JP4209022B2 - Process for producing isocyanoacetic acid alkyl esters - Google Patents
Process for producing isocyanoacetic acid alkyl esters Download PDFInfo
- Publication number
- JP4209022B2 JP4209022B2 JP36751998A JP36751998A JP4209022B2 JP 4209022 B2 JP4209022 B2 JP 4209022B2 JP 36751998 A JP36751998 A JP 36751998A JP 36751998 A JP36751998 A JP 36751998A JP 4209022 B2 JP4209022 B2 JP 4209022B2
- Authority
- JP
- Japan
- Prior art keywords
- solution
- reaction
- isocyanoacetic acid
- producing
- acid alkyl
- 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 - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬品、有機合成品などの原料として広く使われているイソシアノ酢酸アルキルエステル類の製造法に関する。
【０００２】
【従来の技術】
Ｎ−ホルミルグリシンアルキルエステルを脱水してイソシアノ酢酸アルキルエステル類を製造する方法、例えばＮ−ホルミルグリシンエチルエステルを脱水してイソシアノ酢酸エチルエステルを製造する方法としては、オキシ塩化リンを用いる方法（オーガニック シンセシス（Organic Synthesis）Col Vol.VＩ.,620）及びホスゲンを用いる方法（アンゲワント ヘミー(Angew.Chem.)77 p492(1965)）が考えられるが、有毒で窒息性のあるホスゲンを用いる方法は、工業化に際し危険の多い方法であることから、オキシ塩化リンを用いる方法が実用的である。
【０００３】
しかし、従来の合成法では高収率を得るために低温条件下（０℃以下）短時間で反応を行う必要があり、量産時にその条件を満たすことは困難である。すなわち、前記のオーガニック シンセシスCol Vol.VＩ.,620の方法（以下、Ｏ.Ｓ.法という）はトリエチルアミンとＮ−ホルミルグリシンエチルエステルの混合ジクロロメタン溶液にオキシ塩化リンを０℃を保ちながら１５〜２０分で滴下する方法であるが、この方法では発熱が激しい。従って、量産時には、オキシ塩化リンを短時間で滴下することは反応缶の冷却効率の問題から不可能である。その結果オキシ塩化リンを２〜３時間かけて滴下することとなり、その際のエチルイソシアノアセテートの収率は大幅に低下する（約６０％）。これらのことから、反応温度および時間に影響されない量産可能な合成法が望まれる。
又、上記の方法では反応液をアルカリ水で処理して目的物を取得する工程においても、低温かつ短時間での操作が必要という難点がある。
【０００４】
本発明は、反応温度および反応時間に影響されない、工業的規模においても高収率の生成物をえることが可能なイソシアノ酢酸アルキルエチル類の製造法を提供しようとするものである。
【０００５】
【発明が解決しようとする課題】
本発明者らは、前記課題を解決するために鋭意検討した結果、従来のＯ.Ｓ.法とは逆に、トリエチルアミンとＮ−ホルミルグリシンアルキルエステルの溶液をオキシ塩化リン溶液に添加することにより、−２０〜７０℃、３０分〜６時間という幅広い条件下での反応ができ、かつアルカリ水処理においてアルカリ水に該反応液を添加することで、０〜５０℃、１分〜６時間という穏やかな条件下で後処理ができ、従来法よりも高収率でイソシアノ酢酸アルキルエステルが得られることを見出し、本発明を完成するに至った。
【０００６】
【課題を解決するための手段】
