201238940 六、發明說明< … · 【發明所屬之技術領域】 【000 1] 本發明係有關於可作為醫藥品及農藥的中間產物 (intermediate )、並作為工業製品的中間產物的氰基乙酸酯 (cyanoacetate)的製造方法。於本發明中，所謂的氰基乙 酸酯係指該化合物的化學式通常以NCCOH2C〇〇R所表示的氰基 〇 乙酸酯《化學式中，R係選自碳數為1〜10的直鏈或分枝鏈的 飽和碳氫化合物（hydrocarbon residue)、直鏈或分枝鏈的 不飽和碳氳化合物、脂環族（alicyclic)碳氳化合物、芳香 族碳氫化合物及化學式一C^—O—R1所構成群類的化學功能 基〈化學式中，R係碳數為1〜8的直鏈或分枝鏈的飽和碳氫 化合物（hydrocarbon residue)、直鏈或分枝鏈的不飽和碳 氫化合物、脂環族（alicyclic)碳氫化合物、或芳香族碳氫 化合物〉》。 【先前技術】 [0 0 0 2] 過去’氰基乙酸酯的製造方法，一般係在酸催化劑（acid catalyst)的存在下’使氰基乙酸（cyanoacetic扣丨们和 醇類（alcohol)發生脫水酯化反應（dehydration esterification reaction);舉例來說，於專利文獻1中記 101109546 1013203354-0 201238940 載有製造新戊基α-氰基6酸酯（neopentyl α二 -cyanoacetate)的方法，係使氰基乙酸、新戊醇（ne〇pentyl alcohol)、硫酸（sulfuric acid)和甲苯（toluene)在迴 k (ref lux)下反應，生成的水在共彿（3汉〇廿叩^·)下除去， 製造新戊基α-氰基乙酸酯。又，於專利文獻2中記載有製造 &〜Go烧基氰基乙酸酯〜U alkyl cyanoacetate)的方 法，係使氰基乙酸與G〜U烧醇〜C1D alkanol)在水介質 (aqueous medium)中，於催化劑存在下，使其反應並一面 分離G〜Go燒醇/水共彿混合物，製造a%戚基氰基乙酸 酯。再者’於專利文獻3中記載：水介質中的醋化反應中， 該醋化反祕在曱轉雜知· (_tn)pe)的存在下進 行’在反應綱，以論除去水與共相的方法。 【先前技術文獻】 【專利文獻】【0 00 3】 【專利文獻1】制平4_9麵號公報 【專利文獻2】特開平6_157446號公報 【專利文獻3】特開平9-188657號公報 【發明内容】 【發明所欲解決之問題】 101109546 1013203354-0 201238940 [0 0 0 4] 但是，在專利文獻1〜3的内容所揭示之氰基乙酸酯的製 造方法中，卻有氰基乙酸酯產率低下的問題；又，專利文獻】 和3所揭7F之製.造方法巾’由於制甲苯作騎機溶劑，就 有產生過多副產物及毒性太強的問題；又，專利文獻2所揭 示之製造方法中，又有為了酯化必須使用大量醇類的問題。 [0 0 0 5] 有鏗於以上的問題點，本發明的目的，就是提供可以提 咼氰基乙酸s旨的產率、而副產物的產生又很少的氰基乙酸醋 的製造方法。 【為解決問題所採取的方法】 〇 【〇〇〇6】 本發明之發明團隊，在藉由氰基乙酸與具〇H基的有機化 合物在有機溶劑中的酯化反應而製造氰基乙酸酯的方法中， 找出提高氰基乙酸酯的產率的方法，係併用氰基乙酸溶解度 為特定數量以上的第一溶劑和實質上不溶於水的第二溶劑， 藉此使酯化反應有效率地進行，因而提高氰基乙酸酯的產率。 【0 00 7] 1013203354-0 101109546 201238940 亦即，本發明係如下辦架、押· 1. 氰基乙酸與以化學式_表示之有機化合物《式中，R係碳 數1〜ίο的直鏈或分枝鏈的飽和經基（hydrocarb〇n residue)、直鏈或分枝鏈的飽和不飽和羥基、脂環式羥基、 芳香族羥基、及選自化學式一〇_Rl所成群類的化學基 〈式中，R1係碳數1〜8的直鏈或分枝鏈的飽和羥基、直鏈 或分枝鏈的飽和不飽和羥基、脂環式羥基或芳香族羥 土〉》在如述有機化合物以外的有機溶劑中，使之發生醋 化反應，藉由此方法，製造氰基乙酸酯；於本方法中，前 述有機浴劑係由25。(：時氰基乙酸的溶解度為i〔公克 a克冷剜〕以上的第一溶劑、和25。〇時實質地不溶於水的 第劑所確實構成’以此為特徵的氰基乙酸g旨的製造方 法。 2. 別述1.所讀之氰基乙_旨的製造方法，其巾前述第一溶 胃（parameter)係6.G〜1G.G，以此為特徵 之氰基乙酸酯的製造方法。 」述1.或2.所喊之氰基乙㈣的製造方法，相對於前述 亂基乙酸1草rm t \ 旦 、今Uole) ’前述第一溶劑係使用20〜300質 4 Si ’ Μ4特徵之氰基乙触的製造方法。 ，L .之任—者所記載之氰基乙酸酯的製造方法，相 對於前述氰基乙酸 所θ 莫耳，前述第二溶劑係使用20〜150 貝置部分，以此為特徵之I基乙酸酷的製造方法。 6 101109546 1013203354-0 201238940 + 4,之任—者所記载之氰基乙酸醏的製造方法，豆 中前述第一溶劑和第·/衣以万忐具 劑），軌卜 ; 為特徵之氰基乙酸酯的製造方法。 中Γ料^之任—者所記載之餘乙_的製造方法，其 於鼠基乙酸1莫耳，前述有機化合物的量係1〜2倍 莫耳數’以料顧之氰紅__造方法。 一 【發明之成果】 【0008】 本發明之有關於氰基乙酸軸製造方法巾，前述一般化 學式職所表示之有機化合物以外之有機溶劑，係併用氰基 ^酸办解度在特讀量以上的第—賴和實質地不溶於水的 第二溶劑，進行氰基乙酸_旨化反應。此製造方法，因為反 應、系統内為均質、又醋化所生成的水很容易分離醋化反應 ° Μ有效率地進行’其結果產物域s旨·率就可以提 间。又，依據此製造方法，也可以抑制两二酸二乙醋（的別 malonate)等的副產物的產生。 【解決問題所採去的方法】 【0009】 以下將s兒明有關於本發明的一個實施型態，但本發明並 非偈限於此。 101109546 1013203354-0 201238940 本發明相關之氰基乙酸酯的製造方法，係氰基乙酸與以 化學式R0H表示之有機化合物的酯化反應《式中，r係碳數1 〜ίο的直鏈或分枝鏈的飽和羥基（hydrocarbon residue)、 直鏈或分枝鏈的飽和不飽和羥基、脂環式羥基、芳香族羥基、 及選自化學式一GH4—0—R1所成群類的化學基〈式中，Rl係碳 數1〜8的直鏈或分枝鏈的飽和羥基、直鏈或分枝鏈的飽和不 飽和羥基、脂環式羥基或芳香族羥基〉》’在該有機化合物以 外的有機溶劑中進行。詳細地說，此有機溶劑’係由在25t 時氰基乙酸的溶解度為丨〔公克/1〇〇公克溶劑〕以上的第一 心劑、和在25 C時實質地不溶於水的第二溶劑，實質地構成。 所明有機溶劑由前述第一溶劑和前述第二溶劑「實質地構 成」’意指有機溶劑的大部分由前述第一溶劑和前述第二溶劑 的二成份構成，但也容許含有不影響酯化反應的數量的第三 心劑成分。再者，本發明中所使用之有機溶劑，係指相對於 原料之氰基乙酸及前述化學式為R〇H的化合物而言，係惰性溶 劑之意義。 【0 0 10】 1.以化學式表示之有機化合物 本發明中所用之化學式R〇H表示之有機化合物《式中，R 係石反數1〜10的直鏈或分枝鏈的飽和錄、直鏈或分枝鍵的 飽和不飽和雜、脂環式祕、芳香御i基、及選自化學式 8 101109546 1013203354-0 201238940 〇 R所成群類的化學基〈式中，纪係碳數卜8的直 或刀枝鏈的飽和㉙基、直鏈或分枝鏈的飽和不飽和經基、、 脂ί哀式祕絲香御t基〉》，具體來說，魏自脂肪族醇類 Uliphatw alcx^⑷、脂環族醇類（aiicyciic —s)'芳香族醇類（咖响&1地〇13)、和賽膝素 (cellosolves)所成群類之化合物，作為雜反應的原料； 前述_絲德料的魏係1〜1G ;又，前破所表示之 化學基的碳數係1〜8。前述有機化合物的具體實例，可列舉 使用的有.曱醇、〔醇、卜丙醇、2_丙醇、卜丁醇、2_丁醇、 特丁醇、1-戊醇、2-戊醇、3_戊醇、新戊醇（ne〇卿加 alcohoi) '卜己醇、2—己醇、3_己醇、2一乙基丁醇(2娜 butanol )、1-庚醇（heptan〇1 )、2_庚醇、3_庚醇、卜辛醇 (octanol)、2-辛醇、2-乙基己醇、卜癸醇（decan〇1)、卜 壬醇（_anol)、2-甲基-2-丁醇、2_甲基+丁醇、3_甲基 -1-丁醇、3-甲基-2-丁醇、4-甲基-2-戊醇、烯丙醇（allyl alcohol)、2-甲基-2—丙-1-醇 、 3-丁-1-醇（3-butan-l-〇l)、4-戊-卜醇、2-甲基-4-戊-卜醇、 2-乙基-4-戊+醇、2-乙基-5-己-1-醇、5_己+醇、環己醇 (cyclohexanol)、甲基環己醇、2-甲氧基乙醇 (2-methoxyethanol)、2-乙氧基乙醇（2_eth〇Xyethan〇1)、 丁氧基乙私、2-本氧基乙醇（2-phenoxyethanol)、2-(苄 氧基）乙醇（2-(benyloxy) ethanol)、2-(環己氧基）乙醇 101109546 1013203354-0 201238940 (2气0ycl0hexyloxy) ethanol)、2-丙氧基乙醇;· 2-異丙氧 基乙醇（2-isopropoxy ethanol)、2-異丁氧基乙醇、乙基丁 基賽路素（ethyl butyl cell〇solves)、2-特-丁氧基乙醇、 和乙—醇單己基鱗（ethyiene giyC〇i m〇n〇hexyi的匕打）等。 在這些化合物之中，由於氰基乙酸的溶解度要很高，因 此甲醇、乙醇、1-丙醇、2-丙醇、卜丁醇、2_丁醇、特—丁醇、 2-甲氧基乙醇和2-乙氧基乙醇是較為理想的；而甲醇、乙醇、 1丙醇、2-丙醇更為理想。錢化合物的氰基乙酸溶解度高 的情形時，反齡統成辆質狀態，化反應變得更有利。 【0011】 别述有機化合物的數量，相對於氰基乙酸丨莫耳，以J 〜2倍莫耳為合於理想，丨.丨〜丨.8倍莫耳則又較理想，^ 2〜 1. 6倍莫销更合魏想。有機化合物的數量，若未達】倍莫 ^ ’則會雜未反應的氰基乙酸，使氰基乙_旨喊率無法 提高；另-方面’若超過2倍莫耳，則會使製造成本變高。 [0 0 12] 2.第一溶劑 本發明所使用之第-溶劑，係前述化學式麵所示之有 航合物以外之有機溶劑，並且在饥時，氰基乙酸的溶解 度是1〔公克公克溶劑〕以上的有機溶劑。 10 101109546 1013203354-0 201238940 前述第一溶劑’〜在25°C時’氰基乙酸的溶解度必須是1 〔公克/100公克溶劑〕以上的有機溶劑《通常是2〇〇〔公克 /100公克溶劑〕以下》；該溶解度是10〔公克/丨⑽公克溶 劑〕以上較合於理想’20〔公克/100公克溶劑〕以上更為理 想。溶解度若未達1〔公克/1〇〇公克溶劑〕的話，氰基乙酸 無法實質地溶解於第一溶劑中，由於反應系統變得不均質， 其結果是氰基乙酸酿的產率無法提高。 Ο 再者，前述溶解度係表示1〇〇公克溶劑所溶解的氰基乙 酸的質量’其策定方法將描述於後。 [0 0 13] 刖述第一溶劑的溶解度參數（s〇 1 ub i 1 i parameter )《以 下’也稱為「SP值」》以6. 〇〜ι〇· 〇為合於理想，& 5〜9. 5 則更為理想、7· 0〜9. 5又更為理想。SP值未達到6的話，由 〇 於氰基乙酸的溶解性有變壞的傾向，醋化反應的情形變的不 均質’例如氰基乙酸的溶解度無法使高醇類等消耗，則進行 良好醋化反應就變的_;另一方面，sp值超過1{)的話，則 與_化學式表示之有機化合物的親和性會變差，藉由醋化 反應時脫水城_出水巾，前述_化合物讀水一起被 大置餾出，因此，發生酯化反應進行麟的情形。 【0 0 14】 101109546 11 1013203354-0 201238940 “ 本發明中的sp值’係依照以下公式計算而得的。 SP值 {(」H—RT) /V} 1/2 5 : SP值《（卡/亳升）i/2》（（cal/ml)1/2) :莫耳蒸發熱《卡/莫耳》（cai/m〇i) R :氣體常數《1. 98Ή卡/莫耳•絕對溫度》 (1.9871 cal/mol*K) T :絕對溫度《K》 V :莫耳體積《毫升/莫耳》 又’混合系統的SP值，係由以下所求得。 (5®ίχ=Σ (0i«Vi· δ i) ΧΣ ( φί· Vi) 心：溶劑i的SP值 ;谷劑i的體積分率（v〇lume fracti〇n)《此處， Σ 0i = l}201238940 VI. Description of the Invention < (Technical Field of the Invention) [000 1] The present invention relates to an intermediate product which can be used as an intermediate product of pharmaceuticals and agricultural chemicals, and as an intermediate product of industrial products. A method for producing cyanoacetate. In the present invention, the term "cyanoacetate" refers to a cyanoguanidine acetate whose chemical formula is generally represented by NCCOH2C〇〇R. In the chemical formula, R is selected from a linear chain having a carbon number of 1 to 10. Or a branched hydrocarbon chain hydrocarbon residue, a linear or branched chain unsaturated carbon ruthenium compound, an alicyclic carbon ruthenium compound, an aromatic hydrocarbon, and a chemical formula C-O- A chemical functional group of a group consisting of R1. In the chemical formula, R is a linear or branched chain saturated hydrocarbon having a carbon number of 1 to 8, and a linear or branched chain unsaturated hydrocarbon. , alicyclic hydrocarbons, or aromatic hydrocarbons. [Prior Art] [0 0 0 2] In the past, the method for producing cyanoacetate was generally carried out in the presence of an acid catalyst to cause cyanoacetic acid (alcohol) to occur. Dehydration esterification reaction; for example, Patent Document 1 discloses 101109546 1013203354-0 201238940, which contains a method for producing neopentyl α-cyanoacetate. Cyanoacetic acid, ne〇pentyl alcohol, sulfuric acid and toluene are reacted back to k (ref lux), and the water produced is under the common Buddha (3 〇廿叩^·) In addition, a neopentyl α-cyanoacetate is produced, and a method of producing &~Go cyanoacetate to U alkyl cyanoacetate is described in Patent Document 2, and cyanoacetic acid and G are used. ~U-alcohol~C1D alkanol) A-mercaptocyanoacetate was prepared by reacting in the presence of a catalyst in an aqueous medium and separating the G~Go alcohol/water mixture. Further, in Patent Document 3, in the acetification reaction in an aqueous medium, the acetification antisense is carried out in the presence of 曱 杂 · ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The method of phase. [PRIOR ART DOCUMENT] [Patent Document 1] [Patent Document 1] [Patent Document 1] JP-A No. 9-188657 (Patent Document 3) Japanese Laid-Open Patent Publication No. Hei 9-188657 [Problems to be Solved by the Invention] 101109546 1013203354-0 201238940 [0 0 0 4] However, in the method for producing a cyanoacetate disclosed in the contents of Patent Documents 1 to 3, there is a cyanoacetate. The problem of low yield; further, the patent document] and the method of the method of 3F. The method of making a towel has the problem of excessive by-products and too much toxicity due to the use of toluene as a riding solvent; Among the disclosed manufacturing methods, there is a problem that a large amount of alcohol must be used for esterification. [0 0 0 5] In view of the above problems, an object of the present invention is to provide a process for producing cyanoacetic acid vinegar which can improve the yield of cyanoacetic acid and produce little by-products. [Method for Solving the Problem] 〇 [〇〇〇6] The invention team of the present invention produces cyanoacetic acid by esterification reaction of cyanoacetic acid with an organic compound having a ruthenium H group in an organic solvent. In the method of ester, a method for increasing the yield of cyanoacetate is obtained by using a cyanoacetic acid having a solubility of a specific amount or more of a first solvent and a second solvent substantially insoluble in water, thereby effecting an esterification reaction. Efficiently carried out, thus increasing the yield of cyanoacetate. [0 00 7] 1013203354-0 101109546 201238940 That is, the present invention is as follows: 1. Cyanoacetic acid and an organic compound represented by the chemical formula _ wherein R is a linear chain of 1 to ί a hydrocarb〇n residue of a branched chain, a saturated unsaturated hydroxyl group of a linear or branched chain, an alicyclic hydroxyl group, an aromatic hydroxyl group, and a chemical group selected from the group consisting of the chemical formula RR1 In the formula, R1 is a saturated hydroxy group of a linear or branched chain having a carbon number of 1 to 8, a saturated unsaturated hydroxy group of a straight or branched chain, an alicyclic hydroxy group or an aromatic hydroxy sulphate. In the organic solvent other than the above, a acetalization reaction is carried out to produce a cyanoacetate. In the present method, the organic bath is 25. (The solubility of cyanoacetic acid is i [g gram a gram cold 剜] or more of the first solvent, and 25. The 剂 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质 实质2. The method for producing cyanoacetic acid, which is described in 1. The first method of the above-mentioned table is 6.G~1G.G, which is characterized by cyanoacetic acid. A method for producing an ester. The method for producing a cyanoethane (IV) as described in 1. or 2. The method for producing a cyanoethane (IV) is based on the above-mentioned first solvent system using 20 to 300 masses. 