[實施發明的形態] [0014] 以下詳細說明本發明。 本發明之多價縮水甘油基化合物的製造方法的特徵為，將過氧化氫水溶液作為氧化劑使用，將具有碳-碳雙鍵的有機化合物之該碳-碳雙鍵進行環氧化的縮水甘油基化合物之製造方法中，作為前述有機化合物將具有3個以上烯丙基之多價烯丙基化合物作為基質使用，將環氧化反應以1階段進行，所生成的縮水甘油基之水解體的比率在0.5～10%的範圍內時停止反應。 [0015] 在本發明中，作為氧化劑使用過氧化氫水溶液。過氧化氫水溶液的濃度並無特別限制，但一般為1～80質量%，較佳為選自10～60質量%的範圍。由工業上的生產性之觀點及分離時的能量成本之觀點來看，過氧化氫水溶液以高濃度時較佳，另一方面，不使用過度高濃度及/或過剩量的過氧化氫水溶液時由經濟性及安全性等觀點來看為佳。 [0016] 過氧化氫水溶液的使用量並無特別限制。反應系統內之過氧化氫濃度會隨著反應進行而減少。對於該減少，藉由追添補充可使反應系統內的過氧化氫濃度保持在0.1～30質量%，較佳為0.2～10質量%的範圍內。若在0.1質量%以上時生產性為良好，另一方面，若在30質量%以下時，作為溶劑使用醇時，在醇與水之混合組成中之爆發性會受到抑制而可安全地進行反應。且，於反應初期在反應系統內裝入多量過氧化氫時，反應有時會急激地進行而有危險情況產生，故如後述，將過氧化氫慢慢地添加於反應系統內者為佳。 [0017] 本發明之多價縮水甘油基化合物的製造方法中之環氧化反應為，若為可將具有3個以上烯丙基之多價烯丙基化合物藉由過氧化氫水溶液進行環氧(縮水甘油基)化的反應者即可，並無特別限定，但可舉出於鹼金屬的碳酸鹽、碳酸氫鹽等鹼性鹽化合物的存在下將過氧化氫與腈化合物，例如將乙腈與烯丙基化合物的碳-碳雙鍵進行反應的方法以及在鎢酸、磷酸及第四級銨鹽的存在下將過氧化氫作為氧化劑使用而使烯丙基化合物的碳-碳雙鍵進行環氧化的方法等。將多價烯丙基化合物藉由過氧化氫水溶液進行環氧化的方法可配合基質之性質而做適宜選擇。 [0018] 以下對於使用過氧化氫與乙腈使多價烯丙基化合物進行環氧化的方法做詳細敘述。 [0019] 若考慮到在工業上安定地生產，將乙腈與作為基質之多價烯丙基化合物在最初裝入於反應器中，極力保持反應溫度為一定，一邊對於過氧化氫，確認在反應被消費，一邊徐徐加入為佳。若採用如此方法，在反應器內過氧化氫即使因異常分解而產生氧氣，但過氧化氫的累積量較少，而使壓力上昇保持在最小限度。 [0020] 乙腈的反應系統內之濃度在反應進行中控制在5～50mol/L之範圍內者為佳。在另外實施態樣中，乙腈在反應系統內之濃度在反應進行中控制在1～10mol/L的範圍內者為佳。考慮為在乙腈存在下，作為過氧化氫使用氧化劑，將具有碳-碳雙鍵的有機化合物之該碳-碳雙鍵進行環氧化的縮水甘油基化合物之製造方法中，乙腈與過氧化氫反應而產生氧化活性種(過醯亞胺酸)，藉由該氧化活性種可使碳-碳雙鍵氧化。因此，對於該反應的乙腈之理論必要量與有機化合物之碳-碳雙鍵量為等量(等莫耳)，隨著反應進行，反應系統內之乙腈濃度會降低。配合有機化合物之碳-碳雙鍵量，可適宜地選擇乙腈的反應系統內之濃度。反應系統內之濃度若為1mol/L以上或5mol/L以上，反應速度為適當，故生產性良好，另一方面，若在10mol/L以下、或50mol/L以下時，過氧化氫的環氧化選擇率為良好，又對於成本亦為適當。因此，將開始反應時的初期濃度設定在上述濃度範圍，監視反應進行中濃度，於濃度降到上述下限值前，以不超過上限值的範圍下追加添入而控制濃度者為佳。該濃度在6mol/L以上者較佳，另一方面在40mol/L以下者為較佳。在其他實施態樣中，該濃度為1.5mol/L以上者為較佳，在5mol/L以上者為更佳，另一方面在10mol/L以下者為較佳。 [0021] 如上述使用乙腈實施環氧(縮水甘油基)化反應時，於反應系統內將醇作為溶劑而使其共存者為佳。醇作為基質的溶劑時，進一步在基質的黏度高時，可作為欲提高對於基質的過氧化氫之移動速度的黏度稀釋劑之功能。又，醇若在基質的親水性較低時，將含有基質及乙腈的有機層與含有過氧化氫的水層成為均勻系統而有提高反應速度之作用。若為不使醇共存或者使用量不足時，於反應系統中有時會引起二層分離，作為結果，過氧化氫的環氧化選擇率會有降低之情況產生。作為醇，以碳數1～4的醇為佳，較佳為碳數1～4的1級醇，更佳為甲醇、乙醇、1-丙醇。使用於反應的醇對於乙腈之使用量，在裝入量之質量比下以0.1倍～5倍的範圍者為佳，以0.2倍～4倍者為較佳，以0.3倍～3倍的範圍為更佳。將對於乙腈使用量的醇之裝入量設定在上述範圍時，在氧化活性種之過醯亞胺酸的反應系統中的安定性會提高且可有效率地進行反應。 [0022] 乙腈的反應開始時之裝入量為將具有碳-碳雙鍵的有機化合物之碳-碳雙鍵數作為基準，以1.2～5莫耳當量的範圍者為佳，以1.5～3莫耳當量者為較佳。若1.2莫耳當量以上時產率為良好，另一方面，若在5莫耳當量以下時，過氧化氫的環氧化選擇率為良好，又成本亦適當。乙腈的反應開始時之裝入量為上述反應進行中之反應系統內的濃度範圍之5～50mol/L者為佳，較佳為6～40mol/L。在其他實施態樣中，乙腈的反應開始時之裝入量以1～10mol/L者為佳，以1.5～10mol/L者為較佳，以5～10mol/L者為更佳。且，於反應中追加乙腈時，對於使用於反應的基質總使用量的乙腈之總使用量的比例(乙腈/基質的碳-碳雙鍵(莫耳比))亦在上述範圍，即滿足1.2～5者為佳，較佳為1.5～3。 [0023] 對於乙腈的使用量之過氧化氫的使用量比例(過氧化氫/乙腈(莫耳比)以0.1以上者為佳，另一方面以1.1以下為佳，未達1.0者為較佳。因在上述範圍，可抑制水解的同時，亦可將反應在均勻系統中進行，可有效率地進行反應。 [0024] 反應可在完全溶解基質的狀態下進行。特別不會分離為溶解基質的有機層與溶解過氧化氫的水層之2層，在均勻狀態下進行時，可有效率地進行反應。 [0025] 對於本發明之多價縮水甘油基化合物的製造方法，將反應液的pH設定在9～11者為佳，較佳為9.5～11，更佳為10～11的範圍。pH若在9以上時，反應速度為適當，故生產性良好，另一方面，若在11以下時，反應會急激地進行等而產生危險的機率極低故較佳。過氧化氫在高鹼環境下會使分解活躍起來，故即使在反應初期的階段pH必須控制在9～10程度，與過氧化氫的添加之同時，視需要徐徐將反應液之pH控制在10～11程度為較佳。作為基質使用具有3個以上碳-碳雙鍵之多價烯丙基化合物時，藉由反應系統的pH，多價縮水甘油基化合物的產率與選擇性雖會受到影響，若pH在10～11的範圍內時，多價縮水甘油基化合物的產率與選擇性皆可提高故較佳。 [0026] 作為使用於反應系統內之pH調整上的鹼性鹽化合物，例如可舉出碳酸鉀、碳酸氫鉀、氫氧化鉀、氫氧化鈉、氫氧化銫等無機鹽基鹽或甲氧化鉀、乙氧化鉀、甲氧化鈉、乙氧化鈉、氫氧化四甲基銨等有機鹼鹽。碳酸鉀、碳酸氫鉀、氫氧化鉀、氫氧化鈉、甲氧化鉀、乙氧化鉀、甲氧化鈉、乙氧化鈉由可容易進行pH的觀點來看為佳。氫氧化鉀及氫氧化鈉對水及醇的溶解性為高，故對於反應性亦有好處，故較佳。 [0027] 鹼性鹽化合物雖可作為水溶液或醇溶液使用。作為醇溶液的溶劑所使用的醇中，可舉出甲醇、乙醇、丙醇、丁醇等，亦以使用與前述反應溶劑的相同者為佳。鹼性鹽化合物之溶液為欲使反應液的pH不會隨著過氧化氫的添加而比9低而追加者為佳，此時的反應液之溫度為20～100℃的範圍，較佳為保持25～60℃之範圍下追加者為佳。 [0028] 對於本發明之多價縮水甘油基化合物的製造方法，反應溫度通常為20～100℃之範圍，較佳在25～60℃的範圍下進行。又，反應時間會因反應溫度而受到左右，無法一概並論，但一般為4～100小時範圍，較佳為8～80小時範圍下進行。 [0029] 環氧化反應後，作為後步驟，實施停止反應的步驟。停止反應的步驟為，將反應液以含有還原劑的水溶液進行淬火(Quench)而停止。反應停止後，可除去反應系統內之水。本發明之反應停止的判斷為藉由在環氧化反應後期所產生的縮水甘油基之水解體的系統內中之比率(水解率)而進行。將具有3個以上烯丙基的多價烯丙基化合物作為基質使用而進行環氧化的反應中，與將具有1個或2個烯丙基之烯丙基化合物作為基質使用時相比較時，於環氧化反應需要較長時間，且所得之反應中間體的極性為強。因此，可確認反應中隨著反應進行所生成的反應中間體所具有的縮水甘油基之水解反應會進行。縮水甘油基的水解體之生成可藉由氣體層析法(GC)、高速液體層析法(LC)、1
H-NMR等分光學的分析得到確認。水解反應之進行被考慮為藉由作為氧化劑所添加的過氧化氫水溶液使反應液中的水分增加而造成很大影響。欲抑制縮水甘油基的水解體之比率，對於反應後期，在水解體的產生量比率為0.5～10%，較佳為0.5～8%，更佳為0.5～5%之範圍內，進行下個後處理步驟，換言之實施停止反應的步驟。將水解率為10%以內的事項作為下個步驟實施的基準，故可抑制副產物的縮水甘油基之水解體的生成。又，若將水解率設定在0.5%以上時，可在良好產率下得到目的之多價縮水甘油基化合物。 [0030] 縮水甘油基的水解體之系統內中之比率(水解率)，例如可將多價縮水甘油基化合物藉由1
H-NMR分析進行鑑定後，經GC或LC分析決定多價縮水甘油基化合物的檢測時間後，將反應液以GC或LC分析，可由對於全體信號積分強度的合計而言的水解體的信號積分強度之比率求得。對於GC及LC，由標準物質求得保持時間，例如對於逆相管柱，比目的物的保持時間更短時間內所觀測的信號歸屬於水解體之信號。於分析中，例如可使用日本Waters公司製之ACQUITY UPLC(TM)BEH C18，作為溶離溶劑亦可使用乙腈及水。 [0031] 停止反應的步驟對於基質多價烯丙基化合物的烯丙基消費速度而言，在確認縮水甘油基的水解體生成速度超過的時間點時實施者為佳。因此，多價縮水甘油基化合物的製造方法中進一步可含有對於多價烯丙基化合物之烯丙基消費速度而言，確認縮水甘油基的水解體生成速度超過之步驟。對於多價烯丙基化合物的烯丙基消費速度而言，縮水甘油基的水解體生成速度超過時，例如將反應液藉由氣體層析法以每30分鐘進行分析，藉由比較基質吸收峰面積減少率與水解體吸收峰面積增加率而可確認。 [0032] 因反應液通常含有過氧化氫，故於除去反應液中之水分時，必須還原除去過氧化氫。作為所使用的還原劑，可舉出亞硫酸鈉、硫代硫酸鈉等，但並未限定於此等還原劑。欲將此時的反應系統內之水分與含有反應中間體之有機層可有效率地的分離並除去，將與水的相溶性較低的適量有機溶劑加入於反應液者為佳。作為使用的有機溶劑，可舉出甲苯、乙酸乙酯、二氯甲烷等，但並未限定於這些有機溶劑。藉由此處理而除去殘留於反應液中的過氧化氫，同時可分離水層與有機層(有機溶劑)，將含於有機層(有機溶劑)中之反應生成物回收及濃縮，視必要以公知方法(蒸餾、色譜分離、再結晶或昇華等)進行純化後，可得到目的之多價縮水甘油基化合物。目的的多價縮水甘油基化合物之產率若為50%以上可適用於工業上。 [0033] 本發明之多價縮水甘油基化合物的製造方法中，在1階段進行環氧化反應。所謂「1階段」表示停止上述環氧化反應後，不會再開始環氧化反應的意思。因此，藉由上述環氧化反應的停止及除去反應液中之水的步驟，可使反應生成物的損失抑制到最小限而提高產率。 [0034] 在本發明之多價縮水甘油基化合物的製造方法中所使用的基質若為具有3個以上碳-碳雙鍵的有機化合物即可並無特別限制，以烯丙基鍵結於氧原子而形成烯丙基醚基，或鍵結於胺基而形成烯丙基胺基的有機化合物為佳。在另一實施態樣中，對於多價縮水甘油基化合物之製造方法中所使用的基質以具有3個以上的烯丙基醚基之化合物為佳。其中所謂「烯丙基醚基」表示「C＝C-C-O-」鍵結，即烯丙基氧基的意思，所謂「烯丙基胺基」表示或「C＝C-C-NH-」所示基。含於化合物中的碳-碳雙鍵數可為3個，亦可為4個以上。作為碳-碳雙鍵數為3個化合物，可例示出三羥甲基丙烷三烯丙基醚、甘油三烯丙基醚、季戊四醇三烯丙基醚、二三羥甲基丙烷三烯丙基醚、二甘油三烯丙基醚、赤蘚糖醇三烯丙基醚、木糖醇三烯丙基醚、二季戊四醇三烯丙基醚、山梨醇三烯丙基醚、肌醇三烯丙基醚、三烯丙基異氰脲酸酯、二烯丙基胺基酚烯丙基醚等。又，作為4個以上碳-碳雙鍵數之化合物，可例示出季戊四醇四烯丙基醚、二三羥甲基丙烷四烯丙基醚、二甘油四烯丙基醚、赤蘚糖醇四烯丙基醚、木糖醇四烯丙基醚、木糖醇五烯丙基醚、二季戊四醇四烯丙基醚、二季戊四醇五烯丙基醚、二季戊四醇六烯丙基醚、山梨醇四烯丙基醚、山梨醇五烯丙基醚、山梨醇六烯丙基醚、肌醇四烯丙基醚、肌醇五烯丙基醚、肌醇六烯丙基醚、酚酚醛清漆型聚烯丙基醚、甲酚型聚烯丙基醚、萘含有酚醛清漆型聚烯丙基醚、四烯丙基二胺基二苯基甲烷等。 [0035] 具有3個以上碳-碳雙鍵之有機化合物，較佳為鏈式、單環或縮合環化合物。作為具有3個以上碳-碳雙鍵的有機化合物，以脂肪族化合物為佳，以鏈式或單環脂肪族化合物為較佳。其中亦以三羥甲基丙烷三烯丙基醚、甘油三烯丙基醚、季戊四醇三烯丙基醚、季戊四醇四烯丙基醚、二三羥甲基丙烷三烯丙基醚、二三羥甲基丙烷四烯丙基醚、二甘油三烯丙基醚、二甘油四烯丙基醚、赤蘚糖醇三烯丙基醚、赤蘚糖醇四烯丙基醚、木糖醇三烯丙基醚、木糖醇四烯丙基醚、木糖醇五烯丙基醚、二季戊四醇三烯丙基醚、二季戊四醇四烯丙基醚、二季戊四醇五烯丙基醚、二季戊四醇六烯丙基醚、山梨醇三烯丙基醚、山梨醇四烯丙基醚、山梨醇五烯丙基醚、山梨醇六烯丙基醚、肌醇三烯丙基醚、肌醇四烯丙基醚、肌醇五烯丙基醚、肌醇六烯丙基醚、三烯丙基異氰脲酸酯為佳。本發明之多價縮水甘油基化合物的製造方法特別適用於對於容易分解於水系，且容易進行水解反應的化合物，可高產率下得到如此化合物。 [0036] 作為反應槽，並無特別限制，可舉出分批式、連續式等。分批式的情況為，反應槽內之縮水甘油基的水解體為0.5～10%的範圍內時，移至下個槽。又，連續式的情況為，在反應槽的終點縮水甘油基的水解體為0.5～10%之範圍內。 [實施例] [0037] 以下藉由實施例具體說明本發明，但本發明並未受限於以下實施例。 [0038] [反應條件] ・過氧化氫濃度 參考日本特開平6-130051所記載的方法，將碘化鉀、游離碘以硫代硫酸鈉標準液進行滴定而測定過乙酸濃度，再對於過氧化氫中添加大大過剩的碘化鉀水溶液、稀硫酸及鉬酸銨水溶液，將再次游離的碘以硫代硫酸鈉標準液，將澱粉溶液作為呈色試藥，經滴定後側定過氧化氫濃度。 ・水解率 首先，將反應液中之多價縮水甘油基醚化合物藉由管柱層析法(關東化學股份有限公司製之矽膠60(球狀))進行分離，藉由1
H-NMR分析進行鑑定後，以UHPLC進行分析(日本Waters公司製之ACQUITY UPLC(TM)BEH C18、溶離溶劑：乙腈及水、梯度法)，鑑定多價縮水甘油基醚化合物之檢測時間。其次將反應液進行UHPLC分析(日本Waters公司製之ACQUITY UPLC(TM)BEH C18、溶離溶劑：乙腈及水、梯度法)，將多價縮水甘油基醚化合物作為基準，積分各以下(甲)～(丙)的3區域之面積而求得。 (甲)比多價縮水甘油基醚化合物的檢測時間還短的時間之區域：目的物之縮水甘油基水解體 (乙)多價縮水甘油基醚化合物之吸收峰 (丙)比多價縮水甘油基醚化合物的檢測時間還長的時間之區域：推定為反應中間體之烯丙基醚體 水解率藉由以下式子求得。 水解率＝｛(甲)之面積}/｛(甲)(乙)(丙)之面積合計} [0039] [評估] ・粗產率 藉由以下式子算出。 粗產率＝(於後處理後所得之生成物的取得量)/(由裝入量所算出的理論取得量) ・基質之純度 首先，將基質藉由管柱層析法(関東化學股份有限公司製之矽膠60(球狀))進行分離，經1
H-NMR分析進行鑑定後，進行UHPLC分析(日本Waters公司製之ACQUITY UPLC(TM)BEH C18、溶離溶劑：乙腈及水、梯度法)，決定基質之檢測時間。其次將反應液進行UHPLC分析(日本Waters公司製之ACQUITY UPLC(TM)BEH C18、溶離溶劑：乙腈及水、梯度法)，將基質作為基準，積分各以下(甲)～(丙)的3區域之面積後求得。 (甲)比基質的檢測時間還短之時間的區域 (乙)基質之吸收峰 (丙)比基質的檢測時間還長之時間的區域 基質的純度藉由以下式算出。 基質之純度＝｛(乙)之面積}/｛(甲)(乙)(丙)之面積合計} [0040] ・多價縮水甘油基醚化合物之純度 首先，將多價縮水甘油基醚化合物藉由管柱層析法(関東化學股份有限公司製之矽膠60(球狀))進行分離，並由1
