TW565564B - Process for the production of N-phosphonomethylglycine - Google Patents

Abstract

A process for the production of N-phosphonomethylglycine is disclosed. The process includes the step of (a) reacting N-phosphonomethyliminodiacetic acid with an excess amount of peroxide at an elevated temperature to form an intermediate N-phosphonomethyliminodiacetic acid-N-oxide, (b) cooling the reaction mixture of step (a) to room temperature, (c) adding a deoxidizing agent into the reaction mixture of step (a) after step (b) at room temperature for removing substantially all of the peroxide remaining in the reaction mixture, and (d) adding a water-soluble compound into the peroxide-free reaction mixture at an elevated temperature after step (c) to convert the intermediate N-phosphonomethyliminodiacetic acid-N-oxide to N-phosphonomethylglycine.

Description

565564 A 7 B7五、發明説明（1 ) N_膦酸曱基甘胺酸之製法 本發明係有關一種製造N_膦酸甲基甘胺酸之方法， 特.別是有關一種從N-膦酸甲基亞胺二乙酸製造N-膦酸曱 基甘胺酸之方法。 N-膦酸甲基甘胺酸（N-phosphonomethylglycine)，俗 名嘉填塞（glyphosate)，為一種有效的植物毒殺劑，其可 以被配製成用以控制多種雜草的除草組成物。 美國專利號No· 5,023,369揭露一種製造N-膦酸甲基 甘胺酸之方法，該方法係藉由在一種水溶性鎢化合物或 一種水溶性鉬化合物的存在下，以過氧化物氧化N -膦酸 甲基亞胺二乙酸（N-phosphonomethyliminodiacetic acid， PMIDA)以形成一中間產物Ν·膦酸甲基亞胺二乙酸-N-氧 化物（N-phosphonomethyliminodiacetic acid-N-oxide) ’ 其 第一步驟的反應式如下： HO— in565564 A 7 B7 V. Description of the invention (1) Preparation method of N-phosphonic acid phosphoglycine This invention relates to a method for producing N-phosphonic acid methylglycine, especially. Method for the production of N-phosphonophosphonoglycine from methylimine diacetic acid. N-phosphonomethylglycine, commonly known as glycopsate, is an effective plant poison, which can be formulated into a herbicidal composition to control a variety of weeds. U.S. Patent No. 5,023,369 discloses a method for manufacturing N-phosphonic acid methylglycine, which method involves oxidizing N-phosphine with peroxide in the presence of a water-soluble tungsten compound or a water-soluble molybdenum compound. N-phosphonomethyliminodiacetic acid (PMIDA) to form an intermediate N-phosphonomethyliminodiacetic acid-N-oxide ′ its first step The reaction formula is as follows: HO— in

-COOH -COOH 銪酸盥 H2〇2 HO— 4h-COOH -COOH H2〇2 HO— 4h

-COOH -COOH + H2O2 (excess) 甲基亞垃二乙》 (PMDA) N•珙齡申基亞按二乙酴.N.氩化物 (PMroA-N-codde) 之後，藉由與一有效量的催化劑的接觸使該中間產 物被轉化成N-膦酸曱基甘胺酸，其第二步驟的反應式如 下〆 Λ 门 水®性催化翔 Η01Γ-COOH -COOH + H2O2 (excess) Methylidene Diethylene (PMDA) The contact of the catalyst resulted in the conversion of the intermediate product into N-phosphonofluorenylglycine. The reaction formula of the second step is as follows:

-COOH -COOH HO— cIh Ύ ......................裝------卜---------訂.................線 (請先閲讀背面之注意事項再填窝本頁) N.孩酚甲基亞垃二乙酚·Ν·就北物 (PMIDA-N-oxide) N-膊酸甲基甘胺酸 (Glypliosate) 其中，該催化劑係擇自由下列所組成的群組：金屬 第3頁 本紙張尺度適用中國國家標準（CNS) A4規格（2-10X297公釐） 565564 一 B7 五、發明説明（2 鐵、以及水溶性鹽類之釩化合物、亞鐵鹽、或-COOH -COOH HO— cIh Ύ ............ install ------ bu --------- order .. ............... line (please read the precautions on the back before filling in this page) N. Kidanol methylidenephenol · N · Jiubei (PMIDA- N-oxide) N-oxide Glypliosate Wherein, the catalyst is selected from the group consisting of the following: metal page 3 This paper applies Chinese National Standard (CNS) A4 specifications (2-10X297) Mm) 565564 one B7 V. Description of the invention (2 Iron, and vanadium compounds, ferrous salts, or water-soluble salts, or