4 Si ' Μ 4 characteristic cyano B contact manufacturing method. The method for producing a cyanoacetate according to the above, wherein the second solvent is a 20-150-shell portion based on the θ-mol of the cyanoacetic acid, and the first group is characterized by A cool manufacturing method for acetic acid. 6 101109546 1013203354-0 201238940 + 4, the method for producing bismuth cyanoacetate described in the above, the first solvent in the bean and the first/clothing ivory agent, orbital; characteristic cyanide A method for producing a base acetate. In the method of manufacturing the remaining material, the amount of the organic compound is 1 to 2 times the number of moles. method. [Effect of the Invention] The present invention relates to a method for producing a cyanoacetic acid shaft, and the organic solvent other than the organic compound represented by the general chemical formula is used in combination with a cyanoacid The first solvent and the second solvent which are substantially insoluble in water are subjected to a cyanoacetic acid reaction. In this production method, the water produced by the reaction, the homogenization in the system, and the acetification are easily separated from the acetalization reaction. Μ The efficiency of the product can be efficiently carried out. Further, according to this production method, the generation of by-products such as diammonic acid diethyl vinegar (other malonate) can be suppressed. [Method for Solving the Problem] [0009] Hereinafter, an embodiment of the present invention will be described, but the present invention is not limited thereto. 101109546 1013203354-0 201238940 A method for producing a cyanoacetate according to the present invention, which is an esterification reaction of cyanoacetic acid with an organic compound represented by the chemical formula R0H, wherein a linear or fraction of r is a carbon number of 1 to ίο a saturated hydrocarbon residue of a branched chain, a saturated unsaturated hydroxyl group of a linear or branched chain, an alicyclic hydroxyl group, an aromatic hydroxyl group, and a chemical group selected from the group consisting of the chemical formula GH4-0-R1 In the above, R1 is a saturated hydroxyl group of a linear or branched chain having a carbon number of 1 to 8, a saturated unsaturated hydroxyl group of a straight or branched chain, an alicyclic hydroxyl group or an aromatic hydroxyl group, and an organic organic compound other than the organic compound It is carried out in a solvent. In detail, the organic solvent' is a first core agent having a solubility of cyanoacetic acid of more than 5% [g / 1 gram of solvent) at 25 Torr, and a second solvent substantially insoluble in water at 25 C. , substantially constituted. The organic solvent described above is "substantially constituted" from the first solvent and the second solvent. It means that most of the organic solvent is composed of two components of the first solvent and the second solvent, but the content of the second solvent and the second solvent is also allowed to be contained, but the esterification is also allowed to be affected. The amount of the third heart agent component of the reaction. Further, the organic solvent used in the present invention means the meaning of an inert solvent with respect to the cyanoacetic acid of the raw material and the compound of the above formula R〇H. [0 0 10] 1. Organic compound represented by chemical formula The organic compound represented by the chemical formula R〇H used in the present invention is a saturated or straight chain of a linear or branched chain having an inverse number of 1 to 10 of the R system. a saturated unsaturated heterocyclic ring of a chain or a branched bond, an alicyclic formula, an aromatic group, and a chemical group selected from the group consisting of Chemical Formula 8 101109546 1013203354-0 201238940 〇R, wherein the carbon number is 8 Straight or slashed chain of saturated 29-base, linear or branched chain saturated unsaturated thiol, and ί 式 式 秘 秘 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ^(4), a compound of the alicyclic alcohol (aiicyciic-s) 'aromatic alcohols (Calphon & 1 cellar 13), and cellosolves, as a raw material for the heteroreaction; _ silk material of the Wei system 1 ~ 1G; again, the chemical base of the former broken carbon number is 1 ~ 8. Specific examples of the aforementioned organic compound include decyl alcohol, [alcohol, propanol, 2-propanol, butanol, 2-butanol, tert-butanol, 1-pentanol, 2-pentanol , 3_pentanol, neopentyl alcohol (ne〇qing plus alcohoi) 'p-hexanol, 2-hexanol, 3-hexanol, 2-ethylbutanol (2na butanol), 1-heptanol (heptan〇) 1), 2_heptanol, 3-heptanol, octanol, 2-octanol, 2-ethylhexanol, diterpene alcohol (decan〇1), diterpene alcohol (_anol), 2- Methyl-2-butanol, 2-methyl+butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 4-methyl-2-pentanol, allyl alcohol Allyl alcohol), 2-methyl-2-propan-1-ol, 3-butan-1-l-ol, 4-pentanol, 2-methyl-4-pentyl - phenol, 2-ethyl-4-pentanol, 2-ethyl-5-hexan-1-ol, 5-hexanol, cyclohexanol, methylcyclohexanol, 2-methyl 2-methoxyethanol, 2-ethoxyethanol (2_eth〇Xyethan〇1), butoxyethyl, 2-phenoxyethanol, 2-(benzyloxy)ethanol ( 2-(benyloxy) ethanol), 2-(cyclohexyloxy)ethanol 101109546 1013203354-0 201238940 (2 0ycl0hexyloxy) ethanol), 2-propoxyethanol; 2-isopropoxy ethanol, 2-isobutoxyethanol, ethyl butyl cell〇solves, 2-tert-butoxyethanol, and ethyl-hexanol monohexyl scale (ethyiene giyC〇im〇n〇hexyi). Among these compounds, since cyanoacetic acid has a high solubility, methanol, ethanol, 1-propanol, 2-propanol, butanol, 2-butanol, tert-butanol, 2-methoxyl Ethanol and 2-ethoxyethanol are preferred; methanol, ethanol, 1-propanol, 2-propanol are more desirable. When the solubility of the cyanoacetic acid of the money compound is high, the reaction state becomes more favorable when the anti-age is integrated into the host state. [0011] The amount of the organic compound is different from that of the cyanoacetate, and the J 2 to 2 times the molar is ideal, and the 丨.