1286542 A7 B7 五、發明說明（丨） 本發明關於一種製備通式I的丙二酸酯類之方法 〇 0 r\〇AA〇/r 1 其中R係烷基、C3-1(r烯基或芳基-Ci-4-烷基。 兩種習用於製備丙二酸酯類的方法係由氯乙酸之衍生 物開始。在一方法中，氯乙酸之酯與一氧化碳和醇於一種 基於羰基鈷的觸媒之存在下反應(DE-A 23 59 963，DE-A 25 24 389)，而在另一方法中，於第一步驟使氯乙酸的鹽與 氰化物反應以形成氰乙酸酯，然後於第二步驟使此中間物 與醇反應而將其轉化成爲丙二酸酯。後者之方法尤其與安 全性及生態學問題有關，因爲氫氰酸的及氰化物的毒性及 大量的廢物。適當的醇來直接酯化酸而製備酯類的明顯方 法在本案中沒有扮演角色；相反地，由丙二酸酯類(或氰乙 酸)之水解來製備丙二酸。 本發明一目的在於提供一種至丙二酸酯的可選擇之途 徑。由申請專利範圍第1項之方法來達成本發明的此目的 〇 已發現丙二酸的鹼金屬鹽可與通式R-X(II)鹵化物[其 中R係烷基、C3_1(r烯基或芳基-C^-烷基，而X係氯 、溴或碘]於水的存在下反應而產生對應的通式I之丙二酸 酯， 〇 0 r\〇AA〇/r 1 ’ 3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注音？事項再填寫本頁) -- - - ----訂 — 111 —---- 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1286542 A7 B7 五、發明說明（>) 其中R係如上定義，若有相轉移觸媒的存在。 此處及以下中，Cmo-烷基可爲具有1_1〇個碳原子之 線型或分枝的一級、二級或三級烷基，例如甲基、乙基、 丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊 基、異戊基、新戊基、己基、庚基、辛基、壬基、癸基等 〇 C3_1(r烯基係具有3-10個碳原子之線型或分枝的烯基 ，特別是其之雙鍵與自由價經由至少一個飽和碳原子所分 開者，例如烯丙基、甲基烯丙基、2-丁烯基(巴豆基）、3-丁 烯基、2-戊烯基等。 芳基-Cm-烷基特別是一經苯基取代的Cm-烷基，如 苄基、苯乙基或3-苯基丙基，其中苯基亦可帶有一或多個 相同或不同之取代基，如Cm-烷基、Ck烷氧基或鹵素。 此處及以下中，相轉移觸媒係爲慣用於此目的之化合 物，尤其是四級銨或鱗鹽。 作爲丙二酸之鹼金屬鹽，較佳爲使用丙二酸二鈉。 作爲鹵化物R-X(II)，較佳爲使用氯化物或溴化物。 較佳爲使用水溶液形式的丙二酸之鹼金屬鹽。特佳爲 ,在水性鹼金屬氫氧化物的存在下藉催化氧化U-丙二醇而 獲得的溶液。該溶液的製備例如敘述於DE-A 41 07 986中 〇 作爲相轉移觸媒，較佳爲使用四級銨鹽。特佳爲四-正 C4_1G烷基銨、苄基三-正烷基銨及甲基三-正C4_1G烷基 銨鹵化物，其中鹵化物較佳爲氯化物或溴化物。可提及的 4 ^紙張尺度適用中國國家標準（CNS)A4規格（210 x四7公釐） " (請先閱讀背面之注音？事項再填寫本頁) --------訂---------線^一^ · 1286542 A7 B7 五、發明說明（>) 例子爲溴化四丁銨及溴化四己銨和氯化苄基三丁銨。 (請先閱讀背面之注意事項再填寫本頁) 當使用低沸點鹵化物(II)[方便地在超大氣壓力下]時， 可有利地在80-150°C的溫度執行本發明之方法。 除了水外，有利上使甩一種不能與水溶混的惰性溶劑 。此型溶劑的適合例子係爲比較沒反應性的脂族或芳族氯 代烴，如氯苯或酯類如第三丁基甲基醚。 以下實例用於說明本發明方法可進行的方式，但無意 用於限制。 實例1 丙二酸二甲酯 經濟部智慧財產局員工消費合作社印製 在一高壓釜中，使10克(約0.2莫耳）的氯甲烷通入 一由2.96克(20毫莫耳）的丙二酸二鈉和0.64克(2毫莫耳 )的溴化四丁銨在5毫升水中所構成的溶液內，同時在冰 中冷卻。將混合物加熱至l〇〇°C，歷45分鐘，而高壓釜 內的壓力由4巴上升至14巴。在100°C反應3小時後’ 將混合物冷卻至室溫並去除壓力。用1M氫氧化鈉溶液 使水相的pH由4.6至5.7，及用第三丁基甲基醚萃取 (2x10毫升）。合倂的有機相經硫酸鈉乾燥，及經氣相層 析法所分析（內部標準：琥珀酸二甲酯）。 產率：48%。 於其它/相等/條件下，在當作反應介質的第三丁基 甲基醚/水（v:v=8:5)中獲得46%的產率。 5 Ϊ紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 經濟部智慧財產局員工消費合作社印製 1286542 ΚΙ _Β7_ 五、發明說明（W) 實例2 丙二酸二乙酯 在一高壓釜中，將10.9克（0.1莫耳）的溴乙烷加到一 由2.96克（20毫莫耳）的丙二酸二鈉和0.64克（2毫莫耳) 的溴化四丁銨在5毫升水和10毫升四丁基甲基醚中所構 成的溶液內。將混合物加熱至100°C，歷30分鐘，而高 壓釜內的壓力上升至3.5巴。在100°C反應3.5小時後， 將混合物冷卻至室溫並去除壓力。用1M氫氧化鈉溶液 使水相的pH由4.2至5.5，及用第三丁基甲基醚萃取 (2x5毫升）。合倂的有機相經硫酸鈉乾燥，及經氣相層析 法所分析（內部標準：琥珀酸二甲酯）。 產率：45%。 實例3 丙二酸二苄酯 在一高壓釜中，將17.1克(0.1莫耳）的溴甲苯加到一 由2.96克（20毫莫耳）的丙二酸二鈉和0.64克（2毫莫耳） 的溴化四丁銨在5毫升水和10毫升第三丁基甲基醚中所 構成的溶液內。將混合物加熱至10(TC，歷30分鐘，而 高壓釜內的壓力上升至2.5巴。在100°C反應3.5小時後 ，將混合物冷卻至室溫並去除壓力。用1M氫氧化鈉溶 液使水相的pH由1.8至5.8，及用第三丁基甲基醚萃取 (2x5毫升）。合倂的有機相經硫酸鈉乾燥，在迴轉式蒸發 器上蒸餾掉溶劑，及於減壓(1毫巴)下脫除殘留物的溶劑。 6 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)1286542 A7 B7 V. INSTRUCTION DESCRIPTION (丨) The present invention relates to a process for the preparation of malonic esters of the formula I 〇0 r\〇AA〇/r 1 wherein R is alkyl, C3-1 (r alkenyl or Aryl-Ci-4-alkyl. Two methods for preparing malonates are started with derivatives of chloroacetic acid. In one method, an ester of chloroacetic acid with carbon monoxide and an alcohol is based on a cobalt carbonyl-based. In the presence of a catalyst (DE-A 23 59 963, DE-A 25 24 389), in another method, in a first step, a salt of chloroacetic acid is reacted with cyanide to form a cyanoacetate, and then In the second step, the intermediate is reacted with an alcohol to convert it