化物、亞硫酸鹽、或亞硫酸氫鹽化合二 ；，L 化合物之混合物。 物 '水…酸鹽 美國專利號No. 5,043,475揭露另一種製造小膦酸 基甘胺酸之方法，該方法與上述美國專利號知· 5,023,369者係相類似，除了該催化劑為一種擇自由下列 所組成的群組的金屬：鐵、辞、紹、飢、以及銅，或一 種擇自由下列所組成的群組的化合物··水溶性釩化合 物、亞鐵鹽、以及亞銅鹽。 美國專利號No· 5,〇47,579揭露另一種製造…膦酸甲 基甘胺酸之方法，該方法與上述美國專利號 5,〇23,369及Νο· 5,043,475者係相類似，除了該催化劑為 一種偏亞硫酸氫鹽，且必須在一種鉬化合物的存在下。 上述該等方法遭受一共同之缺點，亦即使用不足量 (低於化學計量）的過氧化物，會使膦酸甲基亞胺二乙 酸的氧化不完全。因此，過量（高於化學計量）的過氧化物 是必須的，以使N -膦酸甲基亞胺二乙酸完全氧化。然而， 該過量的過氧化物對於作為將該中間產物轉化成N_膦醆 曱基甘胺酸之水溶性化合物催化劑係有害的，且明顯地 導致降低N-膦酸甲基甘胺酸的產率。為克服此缺點，上 述該等方法均使用過量的過氧化物，且在^膦酸曱基亞 胺二乙酸被氧化後，以一後反應步驟來去除過氧化物， 以及在後反應之後，在反辱混合物中加入過量的催化劑 以將該中間產物轉化.成N-膦酸甲基甘胺酸。 第4頁 本紙張尺度適用中國國家標準（) Α4規格（21〇Χ297公釐〉 ................. i:裝…： {請先閲讀背面之注意事项再填窝本頁) ,Γ訂， :線丨 565564 A7 ______ B7_ 發明説明（3 ) " ~ ^--— 該後反應係將在N-膦酸甲基亞胺二乙酸氧化反應後 之反應混合物維持在約55至65°C之溫度，且授摔數：1寺 的時間以將反應混合物中的過氧化物去除。 其係發現在後反應過程當中，當該過氧化物被完全 從該反應混合物中去除時，該中間產物係可分解成起始 物N-膦酸甲基亞胺二乙酸。因此，其係有必要將氧化後 之反應混合物中的殘留過氧化物降低至一含量，使得該 含量須小到足以將該負面效果減到最低，且又足以防止 在後反應過程中分解該中間產物。然而，在開始後續之 步驟，亦即在將該中間產物轉化成N-膦酸甲基甘胺酸之 前，藉由該後友應來控制反應混合物中殘留過氧化物的 含量係相當困難。即使在使用相同的後反應參數下，其 結果係有相當大的差異。例如，在一實例中，於後反應 之後，有過多的過氧化物殘留在反應混合物中，而在另 一具有相同實驗條件的實例中，於後反應後，係完全沒 有殘留過氧化物，使得兩者皆造成產率的降低，而需要 使用過量的催化劑以防止該中間產物逆轉化成起始物N-膦酸甲基亞胺二乙酸。再者，用於上述該等方法的後反 應通常係延續數個小時，因而降低N-膦酸甲基甘胺酸的 生產率。 因此，本發明之目的在提供一種種製造N-膦酸曱基 甘胺酸之方法，該方法可以克服上述之問·題。 依據本發明，一種製考N -膦酸曱基甘胺酸之方法， 該方法包含·下列之步驟：（a)在升高之溫度下，使N-膦酸 第5頁 本紙張尺度適用中國國家標準（CNS) A4規格（21〇><297公發） (請先閲讀背面之注意事項再填窝本頁) .訂· :線丨 565564 五、發明說明（4 甲基亞胺二乙酸邀禍县 /、通置之過氧化物反應形成一中間產物 N-膦酸甲基亞胺二 一乙酉文卞-氧化物；（b)將步驟（a)所獲得的 反應混合物冷卻至宮、、w 至，皿，（c)在步驟（b)後，於室溫下，在 該反應混合物中加入一插盼_十丨 1… 八 種脫虱劑以去除殘留在反應混合 物中的過氧化物而形# . _ ^ 屯成一無過氧化物反應混合物；以及（d 驟（c)之後，於升高的溫度下，在該無過氧化物反應 口物内加入種水溶性化合物以將該中間產物N-膦酸 甲基亞胺二乙酸^_氧化物轉化成N—膦酸甲基甘胺酸，其 中該水溶性化合物作接白士 切係擇自由釩化合物、亞鐵鹽以及亞銅 鹽所組成的群組。 本發明將於下面的實施例及比較例做更進一步說 明。 本發明之製造N-膦酸曱基甘胺酸之方法包含下列之 步驟·（a)在升向之溫度，於一鎢鹽的存在下，使N_膦酸 曱基亞胺二乙酸與過量之過氧化物反應成一中間產物Ν· 膦酸曱基亞胺二乙酸_Ν_氧化物；（b)將步驟所獲得的反 應混合物冷卻至室溫；（c)在步驟（1))後，於室溫下，在該 反應混合物中加入一種脫氧劑以去除殘留在反應混合物 中的過氧化物而形成一無過氧化物反應混合物；以及（d) 在步驟（c)之後，於室溫下，在該無過氧化物反應混合物 内加入一種水溶性化合物以將該中間產物N-膦酸甲基亞 胺二乙酸氧化物轉化成N-膦酸甲基甘.胺酸，其中該水 溶性化合物係擇自由釩化今物、亞鐵鹽以及亞銅鹽所組 成的群組。> 頁 (請先閲讀背面之注意事項再填窝本頁) 第 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） 565564 \Ί —------ 五、發明説明（5 —' -—-—- 用於本發日月$古 心万法中之適當的鎢鹽可以為上述專利 中所揭露者，曰_ & & 車乂佳為鹼金屬鎢鹽如鎢酸鈉（Na2w〇4)以 及.鎢酸鉀。 數種描述於上述專利中之適當的過氧化物皆可用於 本發明。其中較佳者為過氧化氫。 用於本毛明之該脫氧劑為一種可以與該過氧化物起 ，應的化干化合物，且較佳為對於後續之轉化反應步驟 沒有負面的影響，如降低產率及污染所生成W N-膦酸甲 基甘胺酸。該脫氧劑較佳為亞硫酸氫鈉（NaHS03)。再者， 在步驟（C)中加入該脫氧劑的量較佳為剛好與殘留在該反 應混合物中的過氧化物反應掉使得在步驟（e)之後，沒有 脫氧劑殘留在該無過氧化物反應混合物中。 在過氧化物的存在下，氧化N_膦酸曱基亞胺二乙酸 之溫度可以在20至7〇t的範圍，較佳為5〇至65。〇。在 水溶性化合物的存在下，將…膦酸甲基亞胺二乙酸_N_ 氧化物轉化成N-膦酸曱基甘胺酸的溫度較佳為從4〇至 60°C的範圍。 本發明較佳的水溶性化合物為硫酸氧釩以及硫酸亞 鐵。 · 下列貫施例與比較例係說明本發明相對於習知技術 之不可預期較佳的結果。 實施例1 將239.1 g 95%的，N·膦酸曱基亞胺二乙酸 (PMIDA)、400g的水以及1.13 5 g的鴣酸納加入於一 1 第Ί頁 本紙張尺度適用中國國家標準（CNS) A4規格（210 X 297公釐） ------ ............—........:裝-----.-J!」…訂-------------------線· (請先閲讀背面之注意事項再填窝本頁) 565564 A7 B7 五、發明説明（6 ). 公升的燒瓶内。該混合物被攪拌，且被加熱至65 °C。將 74.8 g 50%的濃過氧化氫滴入該燒瓶内以氧化該 PMIDA。氧化的溫度被維持在65°C，直到獲得一澄清的 溶液，表示形成該中間產物 N-膦酸甲基亞胺二乙酸氧化 物（PMIDA-N-oxide)。 將所獲得的溶液冷卻至室溫，並在該冷卻的溶液内 加入1 g的亞硫酸氫鈉，以與殘留在該溶液内的過氧化氫 起反應。在加入亞硫酸氫納的過程中’以殿粉KI試紙測 試是否仍有過氧化物殘留於該溶液中，其化學反應式如 下： (請先閲讀背面之注意事項再填寫本頁) -裝— 6hCompounds, sulfites, or bisulfites; a mixture of L compounds. U.S. Patent No. 5,043,475 discloses another method for manufacturing small phosphonic glycine, which is similar to the above-mentioned US Patent No. 5,023,369, except that the catalyst is a Groups of metals: iron, iron, copper, copper, or a compound selected from the group consisting of water-soluble vanadium compounds, ferrous salts, and cuprous salts. U.S. Patent No. 5, 〇47,579 discloses another method for manufacturing ... phosphonic acid methylglycine, which is similar to the above-mentioned U.S. Patent Nos. 5, 〇23,369 and No. 5,043,475, except that the catalyst is a partial Bisulfite, and must be in the presence of a molybdenum compound. These methods suffer from a common drawback, that is, the use of insufficient (less than stoichiometric) amounts of peroxides results in incomplete oxidation of the phosphonic acid methylimine diacetic acid. Therefore, excess (higher than stoichiometric) peroxide is necessary