丨~丨.8 times the molar is ideal, ^ 2~ 1 6 times more than the sale of Wei thought. If the amount of the organic compound is less than 5%, then the unreacted cyanoacetic acid will be mixed, so that the cyanoethyl _ 喊 无法 rate cannot be increased; otherwise - if it exceeds 2 times the molar cost, the manufacturing cost will be changed. high. [0 0 12] 2. First solvent The first solvent used in the present invention is an organic solvent other than the above-mentioned chemical formula, and the solubility of cyanoacetic acid is 1 [g] in hunger. Solvent] The above organic solvent. 10 101109546 1013203354-0 201238940 The above first solvent '~ at 25 ° C 'the solubility of cyanoacetic acid must be 1 [g / 100 g solvent] above the organic solvent "usually 2 〇〇 [g / 100 g solvent) The following is more preferable because the solubility is 10 [g/g (10) gg solvent] or more than the ideal '20 [g/100 g solvent]. If the solubility is less than 1 [g/1 gram of the solvent], the cyanoacetic acid cannot be substantially dissolved in the first solvent, and as the reaction system becomes heterogeneous, the yield of the cyanoacetic acid can not be improved. Further, the above solubility means the mass of cyanoacetic acid dissolved in 1 gram of the solvent. The method of the determination will be described later. [0 0 13] Describe the solubility parameter of the first solvent (s〇1 ub i 1 i parameter ) "The following 'also known as "SP value"" is 6. 〇~ι〇· 〇 is ideal, & 5~9. 5 is more ideal, 7·0~9. 5 is more ideal. When the SP value is less than 6, the solubility of cyanoacetic acid tends to be deteriorated, and the acetalization reaction becomes heterogeneous. For example, if the solubility of cyanoacetic acid cannot be consumed by high alcohols, good vinegar is carried out. On the other hand, if the sp value exceeds 1{), the affinity with the organic compound represented by the _chemical formula may be deteriorated, and the hydrated towel may be dehydrated by the hydration reaction, and the aforementioned _ compound is read. The water is largely distilled off together, and therefore, the esterification reaction takes place in the case of Lin. [0 0 14] 101109546 11 1013203354-0 201238940 "The sp value in the present invention" is calculated according to the following formula: SP value {("H-RT) /V} 1/2 5 : SP value "(card /亳升)i/2"((cal/ml)1/2) : Moel evaporating heat "Card/mear" (cai/m〇i) R: Gas constant "1. 98Ή卡/莫耳• Absolute Temperature" (1.9871 cal/mol*K) T: Absolute temperature "K" V: Mohr volume "ml/mole" The SP value of the 'mixed system' is determined by the following. (5®ίχ=Σ(0i«Vi· δ i) ΧΣ ( φί· Vi) Heart: SP value of solvent i; volume fraction of grain i (v〇lume fracti〇n) "here, Σ 0i = l}
Vi :溶劑i的莫耳體積 表1所示之代表性的溶劑的sp值，係在2〇〇c時，從莫耳 蒸發熱和莫耳體積的數值計1出來的。再者，莫耳蒸發熱和 莫耳體積餘據福井弘康崎『以Excel就能朗的化學物 質的物理性質』。 【0015] 作為第/谷劑可以使用的有網類（ket〇n )溶劑、醋類 (ester)溶劑、醯胺類（amide)溶劑、和鍵類（础沉）溶 101109546 1013203354-0 201238940 -.-- . —ϊ — —* 、, .、 .r: ., ;.〇 齊|J Ο ' π 具體的例示，作為酮類溶劑，可以列舉使用的有：1_辛 酮（1-octanone)、2-辛明、1-壬酮（i_nonanone)、2-壬酮、 丙酮（acetone)《SP值 9· 8》、4-庚酮（4-heptanone)、1-己 酮（1-hexanone)、2-己酮、環己酮、甲基環己酮、苯基丙酮 (phenylacetone)、曱乙酮（methylethyiketone)《SP值 9. 2》、甲基異丁基酮（methyl isobutyl ketone)、曱基-n-o 戊基酮（methy卜n-amyl ketone)、甲基-n-丁基酮、曱基-η- 丙基酮、甲基-η-己基酮、甲基-η-庚基酮、乙基-η-丁基酮、 二乙基嗣、二-η-丙基酮（di-n-propyl ketone)、二異丙基 酮、二異丁基酮、乙醯丙酿1 (acetyl-acetone)、己二酮 (acetony卜acetone)、二丙酮醇（Diacetone alcohol)、乙 酿曱醇（acetyl carbinol)、笨乙酮（acetophenone)、曱基 萘基酮（methyl naphtyl ketone)、異佛爾酮（Isophorone)、 Q 碳酸丙稀酯（propylene carbonate)等。 作為酯類溶劑，可以列舉使用的有：醋酸曱酯、醋酸乙 酯《SP值9. 0》、醋酸異丙酯、醋酸丁酯《SP值8. 7》、醋酸 戊醋、醋酸2-乙基己酯、甲酸甲醋（methyl formate)、曱酸 乙酯、曱酸丁酯、曱酸丙醋、乳酸乙酷（ethyl lactate)、 乳酸丁酯、乳酸丙酯、己二酸二乙酯（Diethyl adipate)、 乙酿檸檬酸三乙SI (acetyl triethyl citrate)、笨曱酸乙 酯（ethyl benzoate)、草酸二乙酯（diethyl oxalate)、碳 101109546 1013203354-0 13 201238940 酸二乙醒（diethyicarbonate)、鄰苯二甲酸土乙酯（犯61±^1 phthalate)、丙酸乙酯（ethyl propionate)等。 作為醯胺類溶劑，可以列舉使用的有：N-甲基-2-吡咯烷 酮（N-methyl -2-pyrrolidone)、N, N-二甲基乙醯胺 (N，N-dimethyl actamide)、N，N-二甲基曱醯胺 (N，N-dimethylformamide)、六曱基填醯三胺 (hexamethylphosphoric triamide)、1，3-二曱基-2-咪口坐琳 晒（l，3-dimethyl-2-imidazolidinone)等。 作為鍵類溶劑’可以列舉使用的有：乙二醇（ethylene glycol)《SP 值 15. 9》、二乙二醇醚（或二甘醇；diethylene glycol)、三甘醇（triethylene glycol)等的二醇類溶劑； 另外還有.乙基異戊基鍵、乙基-特-丁基謎、乙基节基鍵 (ethyl benzyl ether)、二曱基醚、二乙基醚、二丙基醚、 二異丙基醚《SP值7. 2》、二丁基醚、二異戊基醚、二苯基醚、 二节基醚、二噁烷（dioxane)、四氫呋喃（tetrahydrofuran) 等可以列舉使用。這些溶劑可以單獨使用或二種以上混合使 用0 【0016】 第一溶劑的使用量，相對於氰基乙酸1莫耳，以使用2〇 〜3〇〇質量部分為合於理想，使用30〜250質量部分更為理 想，使用40〜160質量部分又更為理想。其使用量未達2〇質 101109546 1013203354-0 201238940 、量部分翁，瓶麟《錄職均餘態，氣基乙酸醋 的產率無法提高m超過綱㈣部分的話，也無 法提高氰基乙義率，反使生絲本變高。 【0 0 17] 3.第二溶劑 本發明中所使用之第二溶劑，係在25°c時實質地不溶於 〇 水的有機溶劑，當然就是前述化學式R0H所表示之有機化合 物以外之有機溶劑。