to a malonate. The latter method is particularly relevant to safety and ecological problems due to the toxicity of hydrocyanic acid and cyanide and a large amount of waste. The apparent method of preparing an ester by direct esterification of an acid does not play a role in this case; instead, malonate is prepared by hydrolysis of a malonate (or cyanoacetic acid). It is an object of the present invention to provide a An alternative route to malonate. By the method of claim 1 For this purpose of the invention, it has been found that an alkali metal salt of malonic acid can be combined with a halide of the formula RX(II) [wherein R is an alkyl group, a C3_1 (r alkenyl group or an aryl-C^-alkyl group, and the X system is Chlorine, bromine or iodine] reacts in the presence of water to produce the corresponding malonate of formula I, 〇0 r\〇AA〇/r 1 ' 3 This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) (Please read the phonetic transcription on the back? Please fill out this page again) -- - - ----定 — 111 —---- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed 1285642 A7 B7 V. Description of invention (>) where R is as defined above, if there is a phase transfer catalyst. Here and below, Cmo-alkyl may have 1_1〇 carbon atoms Linear or branched primary, secondary or tertiary alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, pentyl, Isoprenyl, neopentyl, hexyl, heptyl, octyl, decyl, decyl, etc. 3C3_1 (r-alkenyl has a linear or branched alkenyl group of 3 to 10 carbon atoms, Is the double bond and the free valence separated by at least one saturated carbon atom, such as allyl, methallyl, 2-butenyl (crotonyl), 3-butenyl, 2-pentenyl The aryl-Cm-alkyl group is especially a phenyl substituted Cm-alkyl group such as benzyl, phenethyl or 3-phenylpropyl, wherein the phenyl group may also carry one or more of the same or different a substituent such as a Cm-alkyl group, a Ck alkoxy group or a halogen. Here and in the following, a phase transfer catalyst is a compound conventionally used for this purpose, especially a quaternary ammonium or scaly salt. As the metal salt, disodium malonate is preferably used. As the halide R-X(II), it is preferred to use a chloride or a bromide. It is preferred to use an alkali metal salt of malonic acid in the form of an aqueous solution. Particularly preferred is a solution obtained by catalytic oxidation of U-propylene glycol in the presence of an aqueous alkali metal hydroxide. The preparation of this solution is described, for example, in DE-A 41 07 986 〇 as a phase transfer catalyst, preferably a quaternary ammonium salt. Particularly preferred are tetra-n-C4_1G alkylammonium, benzyltri-n-alkylammonium and methyltri-n-C4_1G alkylammonium halides, wherein the halide is preferably a chloride or a bromide. The 4^ paper scale that can be mentioned applies to the Chinese National Standard (CNS) A4 specification (210 x 4 7 mm) " (Please read the phonetic on the back? Please fill out this page again) -------- --------- Line ^一^ · 1286542 A7 B7 V. Description of the invention (>) Examples are tetrabutylammonium bromide and tetrahexammonium bromide and benzyltributylammonium chloride. (Please read the precautions on the back and fill out this page.) When low boiling