to completely oxidize the N-phosphonic acid methylimide diacetic acid. However, this excess peroxide is detrimental to the catalyst as a water-soluble compound that converts this intermediate to N-phosphinofluorenylglycine, and significantly results in a reduction in the production of N-phosphonomethylglycine. rate. In order to overcome this disadvantage, the above-mentioned methods all use an excess of peroxide, and after the phosphonium iminoimide diacetic acid is oxidized, the peroxide is removed in a post-reaction step, and after the post-reaction, Excess catalyst was added to the anti-shaming mixture to convert the intermediate to N-phosphonic acid methylglycine. Page 4 This paper size applies the Chinese National Standard (A4) (21〇 × 297mm) ........ i: installed ...: {Please read the note on the back first Matters need to be refilled on this page), Γ order,: line 丨 565564 A7 ______ B7_ Description of the invention (3) " ~ ^ --— The post-reaction will be after the oxidation reaction of N-phosphonic acid methylimine diacetic acid The reaction mixture was maintained at a temperature of about 55 to 65 ° C, and the number of drops: 1 time to remove the peroxide from the reaction mixture. It was found that during the post-reaction, when the peroxide was completely removed from the reaction mixture, the intermediate product was decomposed into the starting material N-phosphonic acid methylimine diacetic acid. Therefore, it is necessary to reduce the residual peroxide in the oxidized reaction mixture to a content such that the content is small enough to minimize the negative effects and to prevent decomposition of the intermediate during the post-reaction process. product. However, it is quite difficult to control the residual peroxide content in the reaction mixture by this post-initiator before starting the subsequent steps, i.e. before converting the intermediate to N-phosphonic acid methylglycine. Even with the same post-reaction parameters, the results are quite different. For example, in one example, after the reaction, too much peroxide remained in the reaction mixture, and in another example with the same experimental conditions, after the reaction, there was no residual peroxide at all, so that Both cause a reduction in yield, and an excess of catalyst is required to prevent the reverse conversion of this intermediate to the starting material N-phosphonic acid methylimine diacetic acid. Furthermore, the post-reactions used in these methods usually last for several hours, thus reducing the productivity of N-phosphonic acid methylglycine. Therefore, the object of the present invention is to provide a method for producing N-phosphonophosphonoglycine, which can overcome the above-mentioned problems. According to the present invention, a method for preparing N-phosphonophosphonoglycine, the method includes the following steps: (a) making N-phosphonic acid at an elevated temperature. National Standard (CNS) A4 Specification (21〇 > < 297) (Please read the precautions on the back before filling in this page). Order:: line 565564 5. Description of the invention (4 methylimine di Acetic acid invites the prefecture / reaction of peroxides to form an intermediate N-phosphonic acid methylimide diethylstilbene-oxide; (b) cooling the reaction mixture obtained in step (a) to the palace , W to, dish, (c) After step (b), at room temperature, add an insert_ten 丨 1 ... eight kinds of delicetics to remove the remaining residue in the reaction mixture. Oxide 而 形 #. _ ^ To form a peroxide-free reaction mixture; and (d step (c), at elevated temperature, a water-soluble compound is added to the peroxide-free reaction mixture to The intermediate N-phosphonic acid methyliminodiacetic acid is converted into N-phosphonic acid methylglycine, wherein the water-soluble The compound is selected from the group consisting of vanadium compounds, ferrous salts and cuprous salts. The present invention will be further described in the following examples and comparative