由於第二溶劑係實質地不溶於水，酯化 反應時所生成的水就很容易與其分離，因此氰基乙酸酯的產 率就可以提高。 此處，於本發明中，所謂實質地不溶於水，係意指在25 °C時相對於水的溶解度為低於1%質量百分比。 〇 【0018】 作為第二溶劑’可列舉烴類（hydrocarbons)溶劑，具 體的例示有：苯（benzene)、甲苯（toluene)、二甲苯（xylene) 等芳香族烴類溶劑；環己烷、曱基環己烷等脂環族烴類溶劑； 戊院（pentane)、己烧、庚烧（heptane)、辛烧（octane)、 癸烷（decane)等脂族烴類溶劑可以列舉使用。這些溶劑中， 沸點較低、相對毒性比較低的己烷、環己烷、及庚烷較為合 於理想；沸點較高的情形時，酯化反應的溫度變高，產生多 15 101109546 1013203354-0 201238940 量的丙二酸二乙酯（ethyl mal0nate，)等副產物。 【0019】 第二溶劑的使用量’相對於氰基乙酸1莫耳，以使用20 〜150質量部分為合於理想，使用3〇〜13〇質量部分更為理 想，使用40〜120質量部分又更為理想。其使用量未達2〇質 量部分的話，則酯化反應生成的水很難分離，氰基乙酸酯的 產率無法提高；另一方面，超過15〇質量部分的話，也無法 提南氰基乙酸醋的產率，反使生產成本變高。 [00 2 0] 前述第一溶劑和第二溶劑的質量比《第一溶劑/第二溶 劑》，以0. 5〜3. 0為合於理想，〇· 8〜2. 5更合於理想，1 〇 〜2. 0又更合於理想。該質量比未達〇. 5的話，則反應系統内 很難形成均質狀H ’有氰基乙酸g旨的產率無法提高的情形； 另-方面，超過3· G的話’義化反應生成的水很難分離， 容易造成氰基乙酸S旨的產率無法提高。 [002 1] 4.酸催化劑 本發明之酯化反應係在酸催化劑 的存在下進行的 酸催化劑’係使用強的無機酸或有機酸，例如碎妒 ，所謂 鹽酸、 101109546 1013203354-0 16 201238940 —’— 磷酸’苯石黃酸（benzenesulfonic acid)、鄰-甲苯續酸 (o-toluenesulfonic acid)、對曱苯確酸 (P-toluenesulfonic acid)、甲續酸（methanesulfonic acid)、二氣曱石黃酸（trifluoromethanesulfonic acid)、三 氟醋酸（trifluoroacetic acid)、單氣醋酸 (monochloroacetic acid)、二氣醋酸（dichloroacetic acid);及三氯醋酸（trichloroacetic acid)等可以列舉使 〇 用。從容易取得和對搪玻璃（Glass Lining)反應容器的腐 蝕之觀點來看，則硫酸或對甲苯確酸是較為理想的。 酸催化劑的量，相對於氰基乙酸丨莫耳，以〇. 〇1〜〇. 5 莫耳是合於理想的’ 0. 05〜〇· 3莫耳則更合於理想。 醋化反應結束後’用水洗或用碳酸鈉等簡姓水溶液加以 洗淨，可望除去酸催化劑。若省略了酸催化劑的去除作業就 進行氰基乙酸醋的精製蒸顧，則氰基很容易水解，副產物如 ❹ 丙二酸半醋（half的加of mal〇nic 或丙二酸二乙 酯（ethyl malonate)很容易產生。 [0 0 2 2] 5.醋化反應 本發明相關之氰基乙_旨的製造方法，係使用前述原 料’在酸催化劑的存在下，於前述有機溶劑中，進行醋化反 應。醋化反應的進行，係一面使有機溶劑迴流，一面持續除 101109546 17 1013203354-0 201238940 去生成的水。迴流溫度％依據以、'化莩式示之有機化合 物的種類、以及第一溶劑和第二溶劑的種類來決定，但50〜 100°C是合於理想的，55〜9(rc更合於理想，6〇〜8{rc又更合 於理想。迴流溫度在5G〜1GG°C的範圍以外時，可以用加壓或 減壓的方法來調整，但在大氣壓下進行迴流，其操作容易方 便，而較合於理想。迴流溫度低於5(rc的話，則酯化反應的 進行變慢，無法提高氰基乙酸酯的產濾；另一方面，超過1〇〇 °C的話，則會有丙二酸二乙酯等副產物大量產生的情形。 餾出液中不含水的時點到達時，酯化反應就結束了。接 著，將反應液冷卻後，用水或驗性水溶液洗，將酸催化劑中 和’得到分離為三相的反應液。分離的反應液之中，藉由蒸 顧精製上層《有機溶劑相》和中層《氰基乙酸酯相》，可以得 到向純度的亂基乙酸醋。 【實施方式】 [0 0 2 3] 關於本發明的内容，將以實施例和比較例為基礎，具體 地說明’但本發明並非侷限於此處之說明。又’本發明中， 氰基乙酸的溶解度、各種有機化合物的定量、及水的份量， 依照以下方法測定之。 1.測定方法 101109546Vi: Molar volume of solvent i The sp value of the representative solvent shown in Table 1 is from the numerical value 1 of the evaporation heat of the mole and the volume of the molar volume at 2 〇〇c. Furthermore, Mohr's heat of evaporation and the volume of Mohr's volume are based on the physical properties of Fukui Hiroyaki's "chemical properties that can be distinguished by Excel." [0015] As a grazing agent, a ket〇n solvent, an ester solvent, an amide solvent, and a bond may be used. 101109546 1013203354-0 201238940 - .-- . . . ϊ — — — | | | | | | | | | | | | | | | 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体), 2-octyl, 1-nonanone, 2-nonanone, acetone (SP value 9·8), 4-heptanone, 1-hexanone (1-hexanone) ), 2-hexanone, cyclohexanone, methylcyclohexanone, phenylacetone, methylethyiketone, SP value 9.2, methyl isobutyl ketone, Mercapto-no amyl ketone (methy) n-amyl ketone, methyl-n-butyl ketone, decyl-η-propyl ketone, methyl-η-hexyl ketone, methyl-η-heptyl ketone , ethyl-η-butyl ketone, diethyl hydrazine, di-n-propyl ketone, diisopropyl ketone, diisobutyl ketone, acetophenone 1 (acetyl- Acetone), acetony acetone, diacetone alcohol, ethoxylated sterol (acetyl carbinol), acetophenone, methyl naphtyl ketone, Isophorone, Q propylene carbonate, and the like. Examples of the ester solvent include: decyl acetate, ethyl acetate "SP value 9. 0", isopropyl acetate, butyl acetate "SP value 8.7", acetic acid vinegar, acetic acid 2-B Hexyl hexyl ester, methyl formate, ethyl decanoate, butyl citrate, propyl citrate, ethyl lactate, butyl lactate, propyl lactate, diethyl adipate ( Diethyl adipate), acetyl triethyl citrate, ethyl benzoate, diethyl oxalate, carbon 101109546 1013203354-0 13 201238940 acid dithyze (diethyicarbonate) Ethyl phthalate (61±^1 phthalate), ethyl propionate, etc. Examples of the guanamine-based solvent include N-methyl-2-pyrrolidone, N,N-dimethyl actamide, and N. , N, N-dimethylformamide, hexamethylphosphoric triamide, 1,3-dimercapto-2-merylone (l,3-dimethyl -2-imidazolidinone) and so on. Examples of the solvent for the bond include ethylene glycol (SP value of 15.9), diethylene glycol (diethylene glycol), and triethylene glycol. a glycol solvent; additionally an ethyl isoamyl bond, an ethyl-tert-butyl group, an ethyl benzyl ether, a dimethyl ether, a diethyl ether, a dipropyl ether , diisopropyl ether "SP value 7.2", dibutyl ether, diisoamyl ether, diphenyl ether, dihydric ether, dioxane, tetrahydrofuran, etc. can be enumerated . These solvents may be used singly or in combination of two or more. [0016] The amount of the first solvent used is preferably 1 〇 to 3 〇〇 by mass, and 30 to 250, with respect to 1 mA of cyanoacetic acid. The quality part is more ideal, and it is more ideal to use the 40~160 mass part. Its use amount is less than 2 101101109546 1013203354-0 201238940, the amount of Weng, bottle Lin "records the average position, the yield of gas-based acetic acid vinegar can not be increased m more than the outline (four), then can not improve the cyano The rate, on the contrary, makes the raw silk become higher. [0 0 17] 3. Second solvent The second solvent used in the present invention is an organic solvent which is substantially insoluble in hydrophobic at 25 ° C, and is of course an organic solvent other than the organic compound represented by the above formula R0H. . Since the second solvent is substantially insoluble in water, the water formed during the esterification reaction is easily separated therefrom, so that the yield of the cyanoacetate can be increased. Here, in the present invention, the term "substantially insoluble in water" means that the solubility with respect to water at 25 ° C is less than 1% by mass.