TWI660939B - 製備苯基二氫茚化合物的製程 - Google Patents
製備苯基二氫茚化合物的製程 Download PDFInfo
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Abstract
本發明係關於製造5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)的製程,製程包含由異丙苯合成及在存有酸催化劑下二聚合2-甲基-1-(4-(丙-1-烯-2-基)苯基)丙-1-酮。
Description
本發明係關於製造固體與純形態之苯基二氫茚光起始劑(5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚,二聚物異構物5)的位向異構物的製程。
相較於使用單體光起始劑,光聚合使用寡聚光起始劑有數個優點,例如較低光起始劑遷移性及光分解衍生較少揮發性化合物。該等特性就工業用途而言很重要,因為此可降低污染成品的風險。
在已知寡聚光起始劑中,此領域最賞識式A之α-甲基苯乙烯寡聚物的α-羥羰基衍生物,其中n係等於或大於0的數值。
該等光起始劑描述於美國專利案第4,987,159號,且主要由二聚物和三聚物異構物的混合物構成。在室溫下,二聚物與三聚物異構物混合物係高黏性產物,此產物通常需預熱以便於處理。
因而開發出粉末形態的α-甲基苯乙烯寡聚物的α-羥羰基衍生物固體混合物,現為光聚合壓克力系統的常用光起始劑。
上述光起始劑組成和合成描述於EP 1389177。
EP 1389177的α-甲基苯乙烯寡聚物的α-羥羰基衍生物固體混合物含有約90%-98%的兩種二聚物異構物:5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)和6-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物6)。
二聚物異構物5係下式VII之化合物。
二聚物異構物6係下式VIII之化合物。
EP 1389177的製程藉由使α-甲基苯乙烯寡聚物的α-羥羰基衍生物高黏性混合物控制結晶而提供該等固體混合物,合成則描述於如美國專利案第4,987,159號。
兩種二聚物異構物均可有效做為光起始劑,但在光聚合中,二聚物異構物5比二聚物異構物6更具反應性,此亦描述於EP 1389177。
EP 1389177的控制結晶的優點在於提供富含二聚物異構物5的α-甲基苯乙烯寡聚物的α-羥羰基衍生物固體混合物。
製備二聚物異構物V與VI之結晶混合物的製程亦描述於EP 1620382。該製程使用1,1,3-三甲基-1-苯基二氫茚做為起始產物,且適於透過分離中間物而製備個別二聚物異構物V。
EP 1389177的製程和EP 1620382的製程皆藉由醯化α-甲基苯乙烯寡聚物或二聚物來製備α-甲基苯乙烯二聚物的α-羥羰基衍生物。由於醯化將在5-和6-位置進行,故一直會得到5-與6-二聚物混合物,製備富含或隔離形態的二聚物異構物5
暗指必須排出或分離使用較低反應性的二聚物異構物6。
因此,非常期望設計簡短、有效又無異構物6的二聚物異構物5合成方式,且亦得省去昂貴、不便的純化步驟,並提供固體與純形態的產物。
現已發現此目的可由包含由異丙苯合成及在存有酸催化劑下二聚合(環化)2-甲基-1-(4-(丙-1-烯-2-基)苯基)丙-1-酮的製程達成。
因此,本發明的主要目的為提供製備5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)的製程,包含下列步驟:
i.依據下圖,用式Ia之化合物醯化異丙苯,其中X0係Cl或Br,以得式IIa之化合物,及鹵化式IIa之化合物,以得式III之化合物,其中X1係Cl或Br;或者鹵化異丙苯,以得式IIb之化合物,及用式Ia之化合物醯化式IIb之化合物,以得式III之化合物;
ii.依據下圖,用鹼使式III之化合物脫鹵氫,以得式IV之化合物,用酸催化劑環化式IV之化合物,以得式V之化合物,
或用酸催化劑,將式III之化合物直接環化而得式V之化合物;
iii.鹵化式V之化合物,以得式VI之化合物;
iv.使式VI之化合物水解,以得式VII之化合物(二聚物異構物5)。
用式Ia之化合物醯化異丙苯係夫里得-夸夫特(Friedel Craft)醯化反應。特定基材(異丙苯)致使醯化反應極具位置選擇性,並且提供幾乎完全對位取代的異丙苯衍生物(H-NMR測定選擇性為約98%)。
故化合物III很容易以幾個極高選擇性的步驟由異丙苯獲得。
式Ia之化合物可為市售醯基鹵化物。式Ia之化合物較佳為異丁醯基氯化物。
在步驟i中,異丙苯和醯基鹵化物較佳係在無溶劑下或溶於有機溶劑中混合及反應。在醯化條件下呈惰性的任何溶劑皆可使用。可用溶劑實例為二氯甲烷、氯苯、氯化乙烯、1,2-二氯苯、硝基甲烷、四氯乙烷;較佳溶劑為二氯甲烷和氯苯。
每莫耳異丙苯使用1.50至1.10莫耳的醯基鹵化物,較佳為1.10至1.05。
步驟i的醯化反應通常係按每莫耳異丙苯加入1.5至0.1莫耳的路易士酸進行,例如AlCl3、FeCl3、TiCl4、BF3或SnCl4,較佳為AlCl3,且較佳係在-20℃至+20℃下,更佳為-10℃至10℃。反應後處理(work-up)如此領域習知為用水使反應混合物水解及分離可能溶於溶劑的所得產物。
取得定量產率。
鹵化式IIa之化合物係芐基鹵化反應,此可依美國專利案第2007/0161814號所述進行:利用太陽光燈或紫外光(UV)燈照射、或在存有催化量的過氧化二苯甲醯或2,2'-偶氮異丁醯腈(AIBN)下,使式IIa之化合物與N-溴琥珀醯亞胺反應,或在自由基條件(照射或存有催化量的過氧化二苯甲醯或AIBN)下,與氯、溴或硫醯氯或與叔丁基次氯酸鹽反應。鹵化可在和步驟i用於醯化一樣的鹵化溶劑(若有)或在另一相容溶劑中進行,例如二氯甲烷、氯苯、1,2-二氯苯或其他鹵化溶劑。
或者,如同上述芐基鹵化式IIa之化合物,在步驟i中,異丙苯係於芐基位置鹵化,以得式IIb之化合物。
隨後如上述用式Ia之化合物醯化式IIb之化合物,以得式III之化合物。
在步驟ii中,用鹼使式III之化合物脫鹵氫,較佳為用強鹼,例如備於醇的鹼金屬氫氧化物,更佳為用備於醇的NaOH或KOH,最佳為用備於乙醇的KOH,以得式IV之化合物。通常,每莫耳式III化合物使用2至1莫耳的鹼,反應期間的溫度則保持在40℃-100℃,較佳為60℃-80℃。
隨後用酸催化劑環化式IV之化合物,以得式V之化合物。酸催化劑可為無機或有機強酸或路易士酸。較佳酸催化劑為路易士酸、黏土、具磺基之酸性離子交換樹脂、C6-C18-芳基磺酸和三氟甲磺酸。最佳催化劑為路易士酸,特別係AlCl3和無機酸。反應可在40℃至140℃下,在溶劑中或無溶劑時進行。
或者,可在和所述化合物IV環化一樣的一般條件下,用酸催化劑,將式III之化合物直接環化而得式V之化合物。在此情況下,較佳催化劑為具磺基之酸性離子交換樹脂和無機酸。
在步驟iii中,如WO 2004/099111所述使用氯或如EP 161463所述使用溴或硫醯氯來烯醇鹵化式V之化合物,以得式VI之化合物。
在步驟iv中,使式VI之化合物水解。式VI之化合物可與鹼金屬醇氧化物反應,較佳為在甲醇
中與甲醇鈉反應,及用酸性水溶液水解,以得式VII之化合物(二聚物5),此例如描述於EP 0 161463(實例2,階段(D’)與階段(E’))和US 4,987,159(實例4);或者,可用鹼金屬氫氧化物使式VI之化合物直接水解,例如用NaOH 30重量%備於甲醇(此描述於WO 2004/099111(實例1.3))或用NaOH 30重量%備於水,以得式VII之化合物。
藉由從甲苯、異丙醇、乙酸乙酯或其他溶劑結晶,可獲得固體與純形態的式VII化合物,此例如描述於EP 1389177。
在氮中、在室溫下攪拌備於二氯甲烷(280克)的異丙苯(38.3克、0.315莫耳)與異丁醯基氯化物(36.0克、0.331莫耳)溶液。在室溫下,在90分鐘內將氯化鋁(46.0克、0.345莫耳)分批加至溶液。再攪拌1小時後,邊攪拌,邊把溶液倒入冰水中。用水洗滌有機相,在真空中蒸餾掉二氯甲烷,以得60.5克的澄清黃色產物。產率:定量。
H1NMR(CDCl3,δ ppm):1.20(d,6H)、1.26(d,6H)、2.95(m,1H)、3.53(m,1H)、7.30(d,2H)、7.89(d,2H)。
使1-(4-異丙基苯基)-2-甲基丙-1-酮(7.61克、0.04莫耳)溶於氯苯(56克),在室溫下攪拌,並利用氮去氧。接著在-10℃下冷卻溶液,及一次加入叔丁基次氯酸鹽(6.55克、0.06莫耳,依「Organic Syntheses,Coll.Vol.5,184(1973)」所述製備),以得黃色溶液。用300瓦的Osram Ultra Vitalux燈照射攪拌溶液,直到溶液褪色且溫度上升至38℃。冷卻至室溫後,在真空中蒸餾掉溶劑,以得13克的澄清油。產率:定量。
H1NMR(CDCl3,δ ppm):1.20(d,6H)、2.00(s,6H)、3.53(m,1H)、7.27(d,2H)、7.93(d,2H)。
在備於乙醇(10.8毫升、0.0054莫耳)的0.5M KOH溶液中攪拌1-(4-(2-氯丙-2-基)苯基)-2-甲基丙-1-酮樣品(1.05克、0.0047莫耳)。
在60℃下攪伴1小時後,看到KCl沉澱。用二氯甲烷(20毫升)稀釋混合物及用水洗滌。用硫酸鈉乾燥有機相,在真空中蒸餾掉溶劑,以得0.91克的澄清油。產率:96%。
H1NMR(CDCl3,δ ppm):1.21(d,6H)、2.17(s,3H)、3.53(m,1H)、5.20(s,1H)、5.47(s,1H)、7.54(d,2H)、7.92(d,2H)。
使2-甲基-1-(4-(丙-1-烯-2-基)苯基)丙-1-酮(0.90克、0.0048莫耳)溶於二氯甲烷(15克),在迴流下,在2小時內分兩次加入AlCl3(1.80克、0.0135莫耳)。再經1小時後,反應完成(TLC:SiO2、甲苯)。把混合物倒入冰水中,用硫酸鈉乾燥有機相及蒸餾掉溶劑,以得0.80克的高黏性油。產率:89%。
H1NMR(CDCl3,δ ppm):1.00(s,3H)、1.15(m,12H)、1.32(s,3H)、1.70(s,3H)、2.22(d,1H)、2.43(d,1H)、3.50(m,2H)、7.22(m,3H)、7.70(s,1H)、7.81(d,2H)、7.90(d,1H)。
將1.21克(0.009莫耳)硫醯氯慢慢加至0.80克(0.0042莫耳)備於10毫升甲苯的式V化合物中。在45℃下經過2小時後,用水洗滌混合物、中和及在真空中使溶劑蒸發,以得黏性油,油靜置後將凝固。產率:定量。
H1NMR(CDCl3,δ ppm):1.03(s,3H)、1.38(s,3H)、1.73(s,3H)、1.86(m,12H)、2.26(d,1H)、2.47(d,1H)、7.25(m,3H)、7.92(s,1H)、8.07(d,2H)、8.18(d,1H)。
使5-(2-氯-2-甲基-1-側氧-丙-1-基)-3-(4-(2-氯-2-甲基-1-側氧-丙-1-基)苯基)-2,3-二氫-1,1,3-三甲基-1H-茚(5.2克、0.011莫耳)溶於二氯甲烷(30克),及加入30%的NaOH水溶液(7.30克、0.055莫耳)。在存有
四丁基溴化銨(0.10克)下,迴流加熱混合物。經過8小時後,反應完成(TLC SiO2、甲苯:乙酸乙酯=8:2)。用水洗滌有機相並用硫酸鈉乾燥,使溶劑蒸發後可得4.5克、如同油般的化合物I,油靜置後將凝固。在甲苯中使樣品結晶而得白色粉末,熔點為117℃-118℃。
H1NMR(CDCl3,δ ppm):1.04(s,3H)、1.37(s,3H)、1.61(m,12H)、1.73(s,3H)、2.25(d,1H)、2.46(d,1H)、3.90-4.10(bs,2OH)、7.25(m,3H)、7.80(s,1H)、7.92(d,2H)、8.00(d,1H)。
Claims (10)
- 一種製備5-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基]-3-[4-(2-羥基-2-甲基)-1-側氧-丙-1-基-苯基]-2,3-二氫-1,1,3-三甲基-1H-茚(二聚物異構物5)的製程,該製程包含下列步驟:i.依據下圖,用一式Ia之化合物醯化異丙苯,其中X0係Cl或Br,以得一式IIa之化合物,並鹵化該式IIa之化合物,以得一式III之化合物,其中X1係Cl或Br;或者鹵化異丙苯,以得一式IIb之化合物,並用該式Ia之化合物醯化該式IIb之化合物,以得一式III之化合物;ii.依據下圖,用一鹼使該式III之化合物脫鹵氫,以得一式IV之化合物,並用一酸催化劑環化該式IV之化合物,以得一式V之化合物,或用一酸催化劑,將該式III之化合物直接環化而得一式V之化合物;iii.鹵化該式V之化合物,以得一式VI之化合物;iv.使該式VI之化合物水解,以得一式VII之化合物(二聚物異構物5)。
- 如請求項1所述之製備二聚物異構物5的製程,其中該式Ia之化合物係異丁醯基氯化物。
- 如請求項1所述之製備二聚物異構物5的製程,其中在步驟i中,就每莫耳異丙苯使用1.50至1.10莫耳的該式Ia之化合物和1.5至0.1莫耳的一路易士酸。
- 如請求項1所述之製備二聚物異構物5的製程,其中在步驟ii中,該鹼係一鹼金屬氫氧化物。
- 如請求項1所述之製備二聚物異構物5的製程,其中在步驟ii中,用於環化該化合物IV的該酸催化劑係一路易士酸或一無機酸。
- 如請求項1所述之製備二聚物異構物5的製程,其中在步驟iv中,使該式VI之化合物與一鹼金屬醇氧化物反應並與一酸性水溶液反應而水解。
- 如請求項6所述之製備二聚物異構物5的製程,其中該鹼金屬醇氧化物係甲醇鈉。
- 如請求項1所述之製備二聚物異構物5的製程,其中在步驟iv中,使該式VI之化合物與一鹼金屬氫氧化物反應而水解。
- 如請求項8所述之製備二聚物異構物5的製程,其中該鹼金屬氫氧化物係於甲醇或於水中之30重量%的NaOH。
- 如請求項1至9中任一項所述之製備二聚物異構物5的製程,其中在完成步驟iv後,藉由結晶獲得固體且無異構物6之該二聚物異構物5。
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