examples. The production of N-phosphonic acid according to the present invention The method of fluorenylglycine includes the following steps: (a) reacting N-phosphonofluorenimine diacetic acid with an excess of peroxide to an intermediate product in the presence of a tungsten salt at a rising temperature Ν · phosphonoimidodiacetic acid_N_ oxide; (b) cooling the reaction mixture obtained in the step to room temperature; (c) after step (1)), at room temperature, in the reaction Adding a deoxidizing agent to the mixture to remove peroxide remaining in the reaction mixture to form a peroxide-free reaction mixture; and (d) after step (c), at room temperature, in the peroxide-free reaction A water-soluble compound is added to the mixture to convert the intermediate product N-phosphonic acid methylimide diacetic acid oxide into N-phosphonic acid methylglycine. Amino acid, wherein the water-soluble compound is selected from free vanadium compounds, A group of ferrous and cuprous salts. ≫ page (please first Read the notes on the back and fill in this page again.) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 565564 \ Ί ------- 5. Description of the invention (5 — '-—- —- The appropriate tungsten salt used in the Sun Moon Moon Ancient Method can be disclosed in the above patents, and said _ & & Che Jia is an alkali metal tungsten salt such as sodium tungstate (Na2w〇4 ) And potassium tungstate. Several suitable peroxides described in the above patents can be used in the present invention. Among them, hydrogen peroxide is preferred. The deoxidizer used in the present invention is a kind of deoxidizer that can be used with the peroxide. It should be a dry chemical compound, and preferably has no negative effect on the subsequent conversion reaction steps, such as reducing the yield and contaminating the W N-phosphonic acid methylglycine. The deoxidizing agent is preferably sodium bisulfite (NaHS03). Furthermore, the amount of the deoxidizing agent added in step (C) is preferably just reacted with the peroxide remaining in the reaction mixture so that after step (e), no deoxidizing agent remains in the non-peroxide In the reaction mixture. In the presence of a peroxide, the temperature for oxidizing N-phosphonofluorenimide diacetic acid may be in the range of 20 to 70 t, preferably 50 to 65. 〇. In the presence of a water-soluble compound, the temperature at which the phosphonomethyliminodiacetic acid_N_ oxide is converted into N-phosphonofluorenylglycine is preferably in the range from 40 to 60 ° C. Preferred water-soluble compounds of the present invention are vanadyl sulfate and ferrous sulfate. · The following examples and comparative examples illustrate the unexpectedly better results of the present invention over conventional techniques. Example 1 239.1 g of 95% N, phosphonium phosphonium imine diacetic acid (PMIDA), 400 g of water, and 1.13 5 g of sodium phosphonate were added to the first page. Page 1 This paper applies Chinese national standards ( CNS) A4 size (210 X 297 mm) ------ ............-........: pack -----.- J! " … Order ------------------- Line · (Please read the precautions on the back before filling in this page) 565564 A7 B7 V. Description of the invention (6). Liter of Inside the flask. The mixture was stirred and heated to 65 ° C. 74.8 g of 50% concentrated hydrogen peroxide was dropped into the flask to oxidize the PMIDA. The oxidation temperature was maintained at 65 ° C until a clear solution was obtained, indicating the formation of the intermediate N-phosphonic acid methylimide diacetate (PMIDA-N-oxide). The obtained solution was cooled to room temperature, and 1 g of sodium hydrogen sulfite was added to the cooled solution to react with hydrogen peroxide remaining in the solution. In the process of adding sodium bisulfite, use the Dianfen KI test paper to test whether peroxide remains in the solution. The chemical reaction formula is as follows: (Please read the precautions on the back before filling this page) 6h