作为 [0018] The second solvent 'is a hydrocarbon solvent, and specific examples thereof include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and cyclohexane and hydrazine. An alicyclic hydrocarbon solvent such as cyclohexane; an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, octane or decane may be used. Among these solvents, hexane, cyclohexane, and heptane having lower boiling points and relatively lower toxicity are more desirable; in the case of higher boiling point, the temperature of the esterification reaction becomes higher, resulting in more than 15 101109546 1013203354-0 201238940 Amount of by-product such as ethyl mal0nate. [0019] The second solvent is used in an amount of 1 mole relative to cyanoacetic acid, preferably 20 to 150 parts by mass, and more preferably 3 to 13 parts by mass, using 40 to 120 parts by mass. More ideal. If the amount used is less than 2 parts by mass, the water produced by the esterification reaction is difficult to separate, and the yield of cyanoacetate cannot be improved; on the other hand, if the mass portion exceeds 15 〇, the south cyano group cannot be extracted. The yield of acetic acid vinegar makes the production cost higher. [0020] The first solvent and the second solvent are in a ratio of the first solvent to the second solvent. The first solvent/second solvent is 0. 5~3. 0 is ideal, 〇·8~2. , 1 〇 ~ 2. 0 is more ideal. If the mass ratio is less than 〇. 5, it is difficult to form a homogenous H'-containing cyanoacetic acid in the reaction system, and the yield cannot be improved. On the other hand, if it exceeds 3·G, the resulting reaction is formed. Water is difficult to separate, and it is easy to cause the yield of cyanoacetic acid to be improved. 4. Acid Catalyst The esterification reaction of the present invention is carried out in the presence of an acid catalyst, using a strong inorganic or organic acid, such as a mash, so-called hydrochloric acid, 101109546 1013203354-0 16 201238940 — '- Phosphoric acid' benzenesulfonic acid, o-toluenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid, dioxite yellow Trifluoromethanesulfonic acid, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid may be used. Sulfuric acid or p-toluene is preferred from the standpoint of easy availability and corrosion of the glass Lining reaction vessel. The amount of the acid catalyst is 相对. 〇1~〇. 5 Moer is in combination with the ideal ' 0. 05~〇· 3 Moer is more ideal than the 丨. After completion of the acetification reaction, it is expected to remove the acid catalyst by washing with water or washing with an aqueous solution of a simple name such as sodium carbonate. If the purification of the cyanoacetic acid vinegar is carried out by omitting the removal of the acid catalyst, the cyano group is easily hydrolyzed, and by-products such as ❹malonic acid half vinegar (half plus of mal〇nic or diethyl malonate) (ethyl malonate) is easily produced. [0 0 2 2] 5. acetification reaction The method for producing cyanoethane according to the present invention is to use the above-mentioned starting material 'in the presence of an acid catalyst in the aforementioned organic solvent, The acetification reaction is carried out by refluxing the organic solvent while continuing to remove water from 101109546 17 1013203354-0 201238940. The reflux temperature % is based on the type of the organic compound shown in the formula, and The first solvent and the second solvent are determined, but 50~100°C is ideal, 55~9 (rc is more ideal, 6〇~8{rc is more ideal. Reflow temperature is 5G) When it is outside the range of ~1GG °C, it can be adjusted by pressurization or decompression, but it is easy to handle under reflux at atmospheric pressure, and it is more desirable. When the reflux temperature is lower than 5 (rc, ester) The progress of the reaction is slow and cannot be mentioned. On the other hand, if it exceeds 1 ° C, a by-product such as diethyl malonate may be produced in a large amount. When the distillate does not contain water, the ester is obtained. After the reaction solution is cooled, it is washed with water or an aqueous solution, and the acid catalyst is neutralized to obtain a reaction liquid which is separated into three phases. Among the separated reaction liquids, the upper layer is refined by steaming. The organic solvent phase and the middle layer "cyanoacetate phase" can obtain the purity of the vinegar acetate. [Embodiment] [0 0 2 3] The content of the present invention will be based on the examples and comparative examples. Specifically, the present invention is not limited to the description herein. In the present invention, the solubility of cyanoacetic acid, the amount of various organic compounds, and the amount of water are measured according to the following method. 1. Measurement method 101109546