H-NMR分析進行鑑定後，進行UHPLC分析(日本Waters公司製之ACQUITY UPLC(TM)BEH C18、溶離溶劑：乙腈及水、梯度法)，決定多價縮水甘油基醚化合物之檢測時間。其次將反應液藉由UHPLC進行分析(日本Waters公司製之ACQUITY UPLC(TM)BEH C18、溶離溶劑：乙腈及水、梯度法)，將多價縮水甘油基醚化合物作為基準，積分各以下(甲)～(丙)的3區域之面積而求得。 (甲)比多價縮水甘油基醚化合物的檢測時間還短之時間的區域：目的物之縮水甘油基水解體 (乙)多價縮水甘油基醚化合物之吸收峰 (丙)比多價縮水甘油基醚化合物的檢測時間還長的時間之區域：推定為反應中間體之烯丙基醚體 多價縮水甘油基醚化合物之純度藉由以下式子算出。 多價縮水甘油基醚化合物之純度＝｛(乙)之面積}/｛(甲)(乙)(丙)之面積合計} ・多價縮水甘油基醚化合物之純產率 藉由以下式子算出。 純產率＝多價縮水甘油基醚化合物之粗產率×多價縮水甘油基醚化合物之純度 [0041] [基質之合成] 合成例1(季戊四醇四烯丙基醚之合成) 於2.0公升三口圓底燒瓶中放入Neoallyl(註冊商標)P-30M(季戊四醇三烯丙基醚、大創股份有限公司製)400.0g(1.57mol)，將反應裝置系統內以氮氣取代。加入氫氧化鈉水溶液(50質量%，純正化學股份有限公司製)300g(3.8mol)，加熱至80℃，將反應系在約80℃進行1小時攪拌後，將反應系冷卻至約40℃。將反應系統內保持在約40℃下，加入四丁基銨溴化物(東京化成工業股份有限公司製)55.6g(0.2mol)、氯化烯丙基(和光純藥工業股份有限公司製)366g(4.0mol)，進行20小時攪拌。反應終了後，加入乙酸乙酯200g與水100g並分液處理，將有機層以純水50mL/次洗淨至成為中性。將所得之有機層的有機溶劑(乙酸乙酯)餾去，得到純度96%之基質A(季戊四醇四烯丙基醚)487.8g。 [0042] 合成例2(三羥甲基丙烷三烯丙基醚之合成) 於2.0公升三口圓底燒瓶中放入Neoallyl(註冊商標)T-20(三羥甲基丙烷二烯丙基醚、大創股份有限公司製)2000.0g(9.4mol)，將反應裝置系統內以氮氣取代。加入氫氧化鈉水溶液(50質量%)4500g(56.3mol)，將反應系在約80℃下進行1小時攪拌後，冷卻至約40℃。將反應系統內保持在約40℃下，放入四丁基銨溴化物200.0g(0.6mol)、氯化烯丙基2400g(31.4mol)，進行20小時攪拌。反應終了後，加入乙酸乙酯2000g與水1000g並進行分液處理，將有機層以純水500mL/次洗淨至成為中性。將所得之有機層的有機溶劑(乙酸乙酯)餾去，藉由氣體層析法進行測定後得到純度94%之基質B(三羥甲基丙烷三烯丙基醚)2444.3g。 [0043] 合成例3(甘油三烯丙基醚之合成) 於2.0公升三口圓底燒瓶中放入甘油(東京化成工業股份有限公司製)184.2g(2.0mol)，將反應裝置系統內以氮氣取代。加入氫氧化鈉水溶液(50質量%)711g(9.0mol)，將反應系在約80℃下進行1小時攪拌後，冷卻至約40℃。將反應系統內保持在約40℃下，加入四丁基銨溴化物70.8g(0.26mol)、氯化烯丙基659g(7.2mol)並進行16小時攪拌。反應終了後，加入乙酸乙酯400g與水300g進行分液處理，將有機層以純水200mL/次洗淨至成為中性。將所得之有機層之有機溶劑(乙酸乙酯)餾去後，藉由氣體層析法進行測定後得到純度97%之基質C(甘油三烯丙基醚)198.2g。 [0044] 合成例4(二季戊四醇六烯丙基醚之合成) 於2.0公升三口圓底燒瓶放入二季戊四醇(東京化成工業股份有限公司製)254.3g(1.0mol)，將反應裝置系統內以氮氣取代。加入氫氧化鈉水溶液(50質量%)632g(8.0mol)，將反應系在約80℃下進行1小時攪拌後，冷卻至約40℃。將反應系統內保持在約40℃下，加入四丁基銨溴化物70.8g(0.26mol)、氯化烯丙基659g(7.2mol)並進行62小時攪拌。反應終了後，加入乙酸乙酯400g與水300g進行分液處理，將有機層以純水200mL/次洗淨至成為中性。將所得之有機層的有機溶劑(乙酸乙酯)餾去，藉由氣體層析法進行測定，得到純度92%之基質D(二季戊四醇六烯丙基醚)396.7g。 [0045] [多價縮水甘油基醚化合物之合成] 實施例1(季戊四醇四縮水甘油基醚之合成) 將在合成例1所得之季戊四醇四烯丙基醚200g(0.67mol)、乙腈(純正化學股份有限公司製)220g(5.36mol)、甲醇(純正化學股份有限公司製)100g(3.12mol)投入於2公升3口燒瓶中。在該階段的系統內之乙腈濃度為8.84mol/L。繼續加入少量50質量%氫氧化鉀水溶液(和光純藥工業股份有限公司製)，調整反應系統內之pH至約10.5後，在內溫35℃下將45質量%過氧化氫水溶液(日本過氧化物股份有限公司製)160g(2.12mol)在內溫不超過45℃下經18小時滴入。且，因若加入過氧化氫水溶液會使pH下降，故欲將pH維持在10.5，而又另外滴入50質量%氫氧化鉀水溶液。將反應液以UHPLC進行分析，滴入開始30小時後，在水解率為5%的時間點，於反應液中加入亞硫酸鈉2.11g(和光純藥工業股份有限公司製)與甲苯1000g使反應停止，在室溫進行30分鐘攪拌，分離出水層(含有亞硫酸鈉、副產物乙醯胺等)與有機層(含有最終目的物、反應中間體)。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為3.78mol/L。其後將有機層以純水150g洗淨2次，除去殘存之亞硫酸鈉、副產物乙醯胺等雜質，藉由餾去溶劑而得到純度89%，產量190.14g，粗產率為78.2%之反應生成物(目的物)。 [0046] 實施例2(三羥甲基丙烷三縮水甘油基醚之合成) 將在合成例2所得之三羥甲基丙烷三烯丙基醚75g(0.295mol)、乙腈75g(1.83mol)、甲醇72.5g(2.26mol)投入於2公升3口燒瓶中。在該階段的系統內之乙腈濃度為6.99mol/L。繼續加入50質量%氫氧化鉀水溶液，將反應液之pH調整至約10.5後，在內溫35℃將45質量%過氧化氫水溶液116g(1.54mol)在不使內溫超過45℃下經30小時滴入。且，因若加入過氧化氫水溶液會使pH下降，故欲將pH維持在10.5，而又另外滴入50質量%氫氧化鉀水溶液。將反應液以UHPLC進行分析，滴入開始48小時後，在水解率為5%的時間點於反應液加入亞硫酸鈉3.06g與甲苯200g使反應停止，在室溫進行30分鐘攪拌，分離水層(含有亞硫酸鈉、副產物乙醯胺等)與有機層(含有最終目的物、反應中間體)。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為2.72mol/L。其後將有機層以純水80g洗淨2次並除去殘存之亞硫酸鈉、副產物乙醯胺等雜質後，藉由餾去溶劑而得到純度89%、產量66.76g、粗產率72.8%之反應生成物(目的物)。 [0047] 實施例3(甘油三縮水甘油基醚之合成) 將在合成例3所得之甘油三烯丙基醚106g(0.50mol)、乙腈380g(3.1mol)、甲醇70.5g(2.2mol)投入於1公升3口燒瓶中。在該階段之系統內的乙腈濃度為4.59mol/L。繼續加入50質量%氫氧化鉀水溶液，將反應液的pH調整至約10.5後，在內溫35℃將45質量%過氧化氫水溶液170g(2.0mol)在內溫不超過45℃下經8小時滴入。且，因若加入過氧化氫水溶液會使pH下降，故欲將pH維持在10.5，而又另外滴入50質量%氫氧化鉀水溶液。將反應液以UHPLC進行分析，滴入開始10小時後，在水解率為5%的時間點，於反應液中加入亞硫酸鈉3.2g與甲苯400g使反應停止，在室溫進行30分鐘攪拌，分離水層(含有亞硫酸鈉、副產物乙醯胺等)與有機層(含有最終目的物、反應中間體)。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為1.97mol/L。其後將有機層以純水120g洗淨2次後，除去殘存之亞硫酸鈉、副產物乙醯胺等雜質後，藉由餾去溶劑，得到純度92%、產量108g、粗產率82.9%之反應生成物(目的物)。 [0048] 實施例4(二季戊四醇六縮水甘油基醚之合成) 將在合成例4所得之二季戊四醇六烯丙基醚102g(0.20mol)、乙腈294g(2.4mol)、甲醇32.1g(1.0mol)投入於1公升3口燒瓶中。在該階段的系統內之乙腈濃度為4.67mol/L。繼續加入50質量%氫氧化鉀水溶液，將反應液的Ph調整至約10.5後，在內溫35℃將45質量%過氧化氫水溶液135g(1.6mol)在內溫不超過45℃下經48小時滴入。且，因若加入過氧化氫水溶液會使pH下降，故欲將pH維持在10.5，而又另外滴入50質量%氫氧化鉀水溶液。將反應液進行UHPLC分析，滴下開始50小時後，在水解率到達5%之時間點於反應液中加入亞硫酸鈉2.5g與甲苯400g並使反應停止，在室溫進行30分鐘攪拌，分離出水層(含有亞硫酸鈉、副產物乙醯胺等)與有機層(含有最終目的物、反應中間體)。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為2.00mol/L。此後將有機層以純水120g進行2次洗淨，除去殘存亞硫酸鈉、副產物乙醯胺等雜質後，藉由餾去溶劑，可得到純度88%、產量86.9g、粗產率71.8%之反應生成物(目的物)。 [0049] 比較例1(季戊四醇四縮水甘油基醚之合成) 將在合成例1所得之季戊四醇四烯丙基醚200g(0.67mol)、乙腈220g(5.36mol)、甲醇100g(3.12mol)投入於2公升3口燒瓶中。在該階段的系統內乙腈濃度為8.86mol/L。繼續加入少量50質量%氫氧化鉀水溶液，將反應系統內之pH調整於約10.5後，在內溫35℃將45質量%過氧化氫水溶液160g(2.12mol)在內溫未超過45℃下經60小時滴入。且，若加入過氧化氫時會使pH下降，故欲將pH維持在10.5，必須又另外滴入50質量%氫氧化鉀水溶液。將反應液進行UHPLC分析，滴下開始68小時後，在水解率到達14%之時間點時，加入亞硫酸鈉16.3g與甲苯800g，進行30分鐘攪拌，停止反應。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為4.39mol/L。以純水150g進行2次洗淨後，餾去溶劑所得之反應生成物為純度72%、產量93.0g、粗產率38.2%。 [0050] 比較例2(三羥甲基丙烷三縮水甘油基醚之合成) 將在合成例2所得之三羥甲基丙烷三烯丙基醚75g(0.295mol)、乙腈75g(1.83mol)、甲醇73g(2.26mol)投入於1公升3口燒瓶中。在該階段的系統內之乙腈濃度為6.96mol/L。繼續加入50質量%氫氧化鉀水溶液，將反應系統內之pH調整至約10.5後，在內溫35℃將45質量%過氧化氫水溶液116g(1.54mol)在內溫不超過45℃下滴入66小時。且，因加入過氧化氫會使pH下降，故欲將pH維持在10.5，而又另外滴入50質量%氫氧化鉀水溶液。將反應液進行UHPLC分析，滴下開始72小時後，在水解率為22%之時間點時加入甲苯50g與亞硫酸鈉1g，經30分鐘攪拌後停止反應。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為3.13mol/L。以純水20g進行2次洗淨，餾去溶劑後得到反應生成物為純度69%、產量29.4g、粗產率32.1%。
[Mode for Carrying Out the Invention] The present invention will be described in detail below. The method for producing a polyvalent glycidyl compound according to the present invention is characterized in that an aqueous hydrogen peroxide solution is used as an oxidant, and the carbon-carbon double bond of an organic compound having a carbon-carbon double bond is epoxidized. In the manufacturing method, as the organic compound, a polyvalent allyl compound having three or more allyl groups is used as a substrate, and the epoxidation reaction is carried out in one step, and the ratio of the hydrolysate of the glycidyl group formed is 0.5. The reaction is stopped in the range of -10%. [0015] In the present invention, an aqueous hydrogen peroxide solution is used as an oxidant. The concentration of the hydrogen peroxide aqueous solution is not particularly limited, but it is generally 1 to 80% by mass, and preferably selected from the range of 10 to 60% by mass. From the viewpoint of industrial productivity and energy cost at the time of separation, it is preferable that the hydrogen peroxide solution is at a high concentration. On the other hand, when an excessively high concentration and / or an excessive amount of the hydrogen peroxide solution is not used. From the viewpoint of economy and safety, it is better. [0016] The amount of the hydrogen peroxide aqueous solution used is not particularly limited. The concentration of hydrogen peroxide in the reaction system decreases as the reaction proceeds. With regard to this decrease, the hydrogen peroxide concentration in the reaction system can be maintained within the range of 0.1 to 30% by mass, and preferably 0.2 to 10% by mass by supplementary addition. When the productivity