-COOH -C00H H2〇2 HO — 占〆^: ί)Η-COOH -C00H H2〇2 HO — 占 〆 ^: ί) Η

-COOH -COOH + H2O2 (excess)-COOH -COOH + H2O2 (excess)

NaHS03NaHS03

H〇 一占〆^' I OH N.供齡甲基亞按二乙酸 (PMIDA) N-珙酚甲爸亞肢二乙»_Ν·氧北拥 (M»tIDA-N-ooddi) N.供》甲IISSK二 (PMIDA-N-oxiie) 0101 •訂丨 本發明與習知技藝最大的區別就是將上述反應後過 量多餘的H202，利用加入NaHS03的方法予以作用掉。 ;線丨 將0.228 g的硫酸氧釩溶於30.0g的水中。將該硫 酸氧釩水溶液滴入該溶液中，以將該中間產物 PMIDA-N-oxide轉化成N-膦酸甲基甘胺酸。由於該轉化 反應為放熱反應，因此在轉化反應的過程中，反應物的 溫度會從室溫上升，該轉化反應溫度係被控制及維持在 約5 0 °C。在轉化反應之後，，該反應混合物被冷卻至室溫 以容許固體物沉澱出。該反應混合物被過濾，其化學反 第8頁 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐〉 565564 五、發明說明（ 應式如下： H〇1；H〇 一 占 〆 ^ I OH N. Supply of methylidene diacetic acid (PMIDA) N-glycinol daphthylimide diethyl »_N · oxy north support (M» tIDA-N-ooddi) N. 》 A IISSK II (PMIDA-N-oxiie) 0101 • Ordering 丨 The biggest difference between the present invention and the conventional technique is that excess H202 excess after the above reaction is used to add NaHS03. ; Line 丨 Dissolve 0.228 g of vanadyl sulfate in 30.0 g of water. An aqueous vanadyl sulfate solution was dropped into the solution to convert the intermediate product PMIDA-N-oxide into N-phosphonic acid methylglycine. Since the conversion reaction is an exothermic reaction, the temperature of the reactants will rise from room temperature during the conversion reaction, and the conversion reaction temperature is controlled and maintained at about 50 ° C. After the conversion reaction, the reaction mixture was cooled to room temperature to allow solids to precipitate out. The reaction mixture was filtered and its chemical reaction was applied. Page 8 The paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm> 565564) 5. Description of the invention (The application formula is as follows: H〇1;

-COOH -COOH 水瘡性保化翊-COOH -COOH Water Sore Protection

Y N-珙酚甲基亞垃二乙Μ·Ν•氟也物 (PMIDA-N-〇Kide) H〇-ji〆 N-赚甲基甘胺酸 c Glypliosate) 該固體物及該濾液以HPLC分析。所得到N-膦酸甲 基甘胺酸的產率為90.0%。實施例1的產品分析數據如下： (a).M.P. ： 230°C (decompose) (lO’H-NMR (300MHz，D20) : (5 3.23 (d，j=i2.6 Hz，2H，-CH2-P) 5 3·99 (s，2H，-CH2，N) (光譜圖請參見附件—） (c).HPLC分析‘條件： Column :BIO-RAD Aminex i〇n exchange HPX-72S, 3 0 cm x 7.8 mm Mobile phase:0.15 M Ammonium sulfate(aq)，ρΗ = 4·0〜4.1 Detector :210 nm (UV detector) Flow rate ·· 1. 5 ml/min Column temp:40°C (光譜圖請參見附件二） 實施例1至6之操作方法及反應溫度相同，不同的 是所用之反應物（如：Na2W〇4，H2〇2，NaHS03 · · ·)及催 化劑（如：VOS04，FeS04)之種類及用量不同。由於反應 物及催化劑用量不同時則會，影響反應時間。 會施例2 第 頁 本紙張尺度適用中國國家標準（CNS) A4規格（.210X297公釐） (請先閲讀背面之注意寧項再填寫本頁)Y N-Aminophenol methylidene M · N • Fluoride (PMIDA-N-〇Kide) H0-ji〆N-methylglycine c Glypliosate The solid and the filtrate were analyzed by HPLC. analysis. The yield of the obtained N-phosphonic acid methylglycine was 90.0%. The product analysis data of Example 1 are as follows: (a) .MP: 230 ° C (decompose) (10'H-NMR (300MHz, D20): (5 3.23 (d, j = i2.6 Hz, 2H, -CH2 -P) 5 3 · 99 (s, 2H, -CH2, N) (see the appendix for the spectrum chart) (c). Conditions for HPLC analysis: Column: BIO-RAD Aminex i〇n exchange HPX-72S, 3 0 cm x 7.8 mm Mobile phase: 0.15 M Ammonium sulfate (aq), ρΗ = 4.0 · 4.1 ~ Detector: 210 nm (UV detector) Flow rate ·· 1.5 ml / min Column temp: 40 ° C (Spectral chart please (See Annex II) The operating methods and reaction temperatures of Examples 1 to 6 are the same, except that the reactants used (such as: Na2W04, H2O2, NaHS03 · · ·) and catalysts (such as: VOS04, FeS04) The type and amount are different. The reaction time will be affected when the amount of reactants and catalysts is different. Example 2 Page This paper size applies the Chinese National Standard (CNS) A4 specification (.210X297 mm) (Please read the back (Note Ning Xiang then fill out this page)

