TWI547482B - 增加可回收之3-氯-4,5,6-三氟-2-氰吡啶之量的改良方法 - Google Patents

增加可回收之3-氯-4,5,6-三氟-2-氰吡啶之量的改良方法 Download PDF

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TWI547482B
TWI547482B TW104132147A TW104132147A TWI547482B TW I547482 B TWI547482 B TW I547482B TW 104132147 A TW104132147 A TW 104132147A TW 104132147 A TW104132147 A TW 104132147A TW I547482 B TWI547482 B TW I547482B
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cyanopyridine
reaction
chloro
tetrachloro
mixture
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朱遠明
喬治Ｔ 懷克
金Ｅ 安特
詹姆士Ｍ 倫加
羅伯特Ｄ 佛洛賽
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陶氏農業科學公司
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Description

增加可回收之3-氯-4,5,6-三氟-2-氰吡啶之量的改良方法 發明領域
本發明係有關於一種用於製備4-胺基-3-氯-5-氟-6-(經取代的)吡啶甲酸酯的方法。更特別地，本發明係有關於一種用於製備4-胺基-3-氯-5-氟-6-(經取代的)吡啶甲酸酯的方法，其中，5-氟取代基係於此方法流程早期藉由鹵素交換而引入。
發明背景
美國專利第6,297,197 B1號案描述某些4-胺基-3-氯-5-氟-6-(烷氧基或芳氧基)吡啶甲酸酯化合物及其作為除草劑之用途與其它事項。美國專利第6,784,137 B2及7,314,849 B2號案描述某些4-胺基-3-氯-5-氟-6-(芳基)吡啶甲酸酯化合物及其作為除草劑之用途與其它事項。美國專利第7,432,227 B2號案描述某些4-胺基-3-氯-5-氟-6-(烷基)吡啶甲酸酯化合物及其作為除草劑與其它事項。此等專利之每一者描述藉由以1-(氯甲基)-4-氟-1,4-二氮雜雙環[2.2.2]辛烷雙(四氟硼酸鹽)氟化相對應之5-未經取代之吡啶甲酸 酯製造4-胺基-3-氯-5-氟吡啶甲酸酯起始材料。有利的是無需依賴以如1-(氯甲基)-4-氟-1,4-二氮雜雙環[2.2.2]辛烷雙(四氟硼酸鹽)之昂貴氟化劑直接氟化吡啶甲酸酯之5-位置而製造4-胺基-3-氯-5-氟-6-(經取代之)吡啶甲酸酯。
發明概要
本發明係有關於一種用於自3,4,5,6-四氯-2-氰吡啶製備4-胺基-3-氯-5-氟-6-(經取代的)吡啶甲酸酯的方法。更特別地，本發明係有關於一種用於製備具有化學式I之4-胺基-3-氯-5-氟-6-(經取代的)吡啶甲酸酯的方法
其中，R表示C1-C4烷基、環丙基、C2-C4烯基，或以1至4個獨立地選自鹵素、C1-C4烷基、C1-C4鹵烷基、C1-C4烷氧基，或C1-C4鹵烷氧基之取代基取代之苯基；且R1表示C1-C12烷基或一未經取代或經取代的C7-C11芳烷基；此方法包含下列步驟：a)以氟化物離子來源氟化3,4,5,6-四氯-2-氰吡啶(化學式A)
產生3-氯-4,5,6-三氟-2-氰吡啶(化學式B) b)以氨將3-氯-4,5,6-三氟-2-氰吡啶(化學式B)胺化，產生4-胺基-3-氯-5,6-二氟-2-氰吡啶(化學式C) c)將4-胺基-3-氯-5,6-二氟-2-氰吡啶(化學式C)之6-位置之氟取代基與肼反應，產生4-胺基-3-氯-5-氟-6-肼基-2-氰吡啶(化學式D) d)以氯、溴或碘來源將4-胺基-3-氯-5-氟-6-肼基-2-氰吡啶(化學式D)鹵化，產生具有化學式E之4-胺基-3-氯-5-氟-6-鹵-2-氰吡啶
其中，L係Br、Cl或I；e)以強酸及醇(R1OH)將具有化學式E之4-胺基-3-氯-5-氟-6-鹵-2-氰吡啶水解及酯化，產生具有化學式F之4-胺基-3-氯-5-氟-6-鹵吡啶甲酸酯
其中，L及R1係如前所定義；及f)於過渡金屬催化劑存在中，以具化學式G之芳基、烷基或烯基金屬化合物偶合具有化學式F之4-胺基-3-氯-5-氟-6-鹵吡啶甲酸酯R-Met G
其中，R係如前所定義，且Met表示Zn-鹵化物、Zn-R、三-(C1-C4烷基)錫、銅，或B(OR2)(OR3)，其中，R2及R3彼此獨立地係氫、C1-C4烷基，或當一起時形成一伸乙基或伸丙基基團，產生具有化學式I之4-胺基-3-氯-5-氟-6-(經取代的)吡啶甲酸酯。
步驟a)至f)可以如流程I所述般所列示順序實施，或當化學相容性允許時，一些步驟可被重組成不同順序。例如，步驟f)之偶合可於步驟e)之水解及酯化前實施。
本發明之另一方面係有關於一種增加可回收之3-氯-4,5,6-三氟-2-氰吡啶(化學式B)之量的改良方法，
此化合物係自以氟化物離子來源氟化3,4,5,6-四氯-2-氰吡啶(化學式A)而製備，
其中，改良包含步驟：i)自氟化3,4,5,6-四氯-2-氰吡啶分離經過度氟化之3,4,5,6-四氟-2-氰吡啶(H)
副產物；ii)將經分離之3,4,5,6-四氟-2-氰吡啶(H)(a)與氯化鋰(LiCl)，(b)於相轉移催化劑存在中，與3,4,5,6-四氯-2-氰吡啶(化學式A)，或(c)與LiCl及3,4,5,6-四氯-2-氰吡啶之組合物反應，產生主要由3,4,5,6-四氯-2-氰吡啶、單氟-三氯-2-氰吡啶，及二氟-二氯-2-氰吡啶所構成之一混合物；及iii)將主要由3,4,5,6-四氯-2-氰吡啶、單氟-三氯-2-氰吡啶，及二氟-二氯-2-氰吡啶所構成之混合物再回收至製備3-氯-4,5,6-三氟-2-氰吡啶(化學式B)之氟化反應。
本發明之另一方面係於本方法期間製造之新穎中間物，換言之，係化合物：
較佳實施例之詳細說明
“烷基”、“烯基”及“炔基”之用辭與諸如“烷氧基”、“醯基、“烷硫基”及“烷基磺醯基”之衍生用辭於此處使 用時，於其等之範圍內係包含直鍵、分支鏈，及環狀部份。除非其它方式特別表示外，每一者可為未經取代，或以一或多個不受限地選自鹵素、羥基、烷氧基、烷硫基、C1-C6醯基、甲醯基、氰基、芳氧基，或芳基之取代基取代，只要此等取代基係立體上可相容，且化學鍵結及應變能之規則被滿足。“烯基”及“炔基”之用辭係意欲包括一或多個不飽和鍵。
“芳烷基”一辭於此處使用時係指具有總量為7至11個碳原子之一經苯基經取之烷基基團，諸如，苯甲基(-CH2C6H5)、2-甲基萘基(-CH2C10H7)，及1-或2-苯乙基(-CH2CH2C6H5或-CH(CH3)C6H5)。苯基基團本身可為未經取代或以一或多個獨立地選自下列之取代基取代：鹵素、硝基、氰基、C1-C6烷基、C1-C6烷氧基、經鹵化的C1-C6烷基、經鹵化的C1-C6烷氧基、C1-C6烷硫基、C(O)OC1-C6烷基，或其中，二相鄰取代基一起為-O(CH2)nO-，其中，n=1或2，只要此等取代基係立體可相容且化學鍵結及應變能之規則被滿足。
除非其它特別限制外，”鹵素”一辭與諸如”鹵基”之衍生用辭係指氟、氯、溴，及碘。
以1至4個獨立地選自鹵素、C1-C4烷基、C1-C4鹵烷基、C1-C4烷氧基，或C1-C4鹵烷氧基之取代基取代之苯基可為任何位向，但4-經取代之苯基、2,4-二經取代之苯基、2,3,4-三經取代之苯基、2,4,5-三經取代之苯基，及2,3,4,6-四經取代之苯基異構物係較佳。
4-胺基-3-氯-5-氟-6-(經取代的)吡啶甲酸酯係自3,4,5,6-四氯-2-氰吡啶，藉由包括氟交換、胺化、與肼反應、鹵化、水解、酯化，及經過渡金屬輔助之偶合之一系列步驟製備。此等個別步驟可以不同序列實施。
3,4,5,6-四氯-2-氰吡啶起始物料係一已知化合物且可購得。
於氟化物交換反應，經氟化之-2-氰吡啶係藉由將相對應之經氯化的-2-氰吡啶以對於欲被交換之每一環氯取代基為約一當量之氟化物離子來源反應而製備。
典型之氟化物離子來源係鹼金屬氟化物，其包括氟化鈉(NaF)、氟化鉀(KF)，及氟化銫(CsF)，且KF及CsF係較佳。四級烷基或芳基銨或鏻之氟化物亦可作為氟化物來源或作為添加劑。較佳地，此反應係於諸如二甲基亞碸(DMSO)、N-甲基吡咯烷酮(NMP)、N,N-二甲基甲醯胺(DMF)、六甲基磷醯胺(HMPA)或環丁碸之極性非質子溶劑或反應介質中實行。反應進行之溫度並不重要，但一般係從60℃至180℃，且較佳係從70℃至80℃。依於特別反應使用之溶劑而定，最佳溫度會改變。一般而言，溫度愈低，反應會愈緩慢進行。本反應典型上係於足以維持基本上均勻分散之反應物混合物之劇烈攪拌存在中進行。
於進行氟化反應，反應物添加之速率或順序並不 重要。一般，溶劑及鹼金屬氟化物係於經氯化之-2-氰吡啶添加至反應混合物前混合。典型反應一般係需從2至100小時，較佳係從3至6小時，且一般係於環境大氣壓力進行。
雖然反應物之正確量並不重要，但較佳係於起始材料中使用以欲被交換之氯原子之數量為基準會供應至少等莫耳量之氟原子之鹼金屬氟化物之量，即，至少等莫耳量之鹼金屬氟化物。反應完全後，所欲產物係藉由使用標準分離及純化技術回收，諸如，蒸餾、結晶化，或層析術。
於典型氟化物交換，係獲得產物混合物，其包括大量之經過度氟化的副產物3,4,5,6-四氟-2-氰吡啶(化學式H)。
所欲的3-氯-4,5,6-三氟-2-氰吡啶之最終產率可藉由分離經過度氟化的副產物3,4,5,6-四氟-2-氰吡啶且將其再回收產生可接受氟化物交換反應之中間物而提高。此可以數種方式完成。3,4,5,6-四氟-2-氰吡啶與LiCl反應或3,4,5,6-四氟-2-氰吡啶與過量之3,4,5,6-四氯-2-氰吡啶反應，或此二者之組合，具有或不具有溶劑，導致氯-氟-2-氰吡啶之混合物，其中，3-氯異構物可作為用以形成所欲產物之起始物料。因此，3,4,5,6-四氟-2-氰吡啶可與過量之LiCl加熱，產生主要係3,4,5-三氯-6-氟-2-氰吡啶及四氯-2-氰吡啶之混合物。於另一技術，經分離之3,4,5,6-四氟-2-氰吡啶與過量之3,4,5,6- 四氯-2-氰吡啶於相轉移催化劑存在中反應產生主要由單氟-三氯-2-氰吡啶及二氟-二氯-2-氰吡啶所構成之混合物。最後，於相轉移催化劑及1至3當量之LiCl存在中的經分離之3,4,5,6-四氟-2-氰吡啶及3,4,5,6-四氯-2-氰吡啶之相等混合物產生主要係3,4,5-三氯-6-氟-2-氰吡啶及3,4,5,6-四氯-2-氰吡啶之混合物。主要由單氟-三氯-2-氰吡啶及/或二氟-二氯-2-氰吡啶所構成之此等混合物可用於使用鹼金屬氟化物之氟化反應，自3,4,5,6-四氟-2-氰吡啶製備3-氯-4,5,6-三氟-2-氰吡啶。
所欲的3-氯-4,5,6-三氟-2-氰吡啶之最終產率可藉由分離經過度氟化的副產物3,4,5,6-四氟-2-氰吡啶且將其再回收產生可接受氟化物交換反應之中間物而提高。此可以數種方式完成。3,4,5,6-四氟-2-氰吡啶與LiCl反應或3,4,5,6-四氟-2-氰吡啶與過量之3,4,5,6-四氯-2-氰吡啶反應，或此二者之組合，具有或不具有溶劑，導致氯-氟-2-氰吡啶之混合物，其中，3-氯異構物可作為用以形成所欲產物之起始物料。因此，3,4,5,6-四氟-2-氰吡啶可與過量之LiCl加熱，產生主要係3,4,5-三氯-6-氟-2-氰吡啶及四氯-2-氰吡啶之混合物。於另一技術，經分離之3,4,5,6-四氟-2-氰吡啶與過量之3,4,5,6-四氯-2-氰吡啶於相轉移催化劑存在中反應產生主要由單氟-三氯-2-氰吡啶及二氟-二氯-2-氰吡啶所構成之混合物。最後，於相轉移催化劑及1至3當量之LiCl存在中的經分離之3,4,5,6-四氟-2-氰吡啶及3,4,5,6-四氯-2-氰吡啶之相等混合物產生主要係3,4,5-三氯-6-氟-2-氰 吡啶及3,4,5,6-四氯-2-氰吡啶之混合物。主要由單氟-三氯-2-氰吡啶及/或二氟-二氯-2-氰吡啶所構成之此等混合物可用於使用鹼金屬氟化物之氟化反應，自3,4,5,6-四氟-2-氰吡啶製備3-氯-4,5,6-三氟-2-氰吡啶。
90%或更多之此混合物係用於藉由將此混合物再回收經氟交換反應而形成3-氯-4,5,6-三氟-2-氰吡啶。
於其中氟及氯基團被互換之置換反應，3,4,5,6-四氟-2-氰吡啶係與1至3當量之3,4,5,6-四氯-2-氰吡啶，較佳係與2當量之3,4,5,6-四氯-2-氰吡啶反應。此反應係以淨式或於諸如DMSO、NMP、DMF、HMPA或環丁碸之極性非質子溶劑或反應介質中實行。通常方便地係無溶劑地進行此反應。置換反應係於添加劑存在中進行。添加劑包括(a)含有10或更多個碳原子之四級鏻鹽，及(b)普遍稱為冠狀醚之巨環狀聚醚。適合之冠狀醚催化劑不受限地包括18-冠-6；二環己烷并-18-冠-6；二苯并-18-冠-6；15-冠-5。適合之四級鏻鹽包括反-正烷基鏻鹽，此係特別佳。反應進行之溫度並不重要，但通常係從80℃至200℃，且較佳係從150℃至180℃。
於典型置換反應，例如，其中，1當量之3,4,5,6-四氟-2-氰吡啶係與2當量之3,4,5,6-四氯-2-氰吡啶反應，可獲得之下列異構物混合物：3,4,5,6-四氯-2-氰吡啶 (Cl4-PN)、3,5-二氯-4,6-二氟-2-氰吡啶(4,6-F2-PN)、3,4-二氯-5,6-二氟-2-氰吡啶(5,6-F2-PN)、4,5-二氯-3,6-二氟-2-氰吡啶(3,6-F2-PN)、6-氟-3,4,5-三氯-2-氰吡啶(6-F-PN)，及4-氟-3,5,6-三氯-2-氰吡啶(4-F-PN)。
80%之此混合物可用於藉由將此混合物再回收經氟交換反應形成3-氯-4,5,6-三氟-2-氰吡啶。