is 0.1% by mass or more, on the other hand, when the alcohol is used as a solvent at 30% by mass or less, the explosiveness in the mixed composition of alcohol and water is suppressed and the reaction can be performed safely. . In addition, when a large amount of hydrogen peroxide is charged into the reaction system at the initial stage of the reaction, the reaction may proceed rapidly and a dangerous situation may occur. Therefore, as described later, it is preferable to slowly add hydrogen peroxide to the reaction system. [0017] The epoxidation reaction in the method for producing a polyvalent glycidyl compound according to the present invention is that, if it is an epoxy resin having a polyvalent allyl compound having 3 or more allyl groups through an aqueous hydrogen peroxide solution ( The glycidyl group is not particularly limited, and examples include a hydrogen peroxide and a nitrile compound in the presence of a basic salt compound such as a carbonate or bicarbonate of an alkali metal, such as acetonitrile and Method for reacting carbon-carbon double bond of allyl compound and ring-forming carbon-carbon double bond of allyl compound by using hydrogen peroxide as oxidant in presence of tungstic acid, phosphoric acid and quaternary ammonium salt Oxidation methods, etc. The method of epoxidizing a polyvalent allyl compound by an aqueous hydrogen peroxide solution can be appropriately selected according to the properties of the substrate. [0018] A method for epoxidizing a polyvalent allyl compound using hydrogen peroxide and acetonitrile will be described in detail below. [0019] In consideration of industrially stable production, acetonitrile and a polyvalent allyl compound as a matrix were initially charged into the reactor, and the reaction temperature was kept as constant as possible. While the hydrogen peroxide was confirmed in the reaction Being consumed, it is better to join slowly. If this method is adopted, even if hydrogen peroxide is generated in the reactor due to abnormal decomposition, the cumulative amount of hydrogen peroxide is small, and the pressure rise is kept to a minimum. [0020] It is preferable that the concentration in the reaction system of acetonitrile is within a range of 5 to 50 mol / L during the reaction. In another embodiment, the concentration of acetonitrile in the reaction system is preferably controlled to be within a range of 1 to 10 mol / L during the reaction. It is considered that in the production method of a glycidyl compound that epoxidizes a carbon-carbon double bond of an organic compound having a carbon-carbon double bond by using an oxidant as hydrogen peroxide in the presence of acetonitrile, acetonitrile reacts with hydrogen peroxide. An oxidatively active species (perrhenium acid) is generated, and the carbon-carbon double bond can be oxidized by the oxidatively active species. Therefore, the theoretically necessary amount of acetonitrile for the reaction is equal to the carbon-carbon double bond amount of the organic compound (equal moles). As the reaction proceeds, the acetonitrile concentration in the reaction system will decrease. The concentration of the carbon-carbon double bond of the organic compound can be appropriately selected in the reaction system of acetonitrile. If the concentration in the reaction system is 1 mol / L or more or 5 mol / L or more, the reaction rate is appropriate, so the productivity is good. On the other hand, if it is 10 mol / L or less, or 50 mol / L or less, the hydrogen peroxide ring The oxidation selectivity is good, and it is also suitable for cost. Therefore, it is preferable to set the initial concentration at the beginning of the reaction in the above-mentioned concentration range, monitor the concentration in progress of the reaction, and control the concentration by adding more in a range not exceeding the upper limit value before the concentration drops to the lower limit value. The concentration is preferably 6 mol / L or more, while the concentration is preferably 40 mol / L or less. In other embodiments, a concentration of 1.5 mol / L or more is preferred, a concentration of 5 mol / L or more is more preferred, and a concentration of 10 mol / L or less is more preferred. [0021] When the epoxy (glycidyl) reaction is performed using acetonitrile as described above, it is preferable to use alcohol as a solvent in the reaction system to coexist. When an alcohol is used as the solvent of the substrate, when the viscosity of the substrate is high, the alcohol can be used as a viscosity diluent for increasing the movement speed of the hydrogen peroxide to the substrate. When the hydrophilicity of the alcohol is low in the matrix, the organic layer containing the matrix and acetonitrile and the water layer containing hydrogen peroxide become a homogeneous system, thereby increasing the reaction rate. If the alcohol is not allowed to coexist or the amount is insufficient, a two-layer separation may be caused in the reaction system. As a result, the epoxidation selectivity of hydrogen peroxide may decrease. The alcohol is preferably an alcohol having 1 to 4 carbon atoms, more preferably a primary alcohol having 1 to 4 carbon atoms, and more preferably methanol, ethanol, or 1-propanol. The amount of acetonitrile used for the reaction is preferably in the range of 0.1 to 5 times the mass ratio of the loading amount, more preferably in the range of 0.2 to 4 times, and in the range of 0.3 to 3 times. For the better. When the loading amount of the alcohol to the used amount of acetonitrile is within the above-mentioned range, the stability in the reaction system of the peroxidic acid of the oxidation active species is improved, and the reaction can be performed efficiently. [0022] The loading amount of acetonitrile at the beginning of the reaction is based on the number of carbon-carbon double bonds of an organic compound having a carbon-carbon double bond, preferably in the range of 1.2 to 5 mole equivalents, and 1.5 to 3 Molar equivalents are preferred. The yield is good when it is 1.2 mol equivalent or more. On the other hand, when it is 5 mol equivalent or less, the epoxidation selectivity of hydrogen peroxide is good, and the cost is appropriate. The amount of acetonitrile at the beginning of the reaction is preferably 5 to 50 mol / L in the concentration range in the reaction system during the above reaction, and more preferably 6 to 40 mol / L. In other embodiments, the loading of acetonitrile at the beginning of the reaction is preferably 1 to 10 mol / L, more preferably 1.5 to 10 mol / L, and even more preferably 5 to 10 mol / L. In addition, when acetonitrile is added to the reaction, the ratio of the total amount of acetonitrile (acetonitrile / carbon-carbon double bond (molar ratio) of the substrate to