5幻564 A7 -iz _ 4在氧化反應中所使用的為242.5 g 93.6%的PMID A、 _ 〇·0 g的水、1.705 g的鵡酸鈉以及74·8 g 5〇%的濃過 $ .化氫。3 · 0 g的亞硫酸氫鈉被用來去除殘备的過氧化 氡。在轉化反應中所使用的為溶於3(K() g水之〇_228 g的 I氧叙。N-膦酸甲基甘胺酸的產率為89 6%。 f施例3 在氧化反應中所使用的為257·6 g 88.2%的pMIDA、 ~5〇·〇 g的水、1.135 g的鎢酸鈉以及124 6g 3〇%的濃過 ，化氫。5.0 g的亞硫酸氫鈉被用來去除殘留的過氧化 虱。在轉化反應中所使用的為溶於30.0 g水之〇·228 g的 硫酸氧釩。N-膦酸甲基甘胺酸的產率為91.3%。 复施例4 在氧化反應中所使用的為2 3 9 · 1 g 9 5 %的Ρ ΜID A、 233_5 g的水、〇·667 g的鎢酸鈉以及146·8 g 27 8。/。的濃 過氧化氫。4.0 g的亞硫酸氫鈉被用來去除殘留的過氧化 氫。在轉化反應中所使用的為溶於19·8 g水之2·2 g的 硫酸亞鐵。Ν·膦酸甲基甘胺酸的產率為89 〇0/〇。 實施例5 在氧化反應中所使用的為227.3 g 99.9%的P MID A、 233·5 g的水、0.667 g的鎢酸鈉以及81.6 g 50%的濃過 氧化氫。5 · 0 g的亞硫酸氫鈉被用來去除殘留的過氧化 氫。在轉化反應中所使用的為溶於1 9 · 8 g水之1 · 8 g的 硫酸亞鐵。N-膦酸曱基甘胺酸的產率為90.0%。 實施例6 第10頁 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐） • L---------------……裝..........…訂..................緣 {請先閲讀背面之注意事項再填窝本頁} 5655645 Magic 564 A7 -iz _ 4 used in the oxidation reaction is 242.5 g 93.6% of PMID A, _ 〇.0 g of water, 1.705 g of sodium mysterate, and 74.8 g of 50% concentrated .Hydrogen. 3.0 g of sodium bisulfite was used to remove residual plutonium peroxide. The conversion reaction used was oxyhydroxide dissolved in 3 (K () g of water to 228 g. The yield of N-phosphonic acid methylglycine was 89 6%. F Example 3 During oxidation The reaction used was 257.6 g of 88.2% pMIDA, ~ 50.0 g of water, 1.135 g of sodium tungstate, and 124.6 g of 30% concentrated hydrogen peroxide. 5.0 g of sodium bisulfite It was used to remove residual peroxidation. In the conversion reaction, 228 g of vanadyl sulfate dissolved in 30.0 g of water was used. The yield of N-phosphonic acid methylglycine was 91.3%. Example 4 In the oxidation reaction, 2 39 · 1 g of 95% of P MID A, 233_5 g of water, 0 · 667 g of sodium tungstate, and 146.8 g of 27 8% were used. Hydrogen peroxide. 4.0 g of sodium bisulfite was used to remove residual hydrogen peroxide. In the conversion reaction, 2 · 2 g of ferrous sulfate dissolved in 19 · 8 g of water was used. N · phosphonic acid The yield of methylglycine was 8900/0. Example 5 227.3 g of 99.9% P MID A, 233.5 g of water, 0.667 g of sodium tungstate, and 81.6 were used in the oxidation reaction. g 50% concentrated hydrogen peroxide. 5.0 g sodium bisulfite was used to remove the residual The amount of hydrogen peroxide used in the conversion reaction was 1.8 g of ferrous sulfate dissolved in 1.9 g of water. The yield of N-phosphonophosphonoglycine was 90.0%. Example 6 Page 10 This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) • L --------------- …… Loading ............... … Order ........ Famous {Please read the notes on the back before filling this page} 565564

在氧化·反應中所使用的為234·4 g 96 9%的pMIDA、 3 0 0 · 〇 g的水、1 · 1 3 5 g的鎢酸鈉以及7 4 · 8 g 5 〇 %的濃過 氧化氫。2·0 g·的亞硫酸氫鈉被用來去除殘留的過氧化 氫。在轉化反應中所使用的為溶於1 9 · 8 g水之2 · 2 g的 硫酸亞鐵。N-膦酸甲基甘胺酸的產率為9〇 4 %。 下列比較例1與比較例2至7係分別與實施例丨與 實施例4相似，除了比較例i至7之殘留在反應混合物 中的過氧化物的去除係以一後反應而被完成以及比較例 ό與7中所用的硫酸亞鐵的量係不同之外。比較例i中之 3後反應係在5 5 C下反應3 0分鐘而被完成，而比較例2 至7則在55°C·下反應60分鐘以使過氧化物分解。在後反 應之後，5亥反應此合物係被冷卻至室溫以進行後續之轉 化反應，亦即加入催化劑來完成。比較例i至7的產率 如下： 比較例1 N-膦酸甲基甘胺酸的產率為82 〇%。最終產物包含 6.8%的起始物PMIDA，該PMIDA係該中間產物 PMIDA-N-oxide在轉化反應過程中逆反應轉化而成的。 比較例2 N -膦酸曱基甘胺酸的產率為9 〇 . 4 〇/〇。 比較例3 N-膦酸甲基甘胺酸的產率為8 9.8 0/〇。· 比較例4 N-膦酸曱基甘胺酸的產率為84.3 %。最終產物包含 第11頁 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公登） ί……Γ-.....i…裝—i——itri-..................線‘ (請先閲讀背面之注意事項再填窝本頁) 565564In the oxidation and reaction, 2344 g 96 9% pMIDA, 300 g water, 1.1 35 g sodium tungstate, and 7 4 g 8 50% Hydrogen oxide. 2.0 g of sodium bisulfite was used to remove residual hydrogen peroxide. In the conversion reaction, 2 · 2 g of ferrous sulfate dissolved in 19 · 8 g of water was used. The yield of N-phosphonic acid methylglycine was 904%. The following Comparative Examples 1 and 2 to 7 are respectively similar to Example 丨 and Example 4, except that the removal of the peroxide remaining in the reaction mixture from Comparative Examples i to 7 is completed and compared with a subsequent reaction. Example 6 differs from the amount of ferrous sulfate used in 7. The reaction after 3 in Comparative Example i was completed by reacting at 5 5 C for 30 minutes, while Comparative Examples 2 to 7 were reacted at 55 ° C. for 60 minutes to decompose the peroxide. After the post-reaction, the compound was cooled to room temperature for the subsequent conversion reaction, that is, the catalyst was added to complete the reaction. The yields of Comparative Examples i to 7 are as follows: Comparative Example 1 The yield of N-phosphonic acid methylglycine is 82.0%. The final product contains 6.8% of the starting material PMIDA. The PMIDA is the reverse product of the intermediate product PMIDA-N-oxide. Comparative Example 2 The yield of N-phosphonofluorenylglycine was 90.4 / 100. Comparative Example 3 The yield of N-phosphonic acid methylglycine was 89.8 0/0. Comparative Example 4 The yield of N-phosphonofluorenylglycine was 84.3%. The final product contains page 11. This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297). Ί …… Γ -..... i… 装 —i——itri -........ .......... line '(Please read the precautions on the back before filling this page) 565564

