TWI438176B - 製備苯并降莰烯的方法 - Google Patents
製備苯并降莰烯的方法 Download PDFInfo
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Description
本發明係關於9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺的製備。
化合物9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺對於苯并降莰烯殺真菌劑的製備為有價值的中間物,例如,如WO 2007/048556中所述者。
從WO 2007/048556已知藉由下列步驟製備9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺:
a)使式A化合物在亞硝酸烷基酯存在下與式B化合物反應,其中R’和R”為例如C1
-C4
烷基,形成式C化合物:
b)在適當金屬催化劑存在下氫化式C化合物,形成式D化合物:
c)以使用還原劑的後續處理臭氧化式D化合物,形成式E化合物:
d)使式E化合物與三苯膦/四氯化碳反應,形成式F之2,9-二氯亞甲基-5-硝基-苯并降莰烯:
以及
e)在金屬催化劑存在下氫化式F化合物,形成9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺。
此先前技術方法的缺點是很多的反應步驟,此減少產物的產率。除此之外,該難以處理的臭氧分解反應和需要使用三苯膦的昂貴步驟d),使得此方法不經濟且不適合大規模生產。
本發明之目的因此是要提供一種製備9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺的新穎方法,其避免已知方法的缺點,並且使得有可能以經濟上有利的方式用較少的反應步驟以高產率與良好品質製備9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺。
因此,根據本發明,提供一種製備式I之9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺的方法:
該方法包括:
a)使環戊二烯與CXCl3
(其中X為氯或溴;較佳為溴)在自由基引發劑存在下反應,形成式II化合物:
其中X為氯或溴,或者aa)使環戊二烯與CXCl3
(其中X為氯)在金屬催化劑存在下反應,形成式II化合物:
其中X為氯,
b)使式II化合物與鹼在適當溶劑中反應,形成式III化合物:
c)並且使式III化合物在1,2-去氫-6-硝基苯存在下轉化成式IV化合物:
以及
d)在金屬催化劑存在下以氫源氫化式IV化合物。
本方法的一個具體實例包括:
a)使環戊二烯與CXCl3
(其中X為氯或溴)在自由基引發劑存在下反應,形成式II化合物:
其中X為氯或溴。
反應步驟a)和aa):式II化合物可以下列異構物或其混合物出現:
其中X為氯或溴。
反應步驟a)和aa)的產物可原樣用於後面的反應步驟b)。式II之特定異構物或異構物混合物的分離或純化並不必要。式II化合物與其異構物及式IV化合物是新穎的,且是特別為根據本發明之方法所研發,因此構成本發明之進一步目的。
原則上,下列種類的眾多自由基引發劑都可適用於反應步驟a):有機過氧化物(例如過氧化甲基乙基酮、過氧化苯甲醯),有機偶氮化合物,金屬鹽及錯合物(Cu、Ru)。較佳的自由基引發劑係選自於偶氮二異丁腈、過氧化二苯甲醯及過氧二碳酸二(第三丁基環己)酯。尤佳的是偶氮二異丁腈。
反應步驟a)有利地係在升高溫度下,較佳係在20至100℃、較佳60至100℃、最佳80至90℃的溫度下進行。以一溴三氯甲烷的使用為佳,尤其是在過氧化物或偶氮化合物引發作用下。
在尤佳的反應步驟aa)中,環戊二烯係與CCl4
在金屬催化劑存在下反應,形成式II化合物:
其中X為氯。就步驟aa)而言,自由基引發劑的存在並非必要,但可有利於減少催化劑負荷(使用較少的催化劑)。
舉例而言,適合催化劑的金屬係選自於釕、銅、鐵、鈀及銠。較佳的催化劑含有釕(II)或銅(I)錯合物。尤佳的催化劑係選自於下列所組成的群組:Ru(PPh3
)3
Cl2
、Ru(異丙苯)PPh3
Cl2
、Ru(Cp)PPh3
Cl2
、Grubbs I(亞苄基-雙(三環己基膦)-二氯釕),以及與胺配位基,尤其是二胺或三胺配位基結合之CuCl。Grubbs I、CuCl/四甲基伸乙二胺(TMEDA)或五甲基二伸乙基三胺為最佳的催化劑。
當使用Ru-催化劑時,反應步驟aa)可在惰性溶劑存在下,較佳為沒有溶劑下進行。反應步驟aa)有利地係於升高溫度下,尤其是在20至100℃、較佳60至100℃、最佳60°至80℃的溫度下進行。反應步驟aa)的產物為3種可能異構物的混合物。特定異構物或異構物混合物的分離或純化並非必要。
反應步驟aa)的一個較佳具體實例可有效率地進行如下:在0.5至2莫耳%,尤其是1莫耳%的銅I催化劑,較佳為CuCl,與1至4莫耳%、尤其是2莫耳%的四甲基乙烷-1,2-二胺(TMEDA)的存在下,加熱環戊二烯與1.5至3、尤其是2當量的四氯化碳在乙腈中的混合物,以在蒸餾後得到70-80%分離產率的產物。
將催化量(通常1莫耳%)之如上述的自由基引發劑,尤其是N,N-偶氮二異丁腈添加到反應混合物中,可減少催化劑負荷(使用較少的催化劑)。
反應步驟aa)有進一步的優點。CCl4
的使用較不昂貴,與四氯化碳之加成產物(CTCM-環戊烯)比溴衍生物(BTCM-環戊烯)更為穩定,反應顯較不放熱,而因此更適合大規模生產且在後續步驟中沒有溴陰離子產生。
在反應步驟a)和aa)中,CCl3
Br或CCl4
係以對環戊二烯過量使用,對於一當量環戊二烯較佳為1.5-5當量,尤其是2-3當量的CCl3
Br或CCl4
。
對於反應步驟b)較佳的鹼為鹼金屬醇化物,例如第三丁醇鈉和第三丁醇鉀,或為金屬醯胺,如NaNH2
或二異丙胺鋰。
除了酮類和酯類,所有惰性溶劑都可使用。對於反應步驟b)適當的溶劑係選自於甲基-第三丁基醚(MTBE)、甲基環己烷(MCH)或其混合物、四氫呋喃(THF)、二甘二甲醚及甲苯。
對於反應步驟b)進一步適當的溶劑為氯苯。
反應步驟b)有利地係於-20至+20℃的溫度範圍,較佳從-10℃至10℃,最佳從-5℃至5℃的溫度下進行。
在本發明之一較佳具體實例中,式III化合物(其溶液)係未經分離即直接用於下一反應步驟中。式III化合物對於式I化合物之製備唯有價值的中間物。式III化合物係得知於(a)Moberg,C.;Nilsson,M.J. Organomet. Chem . 1973
,49
,243-248.(b)Siemionko,R. K.;Berson,J. A.J. Am. Chem. Soc . 1980
,102
,3870-3882。然而,該參考文獻中所述的製備方法非常不利,因為:1)該方法無法如所述者再現(獲得低產率)。2)使用非常昂貴的發火且有毒的起始物質(二茂鎳)。3)產生大量的金屬廢棄物(含鎳化合物)。4)該方法無法被放大供工業使用(二茂鎳無法以大量取得,大量二茂鎳的危險處理)。
相對於此,從環戊二烯開始製備式III化合物的方法是新穎且非常有效率的方法,因此構成本發明之進一步目的。
因此,本發明之進一步目的是用於製備式III化合物之方法,
該方法包括:
a)使環戊二烯在自由基引發劑存在下與CXCl3
(其中X為氯或溴,較佳為溴)反應,形成式II化合物:
其中X為氯或溴,及b)使式II化合物與鹼在適當溶劑存在下反應。
1,2-去氫-6-硝基苯係當場產生(例如,從式(A)之6-硝基鄰胺苯甲酸開始:
如L.Paquette等人,J
.Amer
.Chem
.Soc
.99
,3734(1977)
與H. Seidel,Chemische Berichte,34,4351(1901)
所述者。)
反應步驟c)係於升高溫度下進行,較佳係在從30℃至60℃,最佳從30至40℃的溫度下進行。
對於氫化反應較佳的金屬催化劑係選自於下列所組成的群組:雷氏(Raney)鎳,鉑,較佳為在載體如碳上之鉑,鈀,較佳為在載體如碳上之鈀,但並不限於該群組。尤佳的催化劑為雷氏鎳。適合的氫源為氫或聯胺,較佳為氫。
反應步驟d)係於低溫至升高溫度下進行,較佳係在從0至80℃,較佳從30至60℃的溫度下進行。
根據本發明之方法的一個較佳變體包括:
aa)使環戊二烯與CXCl3
(其中X為氯)在金屬催化劑存在下反應,其中該催化劑之金屬成分係選自於釕、銅、鐵、鈀及銠,形成式II化合物:
其中X為氯,
b)使式II化合物與選自於鹼金屬醇鹽之鹼在適當溶劑存在下反應,形成式III化合物:
c)並且使式III化合物在1,2-去氫-6-硝基苯存在下轉化成式IV化合物:
以及
d)在金屬催化劑存在下以氫源氫化式IV化合物。
將偶氮二異丁腈(2.5克)溶解於一溴三氯甲烷(250克)中。在惰性氣氛(氮氣)下,將一溴三氯甲烷(650克)裝入玻璃反應器中,並加熱至85℃。將1/3的偶氮二異丁腈溶液(84克)立即加入反應器中,並將反應器內容物再加熱至85℃,接著在2.5小時期間於85℃下,同時添加剩下的2/3的偶氮二異丁腈溶液(168.5克)及環戊二烯(100克,剛蒸餾的)與甲基環己烷(10克)之混合物。將反應混合物於85℃攪拌另1小時,然後冷卻到周圍溫度。在真空(60→70℃,150→50毫巴)中蒸發大量的溶劑(一溴三氯甲烷)。將甲基環己烷(50克)加到蒸餾殘餘物中,並繼續蒸餾(60→70℃,150→15毫巴)。將粗產物(蒸餾殘餘物)在真空中乾燥另30分鐘(70℃,15毫巴)。產出389克呈棕色油形式的式IIa化合物,94%純,92%產率,區域異構物(regioisomer)的混合物。
在惰性氣氛(氮氣)下,將玻璃反應器裝填溴(三氯甲基)環戊烯(27.83克,化合物IIa)、甲基環己烷(62毫升)、甲基第三丁基醚(62毫升)及雙(2-甲氧基乙基)醚(二甘二甲醚,6.7克)。將混合物在冰/NaCl浴中冷卻到-10℃。在10分鐘期間,將第三丁醇鈉(20.3克)以固體加入反應器中,同時保持溫度低於+5℃。當添加完成時,將反應混合物於0-5℃攪拌2小時。將反應混合物用冰冷水(80毫升)與冰塊(40克)的混合物淬滅,然後將水相的pH值用32% HCl(大約3毫升)調整到。將水相分離,並將有機相於0℃下經無水碳酸鉀脫水。將碳酸鉀濾除並以甲基第三丁基醚(10毫升)沖洗。將甲基乙基酮(10克)加到合併的濾液中作為內標準品,然後藉由1
H NMR光譜術測定6,6-二氯富烯(fulvene)(式III化合物)的濃度。產率81%(9.7克9.9%(大約0.53M)溶液)。將該溶液貯存在冷藏室中,之後用於下一步驟。
將先前步驟獲得之6,6-二氯富烯之冷卻溶液(9%於甲基第三丁基醚/甲基環己烷=1:1中)置於玻璃反應器中,並快速加熱到35℃。將亞硝酸第三戊酯(2.66克)加入反應器中,接著在80分鐘期間,於35℃溫度下,同時添加亞硝酸第三戊酯(9.46克)及6-硝基鄰胺苯甲酸(11.6克,96.6%)於甲基乙基酮(42毫升)中之溶液。將反應混合物於相同溫度下攪拌另30分鐘,然後藉由旋轉蒸發除去所有的揮發物。將剩下的殘餘物在+5℃從甲醇(20毫升)結晶15小時。將棕色的結晶物質過濾,用冷甲醇(15毫升)洗滌及在空氣中乾燥。產率7.10克(42%,98%純的產物)。
將熱壓器裝填THF(130毫升)、濕雷氏鎳(2克)及式IV化合物(20克)。將該熱壓器封閉,使內容物開始攪動,用氮氣沖洗三次以除去氧,然後用氫氣沖洗三次。將反應器用氫氣加壓至5巴。然後將熱壓器的內容物加熱至40℃,需要時,以額外的氫氣維持壓力。當氫吸收停止,通常在3-4小時之後,將反應團塊保持在40℃另30分鐘。在這段時間之後,釋放壓力,並將內容物冷卻到周圍溫度。在真空下除去溶劑,所得油狀物在靜置下結晶,產出18克淡黃至淡棕色之式I化合物(96%,94%純的產物)。
將環戊二烯(2.0克)、偶氮二異丁腈(0.5克)、亞苄基-雙(三環己基膦)二氯釕(Grubbs第一代催化劑,12.2毫克,0.05莫耳%)與四氯化碳(14克)之混合物在惰性氣氛(氬氣)下於75℃加熱。轉化反應係以GC監測。在4小時之後,反應完全,以85%產率(GC,使用十二烷作為標準品)產生為三種異構物混合物的氯(三氯甲基)環戊烯。
將氯化銅(I)(0.99克)、四甲基伸乙二胺(TMEDA,2.32克)與乙腈(100毫升)之混合物在氮氣氛圍下於75°C加熱25分鐘,然後冷卻到室溫。
將剛製備的環戊二烯(66.0克)溶解於四氯化碳(307克)中。
在氮氣氛圍下,將乙腈(80克)與40%的催化劑溶液置於在氮氣下的玻璃反應器中。將混合物加熱到75℃的溫度。然後將40%的環戊二烯溶液以一份加入該反應器中,接著同時添加其餘的催化劑溶液及環戊二烯溶液,同時保持溫度在60與70℃之間。環戊二烯溶液在1小時內添加而催化劑溶液在1.5小時內添加。將反應混合物於70℃攪拌另1小時,冷卻到周圍溫度及過濾。將溶劑藉旋轉蒸發除去,並將殘餘物藉真空蒸餾(40-45℃,0.1毫巴)予以分餾。產率170克(75%,97-98%純度),三種區域異構物的混合物。
將第三丁醇鈉(69.2克)與氯苯(175毫升)一起在室溫下攪拌30分鐘,以產生微細懸浮液。
在惰性氣氛(氮氣)下,將玻璃反應器裝填氯(三氯甲基)環戊烯(69.1克)、氯苯(275毫升)及雙(2-甲氧基乙基)醚(二甘二甲醚,21.1克)。將混合物冷卻到-20°C,並於35分鐘期間將第三丁醇鈉的懸浮液逐份加入該反應器中,同時保持溫度低於+3°C。當添加完成時,將反應混合物於-5°C攪拌3小時。將反應混合物用0.5M HCl水溶液(300毫升)與冰塊(200克)的混合物淬滅。將水相的pH值控制在。將水相分離並將有機相用相同的水與冰塊混合物萃取二次(這對於完全除去第三丁醇和二甘二甲醚是必要的)。6,6-二氯富烯的濃度係藉由1
H NMR光譜術使用氯苯(溶劑)作為內標準品來測定。產率75%(510克6.8%(大約0.52M)溶液)。將溶液貯存在冷藏室或乾冰中,之後用於下一步驟。
註:剛在淬滅之後(無進一步萃取)的產率為85%。該溶液在相分離之後損失。
可有利地利用根據本發明之方法製備的較佳苯并降莰烯殺真菌劑為式V之3-二氟甲基-1-甲基-1H-吡唑-4-羧酸(9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基)-醯胺:
式V化合物係敘述於例如WO 2007/048556中。式V化合物可以二種對映異構形式出現。式Va化合物:
其化學命名為3-二氟甲基-1-甲基-1H-吡唑-4-羧酸((1S,4R)-9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基)-醯胺,以及式Vb化合物:
其化學命名為3-二氟甲基-1-甲基-1H-吡唑-4-羧酸((1R,4S)-9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基)-醯胺。旋光角度[α]23.5
分別為-119.26°和+119.23°(在四氫呋喃中)。
Claims (7)
- 一種用於製備式I之9-二氯亞甲基-1,2,3,4-四氫-1,4-橋亞甲基-萘-5-基胺的方法,
- 根據申請專利範圍第1項之方法,該方法包括:a)使環戊二烯與CXCl3 (其中X為氯或溴)在自由基引發劑存在下反應,形成式II化合物:
- 根據申請專利範圍第1項之方法,其中aa)環戊二烯係與CCl4 在金屬催化劑存在下反應,形成式II化合物:
- 根據申請專利範圍第1項之方法,該方法包括:aa)使環戊二烯與CXCl3 (其中X為氯)在金屬催化劑存在下反應,其中該催化劑之金屬成分係選自於釕、銅、鐵、鈀及銠,形成式II化合物:
- 一種式IV化合物,
- 一種用於製備式III化合物之方法,
- 根據申請專利範圍第6項之方法,其中X為溴。
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