the total amount of acetonitrile) used in the reaction is also in the above range, which is 1.2 It is preferably 5 to 5, more preferably 1.5 to 3. [0023] The ratio of the amount of hydrogen peroxide to the amount of acetonitrile used (hydrogen peroxide / acetonitrile (molar ratio) is preferably 0.1 or more, on the other hand, it is preferably 1.1 or less, and it is preferably less than 1.0 .Because it is in the above range, the hydrolysis can be suppressed, and the reaction can also be performed in a homogeneous system, and the reaction can be performed efficiently. [0024] The reaction can be performed in a state of completely dissolving the matrix. In particular, it will not be separated into a dissolving matrix. [0025] In the method for producing a polyvalent glycidyl compound according to the present invention, the reaction layer The pH is preferably set at 9 to 11, more preferably in the range of 9.5 to 11, and more preferably in the range of 10 to 11. When the pH is 9 or more, the reaction rate is appropriate, so the productivity is good. On the other hand, if the pH is 11 In the following cases, the reaction will proceed violently and cause a low probability of danger. Therefore, hydrogen peroxide will activate decomposition in a high-alkali environment. Therefore, the pH must be controlled to 9 to 10 in the initial stage of the reaction. With the addition of hydrogen peroxide, It is better to slowly control the pH of the reaction solution to about 10 to 11. When a polyvalent allyl compound having 3 or more carbon-carbon double bonds is used as a substrate, the polyvalent glycidyl group is affected by the pH of the reaction system. Although the yield and selectivity of the compound are affected, if the pH is in the range of 10 to 11, the yield and selectivity of the polyvalent glycidyl compound can be improved. [0026] As used in the reaction system Examples of the basic salt compounds used for pH adjustment include inorganic base salts such as potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, and cesium hydroxide, or potassium methoxide, potassium ethoxide, and sodium methoxide. , Sodium ethoxide, tetramethylammonium hydroxide and other organic base salts. Potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, potassium methoxide, potassium ethoxide, sodium methoxide, sodium ethoxide It is preferable from the viewpoint of pH. The solubility of potassium hydroxide and sodium hydroxide in water and alcohol is high, so it is also beneficial to reactivity, so it is preferable. [0027] Although the basic salt compound can be used as an aqueous solution or alcohol Solution use. Used as solvent for alcohol solution. Examples of the alcohol include methanol, ethanol, propanol, and butanol, and it is also preferable to use the same as the above-mentioned reaction solvent. The solution of the basic salt compound is such that the pH of the reaction solution does not change with hydrogen peroxide. The addition is preferably lower than 9 and is preferably added, and the temperature of the reaction solution at this time is preferably in the range of 20 to 100 ° C, and preferably it is maintained in the range of 25 to 60 ° C. [0028] In the method for producing a polyvalent glycidyl compound, the reaction temperature is usually in the range of 20 to 100 ° C, preferably in the range of 25 to 60 ° C. Moreover, the reaction time is affected by the reaction temperature and cannot be generalized. However, it is generally performed in a range of 4 to 100 hours, preferably 8 to 80 hours. [0029] After the epoxidation reaction, a step of stopping the reaction is performed as a subsequent step. The reaction is stopped by quenching the reaction solution with an aqueous solution containing a reducing agent. After the reaction is stopped, water in the reaction system can be removed. The reaction stop of the present invention is determined by the ratio (hydrolysis rate) in the system of the hydrolyzed body of the glycidyl group generated at the later stage of the epoxidation reaction. In the case of using an allyl compound having three or more allyl groups as a substrate for epoxidation, compared with the case of using an allyl compound having one or two allyl groups as a substrate, It takes a long time for the epoxidation reaction, and the polarity of the obtained reaction intermediate is strong. Therefore, it was confirmed that the hydrolysis reaction of the glycidyl group possessed by the reaction intermediate produced as the reaction progressed during the reaction proceeded. The formation of a glycidyl hydrolysate can be confirmed by gas chromatography (GC), high-speed liquid chromatography (LC), and 1 H-NMR aliquot optical analysis. The progress of the hydrolysis reaction is considered to have a large effect by increasing the water content in the reaction solution by adding an aqueous hydrogen peroxide solution as an oxidant. In order to suppress the ratio of glycidyl hydrolysate, in the later stage of the reaction, the ratio of the amount of hydrolysate produced is 0.5 to 10%, preferably 0.5 to 8%, and more preferably 0.5 to 5%. The post-processing step, in other words, the step of stopping the reaction. Since the hydrolysis rate is within 10% as the basis for the next step, it is possible to suppress the formation of glycidyl hydrolysate as a by-product. When the hydrolysis rate is set to 0.5% or more, the intended polyvalent glycidyl compound can be obtained in a good yield. [0030] The ratio (hydrolysis rate) in the system of the glycidyl hydrolysate, for example, a polyvalent glycidyl compound can be identified by 1 H-NMR analysis, and then the polyvalent glycidol can be determined by GC or LC analysis. After the detection time of the base compound, the reaction solution is analyzed by GC or LC, and it can be obtained from the ratio of the signal integrated intensity of the hydrolysate to the total of the total signal integrated intensity. For GC and LC, the retention time is obtained from a standard substance, for example, for a reversed-phase column, the signal observed in a shorter time than the retention time of the target substance belongs to the signal of the hydrolysate. In the analysis, for example, ACQUITY UPLC (TM) BEH C18 manufactured by Japan Waters Corporation can be used, and acetonitrile and water can also be used as a dissolution solvent. [0031] The step of stopping the reaction is preferably performed when it is confirmed that the glycidyl hydrolysate formation rate exceeds the time point when the allyl consumption rate of the matrix polyvalent allyl compound is exceeded. Therefore, the method for producing a polyvalent glycidyl compound may further include a step of confirming that the glycidyl hydrolysate production rate exceeds the rate of allylic consumption of the polyvalent allyl compound. When