3·6%的起始物PMIDA，該PMIDA係該中間產物 PMlDHoxide在轉化反應過程中逆反應轉化而成的。 比較例5 N-膦酸甲基甘胺酸的產率為82.4%。最終產物包含 6.8%的起始物PMIDA，該PMIDA係該中間產物 PMlDA-N-oxide在轉化反應過程中逆反應轉化而成的。 比較例6 硫酸亞鐵的用量為5el g。…膦酸甲基甘胺酸的產率 為85 ·6%。雖然最終產物不含起始物PMIDA，但微量的 過氧化氫係在該最終產物中被檢測出，表示在轉化反應 開始之前，過氧化物的去除係不完全^ 比鮫例7 硫酸亞镦的用量為3.9 g。N-膦酸甲基甘.胺酸的產率 為86.1%。雖然最終產物不含起始物pmida，但微量的 過氧化氫係在該最終產物中被檢測出，表示在轉化反應 開始之前，過氧化物的去除係不完全。 下列比較鉤8與9之製備N-膦酸曱基甘胺酸的操作 條件係與實施例4相似，除了過氧化氫的去除步驟係被 省略，且反應物所使用的量也不同之外。 比較例8 在氧化反應中所使用的為234.0 g 97.1%的PMIDA、 2 3 3 · 5 g的水、〇 . 6 6 7 g的鎢酸鈉以及1 46 · 8 g 2 7 · 8 %的濃 過氧化氫。在轉化反應中所使用的為溶於 190.0 g水之 2 1 ·2 g的硫酸亞鐵。.N-膦酸曱基甘胺酸的產率為83.1 %。 第12頁 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公愛〉 ;'u 、· 裝......-…......訂..................緣 {請先閲讀背面之注意事項再填窝本頁} 565564 A7 --------- -B7_______ 五、發明說明（Η ) 大量的硫酸亞鐵係被用於本實施例中以將殘留的過氧化 氫反應掉。 比車交例 9 在氧化反應中所使用的為234.0 g 97.1%的PMIDA、 233·5 g的水、1·135 g的鎢酸鈉以及74.8 g 50%的濃過 氧化氫。在轉化反應中所使用的為溶於4 3.2 g水之4.8 g 的硫酸亞鐵。N-膦酸曱基甘胺酸的產率為84.4%。 下列比較例1 0與11之製備N·膦酸曱基甘胺酸的操 作條件係與實施例1相似，除了在比較例1 〇中，在轉化 反應過程中係不加入催化劑，以及在比較例Π中，在轉 化反應過程中·係以亞硫酸氫鈉替代硫酸氧釩催化劑之 外。此兩個比較例的轉.化反應溫度皆為室溫。 比較例10 在氧化反應與在殘留過氧化物被去除之後，以及在 轉化反應之前，反應混合物包含2.8%的PMIDA、82.5% 的PMIDA_N-oxide以及14.7%的N-膦酸曱基甘胺酸。在 轉化反應之後，最終產物包含3.9%的PMIDA、78.4%的 PMIDA-N-oxide以及17.7%的N_膦酸甲基甘胺酸。 比較例 11 在氧化反應與在殘留過氧化物被去除之後，以及在 轉化反應之前，反應混合物包含2.8%的PMIDA、82.5% 的PMIDA-N-oxide以及14·7%的N-膦酸甲基甘胺酸。在 轉化反應之後，該轉化反應，係藉由加入溶於1 0 7 · 6 g水之 6.0 g的亞碲酸氫鈉而被完成·，其最終產物包含12.0%的 第13頁 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐〉 — -ii-----ί-------------裝......iu-------訂------------------線· {請先閲讀^-面之注意寧項再填窝本頁} 565564 A7 _^_BT__五、發明説明（12 ) PMIDA、66.6% 的 PMIDA-N-oxide 以及 21.4% 的 N-膦酸甲 基甘胺酸。當與比較例1 〇比較時，比較例11中有一明顯 量的中間產物 PMIDA-N-oxide 係逆轉化成起始物 PMIDA。該結果表示雖然亞硫酸氫鈉具有將中間產物催 化成最終所要的產物的效果，但也具有將中間產物逆轉 化成起始物的負面影響。 本發明並不受上述之實施例所限制，該等實施例係 作為舉例說明，且本發明在後附之申請專利範圍中所請 求保護的範圍内可以有多種不同的方式作改變。 (請先閲讀背面之注意事項再填寫本頁) 第14頁 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐)3.6% of the starting material PMIDA, the PMIDA is the intermediate product PMlDHoxide converted in the reverse reaction conversion process. Comparative Example 5 The yield of N-phosphonic acid methylglycine was 82.4%. The final product contains 6.8% of the starting material PMIDA. The PMIDA is the intermediate product PMlDA-N-oxide converted in the reverse reaction process. Comparative Example 6 The amount of ferrous sulfate used was 5 el g. ... the yield of phosphonic acid methylglycine was 85.6%. Although the final product does not contain the starting material PMIDA, a small amount of hydrogen peroxide was detected in the final product, indicating that the removal system of peroxides was not complete before the conversion reaction started. ^ Example 7 The dosage is 3.9 g. The yield of N-phosphonic acid methylglycine was 86.1%. Although the final product does not contain the starting material pmida, a small amount of hydrogen peroxide was detected in the final product, indicating that the peroxide removal system was incomplete before the conversion reaction started. The following operating conditions for the preparation of N-phosphonofluorenylglycinate comparing hooks 8 and 9 are similar to those of Example 4, except that the step of removing hydrogen peroxide is omitted, and the amounts of reactants used are also different. Comparative Example 8 In the oxidation reaction, 234.0 g of 97.1% PMIDA, 2 3 3 · 5 g of water, 0.6 6 7 g of sodium tungstate, and 1 46 · 8 g of 2 7 · 8% hydrogen peroxide. In the conversion reaction, 2 · 1 g of ferrous sulfate dissolved in 190.0 g of water was used. The yield of N-phosphonofluorenylglycine was 83.1%. Page 12 This paper size applies to China National Standard (CNS) A4 specifications (210X297 public love); 'u, · installed ...