1S 1013203354-0 201238940 〇) 1基乙酸的溶解度， 氰基乙酸的溶解度，全部在25t受控制的室内測定。 。100亳升燒杯中’取約8公克氰基乙酸《和光純藥特級 品》’加入燒杯中，加入並儘可能地緩慢攪拌測定溶劑，使用 攪拌棒（Stirring bar)授拌的同時，正確計量其投入量， 直到氰基乙酸完全溶解。達到終點時間前，以每1〇分鐘加入 5公克程度操作，直到終點時，從投入的溶劑重量，計算出 〇 氛基乙酸的溶解度《單位：〔公克/loo公克溶劑；）》。又， 在添加溶劑時，為了抑制溶劑揮發，在燒杯上包覆保鮮膜 (cling wrap or food wrap)0 另一方面，若是n-己烷等溶解度極低的溶劑的時候，將 〇· 1么克《精枰過》氰基乙酸放入5〇· 〇公克溶劑中，攪拌3〇 分鐘後，過濾分離，乾燥濾出的殘渣，計量未溶解的氰基乙 酸，求出溶解量。 〇 表1中顯示代表性的有機化合物、第一溶劑和第二溶劑 的SP值、及氰基乙酸的溶解度。 (2)有機化合物等的定量 有機化合物、各種溶劑、氰基乙酸酯、及丙二酸二乙酯 的定罝分析’利用氣相層析法（GasChromatography)實施。 針對定量，以二噁烷（dioxane)做為内部標準液，作成預先 標準曲線（beforehand standard curve)。 101109546 1013203354-0 19 201238940 … < 氣相層析―法的測定條件〉 管柱：DB-1 ’膜厚5微米（//m)、長度30米、内徑〇. 320毫米、1S 1013203354-0 201238940 〇) The solubility of 1-based acetic acid, the solubility of cyanoacetic acid, all measured in a 25t controlled chamber. . In a 100-liter beaker, take about 8 grams of cyanoacetic acid "Wako Pure Medicine" and add it to the beaker. Add and stir the solvent as slowly as possible. Use a Stirring bar to mix and measure. The amount of input until the cyanoacetic acid is completely dissolved. Before reaching the end time, add 5 grams per 1 minute to the end point, and calculate the solubility of the thiol acetic acid from the weight of the solvent charged. Unit: [grams per gram of solvent;). In addition, when adding a solvent, in order to suppress the volatilization of the solvent, a cling wrap or food wrap is applied to the beaker. On the other hand, if it is a solvent having a very low solubility such as n-hexane, what is the 〇·1?克 "精枰过" cyanoacetic acid was placed in a solvent of 5 〇 〇 gram, stirred for 3 〇 minutes, separated by filtration, and the residue was filtered, and the undissolved cyanoacetic acid was measured to determine the amount of dissolution. 〇 Table 1 shows the representative organic compounds, the SP values of the first solvent and the second solvent, and the solubility of cyanoacetic acid. (2) Quantification of organic compound, etc. The organic compound, various solvents, cyanoacetate, and diethyl malonate were analyzed by gas chromatography (GasChromatography). For the quantification, a dioxane was used as an internal standard solution to prepare a beforehand standard curve. 101109546 1013203354-0 19 201238940 ... <Measurement conditions of gas chromatography-method> Column: DB-1 ′ film thickness 5 μm (//m), length 30 m, inner diameter 〇 320 mm,
分離比（split ratio): 1/3〇、注射器 240°C、檢測器 26(TC 管柱溫度60°C><3分鐘+ 7. 5°C/分鐘X27分鐘+ 260°C X15分鐘 檢測 .火焰離子化偵測器（flame i〇nizati〇n detector ; FID) 内部4示準· 一°惡烧《滯留時間（retention time ; RT) =5. 9 分鐘》 試料量：0.4微升（"L) (3)水份量 用卡爾•費歇爾滴定法（Kar 1 Fischer Method )測定水 的份量。 【0 0 2 4】 【表1】 SP値 氰基乙酸的溶解度 相對於水的溶解度 〔公克/1败克备劑〕 〔質量％〕 ZM 12.9 171 自由混合 第一 甲幺酮 9.2 104 27.5 溶劑 醋酸乙酯 9.0 58 8.08 二翼丙基醚 7.2 32 1.71 (19°〇 第— 9.3 0.1以下 0.188 溶劑 環己烷 8.3 0.1以下 0.0052 庚烷 7.5 0.1以下 0.00024 己烷 7.4 0.1以下 0.0011 101109546 1013203354-0 20 201238940 « 【0 0艺5】 ， 2.氰基乙酸酯的製造 (1)實施例1 在裝配有蛇形冷凝管（Dimroth condenser)、溫度計和 攪拌扇（stirring impeller)的1公升的四口燒瓶中，放入 氰基乙酸85公克、乙醇64公克、醋酸乙酯1〇〇公克，仔細 攪拌直到氰基乙酸溶解。接著，加入η-己烷1〇〇公克，用水 Ο 浴（water bath)調整内部溫度至30°C ;接下來，加入98% 硫酸10公克，以每分鐘1〜2°C的速度加溫至迴流溫度《62 °C)° 從開始迴流1小時以後，在蛇形冷凝管和1公升燒漑之 間設置迪安-斯塔克設備（Dean-Stark apparatus)，捕捉迴 流餾出液，將下層溢流（Overflow) ’不再返回反應容器，取 出下層。 Q 由於開始迴流4小時以後的餾出液中不含水分，將反應 容器降溫至室溫。餾出水的取得量為31. 3公克，該餾出水中 的乙醇量為12. 5公克，水份量為16.1公克。 内部溫度返回至室溫後，加入16%碳酸氫納水溶液；[〇〇 公克’將液體立刻移到分液漏斗’液體已分成三層，個別回 收’得到上層75公克、中層220公克、下層124公克的反應 液。 用氣相層析法分別求得各個反應液中的氰基乙酸酯和丙 101109546 1013203354-0 21 201238940Split ratio: 1/3 inch, syringe 240 ° C, detector 26 (TC column temperature 60 ° C >< 3 minutes + 7. 5 ° C / minute X 27 minutes + 260 ° C X 15 minutes detection Flame ionization detector (FID) internal 4 indications · one ° bad burn "retention time (RT) = 5. 9 minutes" sample amount: 0.4 microliters (" L) (3) Moisture content Determine the amount of water by Karl Fischer Method. [0 0 2 4] [Table 1] Solubility of SP値Cyanoacetic acid relative to water [g] /1 gram of preparation] [% by mass] ZM 12.9 171 Free mixing of the first ketone 9.2 104 27.5 Solvent ethyl acetate 9.0 58 8.08 Di-propyl propyl ether 7.2 32 1.71 (19 ° 〇 - 9.3 0.1 or less 0.188 solvent Cyclohexane 8.3 0.1 or less 0.0052 heptane 7.5 0.1 or less 0.00024 hexane 7.4 0.1 or less 0.0011 101109546 1013203354-0 20 201238940 « [0 0 art 5], 2. Production of cyanoacetate (1) Example 1 In the assembly There is a Dimroth condenser, a thermometer and a stirring fan (stirring impelle) r) in a 1 liter four-necked flask, 85 g of cyanoacetic acid, 64 g of ethanol, and 1 g of ethyl acetate were added, and the mixture was carefully stirred until the cyanoacetic acid was dissolved. Then, η-hexane was added in 1 g. , adjust the internal temperature to 30 ° C with a water bath; then, add 10 g of 98% sulfuric acid, and heat to a reflux temperature of "62 ° C" at a rate of 1 to 2 ° C per minute. After 1 hour, a Dean-Stark apparatus was set up between the serpentine condenser and the 1 liter burnt to capture the reflux distillate, and the lower overflow was no longer returned to the reaction vessel. 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Gram, the amount of water is 16.1 grams. After the internal temperature is returned to room temperature, 16% aqueous solution of sodium hydrogencarbonate is added; [〇〇公克' immediately moves the liquid to the separatory funnel' liquid has been divided into three layers, and individual recovery 'to get the upper layer 75 Gram, 220 grams in the middle layer, 124 grams in the lower layer Liquid. The cyanoacetate and C in each reaction solution were respectively determined by gas chromatography. 101109546 1013203354-0 21 201238940