於反向鹵素交換反應及置換反應之組合，3,4,5,6-四氟-2-氰吡啶係與1至3當量之3,4,5,6-四氯-2-氰吡啶，較佳係與1當量之3,4,5,6-四氯-2-氰吡啶及與1至4當量之LiCl，較佳係與1.5至2.5當量反應。此反應可於淨式或於諸如DMSO、NMP、DMF、HMPA或環丁碸之極性非質子溶劑或反應介質中實行。通常方便地係於無溶劑進行此反應。置換反應係於添加劑存在中進行。添加劑包括(a)含有10或更多個碳原子之四級鏻鹽，及(b)普遍稱為冠狀醚之巨 環狀聚醚。適合之冠狀醚催化劑不受限地包括18-冠-6；二環己烷并-18-冠-6；二苯并-18-冠-6；15-冠-5。適合之四級鏻鹽包括反-正烷基鏻鹽，此係特別佳。反應進行之溫度並不重要，但通常係從80℃至200℃，且較佳係從150℃至180℃。
於典型之反向鹵素交換及置換反應之組合，例如，1當量之3,4,5,6-四氟-2-氰吡啶係與1當量之3,4,5,6-四氯-2-氰吡啶及1.5當量之LiCl反應，且可獲得下列異構物混合物： 92%之此混合物可用於藉由將此混合物再回收經氟交換反應形成3-氯-4,5,6-三氟-2-氰吡啶。
於胺化反應，4-氟-2-氰吡啶係與氨反應而以一胺基基團替換氟原子。
雖然僅需要化學計量之氨，但通常方便地係使用大量過量之氨。通常方便地係使用氨作為反應物及用以中和反應中產生之氟化氫(HF)之鹼。另外，氨可呈溶液型式，諸如，氫氧化銨之水溶液。反應係於無溶劑或於惰性溶劑中實 行。若使用溶劑，惰性溶劑不受限地包括醇、醚、酯、酮、DMSO，及芳香族溶劑。反應進行之溫度並不重要，但通常係從0℃至45℃，且較佳係從10℃至30℃。
典型反應一般需要0.5至5小時，且通常係於環境大氣壓力進行。所欲產物係藉由使用標準分離及純化技術回收。
於與肼反應，6-氟-2-氰吡啶係與肼反應而以一肼基基團替換氟原子。
雖然僅需要化學計量之肼，但通常方便地係使用過量之肼作為反應物及作為用以中和於反應形成之HF之鹼。肼較佳係單水合物。反應係於諸如DMSO、DMF、NMP、乙腈、氯化溶劑、醚、四氫呋喃(THF)或醇之惰性極性溶劑內實行。DMSO與THF之混合物係較佳。反應進行之溫度並不重要，但通常係從環境溫度至150℃，且較佳係從35℃至70℃。
於進行與肼之反應，肼係溶於溶劑，且6-氟-2-氰吡啶添加至反應混合物。典型反應一般需要0.5至5小時，且通常係於大氣壓力進行。所欲產物係使用標準分離及純化技術回收。化合物可藉由將反應混合物以乙腈稀釋且其後過濾而輕易分離。
於鹵化反應，6-鹵-2-氰吡啶係藉由使相對應之6- 肼基-2-氰吡啶與至少1當量之溴化、氯化或碘化劑反應而製備。
適合之碘化、氯化及溴化劑不受限地包括碘、單氯化碘、氯、溴、硫醯氯，及硫醯溴。雖然僅需要化學計量之鹵化劑，通常方便地係使用過量之鹵化劑。反應係於惰性非質子性溶劑中實行。各種溶劑可被使用，諸如，經氯化之溶劑、乙腈、DMSO、二噁烷、DMF，及水。通常較佳係使用經氯化之溶劑。反應進行之溫度並不重要，但通常係從環境溫度至100℃，且較佳係從環境溫度至50℃。
於進行鹵化反應，6-肼基-2-氰吡啶係溶於或懸浮於溶劑，且鹵化劑添加至反應混合物。典型反應一般需要0.5至24小時。所欲產物係藉由使用標準分離及純化技術回收。
於水解及酯化反應，2-氰吡啶係與醇(R1OH)於路易(Lewis)或布忍斯特(Bronsted)酸存在中反應。
布忍斯特酸不受限地包括諸如，氫氯酸、硫酸，及磷酸之酸。路易士酸包括三氟化硼、四鹵化鈦、四烷氧 化鈦、鹵化鋅、鹵化錫，及鏻與銻之五氟化物。諸如硫酸或磷酸之酸典型上係以化學計量使用。反應係於所欲酯之C1-C12烷基醇或未經取代或經取代的C7-C11芳烷基醇中實行。若反應溫度高於醇溶劑之沸點，此反應係於密封反應器內方便地進行。於進行酯化反應，2-氰吡啶或水解中間物吡啶醯胺添加至醇及酸之混合物。雖然反應溫度並不重要，但通常係加熱至80℃至140℃持續2至24小時，較佳係100℃至120℃持續6至8小時。所欲產物係藉由使用標準分離及純化技術回收。
於偶合反應，6-鹵吡啶甲酸酯係與芳基、烷基或烯基金屬化合物於過渡金屬催化劑存在中反應，其中，金屬係Zn-鹵化物、Zn-R、三-(C1-C4烷基)錫、銅，或B(OR2)(OR3)，其中，R2及R3彼此獨立地係氫、C1-C4烷基，或當一起時形成一伸乙基或伸丙基基團。
“催化劑”係過渡金屬催化劑，特別是鈀催化劑，諸如，二乙酸鈀或二氯雙(三苯基膦)鈀(II)，或鎳催化劑，諸如，乙醯基丙酮酸鎳(II)或二氯雙(三苯基膦)鎳(II)。此外，催化劑可於原位自金屬鹽及配位子(諸如，乙酸鈀(II)及三苯基膦或氯化鎳(II)及三苯基膦)製備。此等於原位之催化劑可藉由金屬及配位子之事前反應製備，其後添加至反應混合物，或將金屬鹽及配位子直接個別添加至反應混合物而製備。
典型上，偶合反應係於氧不存在時，使用諸如氮或氬之惰性氣體實行。用以使氧自偶合反應混合物排除之技術，諸如，以惰性氣體噴射，係熟習此項技藝者已知。此等技術之例子係描述於The Manipulation of Air-Sensitive Compounds,2nd ed.,D.F.Shriver,M.A.Drezdzon；Wiley-Interscience,1986。低於化學計量之催化劑被使用，典型上係從0.0001當量至0.1當量。另外量之配位子可選擇性地添加以增加催化劑之安定性及活性。此外，諸如碳酸鈉、碳酸鉀、氟化鉀、氟化銫及氟化鈉之添加劑典型上添加至偶合反應。偶合反應一般需要從1至5當量之此添加劑，較佳係從1至2當量。水可選擇性添加至偶合反應以增加此等添加劑之可溶性。偶合反應一般需要從1至3當量之芳基、烷基或烯基金屬化合物，較佳係從1至1.5當量。反應係於諸如甲苯、THF、二噁烷或乙腈之惰性溶劑內實行。反應進行之溫度並不重要，但通常係從25℃至150℃，且較佳係從50℃至125℃。典型反應一般需要從0.5至24小時。典型上無需特別之反應物添加順序。通常係操作上較簡單地將除了催化劑外之所有反應物混合，然後，將反應溶液脫氧。脫氧後，可添加催化劑以開始偶合反應。
當芳基、烷基或烯基金屬化合物之Met部份係Zn-鹵化物、Zn-R或銅，可能需要保護反應性官能基團。例如，若胺基取代基(-NHR或-NH2)存在，可能需要保護此等反應性基團。各種基團係此項技藝已知用以保護胺基基團免於與有機金屬試劑反應。此等保護基團之例子係描述於 Protective Groups in Organic Synthesis,3rd ed.；T.W.Greene,P.G.M.Wuts,Eds.；Wiley-Interscience,1999。用於R-Met之金屬的選擇係受數種因素影響，諸如，費用、安定性、反應性，及保護反應性官能基團之必要性。
藉由任何此等方法獲得之產物可藉由傳統手段回收，諸如，蒸發或萃取，且可藉由標準程序純化，諸如，藉由再結晶或層析術。
下列範例係用以例示說明本發明而呈現。
範例
氟交換
範例1a 3-氯-4,5,6-三氟-2-氰吡啶
一5-公升(L)之機械式攪拌的燒瓶，於氮氣下注入DMSO(3820毫升(mL))、粉末狀之碳酸鉀(K2CO3；42克(g))，及細微研磨之氟化銫(CsF；1510克)。DMSO(約1公升)藉由於75-80℃(3.5mmHg，0.46kPa)蒸餾而移除。於添加細微研磨之3,4,5,6-四氯-2-氰吡啶(685克)前，漿料於氮氣下冷卻至55℃。添加係於15分鐘(min)期間進行，同時冷卻以使反應溫度保持低於74℃。溫度於緩慢氮氣流下保持於65-70℃持續4小時(h)。反應混合物冷卻至40-50℃，且倒至冰水(H2O；15公升)及二乙基醚(Et2O；3公升)之混合物內。有機相被分離後，水性相以Et2O(2 x 2公升)萃取。有機萃取液被 混合，於硫酸鎂(MgSO4)乾燥，過濾，及於大氣壓力藉由蒸餾而濃縮，產生粗製產物混合物(469克)，呈淡棕色油。此油與相似般製備之另外物料混合產生總量為1669克之粗製產物。此油於真空下使用30盤之Oldershaw塔於80-90℃間之溫度範圍蒸餾，且分餾物係於63、13及2mm Hg(8.4、1.7及0.27kPa)收集。於13mm收集之物料產生457克(22%產率)之固體，其係二種氯三氟-2-氰吡啶之93/7混合物。此固體係於5℃自己烷(420克)及Et2O之混合物再結晶，產生3-氯-4,5,6-三氟-2-氰吡啶(354克，98%純度)，呈細微白色針狀物。小樣品係藉由氣相層析術(GC)第二次再結晶成99.7%純度：mp 41.5-43℃；19F NMR(376MHz,CDCl3)δ -78.1(t,JF-F=23.1Hz,F6),-114.2(dd,JF-F=18.5,22.5Hz,F4),-149.3(dd,JF-F=18.2,22.6Hz,F5)；13C{1H}NMR(101MHz,CDCl3)δ 154.5(ddd,JF-C=270,11,7Hz,C4),151.3(ddd,JF-C=247,13,5Hz,C6),138.0(ddd,JF-C=279,31,13Hz,C5),124.7(ddd,JF-C=16,6,2Hz,C3),124.4(ddd,JF-C=16,7,2Hz,C2),112.2(s,CN)；EIMS m/z 192([M]+)。對於C6ClF3N2之計算分析：C,37.43；N,14.55。發現：C,36.91；N；14.25。
此蒸餾之第一部份(63mm Hg,8.4kPa)產生純的3,4,5,6-四氟-2-氰吡啶(525克，24%)，呈無色油。19F NMR(376MHz,CDCl3)δ -77.6(t,JF-F=23.8Hz,F6),-133.7(q,JF-F=18.8Hz,F4),-134.2(ddd,JF-F=24.2,18.6,10.1Hz,F3),-145.3(ddd,JF-F=24.1,18.2,10.2Hz,F5)；13C{1H} NMR(101MHz,CDCl3)δ 150.4(dm,JF-C=272Hz,C3),148.5(ddd,JF-C=245,12,4Hz,C6),147.3(dm,JF-C=270Hz,C4),138.6(ddd,JF-C=280,33,11Hz,C5),113.4(m,C2),110.20(s,CN)。