-......... Order ......... ......... Yes {Please read the precautions on the back before filling in this page} 565564 A7 --------- -B7 _______ V. Description of the invention (Η) A large amount of ferrous sulfate It was used in this example to react the residual hydrogen peroxide. Compared with the car-passing example 9, 234.0 g 97.1% PMIDA, 233 · 5 g of water, and 1.135 g of tungsten were used in the oxidation reaction. Sodium and 74.8 g of 50% concentrated hydrogen peroxide. 4.8 g of ferrous sulfate dissolved in 4 3.2 g of water were used in the conversion reaction. The yield of N-phosphonophosphonoglycine was 84.4% The operating conditions for the preparation of N · phosphonofluorenylglycine in the following Comparative Examples 10 and 11 are similar to those in Example 1, except that in Comparative Example 10, no catalyst was added during the conversion reaction, and In Example Π, during the conversion reaction, sodium bisulfite was used instead of the vanadium sulfate catalyst. The conversion temperature of these two comparative examples was room temperature. Comparative Example 10 In the oxidation reaction and the residual reaction Oxide After the removal, and before the conversion reaction, the reaction mixture contained 2.8% PMIDA, 82.5% PMIDA_N-oxide, and 14.7% N-phosphonofluorenylglycine. After the conversion reaction, the final product contained 3.9% PMIDA, 78.4% PMIDA-N-oxide and 17.7% N-phosphonic acid methylglycine. Comparative Example 11 After the oxidation reaction and after the residual peroxide was removed, and before the conversion reaction, the reaction mixture contained 2.8% PMIDA, 82.5% of PMIDA-N-oxide, and 14.7% of N-phosphonic acid methylglycine. After the conversion reaction, the conversion reaction was performed by adding 6.0 dissolved in 1.07 · 6 g of water. g of sodium hydrogen tellurite was completed. Its final product contains 12.0%. Page 13 This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) — -ii ----- ί-- ----------- install ... iu ------- order ------------------ line · {Please first Read ^ -Notes on this topic and refill this page} 565564 A7 _ ^ _ BT__ V. Description of the invention (12) PMIDA, 66.6% PMIDA-N-oxide and 21.4% N-phosphonic acid methylglycine When compared with Comparative Example 10, there is an obvious difference in Comparative Example 11. A large amount of the intermediate product PMIDA-N-oxide is reversely converted into the starting material PMIDA. This result indicates that although sodium bisulfite has the effect of catalyzing the intermediate product to the final desired product, it also has the negative effect of reversely converting the intermediate product to the starting product. The present invention is not limited by the above-mentioned embodiments, and these embodiments are provided as examples, and the present invention may be modified in a variety of different ways within the scope claimed in the appended patent application scope. (Please read the precautions on the back before filling out this page) Page 14 This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

565564 b8 C8 D8 六、申請專利範圍 在反應混合物中的該過氧化物完全反應掉，使得在步驟 (C)之後，沒有脫氧劑殘留在該無過氧化物反應混合物 中 頁 6 < 第 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS) A4規格（210X297公釐）565564 b8 C8 D8 6. The scope of the patent application for the peroxide in the reaction mixture is completely reacted, so that after step (C), no deoxidizer remains in the peroxide-free reaction mixture. Page 6 < (Please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm)