TWI242544B - Process for coupling organic compounds - Google Patents

Process for coupling organic compounds Download PDF

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TWI242544B
TWI242544B TW90115188A TW90115188A TWI242544B TW I242544 B TWI242544 B TW I242544B TW 90115188 A TW90115188 A TW 90115188A TW 90115188 A TW90115188 A TW 90115188A TW I242544 B TWI242544 B TW I242544B
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scope
patent application
item
compound containing
microreactor
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TW90115188A
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Chinese (zh)
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Hanns Wurziger
Guido Pieper
Norbert Schwesinger
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Merck Patent Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00835—Comprising catalytically active material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00858—Aspects relating to the size of the reactor
    • B01J2219/0086—Dimensions of the flow channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00858—Aspects relating to the size of the reactor
    • B01J2219/00862—Dimensions of the reaction cavity itself
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00873—Heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00889—Mixing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00905—Separation
    • B01J2219/00916—Separation by chromatography
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • C07C2527/06—Halogens; Compounds thereof
    • C07C2527/122—Compounds comprising a halogen and copper
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • C07C2527/06—Halogens; Compounds thereof
    • C07C2527/128—Compounds comprising a halogen and an iron group metal or a platinum group metal
    • C07C2527/13—Platinum group metals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C07C2531/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/22—Organic complexes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a process for coupling organic compounds, characterized in that at least one organic compound containing at least one leaving group is mixed, in liquid or dissolved form, with at least one organic compound containing a the presence of an least one catalyst, in liquid or dissolved form, in vinylic or acetylenic hydrogen atom, in liquid or dissolved form, in an least one micro-reactor, and reacted for a residence time, and the resultant coupling product is, if desired, isolated from the reaction mixture.

Description

1242544 A7 B7____ 五、發明説明（1 ) 本發明關於一種偶合有機化合物之方法。 偶合有機化合物係化學工業上慣用之方法，且其重要 性亦反映於許多文獻中。 然而，工業規模上進行偶合反應係產生安全性問題和 危險。首先，係慣常使用相對大量之高度毒性化學材料， 其本身已對人體和環境產生相當之危險性；再者，該等反 應通常係爲高度放熱，且隨後當於工業上進行該等反應時 ，會增加爆炸之危險。因此，依據工業規模上進行該等反 應之工廠操作的放射保護法規，獲得官方許可需要相當之 努力。 於是，本發明之目標係提供一種偶合有機化合物之方 法，其避免上述之缺點。詳言之，以簡單、可重覆實施之 方式、增加對人體和環境之安全性且具有良好產率以實施 該方法應爲可能的，且該反應條件應爲非常易於控制的。 藉由本發明之偶合有機化合物之方法可令人驚訝地達 成該目標，其中在至少一種微反應器中，於至少一種液體 或溶解型式之觸媒的存在下，令至少一種液體或溶解型式 之含有至少一個離去基的有機化合物與至少一種液體或溶 解型式之含有乙烯型氫原子或乙炔型氫原子的有機化合物 相混合並於滯留時間發生反應，且如有需要自反應混合物 分離所生成之偶合產物。 本發明方法之優異較佳體系係描述於附屬項中。 本發明之目的係令至少一種含有至少一個離去基之有 機化合物與至少一種含有至少一個乙烯型氫原子或乙炔型 本紙張尺度適用中國國家標準（ CNS ) A4規格（210X297公釐) -~- (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -4- 1242544 經濟部智慧財產局員工消費合作社印製 A7 __ B7 五、發明説明（2 ) 氫原子之有機化合物反應，或所使用之有機化合物同時含 有至少一個離去基和至少一個乙烯型氫原子或乙炔型氫原 子。據此，本發明涵蓋分子間和分子內偶合反應。亦可使 用2種或多種含有至少一個離去基之有機化合物的混合物 及/或2種或多種含有至少一個乙烯型氫原子或乙炔型氫 原子之有機化合物的混合物。適宜地，於每一種情況下僅 有一種含有一個離去基之有機化合物及於每一種情況下僅 有一種含有乙烯型氫原子或乙炔型氫原子之有機化合物係 使用於本發明之方法中。若一個有機化合物含有2個或多 個離去基及/或2個或多個乙烯型氫原子或乙炔型氫原子 ，於每一個情況下該等基團可爲相同或不同。 對於本發明之目的，離去基係任一個基團，其鍵結至 .有機化合物之碳原子的鍵結於偶合反應期間斷裂，且其隨 後遺留該有機化合物。 對於本發明之目的，微反應器係體積<1 000// 1之 反應器，其中液體及/或溶液係最終至少混合一次。該微 反應器之體積係適宜地< 1 0 0 // 1，特別適宜地^ 5 0 // 1 〇 該微反應器適宜地係由彼此連接之薄矽結構所製得。 該微反應器適宜地係小型連續反應器，特別適宜地係 靜態混合器。該微反應器極爲適宜地係 W〇9 6 / 3 0 1 1 3所描述之靜態微混合器，該 W〇9. 6 / 3 0 1 1 3之揭示係倂入本文中充作參考且視 爲本發明之一部份。此類型之微反應器具有小孔道，其中 本紙張尺度適用中國國家標準（CNS ) A4規格（210父297公¥了 (請先閲讀背面之注意事項再填寫本頁)1242544 A7 B7____ 5. Description of the invention (1) The present invention relates to a method for coupling organic compounds. Coupling organic compounds is a method commonly used in the chemical industry, and its importance is reflected in many literatures. However, performing coupling reactions on an industrial scale creates safety issues and dangers. First, it is customary to use a relatively large amount of highly toxic chemical materials, which itself has caused considerable danger to humans and the environment; further, these reactions are usually highly exothermic, and when these reactions are subsequently carried out industrially, Will increase the risk of explosion. Therefore, it takes considerable effort to obtain official permits under the radiation protection regulations for factory operations that conduct these reactions on an industrial scale. It is therefore an object of the present invention to provide a method for coupling organic compounds, which avoids the aforementioned disadvantages. In detail, it should be possible to implement the method in a simple, repeatable manner, with increased safety to humans and the environment, and with good yields, and the reaction conditions should be very easy to control. This goal can be surprisingly achieved by the method of coupling organic compounds of the present invention, in which the presence of at least one liquid or dissolved type of catalyst in at least one micro-reactor in the presence of at least one liquid or dissolved type of catalyst At least one leaving organic compound is mixed with at least one liquid or dissolved organic compound containing ethylene-type hydrogen atoms or acetylene-type hydrogen atoms and reacts at a residence time, and if necessary, a coupling formed by separation from the reaction mixture product. The superior and preferred systems of the method of the present invention are described in the subordinates. The purpose of the present invention is to make at least one organic compound containing at least one leaving group and at least one type containing at least one vinyl-type hydrogen atom or acetylene-type. This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-~- (Please read the notes on the back before filling out this page) Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy -4- 1242544 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy A7 __ B7 V. Description of the invention (2) Hydrogen atom The organic compound is reacted, or the organic compound used contains at least one leaving group and at least one ethylene-type hydrogen atom or acetylene-type hydrogen atom. Accordingly, the present invention encompasses intermolecular