the rate of allyl consumption of a polyvalent allyl compound is higher than the rate of formation of a glycidyl hydrolysate, for example, the reaction solution is analyzed by gas chromatography every 30 minutes, and the matrix absorption peak is compared. The area reduction rate and the increase rate of the area of the absorption peak of the hydrolysate were confirmed. [0032] Since the reaction solution usually contains hydrogen peroxide, when removing water from the reaction solution, it is necessary to reduce and remove the hydrogen peroxide. Examples of the reducing agent used include sodium sulfite, sodium thiosulfate, and the like, but are not limited to these reducing agents. If the water in the reaction system and the organic layer containing the reaction intermediate can be efficiently separated and removed at this time, an appropriate amount of an organic solvent with low compatibility with water is preferably added to the reaction solution. Examples of the organic solvent to be used include toluene, ethyl acetate, methylene chloride, and the like, but are not limited to these organic solvents. By this treatment, the hydrogen peroxide remaining in the reaction solution is removed, and at the same time, the water layer and the organic layer (organic solvent) can be separated, and the reaction product contained in the organic layer (organic solvent) can be recovered and concentrated. After purification by a known method (distillation, chromatographic separation, recrystallization, sublimation, etc.), the desired polyvalent glycidyl compound can be obtained. If the yield of the intended polyvalent glycidyl compound is 50% or more, it can be applied to industry. [0033] In the method for producing a polyvalent glycidyl compound of the present invention, an epoxidation reaction is performed in one stage. The "1-stage" means that after the epoxidation reaction is stopped, the epoxidation reaction does not start again. Therefore, by the steps of stopping the epoxidation reaction and removing water in the reaction solution, the loss of the reaction product can be minimized and the yield can be improved. [0034] The matrix used in the method for producing a polyvalent glycidyl compound of the present invention is not particularly limited as long as it is an organic compound having three or more carbon-carbon double bonds, and is allyl-bonded to oxygen An organic compound which forms an allyl ether group by an atom or an amine group to form an allylamine group is preferred. In another embodiment, the base used in the method for producing a polyvalent glycidyl compound is preferably a compound having three or more allyl ether groups. The so-called "allyl ether group" means "C = CCO-" bonding, which means allyloxy, and the so-called "allylamino group" means Or "C = CC-NH-". The number of carbon-carbon double bonds contained in the compound may be three or four or more. Examples of the compound having three carbon-carbon double bonds include trimethylolpropane triallyl ether, glycerol triallyl ether, pentaerythritol triallyl ether, and ditrimethylolpropane triallyl. Ether, diglyceryl triallyl ether, erythritol triallyl ether, xylitol triallyl ether, dipentaerythritol triallyl ether, sorbitol triallyl ether, inositol triallyl Ether, triallyl isocyanurate, diallyl aminophenol allyl ether, and the like. Examples of the compound having four or more carbon-carbon double bonds include pentaerythritol tetraallyl ether, ditrimethylolpropane tetraallyl ether, diglycerol tetraallyl ether, and erythritol tetral. Allyl ether, xylitol tetraallyl ether, xylitol penallyl ether, dipentaerythritol tetraallyl ether, dipentaerythritol penallyl ether, dipentaerythritol hexaallyl ether, sorbitol tetra Allyl ether, Sorbitol penallyl ether, Sorbitol hexaallyl ether, Inositol tetraallyl ether, Inositol penallyl ether, Inositol hexaallyl ether, Phenolic novolac type poly Allyl ether, cresol-type polyallyl ether, naphthalene contains novolac-type polyallyl ether, tetraallyl diaminodiphenylmethane, and the like. [0035] The organic compound having three or more carbon-carbon double bonds is preferably a chain, monocyclic or condensed ring compound. As the organic compound having three or more carbon-carbon double bonds, an aliphatic compound is preferred, and a chain or monocyclic aliphatic compound is more preferred. Among them, trimethylolpropane triallyl ether, glycerol triallyl ether, pentaerythritol triallyl ether, pentaerythritol tetraallyl ether, ditrimethylolpropane triallyl ether, and ditrihydroxyol Methylpropane tetraallyl ether, diglycerol triallyl ether, diglycerol tetraallyl ether, erythritol triallyl ether, erythritol tetraallyl ether, xylitol triene Propyl ether, xylitol tetraallyl ether, xylitol penallyl ether, dipentaerythritol triallyl ether, dipentaerythritol tetraallyl ether, dipentaerythritol penallyl ether, dipentaerythritol hexaene Propyl ether, sorbitol triallyl ether, sorbitol tetraallyl ether, sorbitol penallyl ether, sorbitol hexaallyl ether, inositol triallyl ether, inositol tetraallyl Ether, inositol pentaallyl ether, inositol hexaallyl ether, and triallyl isocyanurate are preferred. The method for producing a polyvalent glycidyl compound of the present invention is particularly suitable for a compound which is easily decomposed in an aqueous system and is easily subjected to a hydrolysis reaction, and such a compound can be obtained in a high yield. [0036] The reaction tank is not particularly limited, and examples thereof include a batch system and a continuous system. In the case of the batch type, when the hydrolyzed body of the glycidyl group in the reaction tank is within a range of 0.5 to 10%, the process proceeds to the next tank. In the case of the continuous type, the glycidyl hydrolysate at the end of the reaction tank is in a range of 0.5 to 10%. [Examples] [0037] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to the following examples. [Reaction conditions] • The concentration of hydrogen peroxide is determined by referring to the method described in Japanese Patent Application Laid-Open No. 6-130051, and measuring the concentration of peracetic acid by titrating potassium iodide and free iodine with a sodium thiosulfate standard solution. Add a large excess of potassium iodide aqueous solution, dilute sulfuric acid and ammonium molybdate aqueous solution, use the sodium thiosulfate standard solution as the free iodine again, and use the starch solution as the coloring reagent. After titration, determine the hydrogen peroxide concentration.・ Hydrolysis rate First, the polyvalent glycidyl ether compound in the reaction solution was separated by column chromatography (silicone 60 (spherical) made by Kanto Chemical Co., Ltd.), and analyzed by 1 H-NMR. After identification, analysis was performed by UHPLC (ACQUITY UPLC (TM) BEH C18 manufactured by Japan Waters Corporation, dissolution solvent: acetonitrile and water, gradient method), and the detection time of the polyvalent glycidyl ether compound was identified. Next, the reaction solution was subjected to UHPLC analysis (ACQUITY UPLC (TM) BEH C18 manufactured by Japan Waters Corporation, dissolution solvent: acetonitrile and water, gradient method), and the polyvalent glycidyl ether compound was used as a reference. (C). (A) A region shorter than the detection time of the polyvalent glycidyl ether compound: the absorption peak of the glycidyl hydrolysate of the target substance (B), the absorption peak of the polyvalent glycidyl ether compound (C) is higher than the polyvalent glycidol Area where the detection time of the alkyl ether compound is longer: The hydrolysis rate of the allyl ether body estimated as the reaction intermediate is obtained by the following formula. Hydrolysis rate = area of ｛(a)} / total area of ｛(a) (b) (c)} [0039] [Evaluation] • The crude yield was calculated by the following formula. Crude yield = (the amount of product obtained after the post-treatment) / (theoretical amount calculated from the loading amount) • purity of the matrix First, the matrix was subjected to column chromatography (Kanto Chemical Co., Ltd. Silica gel 60 (spherical) manufactured by the company) was separated, identified by 1 H-NMR analysis, and then subjected to UHPLC analysis (ACQUITY UPLC (TM) BEH C18 manufactured by Japan Waters Corporation, dissolution solvent: acetonitrile and water, gradient method) Determine the detection time of the matrix. Next, the reaction solution was subjected to UHPLC analysis (ACQUITY UPLC (TM) BEH C18 manufactured by Japan Waters Corporation, dissolution solvent: acetonitrile and water, gradient method), and the matrix was used as a reference to integrate the following three regions (A) to (C). Find the area. (A) A region shorter than the detection time of the matrix (B) An absorption peak of the matrix (C) A region longer than the detection time of the matrix The purity of the matrix is calculated by the following formula. The purity of the matrix = the area of ｛(B)} / ｛(A) (B) (C) Total area} [0040] ・ Purity of polyvalent glycidyl ether compound First, borrow polyvalent glycidyl ether compound Separated by column chromatography (Silicon 60 (spherical) manufactured by Kanto Chemical Co., Ltd.), identified by 1 H-NMR analysis, and then subjected to UHPLC analysis (ACQUITY UPLC (TM) BEH manufactured by Japan Waters Corporation) C18, dissolution solvent: acetonitrile and water, gradient method), determine the detection time of polyvalent glycidyl ether compounds. Next, the reaction solution was analyzed by UHPLC (ACQUITY UPLC (TM) BEH C18 manufactured by Japan Waters Corporation, dissolution solvent: acetonitrile and water, gradient method), and the polyvalent glycidyl ether compound was used as a reference. ) To (c). (A) A region shorter than the detection time of the polyvalent glycidyl ether compound: the absorption peak (g) of the glycidyl hydrolysate (B) of the target compound, and the polyvalent glycidyl ether compound. Area where the detection time of the alkyl ether compound is longer: The purity of the allyl ether polyvalent glycidyl ether compound estimated as the reaction intermediate is calculated by the following formula. Purity of polyvalent glycidyl ether compound = area of ｛(B)} / total area of ｛(A) (B) (C)} ・ Pure yield of polyvalent glycidyl ether compound is calculated by the following formula . Pure Yield = Crude Yield of Polyvalent Glycidyl Ether Compound × Purity of Polyvalent Glycidyl Ether Compound [0041] [Synthesis of Matrix] Synthesis Example 1 (Synthesis of Pentaerythritol Tetraallyl Ether) in 2.0 Liters of Three Ports In a round bottom flask, 400.0 g (1.57 mol) of Neoallyl (registered trademark) P-30M (Pentaerythritol Triallyl Ether, manufactured by Daiso Corporation) was placed, and the inside of the reaction device system was replaced with nitrogen. 300 g (3.8 mol) of an aqueous sodium hydroxide solution (50% by mass, manufactured by Pure Chemical Co., Ltd.) was added, the mixture was heated to 80 ° C, and the reaction system was stirred at about 80 ° C for 1 hour, and then the reaction system was cooled to about 40 ° C. The reaction system was maintained at about 40 ° C, and 55.6 g (0.2 mol) of tetrabutylammonium bromide (manufactured by Tokyo Chemical Industry Co., Ltd.) and 366 g of allyl chloride (manufactured by Wako Pure Chemical Industries, Ltd.) were added. (4.0 mol) and stirred for 20 hours. After the reaction was completed, 200 g of ethyl acetate and 100 g of water were added and the solution was separated. The organic layer was washed with pure water 50 mL / times to become neutral. The organic solvent (ethyl acetate) of the obtained organic layer was distilled off to obtain 487.8 g of a matrix A (pentaerythritol tetraallyl ether) having a purity of 96%. Synthesis Example 2 (Synthesis of Trimethylolpropane triallyl ether) In a 2.0 liter three-neck round bottom flask, Neoallyl (registered trademark) T-20 (trimethylolpropane diallyl ether, 2000.0 g (9.4 mol) manufactured by Daiso Co., Ltd., and the inside of the reaction device system was replaced with nitrogen. After adding 4500 g (56.3 mol) of an aqueous sodium hydroxide solution (50% by mass), the reaction system was stirred at about 80 ° C for 1 hour, and then cooled to about 40 ° C. While maintaining the inside of the reaction system at about 40 ° C., 200.0 g (0.6 mol) of tetrabutylammonium bromide and 2400 g (31.4 mol) of allyl chloride were added and stirred for 20 hours. After the reaction was completed, 2000 g of ethyl acetate and 1,000 g of water were added to perform a liquid separation treatment, and the organic layer was washed with pure water 500 mL / times to become neutral. The organic solvent (ethyl acetate) of the obtained organic layer was distilled off and measured by gas chromatography to obtain 2444.3 g of a matrix B (trimethylolpropane triallyl ether) having a purity of 94%. Synthesis Example 3 (Synthesis of glycerol triallyl ether) 182.0 g (2.0 mol) of glycerol (manufactured by Tokyo Chemical Industry Co., Ltd.) was placed in a 2.0-liter three-necked round-bottomed flask, and the reaction system was charged with nitrogen. To replace. After adding 711 g (9.0 mol) of an aqueous sodium hydroxide solution (50% by mass), the reaction system was stirred at about 80 ° C for 1 hour, and then cooled to about 40 ° C. While maintaining the inside of the reaction system at about 40 ° C, 70.8 g (0.26 mol) of tetrabutylammonium bromide and 659 g (7.2 mol) of allyl chloride were added and stirred for 16 hours. After the reaction was completed, 400 g of ethyl acetate and 300 g of water were added for liquid separation treatment, and the organic layer was washed with pure water 200 mL / times to become neutral. The organic solvent (ethyl acetate) of the obtained organic layer was distilled off, and then measured by gas chromatography to obtain 198.2 g of a matrix C (glyceryl triallyl ether) having a purity of 97%. Synthesis Example 4 (Synthesis of dipentaerythritol hexaallyl ether) In a 2.0 liter three-neck round bottom flask, 254.3 g (1.0 mol) of dipentaerythritol (manufactured by Tokyo Chemical Industry Co., Ltd.) was placed. Replaced by nitrogen. After adding 632 g (8.0 mol) of an aqueous sodium hydroxide solution (50% by mass), the reaction system was stirred at about 80 ° C for 1 hour, and then cooled to about 40 ° C. While maintaining the inside of the reaction system at about 40 ° C, 70.8 g (0.26 mol) of tetrabutylammonium bromide and 659 g (7.2 mol) of allyl chloride were added and stirred for 62 hours. After the reaction was completed, 400 g of ethyl acetate and 300 g of water were added for liquid separation treatment, and the organic layer was washed with pure water 200 mL / times to become neutral. The organic solvent (ethyl acetate) of the obtained organic layer was distilled off and measured by gas chromatography to obtain 396.7 g of a matrix D (dipentaerythritol hexaallyl ether) having a purity of 92%. [Synthesis of polyvalent glycidyl ether compound] Example 1 (Synthesis of pentaerythritol tetraglycidyl ether) 200 g (0.67 mol) of pentaerythritol tetraallyl ether obtained in Synthesis Example 1 and acetonitrile (pure chemical 220 g (5.36 mol) of the company, and 100 g (3.12 mol) of methanol (manufactured by Pure Chemical Co., Ltd.) were put into a 2-liter 3-necked flask. The acetonitrile concentration in the system at this stage was 8.84 mol / L. Continue to add a small amount of 50% by mass potassium hydroxide aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.), adjust the pH in the reaction system to about 10.5, and then add a 45% by mass aqueous hydrogen peroxide solution (Japanese peroxide) at an internal temperature of 35 ° C. (Made by Co., Ltd.) 160 g (2.12 mol) was dripped in for 18 hours at an internal temperature not exceeding 45 ° C. In addition, since the pH will be lowered if an aqueous hydrogen peroxide solution is added, it is desired to maintain the pH at 10.5, and a 50% by mass potassium hydroxide aqueous solution is added dropwise. The reaction solution was analyzed by UHPLC. After 30 hours from the start of the dropwise addition, at a time point when the hydrolysis rate was 5%, 2.11 g of sodium sulfite (made by Wako Pure Chemical Industries, Ltd.) and 1000 g of toluene were added to stop the reaction. After stirring at room temperature for 30 minutes, the aqueous layer (containing sodium sulfite, byproduct acetamide, etc.) and the organic layer (containing the final target substance and the reaction intermediate) were separated. The acetonitrile concentration in the system at the end of the reaction calculated by using the consumed acetonitrile as a 100% reaction with the substrate was 3.78 mol / L. Thereafter, the organic layer was washed twice with 150 g of pure water to remove residual impurities such as sodium sulfite and byproduct acetamide. The solvent was distilled off to obtain a purity of 89%, a yield of 190.14 g, and a crude yield of 78.2%. Product (object). Example 2 (Synthesis of trimethylolpropane triglycidyl ether) 75 g (0.295 mol) of trimethylolpropane triallyl ether, 75 g (1.83 mol) of acetonitrile obtained in Synthesis Example 2, 72.5 g (2.26 mol) of methanol was placed in a 2-liter 3-necked flask. The acetonitrile concentration in the system at this stage was 6.99 mol / L. After continuously adding a 50% by mass potassium hydroxide aqueous solution to adjust the pH of the reaction solution to about 10.5, 116 g (1.54 mol) of a 45% by mass aqueous hydrogen peroxide solution was added at an internal temperature of 35 ° C over 30 ° C without the internal temperature exceeding 45 ° C. Hours drip. In addition, since the pH will be lowered if an aqueous hydrogen peroxide solution is added, it is desired to maintain the pH at 10.5, and a 50% by mass potassium hydroxide aqueous solution is added dropwise. The reaction solution was analyzed by UHPLC. After 48 hours from the start of the dropwise addition, 3.06 g of sodium sulfite and 200 g of toluene were added to the reaction solution at a time point of 5% hydrolysis to stop the reaction. The mixture was stirred at room temperature for 30 minutes, and the aqueous layer was separated ( Contains sodium sulfite, by-product acetamide, etc.) and an organic layer (contains the final target substance and reaction intermediate). The acetonitrile concentration in the system at the end of the reaction calculated by using the consumed acetonitrile as a 100% reaction with the substrate was 2.72 mol / L. After that, the organic layer was washed twice with 80 g of pure water to remove residual impurities such as sodium sulfite and by-product acetamide, and then the solvent was distilled off to obtain a reaction with a purity of 89%, a yield of 66.76 g, and a crude yield of 72.8%. Product (object). Example 3 (Synthesis of glycerol triglycidyl ether) 106 g (0.50 mol) of glycerol triallyl ether obtained in Synthesis Example 3, 380 g (3.1 mol) of acetonitrile, and 70.5 g (2.2 mol) of methanol were charged. In a 1 liter 3-necked flask. The acetonitrile concentration in the system at this stage was 4.59 mol / L. After continuously adding a 50% by mass potassium hydroxide aqueous solution to adjust the pH of the reaction solution to about 10.5, 170 g (2.0 mol) of a 45% by mass aqueous hydrogen peroxide solution at an internal temperature of 35 ° C. for 8 hours at an internal temperature not exceeding 45 ° C. Drip into. In addition, since the pH will be lowered if an aqueous hydrogen peroxide solution is added, it is desired to maintain the pH at 10.5, and a 50% by mass potassium hydroxide aqueous solution is added dropwise. The reaction solution was analyzed by UHPLC. Ten hours after the dropwise addition, at a time point when the hydrolysis rate was 5%, 3.2 g of sodium sulfite and 400 g of toluene were added to the reaction solution to stop the reaction. The mixture was stirred at room temperature for 30 minutes and water was separated. Layer (containing sodium sulfite, byproduct acetamide, etc.) and an organic layer (containing the final target substance and a reaction intermediate). The acetonitrile concentration in the system at the end of the reaction calculated using the consumed acetonitrile as a 100% reaction with the substrate was 1.97 mol / L. After that, the organic layer was washed twice with 120 g of pure water, and after removing impurities such as residual sodium sulfite and byproduct acetamide, the solvent was distilled