピレンオキシドを常圧又は減圧下に留去した後、減圧蒸留して、２−¹³Ｃ−４−メチル−１，３−ジオキソラン−２−オンを２４０．２ｇ（¹³Ｃ−二酸化炭素からの収率９１．６％，プロピレンオキシドからの収率８１．５％）得る（４ｍｍＨｇで９０〜９３℃）。
【００３０】
実施例１
アンモニア４８ｇを吹き込んだメタノール１８０ｍｌに２−¹³Ｃ−４−メチル−１，３−ジオキソラン−２−オン１２．０ｇを溶解し、オートクレーブ中で１３０℃、１２時間反応する。反応後、冷却し、メタノール及びアンモニアを減圧留去する。残渣にアセトン６０ｍｌを加え、０℃で３０分攪拌する。析出晶を濾取する。濾液のアセトンを減圧留去した後、プロピレングリコールを同じく減圧留去する（ｂｐ．８０℃／０．５ｍｍＨｇ）。この残渣にアセトン１０ｍｌを加え、０℃で３０分攪拌する。結晶を濾取する。先の結晶と合わせエタノールより再結晶して、¹³Ｃ含有尿素６．３８ｇを得る。収率：８９．８％
融点：１３３〜１３４℃、無色プリズム状。
【００３１】
実施例２
封管中にメチルカーバメイト９８０ｍｇ及びメタノールに溶解したアンモニア（アンモニア／メタノール＝１９１ｇ／９００ｍｌ）１７ｍｌを加え、１３０℃で１５時間加熱する。反応液を取り出し、減圧濃縮後エタノールより再結晶して¹³Ｃ含有尿素７２０ｍｇを得る。収率：９１．５％
融点：１３３〜１３４℃、無色プリズム状。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing ¹³ C-containing urea.
[0002]
[Prior art]
Conventional urea synthesis methods include (1) a method of concentrating and separating from urine, (2) a method of producing from ammonium cyanate or ammonium phenyl carbonate, and (3) adding lime nitrogen (CaCN ₂ ) to water and passing through carbon dioxide. , and the obtained cyanamide (CNNH ₂₎ in sulfuric acid process for heating production, (4) the carbon dioxide and ammonia ammonium carbamate obtained through in petroleum (NH ₂ COONH ₄₎ were heated under high pressure (5) A method in which carbon dioxide and ammonia are directly reacted at 150 atm and 200 ° C. (12th revised Japanese Pharmacopoeia, 1991, published by Tokyo Yodogawa Shoten).
[0003]
[Problems to be solved by the invention]
However, when these methods are applied to produce the ¹³ C-containing urea of the present invention, the following disadvantages occur. In other words, the method (1) only provides the target product with a low yield. (2) in the case of the method or (3) a synthetic hard to Get ammonium difficult ¹³ C-containing cyanate, ¹³ C-containing phenyl ammonium carbonate, it must be used ¹³ CNNH ₂ or the like. In the case of the method (5), since ¹³ CO ₂ and ammonia are in an equilibrium reaction, the yield is poor, and expensive and valuable ¹³ CO ₂ is easily wasted. In the case of the method (4) or (5), since the reaction is performed at a high temperature and a high pressure, there is a problem in terms of safety and operability.
[0004]
[Means for Solving the Problems]
An object of the present invention is to provide a method capable of producing a ¹³ C-containing urea from a compound represented by the following general formula (1) in a simple, high yield, high purity and safety.
[0005]
That is, the present invention provides the following general formula (1)
[0006]
[Chemical 6]

[0007]
[Wherein R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom or a lower alkyl group. C ^* indicates ¹³ C. ]
A ¹³ C-containing urea is produced by reacting a cyclic carbonate derivative represented by the formula (II) with ammonia.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
In the present specification, examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups. Can do.
[0009]
The compound of the general formula (1) used as a starting material in the present invention can be produced, for example, according to the method of the following reaction formula-1.
[0010]
[Chemical 7]