point halides (II) [conveniently under superatmospheric pressure] are used, the process of the invention can advantageously be carried out at a temperature of 80-150 °C. In addition to water, it is advantageous to use an inert solvent which is immiscible with water. Suitable examples of this type of solvent are relatively unreactive aliphatic or aromatic chlorinated hydrocarbons such as chlorobenzene or esters such as tert-butyl methyl ether. The following examples are provided to illustrate the manner in which the process of the invention can be carried out, but are not intended to be limiting. Example 1 Dimethyl malonate Ministry of Economics Intellectual Property Bureau Staff Consumer Cooperative printed in an autoclave, allowing 10 grams (about 0.2 moles) of methyl chloride to pass into a 2.96 grams (20 millimoles) of C Disodium diacid and 0.64 g (2 mmol) of tetrabutylammonium bromide in a solution of 5 ml of water were simultaneously cooled in ice. The mixture was heated to 10 ° C for 45 minutes and the pressure in the autoclave was raised from 4 bar to 14 bar. After reacting at 100 ° C for 3 hours, the mixture was cooled to room temperature and the pressure was removed. The pH of the aqueous phase was adjusted from 4.6 to 5.7 with 1M sodium hydroxide and extracted with <RTIgt; The combined organic phase was dried over sodium sulfate and analyzed by gas phase chromatography (internal standard: dimethyl succinate). Yield: 48%. Under other/equal/conditions, a 46% yield was obtained in the third butyl methyl ether/water (v:v = 8:5) as the reaction medium. 5 Ϊ Paper scale applicable to China National Standard (CNS) A4 specification (210 x 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1246542 ΚΙ _Β7_ V. Invention Description (W) Example 2 Diethyl malonate In an autoclave, 10.9 g (0.1 mol) of ethyl bromide was added to 2.96 g (20 mmol) of disodium malonate and 0.64 g (2 mmol) of tetrabutylammonium bromide. 5 ml of water and 10 ml of tetrabutyl methyl ether were formed in the solution. The mixture was heated to 100 ° C for 30 minutes and the pressure in the autoclave was raised to 3.5 bar. After reacting at 100 ° C for 3.5 hours, the mixture was cooled to room temperature and the pressure was removed. The pH of the aqueous phase was adjusted from 4.2 to 5.5 with 1M sodium hydroxide solution and extracted with <RTI ID=0.0>> The combined organic phase was dried over sodium sulfate and analyzed by gas chromatography (internal standard: dimethyl succinate). Yield: 45%. Example 3 Dibenzyl malonate In an autoclave, 17.1 g (0.1 mol) of bromotoluene was added to 2.96 g (20 mmol) of disodium malonate and 0.64 g (2 mmol). The ear) is a solution of tetrabutylammonium bromide in 5 ml of water and 10 ml of t-butyl methyl ether. The mixture was heated to 10 (TC for 30 minutes while the pressure in the autoclave was raised to 2.5 bar. After reacting at 100 ° C for 3.5 hours, the mixture was cooled to room temperature and the pressure was removed. Water was made with 1 M sodium hydroxide solution. The pH of the phase is from 1.8 to 5.8 and extracted with a third butyl methyl ether (2 x 5 mL). The combined organic phase is dried over sodium sulfate, and the solvent is distilled off on a rotary evaporator and under reduced pressure (1 mbar). The solvent for removing the residue. 6 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)