and intramolecular coupling reactions. It is also possible to use a mixture of two or more organic compounds containing at least one leaving group and / or a mixture of two or more organic compounds containing at least one ethylene-type hydrogen atom or acetylene-type hydrogen atom. Suitably, in each case only one organic compound containing a leaving group and in each case only one organic compound containing an ethylene type hydrogen atom or an acetylene type hydrogen atom are used in the method of the present invention. If an organic compound contains 2 or more leaving groups and / or 2 or more vinyl-type hydrogen atoms or acetylene-type hydrogen atoms, the groups may be the same or different in each case. For the purposes of the present invention, the leaving group is any group whose bond to a carbon atom of an organic compound is broken during the coupling reaction, and it subsequently leaves the organic compound behind. For the purposes of the present invention, a microreactor is a reactor having a volume < 1 000/1, wherein the liquid and / or solution is finally mixed at least once. The volume of the microreactor is suitably < 1 0 0 // 1, particularly suitably ^ 5 0 // 1 〇 The microreactor is suitably made of thin silicon structures connected to each other. The microreactor is suitably a small continuous reactor, and particularly suitably a static mixer. The microreactor is very suitably a static micromixer as described in WO 9 6/3 0 1 13, and the disclosure of WO 9/6 0 1 1 3 is incorporated herein by reference and deemed This is part of the invention. This type of microreactor has small channels, of which the paper size applies the Chinese National Standard (CNS) A4 specification (210 parent 297 public ¥) (Please read the precautions on the back before filling this page)

-5- 1242544 A7 經濟部智慧財產局員工消費合作社印製 B7___五、發明説明（3 ) _由流動液體及/或溶液之動力能量令其溶液型式之化合 物及/或液體相混合。 該微反應器之孔道直徑係適宜地1 0至1 0 0 0 //m ，特別適宜地2 0至8 0 0 // m，且極爲適宜地3〇至 4 , 〇 〇 // m。 適宜地利用泵抽將液體及/或溶液導入該微反應器中 ，使得其流經微反應器之流速爲0 . 〇 1 // 1 /分至 1 〇 0 m 1 /分，特別適宜地係1 // 1 /分至1 m 1 /分 〇 .依據本發明，該微反應器適宜地係可加熱的。 依據本發明，該微反應器適宜地係經由出口管連接至 至少一個滯留區，適宜地係毛細管，特別適宜地係可加熱 之毛細管。經於該微反應器中混合後，將液體及/或溶液 餵入該滯留區或毛細管中，以延長其滯留時間。 對於本發明之目的，滯留時間係介於混合起始物與處 理所生成之反應溶液以分析或分離所欲之產物間的時間。 本發明之方法所需要之滯留時間係取決於許多不同之 參數，諸如，例如，起始物之溫度或反應性。熟習此技藝 之人士亦可使用與該參數相配之滯留時間以達成該反應之 最佳狀態。 於所使用之包含至少一個微反應器和如有需要之滯留 區的系統中之反應溶液的滯留時間可藉由選擇所使用之液 體及/.或溶液的流速加以調整。 該反應混合物可適宜地通過2個或多個系列連接之微 本紙張尺度適财關家鮮（（：叫八4規格（2獻297公釐) ~ -- -6- (請先閲讀背面之注意事項再填寫本頁) 1242544 A7 B7 五、發明説明（4 ) 反應器。此達成延長滯留時間，甚至於增加之流速下亦然 ，且令所使用之偶合反應成份反應以達到所欲之偶合產物 的最佳產率。 (請先閲讀背面之注意事項再填寫本頁) 於進一步之較佳體系中，該反應混合物係通過2個或 多個並排之微反應器以增加產出。 於本發明方法之另一個較佳體系中，可改變丨個或多 個微反應器中孔道之數量和排列方式，使得滯留時間延長 ，可於增加流速F以相同之時間得到所欲偶合產物之最佳 產率。 該微反應益中反應ί谷液之滯留時間（於該微反應器和 毛細管中之適當的滯留時間）係適宜地< 1 5小時，較適宜 地< 3小時，特別適宜地< 1小時。 經濟部智慧財產局員工消費合作社印製 可於非常寬廣之溫度範圍內實施本發明之方法，其係 主要受限於用於建構該微反應器、任何滯留區和另外成份 ，諸如，例如，連接器和密封器所使用之材料的耐熱性， 及所使用之溶液及/或液體之物理性質。實施本發明之方 法的適宜溫度係介於一 1 0 0至+ 2 5 0 °C，適宜地介於 一 78至+150 °C，特別適宜地介於〇至+ 40 t：。 通常，實施本發明之用於偶合有機化合物的方法可無 需使用保護性氣體。然而，亦可於保護性氣體之環境下， 實施本發明之.方法。若於保護性氣體之環境下實施本發明 之方法，其適宜地係於氮氣及/或氬氣之環境下實施。 可以連續或批式之方式實施本發明之方法。適宜地係 以連續之方式實施。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) 1242544 A7 B7 五、發明説明（5 ) (請先閲讀背面之注意事項再填寫本頁) 爲實施本發明之用於偶合有機化合物之方法，儘可能 地於不含有固體顆粒或僅含有極少量之固體顆粒的均勻液 相中實施該偶合反應係必要的，因爲若存有固體顆粒則該 微反應器中之孔道將會阻塞。 利用熟習此技藝之人士所習知之各種分析方法可追蹤 本發明之方法的偶合反應進程，且若有需要加以調控。適 宜地藉由層析，特別適宜地藉由高效液相層析，以追蹤該 反應之進程，且若有需要加以調控。於此情況下，與已知 之方法相比較，該反應之控制已獲得顯著地改善。 於反應後如有需要，可分離所生成之偶合產物。適宜 地係藉由萃取自反應混合物中分離所生成之偶合產物。 可使用於本發明之方法中的含有至少一個離去基之有 機化合物係熟習此技藝之人士所習知之充作偶合反應之基 質的含有至少一個離去基之所有有機化合物。 經濟部智慧財產局員工消費合作社印製 本發明方法所使用之含有至少一個離去基的有機化合 物係適宜地可爲芳基鹵（特別適宜地係芳基溴或芳基碘， 極爲適宜地係芳基碘，雜芳基鹵（特別適宜地係雜芳基溴 或雜芳基碘，極爲適宜地係雜芳基碘），鹵乙烯（特別適 宜地係溴乙烯或碘乙烯，極爲適宜地係碘乙烯），或至少 2個上述化合物之混合物。 本發明之方法所使用之含有至少一個離去基的化合物 可適宜地爲有機氟烷基磺酸酯（適宜地爲氟烷基磺酸芳酯 、氟烷基磺酸雜芳酯或氟烷基磺酸乙烯酯），或有機多氟 烷基磺酸酯（適宜地爲多氟烷基磺酸芳酯、多氟烷基磺酸 本紙張尺度適用中國國家標準（CNS ) A4規格（210X29*7公釐) -8 - 1242544 經濟部智慧財產局員工消費合作社印製 A7 _B7_五、發明説明（6 ) 雜芳酯或多氟烷基磺酸乙烯酯），或至少2個上述化合物 之混合物。 本發明之方法所使用之多氟烷基磺酸酯可特別適宜地 爲三氟甲烷磺酸芳酯、三氟甲烷磺酸雜芳酯、三氟甲烷磺 酸乙烯酯、或至少2個上述化合物之混合物。 於本發明方法之進一步特定較佳體系中，所使用之多 氟烷基磺酸酯可爲九氟丁烷擴、酸芳酯、九氟丁烷磺酸雜芳 酯、九氟丁烷磺酸乙烯酯、或至少2個上述化合物之混合 物。 對於本發明之目的，芳基鹵，氟烷基磺酸芳酯及多氟 烷基磺酸芳酯亦包括芳族有機化合物，其中該鹵，氟烷基 磺酸酯或多氟烷基磺酸酯基團並未直接地鍵結至該芳基基 .團之芳族環上，而是例如經由亞甲基鍵結至該芳基基團之 芳族環上，其諸如，例如，苄基鹵、三氟甲烷磺酸苄酯或 九氟丁烷磺酸苄酯。 對於本發明之目的，雜芳基鹵、氟烷基磺酸雜芳酯及 多氟院基磺酸雜芳酯亦包括芳族有機化合物，其中該鹵、 氟烷基磺酸酯或多氟烷基磺酸酯基團並未直接地鍵結至該 雜芳基基團之芳族環上，而是例如經由亞甲基鍵結至該芳 基基團之芳族環上。該等雜芳基基團適宜地含有至少一個 氧及/或氮及./或硫原子以充作雜原子。 本發明之方法可使用之含有至少一個乙烯型氫原子或 乙炔型氫原子的有機化合物可爲熟習此技藝之人士所習知 之且適於充作偶合反應之基質的任一含有至少一個乙烯型 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) -9- 1242544 A7 經濟部智慧財產局員工消費合作社印製 ___B7____五、發明説明（7 ) 氫原子或乙炔型氫原子的有機化合物。適用於本發明之方 法者係爲至少一種非支鏈、支鏈、環狀、芳族或雜芳族烯 或炔，特別適宜者係爲至少一種非支鏈、支鏈、環狀、芳 族或雜芳族烯。 對於本發明之目的，含有至少一個乙烯型氧原子或乙 烯型氫原子之芳族化合物亦包括含有單環及/或多環之同 芳族基本結構或其對應部份結構（例如，以取代基之型式 )及乙烯型氫原子或乙炔型氫原子的有機化合物及/或其 衍生物。 對於本發明之目的，含有至少一個乙烯型氫原子或乙 烯型氫原子之雜芳族化合物亦包括含有單環及/或多環之 雜芳族基本結構或其對應部份結構（例如，以取代基之型 .式）及至少一個乙烯型氫原子或乙烯型氫原子的有機化合 物及/或其衍生物。該等雜芳族基本結構或部份結構特別 適宜地包括至少一個氧及/或氮及/或硫原子。 本發明之方法可使用之觸媒係爲熟習此技藝之人士所 習知之且適用於有機化合物之偶合反應的所有觸媒或至少 2種該等觸媒之混合物。適宜地，每一種情況僅使用一種 觸媒。對於本發明之目的，該觸媒亦包括原位所形成之觸 媒，即於偶合反應之前或期間所立即形成之觸媒。於本發 明之進一步較佳體系中，所使用之觸媒係爲至少一種含有 氧化狀態爲0之鈀的化合物。該含有氧化狀態爲0之鈀的 化合物係適宜地爲三（二苄叉丙酮）二鈀。 在至少一種鹼之存在下，如有需要在至少一種無機鹽 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） · ~ -10- (請先閱讀背面之注意事項再填寫本頁) 1242544 A7 ___ B7 _ 五、發明説明（8 ) (請先閲讀背面之注意事項再填寫本頁) 之存在下且如有需要在至少一種配體之存在下，本發明之 方法所使用之觸媒係適宜地爲至少一種含有氧化狀態爲 + 2之鈀的化合物。 本發明之方法所使用之含有氧化狀態爲+ 2之鈀的鈀 化合物可適宜地爲氯化鈀（Π )，乙酸鈀（Π )，二（三 苯膦）二氯化鈀（Π )或至少2種該等化合物之混合物。 本發明之方法所使用之鹼可爲熟習此技藝之人士所習 知之且適用於有機化合物之偶合反應的任何鹼。所使用之 鹼可適宜地爲有機胺（特別適宜地係三乙胺，二乙胺或三 正丁胺），含氮可選擇之芳族雜環（特別適宜地係吡啶或 N -甲基吡咯烷酮），或至少2個上述化合物之混合物。 本發明之方法所用之無機鹽可爲熟習此技藝之人士所 習知之且適用於有機化合物之偶合反應的任一無機鹽。所 使用之無機鹽適宜地係碘化銅（I )。 經濟部智慧財產局員工消費合作社印製 於本發明之方法的進一步較佳體系中，以含有至少一 個離去基之有機化合物爲基底計，使用之觸媒量係 0 · 01至1 10莫耳％，適宜地0 · 01至5 0%莫耳 %，特別適宜地0 · 0 1至1莫耳％。 於本發明之方法中，適宜地係使用等莫耳比例之含有 至少一個離去基之有機化合物和含有至少一個乙烯型氫原 子或乙炔型氫原子之有機化合物。於本發明之方法的另一 個較佳體系中，以含有至少一個離去基之有機化合物爲基 底計，該含有至少一個乙烯型氫原子或乙炔型氫原子之有 機化合物的使用量係爲1 · 5至2倍莫耳過量，特別適宜 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） " -11- 1242544 ΚΊ __ Β7 _ _ 五、發明説明（9 ) 地係爲1 · 1至1 · 6倍過量，極爲適宜地係1 · 2至 1 · 5倍過量。 (請先閱讀背面之注意事項再填寫本頁) 反應之選擇性係取決於所使用之反應試劑的濃度及許 多其他之參數，諸如，例如，溫度、離去基種類、觸媒種 類及滯留時間。熟習此技藝之人士亦可於各別之反應選擇 使用不同之參數以得到所欲之偶合產物。 於本發明之方法中，使用液體型式或溶解型式之有機 化合物和觸媒係必要的。若所使用之反應成份之一或觸媒 係爲液體型式，則其如有必要亦可充作其他反應成份或觸 媒之溶劑。若其本身非爲液體型式，則其必須於實施本發 明之方法前溶解於適當之溶劑中。適宜之溶劑係鹵化溶劑 (特別適宜者係二氯甲烷、氯仿、1，2 -二氯乙烷或1 ，1，2， 2 -四氯乙烷），直鏈、支鏈或環狀之鏈烷烴 經濟部智慧財產局員工消費合作社印製 (特別適宜者係戊烷、己烷、庚烷、辛烷、環戊烷、環己 烷、環庚烷或環辛烷），或直鏈、支鏈或環狀之醚類（特 別適宜者係二乙醚、甲基特丁醚、四氫呋喃或二噁烷）， 芳族溶劑（特別適宜者係甲苯、二甲苯、石油英或苯醚） ，含氮雜環溶劑（特別適宜者係吡啶或N -甲基吡咯烷酮 )，或至少2種上述溶劑之混合物。 於本發明之方法中，因所釋出之化學物所造成之對人 體和環境之危害係顯著地降低，因此能於操作有害物質時 增加安全性。與慣用之方法相比較，於本發明之方法中， 偶合有機化合物進一步能夠較佳地控制反應條件，諸如， 例如，反應時間和反應溫度。再者，本發明之方法能夠顯 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） -12- 1242544 A7 B7 五、發明説明（10) 者地1¾:低於非吊局放熱性偶合反應之情況下爆炸之危險性 。可各別地選用溫度並令其於每一個系統之體積單元中保 持一定。本發明之方法可非常快速地且精確地調控偶合反 應之反應進展。因此，可得到具有非常良好且可重覆之產 率的所欲偶合產物◦本發明之方法的進一步優點係在於在 無保護性氣體環境下，可使用通常必須於保護性氣體環境 下操作的對氧化作用敏感之有機化合物和觸媒。 亦爲特別有利的是可連續地實施本發明之方法。與慣 用之方法相比較，本發明之方法較爲快速且較不昂貴，且 於不存有主要之測量和控制下，本發明之方法可製備所欲 之偶合產物的任一所欲之產量。 本發明係以實施例加以說明。該實施例僅用於說明本 發明，而非限制本發明之一般發明槪念。 實施例 偶合苯基碘和苯乙烯以產生反式甚 於具有大小爲4 0 m m X 2 5 m m X 1 m m且總計爲 1 1個混合階段（每一個體積爲0 · 1 2 5 μ 1 )之靜態 微混合器（Technical University of Ilmenau，Faculty of Machine Construction, Dr.-Ing. Norbert Schwesinger, P〇 Box 1 00565, D-9 8684，Ilmenau )中，在乙酸鈀（Π )，三 苯膦及三正丁胺之存在下，進行苯基碘和苯乙烯之偶合以 產生反式芪。總壓力損失爲約1 0 0 0 P a。 該靜態微混合器係經由出口管和Omni fit介質-壓力 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 一 (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -13- 1242544 A7 B7 五、發明説明（11) Η P L C 連接器（Omnifit，Great Britain )連接至 Teflon 毛細管（內徑〇· 4 9 m m，長度1 · 0 m )。於8 0， (請先閱讀背面之注意事項再填寫本頁) 1 0 0, 1 3 0及1 6 0 °C下，進行該反應。對此，於恒 溫雙層槽中，令該靜態微混合器和Teflon毛細管維持於各 別之溫度下。 將1份溶液〔苯乙烯（6 5〇m g， 6 · 2 5 mmo 1 )和三正丁胺（1· 2g， 6 · 25mm〇 1 ) 之N -甲基吡咯烷酮（4 0 m 1 )溶液〕塡充至可丟棄之 針筒（2 m 1 )中，且將1份溶液〔苯基碘（1 g，5 mmo 1)，三苯膦（100mg, 0 · 4mmo 1)及 乙酸把（Π) (20mg， O.lmmol)之 Ν —甲基 吡咯烷酮（4 0 m 1 )溶液〕塡充至另一個可丟棄之針筒 (2ml )中。隨後，藉由利用計量泵（Harvard .-5- 1242544 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs B7___ V. Description of the Invention (3) _ The solution type compounds and / or liquids are mixed by the kinetic energy of the flowing liquid and / or solution. The diameter of the channel of the microreactor is suitably 10 to 100 0 // m, particularly 20 to 80 0 // m, and extremely suitable 30 to 4, 〇 〇 // m. The liquid and / or solution is suitably introduced into the microreactor by pumping so that the flow rate of the microreactor through the microreactor is 0. 〇1 // 1 / minute to 100 m 1 / minute, which is particularly suitable. 1 // 1 / min to 1 m 1 / min. 0. According to the invention, the microreactor is suitably heatable. According to the invention, the microreactor is suitably connected to at least one retention zone via an outlet tube, suitably a capillary tube, particularly a heatable capillary tube. After mixing in the microreactor, the liquid and / or solution is fed into the retention zone or capillary to extend its retention time. For the purposes of the present invention, the residence time is the time between mixing the starting materials and processing the reaction solution produced to analyze or separate the desired product. The residence time required for the method of the present invention depends on many different parameters, such as, for example, the temperature or reactivity of the starting material. Those who are familiar with this technique can also use the residence time matched with this parameter to achieve the best state of the reaction. The residence time of the reaction solution in the system used including at least one microreactor and a retention zone if necessary can be adjusted by selecting the liquid used and / or the flow rate of the solution. The reaction mixture can be suitably connected through two or more series of micro-paper sizes suitable for home and family ((: called 8 4 size (2 297 mm)) ~--6- (Please read the back Note: Please fill in this page again) 1242544 A7 B7 V. Description of the invention (4) Reactor. This achieves extended residence time, even at increased flow rates, and reacts the used coupling reaction components to achieve the desired coupling. The best yield of the product. (Please read the notes on the back before filling this page.) In a further preferred system, the reaction mixture is passed through two or more side-by-side microreactors to increase output. In another preferred system of the inventive method, the number and arrangement of the channels in one or more microreactors can be changed, so that the residence time is extended, and the optimal coupling product can be obtained at the same time by increasing the flow rate F. Yield: The retention time of the reaction solution (the appropriate retention time in the microreactor and the capillary) of the microreaction is suitably < 15 hours, more suitably < 3 hours, and particularly suitably < 1 hour The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed a method that can implement the present invention over a very wide temperature range, which is mainly limited to the construction of the microreactor, any retention zones, and additional components such as, for example, connections The heat resistance of the materials used in the device and the seal, and the physical properties of the solution and / or liquid used. The suitable temperature for carrying out the method of the present invention is between -100 to +250 ° C, suitably Between -78 and +150 ° C, particularly suitably between 0 and +40 t: In general, the method for coupling organic compounds of the present invention can be carried out without using a protective gas. However, protective gas can also be used. In the environment, the method of the present invention is implemented. If the method of the present invention is implemented in a protective gas environment, it is suitably carried out in an environment of nitrogen and / or argon. The method can be implemented continuously or batchwise. The method of invention. It is suitably implemented in a continuous manner. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1242544 A7 B7 V. Description of the invention (5) (Please read the back first Please fill in this page again.) In order to implement the method for coupling organic compounds of the present invention, it is necessary to perform the coupling reaction in a homogeneous liquid phase containing no solid particles or only a small amount of solid particles. Because if there are solid particles, the pores in the microreactor will be blocked. Using various analytical methods known to those skilled in the art, the coupling reaction process of the method of the present invention can be tracked and adjusted if necessary. Suitable Chromatography, particularly suitable for high performance liquid chromatography to track the progress of the reaction, and if necessary to regulate it. In this case, compared with known methods, the control of the reaction has achieved significant To improve. After the reaction, if necessary, the formed coupling products can be separated. Suitably, the resulting coupled product is separated from the reaction mixture by extraction. Organic compounds containing at least one leaving group which can be used in the method of the present invention are all organic compounds containing at least one leaving group which are used as a substrate for a coupling reaction and are known to those skilled in the art. The organic compound containing at least one leaving group used by the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to print the method of the present invention may suitably be an aryl halide (particularly suitable is aryl bromide or aryl iodide, which is extremely suitable for Aryl iodide, heteroaryl halide (especially suitable as heteroaryl bromide or heteroaryl iodide, very suitable as heteroaryl iodide), vinyl halide (especially suitable as ethylene bromide or vinyl iodo, very suitable Ethylene iodo), or a mixture of at least two of the above compounds. The compound containing at least one leaving group used in the method of the present invention may suitably be an organic fluoroalkyl sulfonate (suitably an aryl fluoroalkyl sulfonate) , Heteroaryl fluoroalkyl sulfonate or vinyl fluoroalkyl sulfonate), or organic polyfluoroalkyl sulfonate (suitably aryl polyfluoroalkyl sulfonate, polyfluoroalkyl sulfonate) Paper size Applicable to Chinese National Standard (CNS) A4 specification (210X29 * 7mm) -8-1242544 Printed by A7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs _B7_ V. Description of the invention (6) Heteroaryl ester or polyfluoroalkyl sulfonic acid Vinyl ester), or at least 2 of the above The polyfluoroalkyl sulfonate used in the method of the present invention may be particularly suitably aryl trifluoromethanesulfonate, heteroaryl trifluoromethanesulfonate, vinyl trifluoromethanesulfonate, or at least A mixture of two of the above compounds. In a further specific and preferred system of the method of the present invention, the polyfluoroalkyl sulfonate may be nonafluorobutane, acid aryl, nonafluorobutane sulfonate , Vinyl nonafluorobutane sulfonate, or a mixture of at least two of the above compounds. For the purposes of this invention, aryl halides, aryl fluoroalkyl sulfonates, and aryl polyfluoro alkyl sulfonates also include aromatic organics. Compounds in which the halo, fluoroalkylsulfonate or polyfluoroalkylsulfonate group is not directly bonded to the aromatic ring of the aryl group, but is bonded, for example, via a methylene group To the aromatic ring of the aryl group, such as, for example, benzyl halide, benzyl trifluoromethanesulfonate or benzyl nonafluorobutanesulfonate. For the purposes of the present invention, heteroaryl halide, fluorine Heteroaryl sulfonates and heteroaryl polyfluoroalkyl sulfonates also include aromatic organic compounds, in which the The fluoroalkylsulfonate or polyfluoroalkylsulfonate group is not directly bonded to the aromatic ring of the heteroaryl group, but is bonded to the aryl group, for example, via a methylene group. On the aromatic ring of the group. The heteroaryl groups suitably contain at least one oxygen and / or nitrogen and / or sulfur atom to act as a heteroatom. The method of the present invention can be used which contains at least one vinyl-type hydrogen atom Or organic compounds of acetylene type hydrogen atom can be any one known to those skilled in the art and suitable as a substrate for the coupling reaction. It contains at least one vinyl type. The size of this paper is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back before filling this page) -9- 1242544 A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ___B7____ V. Description of the invention (7) Hydrogen atom or acetylene type hydrogen atom Organic compounds. Suitable for the method of the present invention is at least one unbranched, branched, cyclic, aromatic or heteroaromatic olefin or alkyne, particularly suitable is at least one unbranched, branched, cyclic, aromatic Or heteroaromatic olefins. For the purposes of the present invention, aromatic compounds containing at least one ethylene-type oxygen atom or ethylene-type hydrogen atom also include monocyclic and / or polycyclic homoaromatic basic structures or their corresponding partial structures (for example, by substituents) Type) and organic compounds and / or derivatives thereof of ethylene type hydrogen atom or acetylene type hydrogen atom. For the purposes of the present invention, heteroaromatic compounds containing at least one vinyl-type hydrogen atom or vinyl-type hydrogen atom also include monocyclic and / or polycyclic heteroaromatic basic structures or their corresponding partial structures (for example, to replace Base type. Formula) and at least one ethylene-type hydrogen atom or an organic compound and / or derivative thereof. Such heteroaromatic basic structures or partial structures particularly suitably include at least one oxygen and / or nitrogen and / or sulfur atom. The catalysts usable in the method of the present invention are all catalysts known to those skilled in the art and suitable for coupling reactions of organic compounds or a mixture of at least two such catalysts. Suitably, only one catalyst is used in each case. For the purposes of the present invention, the catalyst also includes a catalyst formed in situ, that is, a catalyst formed immediately before or during the coupling reaction. In a further preferred system of the present invention, the catalyst used is at least one compound containing palladium with an oxidation state of zero. The compound containing palladium having an oxidation state of 0 is suitably tris (dibenzylideneacetone) dipalladium. In the presence of at least one alkali, if necessary, the Chinese National Standard (CNS) A4 specification (210X297 mm) is applied to the paper size of the at least one inorganic salt. ~ -10- (Please read the precautions on the back before filling this page ) 1242544 A7 ___ B7 _ V. Description of the invention (8) (Please read the precautions on the back before filling out this page) and if necessary in the presence of at least one ligand, the contact used in the method of the present invention The medium is suitably at least one compound containing palladium having an oxidation state of +2. The palladium compound containing palladium having an oxidation state of + 2 used in the method of the present invention may suitably be palladium chloride (Π), palladium acetate (Π), bis (triphenylphosphine) palladium dichloride (Π) or at least A mixture of two of these compounds. The base used in the method of the present invention may be any base known to those skilled in the art and suitable for the coupling reaction of organic compounds. The base used may suitably be an organic amine (especially suitably triethylamine, diethylamine or tri-n-butylamine), a nitrogen-containing optional aromatic heterocycle (especially suitably pyridine or N-methylpyrrolidone) ), Or a mixture of at least two of the above compounds. The inorganic salt used in the method of the present invention may be any inorganic salt known to those skilled in the art and suitable for the coupling reaction of organic compounds. The inorganic salt used is suitably copper (I) iodide. The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed in a further preferred system of the method of the present invention, based on an organic compound containing at least one leaving group as the base, and the amount of the catalyst used is 0. 01 to 1 10 moles. %, Suitably from 0.01 to 50% mole%, particularly suitably from 0.1 to 1 mole%. In the method of the present invention, an organic compound containing at least one leaving group and an organic compound containing at least one ethylene-type hydrogen atom or acetylene-type hydrogen atom are suitably used in an equimolar ratio. In another preferred system of the method of the present invention, based on an organic compound containing at least one leaving group, the amount of the organic compound containing at least one ethylene-type hydrogen atom or acetylene-type hydrogen atom is 1 · 5 to 2 times Molar excess, especially suitable for Chinese paper standard (CNS) A4 size (210X297 mm) " -11- 1242544 ΚΊ __ Β7 _ _ 5. The description of the invention (9) is 1 · A 1- to 6-fold excess is most suitably a 1.2- to 1.5-fold excess. (Please read the notes on the back before filling this page) The selectivity of the reaction depends on the concentration of the reagent used and many other parameters, such as, for example, temperature, type of leaving group, type of catalyst, and residence time . Those who are familiar with this technique can also choose to use different parameters in each reaction to obtain the desired coupling product. In the method of the present invention, it is necessary to use a liquid type or a dissolved type organic compound and a catalyst. If one of the reaction components or catalysts used is a liquid type, it can also be used as a solvent for other reaction components or catalysts if necessary. If it is not in a liquid form, it must be dissolved in a suitable solvent before carrying out the method of the present invention. Suitable solvents are halogenated solvents (especially suitable are methylene chloride, chloroform, 1,2-dichloroethane or 1,1,2,2-tetrachloroethane), straight chain, branched chain or cyclic chain Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Alkanes Economy (particularly suitable is pentane, hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane or cyclooctane), or straight chain, branched Chain or cyclic ethers (especially suitable are diethyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane), aromatic solvents (especially suitable are toluene, xylene, petroleum spirit or phenyl ether), containing nitrogen Heterocyclic solvents (particularly suitable are pyridine or N-methylpyrrolidone), or a mixture of at least two of the above solvents. In the method of the present invention, the harm to the human body and the environment caused by the released chemicals is significantly reduced, so that safety can be increased when handling harmful substances. Compared with the conventional method, in the method of the present invention, the coupling organic compound can further better control the reaction conditions such as, for example, the reaction time and the reaction temperature. Furthermore, the method of the present invention can show that the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -12- 1242544 A7 B7 V. Description of the invention (10) The place 1¾: lower than the non-suspended bureau Danger of explosion in case of exothermic coupling reaction. The temperature can be selected individually and kept constant in the volume unit of each system. The method of the present invention can very quickly and precisely regulate the reaction progress of the coupling reaction. Therefore, a desired coupling product having a very good and repeatable yield can be obtained. A further advantage of the method of the present invention is that in a non-protective gas environment, it is possible to use a pair of compounds which must normally be operated in a protective gas environment. Organic compounds and catalysts sensitive to oxidation. It is also particularly advantageous that the method of the invention can be carried out continuously. Compared with the conventional method, the method of the present invention is faster and less expensive, and without major measurement and control, the method of the present invention can produce any desired yield of the desired coupling product. The invention is illustrated by examples. This embodiment is only used to illustrate the present invention, and not to limit the general inventive concept of the present invention. The example couples phenyl iodide and styrene to produce a trans-form that has a size of 40 mm X 2 5 mm X 1 mm and a total of 11 mixing stages (each with a volume of 0 · 1 2 5 μ 1) Static Micromixer (Technical University of Ilmenau, Faculty of Machine Construction, Dr.-Ing. Norbert Schwesinger, Po Box 1 00565, D-9 8684, Ilmenau), in palladium acetate (Π), triphenylphosphine and triphenylphosphine The coupling of phenyliodide and styrene is performed in the presence of n-butylamine to produce trans-stilbene. The total pressure loss is about 1 0 0 0 Pa. The static micromixer is through the outlet tube and the Omni fit medium-pressure. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). (Please read the precautions on the back before filling this page.) Order the wisdom of the Ministry of Economic Affairs Printed by the Consumer Affairs Cooperative of the Property Bureau-13- 1242544 A7 B7 V. Description of the invention (11) Η The PLC connector (Omnifit, Great Britain) is connected to the Teflon capillary (inner diameter 0.49 mm, length 1.0m). At 80, (please read the notes on the back before filling this page) at 1 0 0, 1 3 0 and 16 0 ° C. To this end, the static micromixer and the Teflon capillary were maintained at separate temperatures in a constant temperature double-layered tank. 1 part of a solution [a solution of styrene (650 mg, 6.25 mmo 1) and tri-n-butylamine (1.2 g, 6.25 mm01) in N-methylpyrrolidone (40 m 1)] Fill a disposable syringe (2 m 1) with 1 part solution [phenyliodide (1 g, 5 mmo 1), triphenylphosphine (100 mg, 0.4 mmo 1) and acetic acid (Π) (20 mg, 0.1 mmol) of N-methylpyrrolidone (40 m 1) solution] was filled into another disposable syringe (2 ml). Subsequently, by using a metering pump (Harvard.

Apparatus Inc., Pump 22，South Natick，Massachusetts, US A )將該2個針筒之內容物轉移至該靜態微混合器中。 於反應進行前，依據取決於泵流速之滯留時間校正實 驗裝置。設定滯留時間爲3 · 5， 7 · 5， 1 5， 3 0， 經濟部智慧財產局員工消費合作社印製 6 〇及 1 2 〇分鐘。利用 Merck Hitachi LaChrom HPLC 儀 器追蹤反應之進行。於上述儀器中藉由Η P L C測定對應 於各別滯留時間之起始物對產物之比例。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) -14- 1242544 (由本局填寫)Apparatus Inc., Pump 22, South Natick, Massachusetts, US A) transferred the contents of the 2 syringes to the static micromixer. Prior to the reaction, the experimental device was calibrated based on the residence time depending on the pump flow rate. The residence time is set to 3, 5, 7, 5, 15, 30, and printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs for 60 minutes and 120 minutes. The reaction was tracked using a Merck Hitachi LaChrom HPLC instrument. The ratio of the starting material to the product corresponding to the respective residence time was determined in the above instrument by ΗPLC. This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) -14- 1242544 (to be filled in by this bureau)

和% J "ΤΠΤ A 6 ——- B6 本案已向： 國（地區）申請專利，申請日期.： 案號： ，□有□無主張優先權 德國 2000年 6月28日 100 31 381.7 0有主張優先權 有關微生物已寄存於： 寄存日期： 寄存號碼： --裝----- (請先閲讀背面之注意事項再填寫本頁各欄) \Ψ .........- HI ft -口 ?£齊郎皆逄时產¾員X消費合泎7i印製 本纸張尺度適用中國國家標卓（CNS ) A4規格（210X 297公釐）And% J " ΤΠΤ A 6 ——- B6 The case has been applied for: country (region) patent, date of application .: Case No .: □ Yes □ No claim of priority Germany June 28, 2000 100 31 381.7 0 Yes Related microorganisms claiming priority have been deposited in: Date of deposit: Number of deposit: --- (Please read the precautions on the back before filling in the columns on this page) \) .........- HI ft-Mouth-to-Knife, all of them are produced at the same time, X members are consumed, and 7i is printed. The paper size is applicable to China National Standards (CNS) A4 specifications (210X 297 mm)

Claims (1)

1242544 A8 B8 C8 D8 六、申請專利範圍 附件：2A 第9011 5 1 S8號專利申請案 中文申請專利範圍替換本 民國94年7月21日修正 1 . 一種偶合有機化合物之方法，其特徵在於在至少 一種微反應器中，於至少一種液體或溶解型式之觸媒的存 在下，令至少一種液體或溶解型式之含有至少一個離去基 的有機化合物與至少一種液體或溶解型式之含有乙烯型氫 原子或乙炔型氫原子的有機化合物相混合並於滯留時間發 生反應，且如有需要自反應混合物分離所生成之偶合產物 ，其中該微反應器具有直徑從1 0至1 〇 〇 〇 Z/m之孔道 ，反應混合物係以流速從0 . 0 1 // 1 /分至1 〇 〇 m 1 /分流經該微反應器，該微反應器中所使用之化合物的滯 留時間（於該微反應器和毛細管中之適當的滯留時間）係 < 1 5小時，及該方法係在溫度從—7 8至+ 1 5 0 °C間 進行。 2 .如申請專利範圍第1項之方法，其特徵在於該微 反應器係小型連續反應器。 3 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器係靜態微混合器。 4 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器係經由出口管連接毛細管。 5 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器係經由出口管連接可加熱之毛細管。 本紙張尺度適用中國國家#準（CNS)A4規格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁) ,裝· 經濟部智慧財產局員工消費合作社印製 1242544 A8 B8 C8 D8 六、申請專利範圍 6 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器之體積係S100//1。 7 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器之體積係^50//1。 8 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器係可加熱的。 9 ·如申請專利範圍第1或2項之方法，其特徵在於 該微反應器具有孔道，該孔道之直徑係20至8〇〇 〇 1 〇 .如申請專利範圍第1或2項之方法，其特徵在 於該微反應器具有孔道，該孔道之直徑係30至400 β m 。 1 1 ·如申請專利範圍第1或2項之方法，其特徵在 於流經該微反應器之反應混合物的流速係係1 // 1 /分至 1 m 1 / 分。 1 2 ·如申請專利範圍第1或2項之方法，其特徵在 於該微反應器中所使用之化合物的滯留時間（於該微反應 器和毛細管中之適當的滯留時間）係< 3小時。 1 3 .如申請專利範圍第1或2項之方法，其特徵在 於該微反應器中所使用之化合物的滯留時間（於該微反應 器和毛細管中之適當的滯留時間）係< 1小時。 1 4 .如申請專利範圍第1或2項之方法，其特徵在 於進行該方法之溫度係介於—1 0 〇至+ 2 5 0 °C。 1 5 .如申請專利範圍第1或2項之方法，其特徵在 本纸張尺度適用中國國家標準（CNS ) A料見格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂 — 經濟部智慧財產局員工涓費合作社印製 -2- 12425441242544 A8 B8 C8 D8 Appendix of patent application scope: 2A No. 9011 5 1 S8 Patent application Chinese application patent scope replaces July 21, 1994 Amendment 1. A method for coupling organic compounds, characterized in that at least In a microreactor, in the presence of at least one liquid or dissolved type catalyst, at least one liquid or dissolved type organic compound containing at least one leaving group and at least one liquid or dissolved type containing ethylene type hydrogen atom Or acetylene-type hydrogen atom organic compounds are mixed and reacted during the residence time, and if necessary, the generated coupling products are separated from the reaction mixture, wherein the microreactor has a diameter from 10 to 10000Z / m In the channel, the reaction mixture flows through the microreactor at a flow rate from 0.0 1 // 1 / min to 1000 m 1 / min. The residence time of the compounds used in the microreactor (in the microreactor and Appropriate residence time in the capillary) is < 15 hours, and the method is performed at a temperature from -78 to + 150 ° C. 2. The method according to item 1 of the scope of patent application, characterized in that the microreactor is a small continuous reactor. 3. The method according to item 1 or 2 of the scope of patent application, characterized in that the microreactor is a static micromixer. 4. The method according to item 1 or 2 of the scope of patent application, characterized in that the microreactor is connected to a capillary via an outlet tube. 5. The method according to item 1 or 2 of the scope of patent application, characterized in that the microreactor is connected to a heatable capillary via an outlet tube. This paper size applies to China National Standard #CNS (A4) (210X 297 mm) (Please read the precautions on the back before filling out this page), printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperative Cooperative 1242544 A8 B8 C8 D8 6. Scope of patent application 6 · The method of the scope of patent application item 1 or 2 is characterized in that the volume of the microreactor is S100 // 1. 7. The method according to item 1 or 2 of the scope of patent application, characterized in that the volume of the microreactor is ^ 50 // 1. 8. The method of claim 1 or 2, characterized in that the microreactor is heatable. 9 · The method according to item 1 or 2 of the scope of patent application, characterized in that the microreactor has a channel, and the diameter of the channel is 20 to 800,000. It is characterized in that the microreactor has a channel, and the diameter of the channel is 30 to 400 β m. 1 1 · The method according to item 1 or 2 of the scope of patent application, characterized in that the flow rate of the reaction mixture flowing through the microreactor is 1 // 1 / minute to 1 m 1 / minute. 1 2 · The method according to item 1 or 2 of the scope of patent application, characterized in that the residence time of the compound used in the microreactor (appropriate residence time in the microreactor and capillary) is < 3 hours . 13. The method according to item 1 or 2 of the scope of patent application, characterized in that the residence time of the compound used in the microreactor (appropriate residence time in the microreactor and capillary) is < 1 hour . 14. The method according to item 1 or 2 of the scope of patent application, characterized in that the temperature at which the method is performed is between -100 to + 250 ° C. 1 5. If the method of item 1 or 2 of the scope of patent application, the characteristics of this paper apply Chinese National Standard (CNS) A material see the grid (210X297 mm) (Please read the precautions on the back before filling this page ) Order — Printed by the staff of the Intellectual Property Bureau of the Ministry of Economy -2- 1242544 六、申請專利範圍 於進行該方法之溫度係介於〇至+ 4 0 °C。 1 6 ·如申請專利範圍第1或2項之方法，其特徵在 於該方法係於保護性氣體環境下進行。 1 7 ·如申請專利範圍第1或2項之方法，其特徵在 於該方法係於氮氣及/或氬氣環境下進行。 1 8 ·如申請專利範圍第1或2項之方法，其特徵$ 於在該反應過程後係進行層析，且如有需要予以調控。 1 9 ·如申請專利範圍第1或2項之方法，其特徵$ 於在該反應過程後係進行高效液相層析且如有需要予以_ 控。 2 0 ·如申請專利範圍第1或2項之方法，其特徴# 於藉由萃取自該反應混合物中分離所生成之偶合產物。 2 1 ·如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物係芳基鹵，雜芳棊國 ，鹵乙烯，或至少2個上述之化合物的混合物。 經濟部智慧財產局員工消費合作社印製 2 2 ·如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物係芳基溴，芳基碘’ 雜芳基溴、雜芳基碘，溴乙烯或碘乙烯，或至少2個上述 之化合物的混合物。 2 3 .如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物係芳基碘，雜芳基碘 ，碘乙烯，或至少2個上述之化合物的混合物。 2 4 ·如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物係有機氟院基擴酸酯 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 1242544 A8 B8 C8 D8 六、申請專利範圍 ，有機多氟烷基磺酸酯，或至少2個上述之化合物的混g 物。 2 5 .如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物係氟烷基磺酸芳酯， 氟烷基磺酸雜芳酯，氟烷基磺酸乙烯酯，多氟烷基磺酸芳 酯，多氟烷基磺酸雜芳酯或多氟烷基磺酸乙烯酯，或至少 2個上述之化合物的混合物。 2 6 .如申請專利範圍第2 4項之方法，其特徵在於 所使用之有機多氟烷基磺酸酯係三氟甲烷磺酸芳酯，三氟 甲烷磺酸雜芳酯，三氟甲烷磺酸乙烯酯或至少2個上述之 化合物的混合物。 2 7 .如申請專利範圍第2 4項之方法，其特徵在於 所使用之有機多氟烷基磺酸酯係九氟丁烷磺酸芳酯，九氟 丁烷磺酸雜芳酯，九氟丁烷磺酸乙烯酯，或至少2個上述 之化合物的混合物。 2 8 ·如申請專利範圍第1或2項之方法，其特徵在 於該含有至少一個乙烯型氫原子或乙炔型氫原子之化合物 係至少一種非支鏈，支鏈，環狀，芳族或雜芳族烯或炔。 經濟部智慧財產局員工消費合作社印製 2 9 .如申請專利範圍第1或2項之方法，其特徵在 於該含有至少一個乙烯型氫原子或乙炔型氫原子之化合物 係至少一種非支鏈，支鏈，環狀，芳族或雜芳族烯。 3 0 ·如申請專利範圍第1或2項之方法，其特徵在 於所使用之觸媒係至少一種含有氧化狀態爲0之鈀的化合 物。 -4 - 本纸張尺度適用中國國家標準（CNS ) A4規格（2】0X297公釐） 1242544 B8 C8 D8 六、申請專利範圍 3 1 ·如申請專利範圍第3 〇項之方法，其特徵在於 所使用之觸媒係三（二苄叉丙酮）二I巴。 3 2 ·如申請專利範圍第1或2項之方法，其特徵在 於在至少一種驗之存在下，如有需要在至少一種無機鹽之 存在下且如有需要在至少一種配體之存在下，所使用之觸 媒係至少一種含有氧化狀態爲+ 2之鈀的化合物。 3 3 ·如申請專利範圍第3 2項之方法，其特徵在於 所使用之銷化合物係氯化鈀（π )，乙酸鈀（π )，二（ 二本膦）一氯化銷（π )或該等化合物之混合物。 3 4 ·如申請專利範圍第3 2項之方法，其特徵在於 所使用之鹼係有機胺，含氮可選擇之芳族雜環，或至少2 個上述之化合物的混合物。 3 5 ·如申請專利範圍第3 2項之方法，其中該有機 胺爲三乙胺，二乙胺或三正丁胺，及該芳基雑環爲吡啶或 Ν -甲基吡咯院酮。 3 6 .如申請專利範圍第3 2項之方法，其特徵在於 所使用之無機鹽係碘化銅（I )。 3 7 .如申請專利範圍第3 2項之方法，其特徵在於 所使用之配體係膦，胺，亞胺，或至少2個上述之化合物 的混合物。 3 8 .如申請專利範圍第3 2項之方法，其中該膦爲 三苯膦。 3 9 ·如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物對含有至少一個乙烯 本紙張尺度適用中國國家標準（CNS ) Α4規格（210χ 297公釐） I 旁 經濟部智慧財產局員工消費合作社印製 -5 - 1242544 Α8 Β8 C8 D8 六、申請專利範圍 型氫原子或乙炔型氫原子之有機化合物的莫耳比係爲等莫 耳，或在於基於該含有至少一個離去基之有機化合物，該 含有至少一個乙烯型氫原子或乙炔型氫原子之有機化合物 的量係爲1 · 0 5至2倍過量。' 4〇.如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物對含有至少一個乙烯 型氫原子或乙炔型氫原子之有機化合物的莫耳比係爲等莫 耳，或在於基於該含有至少一個離去基之有機化合物，該 含有至少一個乙烯型氫原子或乙炔型氫原子之有機化合物 的量係爲1 · 1至1 · 6倍過量。 4 1 ·如申請專利範圍第1或2項之方法，其特徵在 於含有至少一個離去基之有機化合物對含有至少一個乙烯 型氫原子或乙炔型氫原子之有機化合物的莫耳比係爲等莫 耳，或在於基於該含有至少一個離去基之有機化合物，該 含有至少一個乙烯型氫原子或乙炔型氫原子之有機化合物 的量係爲1 · 2至1 · 5倍過量。 經濟部智慧財產局員工消費合作社印製 4 2 ·如申請專利範圍第1或2項之方法，其特徵在 於基於該含有至少一個離去基之化合物，所使用之觸媒量 係介於0·〇1至11〇莫耳％。 4 3 ·如申請專利範圍第1或2項之方法，其特徵在 於基於該含有至少一個離去基之化合物，所使用之觸媒量 係介於0 · 〇 1至5 0莫耳％。 4 4 ·如申請專利範圍第1或2項之方法，其特徵在 於基於該含有至少一個離去基之化合物，所使用之觸媒量 本纸張尺度適用中國國家標準（CNS ) Α4規格（2】0Χ 297公釐） -6- 1242544 六、申請專利範圍 係介於0 . 0 1至1莫耳％。 8 8 8 8 ABCD (請先閱讀背面之注意事項再填寫本頁) •I裝· 甘填寫太 訂 經濟部智慧財產局員工消費合作社印製 本纸張尺度適用中國國家標準（CNS ) 格（2]〇X297公釐） -7-6. Scope of patent application The temperature for carrying out the method is between 0 and + 40 ° C. 16 · The method according to item 1 or 2 of the scope of patent application, characterized in that the method is performed in a protective gas environment. 17 · The method according to item 1 or 2 of the scope of patent application, characterized in that the method is carried out in a nitrogen and / or argon environment. 1 8 · If the method in the scope of patent application No. 1 or 2 is used, it is characterized in that chromatography is performed after the reaction process, and it is adjusted if necessary. 19 · The method according to item 1 or 2 of the scope of patent application, which is characterized by performing high-performance liquid chromatography after the reaction process and controlling it if necessary. 2 0. The method according to item 1 or 2 of the scope of patent application, which is characterized in that the coupling product formed is separated from the reaction mixture by extraction. 21 · The method according to item 1 or 2 of the scope of patent application, characterized in that the organic compound containing at least one leaving group is an aryl halide, a heteroaryl compound, ethylene halide, or a mixture of at least two of the above compounds. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 2 · The method of item 1 or 2 of the scope of patent application, characterized in that the organic compound containing at least one leaving group is aryl bromide, aryl iodo 'heteroaryl bromide , Heteroaryl iodide, ethylene bromide or ethylene iodo, or a mixture of at least two of the above compounds. 2 3. The method according to item 1 or 2 of the scope of patent application, characterized in that the organic compound containing at least one leaving group is aryl iodide, heteroaryl iodide, ethylene iodo, or a mixture of at least two of the above compounds. 2 4 · The method according to item 1 or 2 of the scope of patent application, which is characterized in that the organic compound containing at least one leaving group is an organic fluorine-based expanded ester. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1242544 A8 B8 C8 D8 6. Scope of patent application, organic polyfluoroalkyl sulfonate, or a mixture of at least two of the above compounds. 25. The method according to item 1 or 2 of the scope of patent application, characterized in that the organic compound containing at least one leaving group is aryl fluoroalkyl sulfonate, heteroaryl fluoroalkyl sulfonate, fluoroalkyl sulfonic acid Vinyl ester, aryl polyfluoroalkylsulfonate, heteroaryl polyfluoroalkylsulfonate or vinyl polyfluoroalkylsulfonate, or a mixture of at least two of the above compounds. 26. The method according to item 24 of the scope of patent application, characterized in that the organic polyfluoroalkyl sulfonate is aryl trifluoromethanesulfonate, heteroaryl trifluoromethanesulfonate, trifluoromethanesulfonate Acid vinyl ester or a mixture of at least two of the above compounds. 27. The method according to item 24 of the scope of patent application, characterized in that the organic polyfluoroalkyl sulfonate used is aryl nonafluorobutane sulfonate, heteroaryl nonafluorobutane sulfonate, nonafluoro Vinyl butanesulfonate, or a mixture of at least two of the above compounds. 28. The method according to item 1 or 2 of the scope of patent application, characterized in that the compound containing at least one vinyl-type hydrogen atom or acetylene-type hydrogen atom is at least one kind of unbranched, branched, cyclic, aromatic or heterocyclic Aromatic alkenes or alkynes. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 9. If the method of claim 1 or 2 of the patent application scope is characterized in that the compound containing at least one ethylene-type hydrogen atom or acetylene-type hydrogen atom is at least one non-branched chain, Branched, cyclic, aromatic or heteroaromatic olefins. 30. The method of claim 1 or 2 is characterized in that the catalyst used is at least one compound containing palladium with an oxidation state of 0. -4-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2) 0X297 mm 1242544 B8 C8 D8 VI. Application scope of patent 3 1 · As for the method of application scope No. 30, it is characterized by The catalyst used was tris (dibenzylideneacetone) dibar. 3 2 · The method according to item 1 or 2 of the scope of patent application, characterized in that in the presence of at least one test, if necessary in the presence of at least one inorganic salt and if necessary in the presence of at least one ligand, The catalyst used is at least one compound containing palladium with an oxidation state of +2. 3 3 · The method according to item 32 of the scope of patent application, characterized in that the pin compound used is palladium chloride (π), palladium acetate (π), bis (diphosphine) monochloride pin (π) or A mixture of these compounds. 34. The method according to item 32 of the scope of patent application, characterized in that the base organic amine used, the nitrogen-containing optional aromatic heterocyclic ring, or a mixture of at least two of the above compounds are used. 35. The method according to item 32 of the scope of patent application, wherein the organic amine is triethylamine, diethylamine or tri-n-butylamine, and the arylfluorene ring is pyridine or N-methylpyrrolidinone. 36. The method according to item 32 of the scope of patent application, characterized in that the inorganic salt used is copper (I) iodide. 37. The method according to item 32 of the scope of patent application, characterized in that a phosphine, amine, imine, or a mixture of at least two of the above-mentioned compounds is used. 38. The method of claim 32, wherein the phosphine is triphenylphosphine. 3 9 · The method according to item 1 or 2 of the scope of patent application, characterized in that the organic compound containing at least one leaving group is applicable to the Chinese National Standard (CNS) A4 specification (210χ 297 mm) for paper containing at least one vinyl. I Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-5-1242544 Α8 B8 C8 D8 VI. The molar ratio of organic compounds with a patent-type hydrogen atom or an acetylene-type hydrogen atom is equal to the molar ratio, or is based on The organic compound containing at least one leaving group has an organic compound containing at least one vinyl-type hydrogen atom or acetylene-type hydrogen atom in an amount of 1.05 to 2 times excess. 40. The method according to item 1 or 2 of the scope of patent application, characterized in that the molar ratio of the organic compound containing at least one leaving group to the organic compound containing at least one ethylene-type hydrogen atom or acetylene-type hydrogen atom is It is equivalent to that, based on the organic compound containing at least one leaving group, the amount of the organic compound containing at least one vinyl-type hydrogen atom or acetylene-type hydrogen atom is 1.1-1.6 times excess. 4 1 · The method according to item 1 or 2 of the scope of patent application, characterized in that the molar ratio of the organic compound containing at least one leaving group to the organic compound containing at least one vinyl-type hydrogen atom or acetylene-type hydrogen atom is equal. Moore, or based on the organic compound containing at least one leaving group, the amount of the organic compound containing at least one vinyl-type hydrogen atom or acetylene-type hydrogen atom is a 1.2- to 1.5-fold excess. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 4 2 · If the method of the scope of patent application for item 1 or 2 is characterized, based on the compound containing at least one leaving group, the amount of catalyst used is 0 · Mol to 11 mol%. 43. The method according to item 1 or 2 of the scope of patent application, characterized in that the amount of the catalyst used is based on the compound containing at least one leaving group in the range of 0. 0.001 to 50 mol%. 4 4 · The method according to item 1 or 2 of the scope of patent application, characterized in that the amount of catalyst used is based on the compound containing at least one leaving group. The paper size applies the Chinese National Standard (CNS) A4 specification (2 ] 0 × 297 mm) -6- 1242544 6. The scope of patent application is between 0.01 and 1 mole%. 8 8 8 8 ABCD (Please read the precautions on the back before filling out this page) • I pack · Please fill in Taiding Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Employee Consumption Cooperatives The paper dimensions are applicable to the Chinese National Standard (CNS) grid (2 ] 〇X297 mm) -7-
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