[0011]
[Wherein R ¹ , R ² , R ³ , R ⁴ and C ^* are the same as above. ]
The reaction of the compound (2) and the compound (3) can be carried out in the presence of a Lewis acid and an onium salt or a Lewis acid and a Lewis base in the absence of a solvent.
[0012]
Examples of Lewis acids include zinc chloride, zinc bromide, zinc iodide, ferric chloride, aluminum chloride, aluminum iodide, titanium tetrachloride, chromium trichloride, molybdenum trichloride, molybdenum pentachloride, tungsten hexachloride, two Mention may be made of metal halides such as cobalt chloride and nickel dibromide.
[0013]
Examples of onium salts include tetra-n-butylammonium iodide, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, acetyl iodide, trimethylammonium iodide, ethyl iodide, dimethyl, phenylammonium, and iodide. On amino groups such as tetraethylammonium iodide, n-butyl iodide, triethylammonium iodide, tri-n-butyl iodide, methylammonium iodide, tri-n-decyl iodide, methylammonium iodide, (1-phenethyl) trimethylammonium iodide, etc. An ammonium halide having four groups selected from the group consisting of a linear or branched alkyl group having 1 to 10 carbon atoms, a lower alkanoyl group, a phenyl group and a phenyl lower alkyl group as a substituent, n-butylphosphonium, tetra-n-butylphosphonium bromide Phosphoniums having four identical or different lower alkyl groups such as tetra-n-butylphosphonium iodide, antimonium halides having four phenyl groups such as tetraphenylantimonium bromide, iodine Mention may be made of halogenated sulfoniums having 3 identical or different lower alkyl groups such as triethylsulfonium.
[0014]
Examples of the Lewis base include phosphorus compounds such as triphenylphosphine and tri-n-butylphosphine, and tertiary amines such as triethylamine.
[0015]
The reaction between the compound (2) and the compound (3) is usually performed at 0 ° C. to around room temperature, and the carbon dioxide pressure is usually normal pressure to 10 kg / cm ² , preferably normal pressure to 7 kg / cm ² . Is generally completed in about 1 to 10 hours. The amount of compound (2) to be used is at least equivalent, preferably equivalent to 1.5 equivalents, relative to compound (3). The amount of the Lewis acid used is usually 0.001 to 0.5 times mol, preferably 0.001 to 0.3 times mol for the compound (2). The amount of the onium salt used is usually 0.01 to 0.1 times the molar amount, preferably 0.01 to 0.07 times the molar amount relative to the compound (2), and the amount of Lewis base used. Is usually 0.01 to 0.5 times the molar amount, preferably 0.01 to 0.1 times the molar amount relative to the compound (2).
[0016]
According to the above reaction formula-1, the ¹³ C-containing cyclic carbonate derivative (1) can be obtained easily and with high yield and high purity without wasting expensive and precious ¹³ CO ₂ .
[0017]
According to the present invention, the desired ¹³ C-containing urea can be easily produced by reacting the ¹³ C-containing cyclic carbonate derivative (1) obtained above with ammonia.
[0018]
In the method of the present invention, the reaction proceeds usually at 100 to 180 ° C., preferably near 100 to 150 ° C. in a suitable solvent in an autoclave, and the reaction is generally completed in about 1 to 15 hours. The amount of ammonia used is usually a large excess amount, preferably 10 to 30 times the molar amount of the compound of the general formula (1). Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. it can.
[0019]
In the reaction system of the present invention, Lewis acid, copper or the like may be added as a catalyst. Examples of ruyl acid include alkyltin oxides such as n-butyltin oxide, aluminum alkoxides such as aluminum isoprooxide, copper compounds such as copper acetate, and tin compounds such as stannic chloride and tin oxalate. .
[0020]
As a reaction product between compound (1) and ammonia, an intermediate in the reaction system
[Chemical 8]

[0022]
These can be derived into the final compound ¹³ C-containing urea without isolation.
[0023]
Even if the intermediate compound (4) or (5) is isolated and reacted with ammonia under the same conditions as in the reaction between the compound (1) and ammonia, the ¹³ C-containing urea can be obtained. It can be produced simply and with high yield and high purity.
[0024]
Further, as shown in the following reaction formula-2, the intermediate compound (4) or (5) may be converted into a carbamate derivative and then reacted under the same conditions as the reaction of the compound (1) with ammonia. ¹³ C-containing urea can be produced.
[0025]
[Chemical 9]

[0026]
[Wherein R ¹ , R ² , R ³ , R ⁴ and C ^* are the same as above. R ⁵ represents a lower alkyl group. ]
The reaction between compound (4) or compound (5) and compound (6) and the reaction between compound (7) and ammonia (8) are all carried out under the same conditions as in the reaction between compound (1) and ammonia. Done. ¹³ C-containing carbamate derivative (7) can be synthesized by various conventional methods, can be prepared according to the method of the present invention ¹³ C containing carbamate derivative (7) yield, high purity, and ¹³ C containing By reacting the carbamate derivative (7) with ammonia (8), ¹³ C-containing urea can be easily produced in high yield and high purity.
[0027]
【The invention's effect】
According to the present invention, ¹³ C-containing urea can be easily produced from the compound of the above general formula (1) with high yield, high purity and safety.
[0028]
【Example】
Hereinafter, the present invention will be further clarified with reference examples and examples.
[0029]
Reference example 1
200 ml of propylene oxide is added to 16.9 g of tetra-n-butylammonium iodide and 1.56 g of zinc chloride while performing a nitrogen stream under ice cooling. Depressurize the system. Then, ¹³ C-carbon dioxide is introduced at 1.5 to 4.5 kg / cm ² . When absorption stops, it leaks, and the system is depressurized again, and then ¹³ C-carbon dioxide is introduced. This operation is repeated to absorb about 0.9 equivalent of ¹³ C-carbon dioxide with respect to propylene oxide. After completion of the reaction, the atmospheric pressure or propylene oxide unreacted was distilled off under reduced pressure, and distilled under reduced pressure, ^2-13 C-4-methyl-1,3-dioxolan-2-one 240.2g ⁽¹³ (91.6% yield from C-carbon dioxide, 81.5% yield from propylene oxide)) (90-93 ° C. at 4 mmHg).
[0030]
Example 1
Methanol 180ml blown ammonia 48g was dissolved ^2-13 C-4-methyl-1,3-dioxolan-2-one 12.0 g, 130 ° C. in an autoclave, for 12 hours. After the reaction, the mixture is cooled and methanol and ammonia are distilled off under reduced pressure. Add 60 ml of acetone to the residue and stir at 0 ° C. for 30 minutes. The precipitated crystals are collected by filtration. After the acetone in the filtrate was distilled off under reduced pressure, propylene glycol was also distilled off under reduced pressure (bp. 80 ° C./0.5 mmHg). Add 10 ml of acetone to the residue and stir at 0 ° C. for 30 minutes. The crystals are collected by filtration. Combined with the previous crystals, recrystallized from ethanol to obtain 6.38 g of ¹³ C-containing urea. Yield: 89.8%
Melting point: 133-134 ° C., colorless prism shape.
[0031]
Example 2
In a sealed tube, 980 mg of methyl carbamate and 17 ml of ammonia (ammonia / methanol = 191 g / 900 ml) dissolved in methanol are added and heated at 130 ° C. for 15 hours. The reaction solution is taken out, concentrated under reduced pressure, and recrystallized from ethanol to obtain 720 mg of ¹³ C-containing urea. Yield: 91.5%
Melting point: 133-134 ° C., colorless prism shape.

Claims (1)

General formula

[Wherein R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom or a lower alkyl group. ]
And a general formula obtained in the first step, wherein ¹³ C-carbon dioxide is reacted at 0 ° C. to around room temperature.

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. C ^* indicates ¹³ C. ]
A process for producing ¹³ C-containing urea comprising a second step of reacting a cyclic carbonate derivative represented by formula (II) with ammonia in a solvent at 100 to 150 ° C,
In the first step, at least an equivalent amount of the compound of the general formula (2) is used with respect to ¹³ C-carbon dioxide.
^A method for producing ¹³ C-containing urea.