經濟部智慧財產局員工消費合作社印製 1286542 A7 _B7_ 五、發明說明（< ) 產率：2.43 克(43%)。 4 NMR (CDCb，400MHz) : δ=7.25-7·40(ιη，10H) ; 5.16(s， 4H); 3.47 (s，2H)。 當使用氯甲苯代替溴甲苯時，於同等的反應條件下 獲得34%的產率。 實例4 丙二酸二烯丙酯 在一高壓釜中，將7.65克（0.1莫耳）的烯丙基氯化物 加到一由2.96克（20毫莫耳）的丙二酸二鈉和0.64克（2毫 莫耳）的溴化四丁銨在5毫升水和10毫升氯苯所構成的 溶液內。將混合物加熱至10CTC，歷30分鐘，而高壓釜 內的壓力上升至2.5巴。在100°C反應3.5小時後，將混 合物冷卻至室溫並去除壓力。用第三丁基甲基醚萃取 (2x5毫升)水相。合倂的有機相經硫酸鈉乾燥，及經氣相 層析術所分析（內部標準：琥珀酸二甲酯）。 產率·· 16 %。 實例5-12 丙二酸二甲酯 一般程序： 在一高壓釜中，將10克（約0.2莫耳）的氯甲烷通入 一由2.96克（20毫莫耳）的丙二酸二鈉和0.1當量（2毫莫 耳）的相轉移觸媒在5毫升水和10毫升氯苯所構成的溶 7 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1286542 A7 _B7_ V. Invention description (<) Yield: 2.43 g (43%). 4 NMR (CDCb, 400 MHz): δ = 7.25-7.40 (m, 10H); 5.16 (s, 4H); 3.47 (s, 2H). When chlorotoluene was used instead of bromotoluene, a yield of 34% was obtained under the same reaction conditions. Example 4 Diallyl malonate In an autoclave, 7.65 grams (0.1 mole) of allyl chloride was added to a solution of 2.96 grams (20 millimoles) of disodium malonate and 0.64 grams. (2 mmol) of tetrabutylammonium bromide in a solution of 5 ml of water and 10 ml of chlorobenzene. The mixture was heated to 10 CTC for 30 minutes and the pressure in the autoclave was raised to 2.5 bar. After reacting at 100 ° C for 3.5 hours, the mixture was cooled to room temperature and the pressure was removed. The aqueous phase was extracted with a third butyl methyl ether (2 x 5 mL). The combined organic phase was dried over sodium sulfate and analyzed by gas chromatography (internal standard: dimethyl succinate). Yield·· 16%. EXAMPLES 5-12 General procedure for dimethyl malonate: In an autoclave, 10 grams (about 0.2 moles) of methyl chloride is passed through a 2.96 grams (20 millimoles) of disodium malonate and 0.1 equivalent (2 mmol) of phase transfer catalyst in a volume of 7 ml of water and 10 ml of chlorobenzene is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read first) Note on the back and fill out this page)
A7A7
經濟部智慧財產局員工消費合作社印製 1286542 B7 五、發明說明（V ) 液內，並在冰中冷卻。將混合物加熱至所欲的溫度，歷 30分鐘。在適當的溫度反應3小時後，將混合物冷卻至 室溫並去除壓力。用1M氫氧化鈉溶液使水相的pH至 5.5-6.5，及用第三丁基甲基醚萃取（2xl〇毫升）水相。合 倂的有機相經硫酸鈉乾燥，及經氣相層析法所分析（內部 標準：琥珀酸二甲酯）。反應條件及所達成的產率係摘述 於以下表1中。 表1 125 100 溴化四丁銨， 溴化四己銨， BTBAC1=氯化苄基三丁銨 )GC，內部檩準：琥珀酸二甲酯 2)添加莫耳％的尺价 (請先閱讀背面之注意事項再填寫本頁)Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1286542 B7 V. Invention description (V) In the liquid, and cooled in ice. The mixture was heated to the desired temperature for 30 minutes. After reacting at the appropriate temperature for 3 hours, the mixture was cooled to room temperature and the pressure was removed. The pH of the aqueous phase was adjusted to 5.5-6.5 with 1M aqueous sodium hydroxide and aqueous (2.times. The combined organic phase was dried over sodium sulfate and analyzed by gas chromatography (internal standard: dimethyl succinate). The reaction conditions and the yields obtained are summarized in Table 1 below. Table 1 125 100 tetrabutylammonium bromide, tetrahexammonium bromide, BTBAC1 = benzyl tributylammonium chloride) GC, internal standard: dimethyl succinate 2) molar price of mol% added (please read first) Note on the back and fill out this page)