此蒸餾之第三部份(2mm Hg,0.27kPa)產生3,5-二氯-4,6-二氟-2-氰吡啶(48克，98%純度)，呈白色固體：mp 78-79℃；19F NMR(376MHz,CDCl3)δ -63.65(d,JF-F=18.7Hz,F6),-92.52(d,JF-F=18.5Hz,F4)；13C{1H}NMR(101MHz,CDCl3)δ 162.6(dd,JF-C=269,6Hz,C4),157.8(dd,JF-C=245,5Hz,C6),127.6(dd,JF-C=17,3Hz,C3),123.5(dd,JF-C=18,6Hz,C2),112.4(dd,JF-C=36,21Hz,C5),112.3(CN)。
範例1b 3,4,5,6-四氟-2-氰吡啶與氯化鉀之反向鹵素交換反應
3,4,5,6-四氟2-氰基吡啶(17克，0.1莫耳(mol))與乾燥LiCl(25.4克，0.6莫耳)之混合物於乾燥DMSO(200毫升)內加熱。反應係藉由自H2O萃取至Et2O之等分樣品之GC分析而監測。開始時，反應加熱至120℃，且所有之LiCl溶解。於120℃時5分鐘後，所有之起始物料及氯三氟-PN異構物被消耗掉，產生3,6-F2-PN(83%)及6-F-PN(14%)之混合物。反 應溫度上升至135℃，且於總共75分鐘後，藉由GC分析。混合物被測定係3,6-F2-PN/6-F-PN/Cl4-PN之8：80：12混合物。
範例1ca 3,4,5,6-四氟-2-氰吡啶之置換
3,4,5,6-四氯-2-氰吡啶(16.1克，66毫莫耳(mmol))及3,4,5,6-四氟-2-氰吡啶(5.9克，33毫莫耳)之混合物於氮氣下加熱至160℃，形成一溶液。對此攪拌溶液，添加四丁基氯化鏻(Bu4PCl；0.36克，1.2毫莫耳)，且溶液於160℃保持1小時。等分樣品溶於二氯甲烷(CH2Cl2)，且於GC分析前，通過短的矽石凝膠墊。經鹵化之-2-氰吡啶之分佈係：11.2%之Cl4-PN；11.3%之4,6-F2-PN；2.3%之5,6-F2-PN；19%之3,6-F2-PN；52.6%之6-F-PN，及3.6%之4-F-PN。80%之此混合物係用於鹵素交換反應，產生3-氯-4,5,6-三氟-2-氰吡啶。
範例1cb 自3,4,5,6-四氟-2-氰吡啶之置換再回收
裝設一短路徑蒸餾頭之一反應燒瓶被注入經細微研磨之CsF(35.1克，0.23莫耳)及乾燥DMSO(175毫升)。反應器於真空下(0.1mm)攪拌及加熱至70-75℃，至DMSO(75毫升)蒸餾為止。此漿料於氮氣下冷卻至50℃，且添加得自上述之熔融反應混合物(21.7克)。反應混合物加熱至70℃持續2.5小時，並且良好地攪拌。添加至水之一等分樣品之二乙基醚萃取液藉由GC檢測，且發現含有：61%之3,4,5,6-四氟-2-氰吡啶；31%之3-氯-4,5,6-三氟-2-氰吡啶；3.4%之5-氯-3,5,6-三氟-2-氰吡啶，及4.8%之3,5-二氯-4,6-二氟-2-氰吡啶。此比以純的3,4,5,6-四氯-2-氰吡啶開始進行相似反應時之38-42%之典型粗製GC純度還要好。
範例1d 3,4,5,6-四氟-2-氰吡啶之經LiCl輔助之置換
3,4,5,6-四氯-2-氰吡啶(12.2克，50毫莫耳)及3,4,5,6-四氟-2-氰吡啶(8.8克，50毫莫耳)之混合物於氮氣下加熱至160℃，達成一澄清溶液。對此添加Bu4PCl(0.36克，1.2毫莫耳)。於添加乾燥LiCl(4.2克，0.1莫耳)前，反應溶液於160℃保持15分鐘。60分鐘後，添加更多之LiCl(2.2克，50毫莫耳)，且反應混合物攪拌11小時。自水之乙醚萃取液之GC分析顯示3,6-F2-PN/6-F-PN/Cl4-PN之8：75：17混合物。
胺化
範例2 4-胺基-3-氯-5,6-二氟-2-氰吡啶
於乙酸乙酯(EtOAc；3公升)內之3-氯-4,5,6-三氟-2-氰吡啶(200克)之溶液冷卻至10℃。對此緩慢添加14%之含水氫氧化銨(NH4OH；1296克)，使溫度保持於18-23℃。水溶液與有機溶液分離。有機相依序以含水飽和NaCl及水之50/50溶液(500毫升)及飽和NaCl溶液(250毫升)清洗。有機相於50℃之真空下濃縮成500毫升體積，產物結晶出。對此漿料添加庚烷(1公升)，且剩餘之EtOAc於真空下移除，產生最終漿料。固體藉由過濾收集。此固體以戊烷清洗，且於真空下乾燥，產生4-胺基-3-氯-5,6-二氟-2-氰吡啶(173.8克，90%，99.6%純度)，呈白色結晶固體：mp 190-191.5℃；13C{1H}NMR(101MHz,DMSO-d6)δ 150.03(dd,J=232.4,12.5Hz,C6),144.29(dd,J=11.4,6.9Hz,C4),133.72(dd,J=257.9,30.8Hz,C5),122.14(dd,J=19.6,4.9Hz,C2),119.31(s,C3),114.25(s,CN)；19F NMR(376MHz,DMSO-d6)δ -91.24(d,J=24.2Hz),-154.97(d,J=24.2Hz)；EIMS m/z 189([M]+)。對於C6H2ClF2N3之計算分析：C,38.02；H,1.06；N,22.17。發現：C.37.91；H.1.00；22.02。
與肼反應
範例3 4-胺基-3-氯-5-氟-6-肼基-2-氰吡啶
對於THF(15毫升)及DMSO(10毫升)內之肼水合物(3.9克，78毫莫耳)之溶液，以於DMSO內之溶液(5毫升)添加4-胺基-3-氯-5,6-二氟-2-氰吡啶(5克，26毫莫耳)。此溶液加熱至65℃持續45分鐘，冷卻，及以乙腈(30毫升)稀釋，產物以淡棕色固體沉澱。此固體於40℃之真空下乾燥3小時，產生4-胺基-3-氯-5-氟-6-肼基-2-氰吡啶(5.1克，98%)：mp 215-220℃ dec；1H NMR(400MHz,DMSO-d6)7.9(br,1H),6.5(br,2H),4.0(br,2H)；13C{1H}NMR(101MHz,DMSO-d6)δ 149.34(d,J=10.5Hz,C6),138.28(d,J=11.6Hz,C4),133.81(d,J=251.6Hz,C5),123.74(d,J=5.3Hz,C2),115.87(s,C3),112.57(s,CN)；19F NMR(376MHz,DMSO-d6)δ -154.6；ESIMS m/z 203([M+H]+)。對於C6H5ClFN5之計算分析：C,35.75；H,2.50；N,34.74。發現：C,35.97；H,2.70：N,35.01。
鹵化
範例4 4-胺基-3,6-二氯-5-氟-2-氰吡啶
對於CH2Cl2(150毫升)內之4-胺基-3-氯-5-氟-6-肼基-2-氰吡啶(9.04克，44.8毫莫耳)之懸浮液，添加硫醯氯(7.20毫 升，89毫莫耳)。混合物於室溫攪拌40小時。溶劑於減壓下移除，且殘質以飽和含水碳酸氫鈉(NaHCO3)及EtOAc分配。有機相被分離，於Na2SO4乾燥，及過濾。溶液被濃縮，且殘質藉由矽石凝膠層析術純化，產生產物(7.01克，76%)，呈灰白色固體。1H NMR(300MHz,DMSO-d6)δ 7.55(s,2H)；13C NMR(101MHz,DMSO-d6)δ 143.26(d,J=259.2Hz,C5),142.69(d,J=14.0Hz,C4),135.53(d,J=17.6Hz.C6),126.07(d,J=4.4Hz,C2),120.14(d,J=4.3Hz,C3),114.36(s,CN)；19F NMR(376MHz,DMSO-d6)δ -132.30(s)；ESIMS m/z 203([M+H]+),206。
水解及酯化
範例5 4-胺基-3,6-二氯-5-氟吡啶甲酸甲酯
濃硫酸(2.0毫升，37.5毫莫耳)緩慢添加至甲醇(8毫升)，並且冷卻。然後，4-胺基-3,6-二氯-5-氟-2-氰吡啶(0.20克，0.97毫莫耳)添加至溶液，且混合物迴流攪拌29小時。溶劑於真空下移除，且殘質倒至冰內，並且攪拌15分鐘。產物以EtOAc(3x)萃取。有機萃取液被混合，以鹽水清洗，於MgSO4乾燥，過濾，及藉由矽石凝膠管柱純化產生4-胺基-3,6-二氯-5-氟吡啶甲酸甲酯(0.085克，37%)，呈白色固體。1H NMR(400MHz,CDCl3)δ 5.08(s,2H),3.97(s,3H)；13C NMR(101MHz,CDCl3)δ 163.57(s,C=O),143.29(d,J =258.1Hz,C5),141.73(d,J=5.1Hz,C2),141.05(d,J=12.7Hz,C4),135.32(d,J=16.8Hz,C6),116.26(s,C3),53.24(s,OMe)；19F NMR(376MHz,CDCl3)δ -135.63(s)。
偶合
範例6a 4-胺基-3-氯-5-氟-6-(4-氯-2-氟-3-甲氧基-苯基)吡啶甲酸甲酯
具有一迴流冷凝器、一氮氣入口，及一熱偶之一250毫升之三頸燒瓶，被注入4-胺基-3,6-二氯-5-氟吡啶甲酸甲酯(9.965克，41.7毫莫耳)、2-(4-氯-2-氟-3-甲氧基苯基)-1,3,2-二氧雜硼烷(12.74克，52.1毫莫耳)，及KF(4.84克，83毫莫耳)。添加乙腈(78毫升)及水(26毫升)。反應混合物以氮氣沖洗。添加二氯雙(三苯基膦)鈀(II)(Pd(PPh3)2Cl2；1.477克，2.10毫莫耳，5莫耳%)，且溶液於氮氣下加熱至70℃持續2小時。冷卻至室溫時，形成沉澱物，其被過濾，且以水清洗。沉澱物溶於EtOAc(約500毫升)，且以水清洗，然後，以鹽水清洗。有機層被乾燥(MgSO4)，且溶劑係使用旋轉式蒸發器移除，產生橙色固體，其於50℃之真空爐乾燥(11.46克，76%產率)：mp 169-170.5℃；1H NMR(400MHz,DMSO-d6)δ 7.48(d,J=8.4Hz,1H),7.32(t,J=7.7Hz,1H),7.15(s,2H),3.96(s,3H),3.90(s,3H)；13C{1H}NMR(101 MHz,DMSO-d6)δ 164.85(s),153.11(d,J=252.5Hz),146.29(s),144.52(d,J=4.3Hz),143.74(s),142.75(dd,J=227.1,14.0Hz),136.38(d,J=13.4Hz),128.58(d,J=3.2Hz),125.87(s),125.54(d,J=3.5Hz),122.89(dd,J=13.8,4.0Hz),113.01(d,J=3.0Hz),61.61(d,J=4.2Hz),52.70(s)；ESIMS m/z 364([M+H]+)。對於C14H10Cl2F2N2O3之計算分析：C,46.30；H,2.78；N,7.71。發現：C,46.60；H,2.68；N,7.51。
範例6b4-胺基-3-氯-5-氟-6-(4-氯-2-氟-3-甲氧基-苯基)-2-氰吡啶
4-胺基-3,6-二氯-5-氟-2-氰吡啶(0.37克，1.80毫莫耳)、2-(4-氯-2-氟-3-甲氧基苯基)-1,3,2-二氧雜硼烷(0.549克，2.24毫莫耳)及KF(0.209克，3.59毫莫耳)之混合物被取至乙腈(6.75毫升)及水(2.25毫升)內。混合物被攪拌且以氮氛圍噴射。添加Pd(PPh3)2Cl2(63毫克，0.1毫莫耳)，且混合物再次以氮氣噴射。然後，溶液於氮氣下加熱至75℃持續2小時。冷卻時，沉澱物形成且藉由過濾收集，以水清洗，且於真空下乾燥，產生產物(0.34克)，呈灰白色固體。水性相以EtOAc(3x)萃取，且混合之有機萃取液以鹽水清洗，乾燥，及濃縮。藉由矽石凝膠層析術純化產生另外產物(0.12 克)，呈白色固體。總產率78%。1H NMR(400MHz,DMSO-d6)δ 7.50(dd,J=8.5,1.4Hz,1H),7.45(s,2H),7.33(dd,J=8.5,7.2Hz,1H),3.94(s,3H)；13C{1H}NMR(101MHz,DMSO-d6)δ 152.97(d,J=253.2Hz),145.73(d,J=260.8Hz),143.82(d,J=13.7Hz),141.83(d,J=14.7Hz),138.45(d,J=14.8Hz),133.93-132.79(m),128.93(d,J=3.3Hz),127.74(s),126.37-125.10(m),122.08(dd,J=13.6,3.9Hz),119.34(d,J=4.5Hz),114.99(s),61.61(s)；19F NMR(376MHz,DMSO-d6)δ -129.00(dd,J=28.2,7.0Hz,1F),-133.76(d,J=28.2Hz,1F)；ESIMS m/z 330.1([M+H]+)。

Claims (1)

  1. 一種增加可回收之3-氯-4,5,6-三氟-2-氰吡啶(化學式B)之量的改良方法， 該化合物係自以氟化物離子來源氟化3,4,5,6-四氯-2-氰吡啶(化學式A)而製備， 其中，該改良包含步驟：i)自氟化3,4,5,6-四氯-2-氰吡啶分離經過度氟化之3,4,5,6-四氟-2-氰吡啶(H) 副產物；ii)將該經分離之3,4,5,6-四氟-2-氰吡啶(H)(a)與氯化鋰(LiCl)，(b)於相轉移催化劑存在中，與3,4,5,6-四氯-2-氰吡啶(化學式A)，或(c)與LiCl及3,4,5,6-四氯-2-氰吡啶之組合物反應，產生主要由3,4,5,6-四氯-2-氰吡啶、單氟-三氯-2-氰吡啶，及二氟-二氯-2-氰吡啶所構成之一混合 物；及iii)將主要由3,4,5,6-四氯-2-氰吡啶、單氟-三氯-2-氰吡啶，及二氟-二氯-2-氰吡啶所構成之混合物再回收至製備3-氯-4,5,6-三氟-2-氰吡啶(化學式B)之氟化反應。
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