二酸-比， 是：上層9·4%、中層44.6%、下# _曰的巧 氰基乙酸酯的產量是105. 2公克°胃和中層合併的 克，同樣地，求得丙二酸二乙 醋的生成量為U公克。相對於投人的氰基乙酸^ 视為氰基乙酸㈣」莫耳= 各種評價結果，彙整顯示於表2。 ·、-1·。 [0026] (2)實施例2〜6 醋化反應姻之第—溶劑和第二賴如表2所示做了變 更以外，以與實施例丨相同的方法製造氰基乙酸醋^所得到 之氰基乙咖，依照前述方法加奶帽，其結果顯示在表2。 【0027] (3)比較例1 在裝配有蛇形冷凝管（Dimroth condenser)、溫度計、 氣氣吹風管和授拌扇（stirring impeller)的1公升的四口 燒瓶中’放入氰基乙酸85公克、乙醇64公克，仔細擾拌直 到氰基乙酸溶解。接著，加入n—己烷1〇〇公克，其後與實施 例1相同的操作，製造氰基乙酸酯。 其s平價結果，顯示於表2。 101109546 1013203354-0 22 201238940 【0028】 (4)比較例2、3 醋化反應_之第—溶輪一 更以外，以與比較例1相同的一'奋劑如表2所示做了變 J的方法製造氰基乙酸g旨。所得到 之氰基乙義’依照前迷方法加以評價，其結果顯示在表2。 [0029] 【表2】 ΟThe diacid-ratio is: the yield of the upper layer 9.4%, the middle layer 44.6%, and the lower # _ 曰 氰 cyanoacetate is 105. 2 gram ° the stomach and the middle layer combined grams, in the same way, obtain the propylene The amount of acid diethyl vinegar produced is U grams. Relative to the investment of cyanoacetic acid ^ as cyanoacetic acid (four) "mole = various evaluation results, the consolidation is shown in Table 2. ·,-1·. (2) Examples 2 to 6 The acetalization reaction was carried out in the same manner as in Example 2 except that the solvent and the second solvent were changed as shown in Table 2, and the cyanoacetic acid vinegar was obtained. The cyanoacetin was added to the milk cap according to the method described above, and the results are shown in Table 2. (3) Comparative Example 1 'Into a 1 liter four-necked flask equipped with a Dimroth condenser, a thermometer, a gas blowing tube, and a stirring impeller, 'put cyanoacetic acid 85 Gram, ethanol 64 grams, carefully disturbed until cyanoacetic acid dissolved. Then, n-hexane was added in an amount of 1 gram, and then the same operation as in Example 1 was carried out to produce a cyanoacetate. Its s parity results are shown in Table 2. 101109546 1013203354-0 22 201238940 [0028] (4) Comparative Example 2, 3 The vinegarization reaction _ the first - the melting wheel was changed, and the same one as the comparative example 1 was changed as shown in Table 2. The method of producing cyanoacetic acid g. The obtained cyanosine was evaluated according to the previous method, and the results are shown in Table 2. [0029] [Table 2] Ο
G 實施 例1 實施 例2 投入 量 (公克） 氰基醋酸 85 85 乙醇 64 64 第一 溶劑 醋酸 乙酯 100 甲乙 酮 100 二異 丙基 醚 第二 溶劑 η-己 烷 100 100 η-庚 烷 甲苯 98%硫酸 10 10 酯化 條件 迴流離 62 61 評價 結果 氰基乙酸酯 的產率 (莫耳％) 93.1 93.8 丙二酸二乙 酯的產率 漠耳％) 1.1 1.3 餾出水的質 量（公克） 31.3 29.8 86.4 1.6 實施 例4 實施 例5 實施 例6 比較 例1 比較 例2 比較 例3 85 85 85 85 85 85 ^ 64 64 64 64 64 64 — 100 " 100 150 50 100 100 50 100 100 10 10 1 10 10 10 10 V 63 63 74 79 75 95.8 79.0 96.7 95.4 76.5 76.7 0.6 0.5 0.5 3.5 4.5 3.2 26.5 26.1 26.4 32.1 33.1 無法 分離 101109546 23 1013203354-0 201238940 【0030】 ' 如表2所示，在實施例1〜6的製造方法中，要得到高產率 的氰基乙酸S旨，是可以達成的；還有’抑制副產物丙二酸二 乙酯的生成也可以做到。即使是這種程度的丙二酸二乙醋數 量’藉由蒸顧精製，就可以充分地移除，因此可以得到最後 的高純度氰基乙酸酯。 另一方面’未使用第一溶劑而僅使用第二溶劑的比較例1 和2中’其結果是氰基乙酸酯的產率很低；並且，副產物丙二 酸二乙酯的生成率卻很高。即使只用第一溶劑的比較例3，其 亂基乙酸醋的產率也很低。 【產業方面的可能應用】 【00 3 1] 本發明相_氰基乙酸g旨的製造方法，可以得到高產率的 氰基乙酸自旨；此外，也可以抑制丙二酸二乙醋等副產物的生成 。因此，醫藥及農藥的中間產物（intermediate)、以及工業製 。。的中間產物疋氰基乙酸醋的情形時，是很有用的製造方法。 24 101109546 1013203354-0G Example 1 Example 2 Input amount (g) Cyanoacetic acid 85 85 Ethanol 64 64 First solvent ethyl acetate 100 Methyl ethyl ketone 100 Diisopropyl ether Second solvent η-hexane 100 100 η-heptane toluene 98% Sulfuric acid 10 10 Esterification conditions refluxed 62 61 Evaluation results Cyanoacetate yield (mol%) 93.1 93.8 Yield of diethyl malonate %) 1.1 1.3 Distillate quality (g) 31.3 29.8 86.4 1.6 Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 85 85 85 85 85 85 ^ 64 64 64 64 64 64 — 100 " 100 150 50 100 100 50 100 100 10 10 1 10 10 10 10 V 63 63 74 79 75 95.8 79.0 96.7 95.4 76.5 76.7 0.6 0.5 0.5 3.5 4.5 3.2 26.5 26.1 26.4 32.1 33.1 Unable to separate 101109546 23 1013203354-0 201238940 [0030] ' As shown in Table 2, in Examples 1 to 6 In the production method, it is possible to obtain a high yield of cyanoacetic acid S; and it is also possible to suppress the formation of the by-product diethyl malonate. Even if the amount of malonic acid diacetate is reduced by evaporation, it can be sufficiently removed, so that the final high-purity cyanoacetate can be obtained. On the other hand, in Comparative Examples 1 and 2 in which the first solvent was not used but only the second solvent was used, the result was that the yield of the cyanoacetate was very low; and the production rate of the by-product diethyl malonate was also low. It is very high. Even in Comparative Example 3 using only the first solvent, the yield of the vinegar acetate was low. [Probable application in the industry] [00 3 1] The method for producing cyanoacetic acid g of the present invention can obtain a high yield of cyanoacetic acid, and can also inhibit by-products such as malonic acid and diethyl vinegar. Generation. Therefore, the intermediates of medicines and pesticides, and industrial products. . The intermediate product, in the case of phthalocyanine vinegar, is a very useful manufacturing method. 24 101109546 1013203354-0