off to obtain a reaction with a purity of 92%, a yield of 108 g, and a crude yield of 82.9%. Product (object). Example 4 (Synthesis of dipentaerythritol hexaglycidyl ether) 102 g (0.20 mol) of dipentaerythritol hexaallyl ether obtained in Synthesis Example 4, 294 g (2.4 mol) of acetonitrile, 32.1 g (1.0 mol) of methanol ) Into a 1 liter 3-necked flask. The acetonitrile concentration in the system at this stage was 4.67 mol / L. Continue to add a 50% by mass potassium hydroxide aqueous solution to adjust the pH of the reaction solution to about 10.5, and then 135g (1.6mol) of a 45% by mass aqueous hydrogen peroxide solution at an internal temperature of 35 ° C for 48 hours at an internal temperature not exceeding 45 ° C. Drip into. In addition, since the pH will be lowered if an aqueous hydrogen peroxide solution is added, it is desired to maintain the pH at 10.5, and a 50% by mass potassium hydroxide aqueous solution is added dropwise. The reaction solution was analyzed by UHPLC. After 50 hours from the start of dropping, 2.5 g of sodium sulfite and 400 g of toluene were added to the reaction solution when the hydrolysis rate reached 5%, and the reaction was stopped. The mixture was stirred at room temperature for 30 minutes, and the aqueous layer was separated ( Contains sodium sulfite, by-product acetamide, etc.) and an organic layer (contains the final target substance and reaction intermediate). The acetonitrile concentration in the system at the end of the reaction calculated using the consumed acetonitrile as a 100% reaction with the substrate was 2.00 mol / L. Thereafter, the organic layer was washed twice with 120 g of pure water to remove impurities such as residual sodium sulfite and byproduct acetamide, and the solvent was distilled off to obtain a reaction with a purity of 88%, a yield of 86.9 g, and a crude yield of 71.8%. Product (object). Comparative Example 1 (Synthesis of Pentaerythritol Tetraglycidyl Ether) 200 g (0.67 mol) of pentaerythritol tetraallyl ether, 220 g (5.36 mol) of acetonitrile, and 100 g (3.12 mol) of methanol were charged in Synthesis Example 1. 2 liter 3-necked flask. The acetonitrile concentration in the system at this stage was 8.86 mol / L. Continue to add a small amount of a 50% by mass potassium hydroxide aqueous solution, adjust the pH in the reaction system to about 10.5, and then add 160g (2.12mol) of a 45% by mass aqueous hydrogen peroxide solution at an internal temperature of 35 ° C. Drop in for 60 hours. In addition, if the pH is lowered when hydrogen peroxide is added, in order to maintain the pH at 10.5, an additional 50% by mass potassium hydroxide aqueous solution must be added dropwise. The reaction solution was analyzed by UHPLC. After 68 hours from the start of dropping, when the hydrolysis rate reached 14%, 16.3 g of sodium sulfite and 800 g of toluene were added, and the reaction was stopped by stirring for 30 minutes. The acetonitrile concentration in the system at the end of the reaction calculated by using the consumed acetonitrile as a 100% reaction with the substrate was 4.39 mol / L. After washing twice with 150 g of pure water, the reaction product obtained by distilling off the solvent had a purity of 72%, a yield of 93.0 g, and a crude yield of 38.2%. Comparative Example 2 (Synthesis of trimethylolpropane triglycidyl ether) 75 g (0.295 mol) of trimethylolpropane triallyl ether, 75 g (1.83 mol) of acetonitrile obtained in Synthesis Example 2, 73 g (2.26 mol) of methanol was placed in a 1 liter 3-necked flask. The acetonitrile concentration in the system at this stage was 6.96 mol / L. Continue to add a 50% by mass potassium hydroxide aqueous solution to adjust the pH in the reaction system to about 10.5, and then drop 116 g (1.54mol) of a 45% by mass aqueous hydrogen peroxide solution at an internal temperature of 35 ° C at an internal temperature not exceeding 45 ° C. 66 hours. In addition, since the pH is lowered by the addition of hydrogen peroxide, it is desired to maintain the pH at 10.5, and another 50% by mass potassium hydroxide aqueous solution is added dropwise. The reaction solution was analyzed by UHPLC. After 72 hours from the start of dropping, 50 g of toluene and 1 g of sodium sulfite were added at the time point when the hydrolysis rate was 22%, and the reaction was stopped after 30 minutes of stirring. The acetonitrile concentration in the system at the end of the reaction calculated by using the consumed acetonitrile as a 100% reaction with the substrate was 3.13 mol / L. After washing twice with 20 g of pure water, the reaction product obtained after distilling off the solvent had a purity of 69%, a yield of 29.4 g, and a crude yield of 32.1%.
比較例3(季戊四醇四縮水甘油基醚之合成)
Comparative example 3 (synthesis of pentaerythritol tetraglycidyl ether)
在與比較例1之相同程序及投入比下開始反應。過氧化氫滴下開始20小時後將反應液進行UHPLC分析，確認水解率為未達0.5%。加入亞硫酸鈉16.3g與甲苯800g，進行30分鐘攪拌使反應停止。將被消費的乙腈作為與基質進行100%反應時所算出的反應終了時之系統內乙腈濃度為5.83mol/L。以純水150g進行2次洗淨後，餾去溶劑所得之反應生成物為純度30%、產量227g、粗產率93.3%。
The reaction was started under the same procedure and input ratio as in Comparative Example 1. Twenty hours after the start of hydrogen peroxide dropping, the reaction solution was analyzed by UHPLC, and it was confirmed that the hydrolysis rate was less than 0.5%. 16.3 g of sodium sulfite and 800 g of toluene were added, and the reaction was stopped by stirring for 30 minutes. When the consumed acetonitrile was used as a 100% reaction with the substrate, the calculated acetonitrile concentration in the system at the end of the reaction was 5.83 mol / L. After washing twice with 150 g of pure water, the reaction product obtained by distilling off the solvent had a purity of 30%, a yield of 227 g, and a crude yield of 93.3%.
實施例1~4、及比較例1~3的結果如表1所示。
The results of Examples 1 to 4 and Comparative Examples 1 to 3 are shown in Table 1.
[0053] 在水解率為10%以下的時間點時停止反應的實施例1～4為純產率良好。另一方面，自進行水解反應後停止反應的比較例1與2及水解率未達0.5%之比較例3則目的物之純度及純產率為低。 [產業上可利用性] [0054] 本發明之多價縮水甘油基化合物的製造方法為自具有3個以上烯丙基之多價烯丙基化合物與過氧化氫之反應可簡便地操作且安全下高產率，且低成本地製造出多價縮水甘油基化合物，故在工業上為有用。[0053] Examples 1 to 4 in which the reaction was stopped at a time point when the hydrolysis rate was 10% or less were good in pure yield. On the other hand, in Comparative Examples 1 and 2 in which the reaction was stopped after the hydrolysis reaction was performed, and Comparative Example 3 in which the hydrolysis rate was less than 0.5%, the purity and pure yield of the target product were low. [Industrial Applicability] [0054] The method for producing the polyvalent glycidyl compound of the present invention is that the reaction between a polyvalent allyl compound having three or more allyl groups and hydrogen peroxide can be easily handled and is safe. The polyvalent glycidyl compound is produced at a high yield and at a low cost, and is therefore industrially useful.