即ち本発明は、Ｎ−ホルミルグリシンアルキルエステルをトリエチルアミンの存在下にオキシ塩化リンで脱水してイソシアノ酢酸アルキルエステル類を製造するにあたり、該オキシ塩化リン溶液中に該トリエチルアミン及び該Ｎ−ホルミルグリシンアルキルエステルの溶液を添加して反応を行い、次いで該反応液をアルカリ水溶液に添加した後、イソシアノ酢酸アルキルエステル類を取得することを特徴とするイソシアノ酢酸アルキルエステル類の製造法に関する。
【０００７】
【発明の実施の形態】
本発明の方法では、まずオキシ塩化リン（以下ＰＯＣｌ3という）溶液に、トリエチルアミン（以下、ＴＥＡという）とＮ−ホルミルグリシルアルキルエステル（以下、ＮＦＥという）の溶液を添加（滴下）することが特徴である。ＰＯＣｌ3溶液に、ＴＥＡとＮＦＥは混合溶液として添加（滴下）しても、又ＮＦＥ溶液及びＴＥＡ溶液を別々に添加（滴下）してもよい。
本発明の方法で使用されるＮＦＥのアルキルエステル種としては、メチル、エチル、ｎ−プロピル、ｉＳＯ−プロピル、ｎ−ブチル、ｉｓｏ−ブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル等が例示される。
【０００８】
ＮＦＥ、脱水剤であるＰＯＣｌ3およびＴＥＡの使用モル比はＮＦＥ／ＰＯＣｌ3／ＴＥＡ＝１．０／０．９／１．８〜１．０／１．５／４．０であり、好ましくは１．０／１．０／２．０〜１．０／１．３／３．０である。
【０００９】
本発明の方法において添加（滴下）溶液及び添加（滴下）される溶液の双方に用いられる溶媒としては、トルエン、キシレン、酢酸エチル、ｎ−ヘキサン、ジクロロメタン、四塩化炭素または１，２−ジクロロエタン（以下、ＥＤＣという）などが使用可能であるが、取り扱い易さ及び良好な収率をもたらすという点から、ＥＤＣがとくに好ましい。
溶媒の使用モル比は、ＮＦＥ１モルに対してＰＯＣｌ3用溶媒が３．０〜３０．０モル、好ましくは６．０〜１５．０、ＴＥＡ及びＮＦＥ用溶媒が２．０〜２０．０、好ましくは４．０〜１０．０である。
【００１０】
本発明の方法は、溶媒に溶解したＮＦＥおよびＴＥＡの溶液を（混合溶液または単独溶液を同時に）、溶媒に溶解したＰＯＣｌ3の溶液に、滴下時間３０分〜６時間、好適には３０分〜３時間で滴下させながら、反応温度−２０〜７０℃、好適には０〜５０℃にて反応させることにより実施される。その結果、Ｏ.Ｓ.法よりも高収率でエチルイソシアノアセテートが得られる。そのなかでも最も好ましい条件は、２０℃前後で１．５時間の滴下である。
【００１１】
滴下終了後、１５〜２５℃で１時間程度熟成を行う。
本発明のもう一つの特徴はこの反応液を炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウムなどのアルカリ水溶液に滴下する点である。
これにより脱水反応が完結する。
アルカリ水溶液を反応液に添加すると、添加時間の僅かな長短や処理温度の僅かな高低で目的物の収率が大きく変動し、著しい時は実用にならない程に収率低下がおこり易いので、工業的規模での実施に当たって極めて厳密な工程管理が必要となる欠点がでる。
この際、用いられるアルカリの使用量はＮＦＥ１モルに対して１．５〜３．０モル、好ましくは１．７〜２．０モルである。その後、加水して系内の結晶を溶かし分液し、分液した水層をＥＤＣで洗浄したのち、ＥＤＣ層をひとまとめにして水洗後に濃縮する。
【００１２】
【実施例】
以下、実施例をあげて本発明をさらに詳細に説明するが、本発明はもとよりこれらに限定されるものではない。
【００１３】
実施例１
１，２−ジクロロエタン５００ｇにオキシ塩化リン７３．６１ｇ（０．４８モル）を溶解し、該溶液を反応缶に入れ２０℃に保った。
次に１，２−ジクロロエタン２５０ｇにトリエチルアミン９９．７５ｇ（０．９８モル）とＮ−ホルミルグリシンエチルエステル６０．３０ｇ（０．４０モル）を加えた混合溶液を上記反応缶に１．５時間かけて滴下した。この間反応温度は２０〜２２℃に保った。
滴下終了後、２０℃前後に保ったまま１時間攪拌した。この反応液を、水３２０ｇに無水炭酸ナトリウム８０ｇ（０．７５モル）を溶解した水溶液中に、３０℃、１時間で滴下した。アルカリ処理後１時間攪拌し、その後水７００ｍｌを加え、反応液中の結晶を完全に溶解させた。水層と１，２−ジクロロエタン層の２層に分離し、それらを分液した後、水層を１，２−ジクロロエタン３３０ｇで洗浄した。１，２−ジクロロエタン層をひとまとめにし、水１３０ｇで洗浄し、分液後１，２−ジクロロエタン層をエバポレーターで濃縮した。
【００１４】
濃縮後分析を行った結果、３７．６７ｇ（純度７９．７％）のイソシアノ酢酸エチルエステルがえられ、収率は８５．８％であった。
分析値を以下に示す。
【００１５】
ＩＲ（ｃｍ-1）
１７８０（カルボニル基）
２２００（イソニトリル基）
1Ｈ−ＮＭＲ（溶媒；重水素化クロロホルム、基準；テトラメチルシラン）
δ＝１．３（ｔ、３Ｈ） −ＣＨ2 ＣＨ 3
δ＝４．２５（ｓ、２Ｈ） ＣＮ−ＣＨ 2−
δ＝４．２８（ｑ、２Ｈ） −ＣＨ 2ＣＨ3
【００１６】
実施例２〜８
実施例１において反応条件を０〜５０℃の間で種々変更して実験を行った。結果を表１に示す。
【００１７】
【表１】
実施例９
実施例１におけるＮ−ホルミルグリシンエチルエステルに変えてＮ−ホルミルグリシンｔ−ブチルエステルを使用して同様の実験を行った。(但し反応温度は１０℃とした)
イソシアノ酢酸ｔ−ブチルエステルが収率８８．４％でえられた。
分析値を以下に示す。
【００１９】
ＩＲ（ｃｍ-1）
１７８０（カルボニル基）
２２００（イソニトリル基）
1Ｈ−ＮＭＲ（溶媒；重水素化クロロホルム、基準；テトラメチルシラン）
δ＝１．５（ｓ、９Ｈ） ｔ−Ｂｕ
δ＝４．１（ｓ、２Ｈ） ＣＮ−ＣＨ 2−
【００２０】
比較例１（オーガニック シンセシス Col Vol.VＩ.，６２０の方法）
Ｎ−ホルミルグリシンエチルエステル６５．５ｇ（０．５モル）と、トリエチルアミン１２５．０ｇ（１．２３４モル）及び５００ｍｌのジクロロメタンを反応缶に仕込んだ。
その反応缶を氷塩浴で０〜２℃に冷却した。オキシ塩化リン７６．５ｇ（０．４９８モル）を１５〜２０分で反応器内を０℃に保ちながら滴下した。
滴下後０℃のまま１時間熟成した。水４００ｍｌに無水炭酸ナトリウム１００ｇを溶解した溶液を前記反応缶に滴下した。
その際、反応器を水浴につけ２５〜３０℃に保った。２層系の反応液となるがそれを３０分攪拌し、その後水層が１リットルになるまで水を加えた。水槽を分液したのち、ジクロロメタン２５０ｍｌで２回抽出し、ジクロロメタン層をひとまとめにし、飽和食塩水で洗浄し、無水炭酸カルシウムで脱水した。その後減圧濃縮し、４４ｇ（収率７８％）のイソシアノ酢酸エチルエステルをえた。
【００２１】
比較例２
溶媒をジクロロメタンのかわりに１，２−ジクロロエタンとしたほかは比較例１と同様の実験を行った結果、イソシアノ酢酸エチルエステルの収率は８４．９％であり、１，２−ジクロロエタンを使用することで従来法より収率が向上することがわかった。
【００２２】
比較例３
オキシ塩化リンの滴下時間を３時間（工業的な実施における常識的な滴下時間）としたほかは比較例２と同様の実験を行った。その結果、イソシアノ酢酸エチルエステルの収率は６２．０％と比較例２よりも低下し、従来の滴下方法では、オキシ塩化リンは短時間で仕込む必要があることがわかった。
【００２３】
比較例４
反応温度を５℃、オキシ塩化リンの滴下時間を２０分として比較例２と同様の実験を行った。その結果、イソシアノ酢酸エチルエステルの収率は７６．９％と比較例２よりも低下し、従来の滴下方法では、反応温度は０℃に保つ必要があることがわかった。
【００２４】
比較例５
実施例１においてアルカリ水溶液を反応液に滴下した以外は同じ実験を行った。
イソシアノ酢酸エチルエステルの収率は０．５％に低下した。
【００２５】
これらの例から、本発明の方法では反応温度、滴下時間の影響をほとんど受けず、しかも従来法よりも高収率であることがわかる。
【００２６】
【発明の効果】
本発明の方法によれば、反応時間および反応温度の影響を受けることなく、工業的規模において高収率にイソシアノ酢酸エステル類が得られる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing isocyanoacetic acid alkyl esters widely used as raw materials for pharmaceuticals, organic synthetic products and the like.
[0002]
[Prior art]
As a method for producing isocyanoacetic acid alkyl esters by dehydrating N-formylglycine alkyl ester, for example, a method for producing isocyanoacetic acid ethyl ester by dehydrating N-formylglycine ethyl ester (organic method) (organic) Organic Synthesis Col Vol. VI., 620) and a method using phosgene (Angew. Chem. 77 p492 (1965)), a method using toxic and suffocating phosgene, A method using phosphorus oxychloride is practical because it is a dangerous method for industrialization.
[0003]
However, in the conventional synthesis method, in order to obtain a high yield, it is necessary to carry out the reaction under a low temperature condition (0 ° C. or less) in a short time, and it is difficult to satisfy the condition at the time of mass production. That is, the organic synthesis Col Vol.VI., 620 method (hereinafter referred to as the OS method) is a method in which phosphorus oxychloride is added to a mixed dichloromethane solution of triethylamine and N-formylglycine ethyl ester at 15 ° C. Although it is a method of dripping in 20 minutes, this method generates intense heat. Therefore, in mass production, it is impossible to add phosphorus oxychloride dropwise in a short time due to the cooling efficiency of the reaction can. As a result, phosphorus oxychloride is dropped over 2 to 3 hours, and the yield of ethyl isocyanoacetate at that time is greatly reduced (about 60%). From these facts, a synthesis method capable of mass production that is not affected by the reaction temperature and time is desired.
In addition, the above-described method has a drawback that it is necessary to operate at a low temperature in a short time even in the step of obtaining the target product by treating the reaction solution with alkaline water.
[0004]
The present invention seeks to provide a process for producing alkylethyl isocyanoacetates that are not affected by the reaction temperature and reaction time and that can provide a high yield of product even on an industrial scale.
[0005]
[Problems to be solved by the invention]
As a result of intensive studies to solve the above problems, the present inventors have added a solution of triethylamine and N-formylglycine alkyl ester to the phosphorus oxychloride solution, contrary to the conventional OS method. The reaction can be performed under a wide range of conditions such as −20 to 70 ° C. and 30 minutes to 6 hours, and the reaction solution is added to the alkaline water in the alkaline water treatment to be 0 to 50 ° C. and 1 minute to 6 hours. It has been found that an isocyanoacetic acid alkyl ester can be obtained by a post-treatment under mild conditions and in a higher yield than the conventional method, and the present invention has been completed.
[0006]
[Means for Solving the Problems]
That is, the present invention provides a method for producing an isocyanoacetic acid alkyl ester by dehydrating an N-formylglycine alkyl ester with phosphorus oxychloride in the presence of triethylamine. The triethylamine and the N-formylglycine alkyl ester are contained in the phosphorus oxychloride solution. The present invention relates to a process for producing an isocyanoacetic acid alkyl ester characterized by adding an ester solution to carry out the reaction and then adding the reaction liquid to an alkaline aqueous solution and then obtaining isocyanoacetic acid alkyl ester.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
In the method of the present invention, first, a solution of triethylamine (hereinafter referred to as TEA) and N-formylglycylalkyl ester (hereinafter referred to as NFE) is added (dropped) to a phosphorus oxychloride (hereinafter referred to as POCl 3 ) solution. It is a feature. TEA and NFE may be added (dropped) as a mixed solution to the POCl 3 solution, or the NFE solution and the TEA solution may be added (dropped) separately.
Examples of NFE alkyl ester species used in the method of the present invention include methyl, ethyl, n-propyl, iSO-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and the like.
[0008]
The molar ratio of NFE, the dehydrating agent POCl 3 and TEA is NFE / POCl 3 /TEA=1.0/0.9/1.8 to 1.0 / 1.5 / 4.0, preferably 1.0 / 1.0 / 2.0 to 1.0 / 1.3 / 3.0.
[0009]
Solvents used for both the added (dropped) solution and the added (dropped) solution in the method of the present invention include toluene, xylene, ethyl acetate, n-hexane, dichloromethane, carbon tetrachloride or 1,2-dichloroethane ( (Hereinafter referred to as EDC) can be used, but EDC is particularly preferred because it is easy to handle and provides a good yield.
The molar ratio of the solvent used is 3.0 to 30.0 mol, preferably 6.0 to 15.0 for the solvent for POCl 3 with respect to 1 mol of NFE, 2.0 to 20.0 for the solvent for TEA and NFE, Preferably it is 4.0-10.0.
[0010]
In the method of the present invention, a solution of NFE and TEA dissolved in a solvent (a mixed solution or a single solution at the same time) is added to a solution of POCl 3 dissolved in a solvent at a dropping time of 30 minutes to 6 hours, preferably 30 minutes to The reaction is carried out at a reaction temperature of −20 to 70 ° C., preferably 0 to 50 ° C. while dropping in 3 hours. As a result, ethyl isocyanoacetate can be obtained in a higher yield than the OS method. Among these, the most preferable condition is dropping at around 20 ° C. for 1.5 hours.
[0011]
After completion of dropping, aging is carried out at 15 to 25 ° C. for about 1 hour.
Another feature of the present invention is that this reaction solution is dropped into an alkaline aqueous solution such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or the like.
This completes the dehydration reaction.
When an alkaline aqueous solution is added to the reaction solution, the yield of the target product greatly fluctuates due to the slightly longer or shorter addition time and the slightly higher or lower processing temperature. There is a disadvantage that very strict process control is required for implementation on a target scale.
Under the present circumstances, the usage-amount of the alkali used is 1.5-3.0 mol with respect to 1 mol of NFE, Preferably it is 1.7-2.0 mol. Thereafter, the mixture is hydrolyzed to dissolve and separate the crystals in the system, and the separated aqueous layer is washed with EDC, and then the EDC layer is collectively concentrated after washing with water.
[0012]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these from the first.
[0013]
Example 1
73.61 g (0.48 mol) of phosphorus oxychloride was dissolved in 500 g of 1,2-dichloroethane, and the solution was put in a reaction vessel and kept at 20 ° C.
Next, a mixed solution obtained by adding 99.75 g (0.98 mol) of triethylamine and 60.30 g (0.40 mol) of N-formylglycine ethyl ester to 250 g of 1,2-dichloroethane was added to the reaction vessel over 1.5 hours. And dripped. During this period, the reaction temperature was kept at 20-22 ° C.
After completion of the dropwise addition, the mixture was stirred for 1 hour while being kept at around 20 ° C. This reaction solution was added dropwise at 30 ° C. for 1 hour in an aqueous solution obtained by dissolving 80 g (0.75 mol) of anhydrous sodium carbonate in 320 g of water. After the alkali treatment, the mixture was stirred for 1 hour, and then 700 ml of water was added to completely dissolve the crystals in the reaction solution. After separating into two layers, an aqueous layer and a 1,2-dichloroethane layer, and separating them, the aqueous layer was washed with 330 g of 1,2-dichloroethane. The 1,2-dichloroethane layer was collected together, washed with 130 g of water, and after liquid separation, the 1,2-dichloroethane layer was concentrated with an evaporator.
[0014]
As a result of analysis after concentration, 37.67 g (purity 79.7%) of isocyanoacetic acid ethyl ester was obtained, and the yield was 85.8%.
Analytical values are shown below.
[0015]
IR (cm -1 )
1780 (carbonyl group)
2200 (Isonitrile group)
1 H-NMR (solvent: deuterated chloroform, standard: tetramethylsilane)
δ = 1.3 (t, 3H) —CH 2 CH 3
δ = 4.25 (s, 2H) CN— CH 2 —
δ = 4.28 (q, 2H) —CH 2 CH 3
[0016]
Examples 2-8
In Example 1, the experiment was performed by changing the reaction conditions between 0 ° C. and 50 ° C. in various ways. The results are shown in Table 1.
[0017]
[Table 1]
Example 9
A similar experiment was conducted using N-formylglycine t-butyl ester instead of N-formylglycine ethyl ester in Example 1. (However, the reaction temperature was 10 ° C.)
Isocyanoacetic acid t-butyl ester was obtained in a yield of 88.4%.
Analytical values are shown below.
[0019]
IR (cm -1 )
1780 (carbonyl group)
2200 (Isonitrile group)
1 H-NMR (solvent: deuterated chloroform, standard: tetramethylsilane)
δ = 1.5 (s, 9H) t-Bu
δ = 4.1 (s, 2H) CN— CH 2 —
[0020]
Comparative Example 1 (Method of Organic Synthesis Col Vol.VI., 620)
A reaction vessel was charged with 65.5 g (0.5 mol) of N-formylglycine ethyl ester, 125.0 g (1.234 mol) of triethylamine and 500 ml of dichloromethane.
The reaction vessel was cooled to 0-2 ° C. with an ice-salt bath. 76.5 g (0.498 mol) of phosphorus oxychloride was added dropwise over 15 to 20 minutes while maintaining the inside of the reactor at 0 ° C.
After dropping, the mixture was aged for 1 hour while maintaining at 0 ° C. A solution prepared by dissolving 100 g of anhydrous sodium carbonate in 400 ml of water was dropped into the reaction vessel.
At that time, the reactor was placed in a water bath and kept at 25-30 ° C. Although it became a two-layer reaction liquid, it was stirred for 30 minutes, and then water was added until the water layer became 1 liter. After separation of the water bath, extraction was performed twice with 250 ml of dichloromethane, and the dichloromethane layers were combined, washed with saturated brine, and dehydrated with anhydrous calcium carbonate. Thereafter, the mixture was concentrated under reduced pressure to obtain 44 g (yield 78%) of isocyanoacetic acid ethyl ester.
[0021]
Comparative Example 2
As a result of conducting an experiment similar to Comparative Example 1 except that 1,2-dichloroethane was used in place of dichloromethane, the yield of isocyanoacetic acid ethyl ester was 84.9%, and 1,2-dichloroethane was used. As a result, it was found that the yield was improved over the conventional method.
[0022]
Comparative Example 3
The same experiment as Comparative Example 2 was performed except that the dropping time of phosphorus oxychloride was 3 hours (a common dropping time in industrial implementation). As a result, the yield of isocyanoacetic acid ethyl ester was 62.0%, which was lower than that of Comparative Example 2. It was found that phosphorus oxychloride needs to be charged in a short time by the conventional dropping method.
[0023]
Comparative Example 4
The same experiment as in Comparative Example 2 was performed at a reaction temperature of 5 ° C. and a dropping time of phosphorus oxychloride of 20 minutes. As a result, the yield of isocyanoacetic acid ethyl ester was 76.9%, which was lower than that of Comparative Example 2, and it was found that the reaction temperature had to be kept at 0 ° C. in the conventional dropping method.
[0024]
Comparative Example 5
The same experiment was performed except that the alkaline aqueous solution was dropped into the reaction solution in Example 1.
The yield of isocyanoacetic acid ethyl ester was reduced to 0.5%.
[0025]
From these examples, it can be seen that the method of the present invention is hardly affected by the reaction temperature and the dropping time, and has a higher yield than the conventional method.
[0026]
【The invention's effect】
According to the method of the present invention, isocyanoacetic acid esters can be obtained in high yield on an industrial scale without being affected by the reaction time and reaction temperature.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36751998A JP4209022B2 (en) | 1998-12-24 | 1998-12-24 | Process for producing isocyanoacetic acid alkyl esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36751998A JP4209022B2 (en) | 1998-12-24 | 1998-12-24 | Process for producing isocyanoacetic acid alkyl esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000191620A JP2000191620A (en) | 2000-07-11 |
| JP4209022B2 true JP4209022B2 (en) | 2009-01-14 |
Family
ID=18489518
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP36751998A Expired - Fee Related JP4209022B2 (en) | 1998-12-24 | 1998-12-24 | Process for producing isocyanoacetic acid alkyl esters |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4209022B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5006137B2 (en) * | 2007-08-28 | 2012-08-22 | 日本合成化学工業株式会社 | Isocyanoacetic acid alkyl ester liquid composition and storage method thereof |
| CN102976970B (en) * | 2012-12-05 | 2014-12-17 | 南京理工大学 | Preparation method of isocyano compound |
-
1998
- 1998-12-24 JP JP36751998A patent/JP4209022B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000191620A (en) | 2000-07-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2016202252A1 (en) | Method for synthesizing d-para-hydroxyphenylglycine methyl ester | |
| JP4209022B2 (en) | Process for producing isocyanoacetic acid alkyl esters | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN104974051A (en) | Synthetic method for (1S,4R)-cis-4-amino-2-cyclopentene-1-methanol hydrochloride | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| KR100527648B1 (en) | Methods for crystallization of n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-l-alanine n-carboxyanhydride | |
| RU2228929C2 (en) | Method for preparing (3s)-3-amino-3-pyridylpropionic acid and intermediate substance | |
| CN105330612B (en) | The synthesis technique of 2 (base of 5 amino, 1,2,4 thiadiazoles 3) 2 methoxyimino acetic acid | |
| CN117186116B (en) | Preparation method of cefvicin intermediate | |
| CN111978185B (en) | Preparation method of salicylamine acetate | |
| EP0021644B1 (en) | A salt of 3-thienylmalonic acid and a process for the preparation of 3-thienylmalonic acid | |
| CN104592253B (en) | Novel synthesis method of temsirolimus | |
| CN115417803B (en) | Synthesis method of Wu Pa tenib intermediate (3R, 4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid | |
| CN102796056B (en) | Peramivir intermediate and preparation method for analogue | |
| CN101654426A (en) | Method for preparing ilomastat | |
| KR102055702B1 (en) | Method for the preparation of optically active 2-Octylglycine ester | |
| JP3523661B2 (en) | Method for purifying 2-alkyl-4-halogeno-5-formylimidazole | |
| EA010569B1 (en) | Process for the preparation of chirally-pure crystalline modification of nateglinide | |
| JPS588045A (en) | Preparation of alpha-phenylpropionic ester | |
| JPH06104670B2 (en) | New manufacturing method of chemical compounds | |
| JPH0753524A (en) | Production of 2-butyl-4-chloroimidazole-5-carbaldehyde | |
| CN117624009A (en) | Continuous synthesis method of JAK inhibitor drug heterocyclic intermediate | |
| CN116789559A (en) | Synthesis method of aspergillin A and analogues thereof | |
| JPH04108793A (en) | Esterification of penicillins | |
| CN115947729A (en) | Preparation method of intermediate of aldose reductase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20051118 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20081009 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20081022 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111031 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111031 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111031 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111031 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121031 Year of fee payment: 4 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121031 Year of fee payment: 4 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121031 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121031 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131031 Year of fee payment: 5 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |