CN102875428B - 利用羧酸对环己基氮杂环丙烷开环的方法 - Google Patents
利用羧酸对环己基氮杂环丙烷开环的方法 Download PDFInfo
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Abstract
本发明公开了一种利用羧酸对环己基氮杂环丙烷开环的方法,是在极性非质子性溶剂体系中,以碱金属类无机碱为催化剂,使用一元羧酸作为亲核试剂,对甲苯磺酰基活化的环己烷氮杂环丙烷进行开环反应。本发明开环反应过程简单,条件温和,采用溶剂对环境友好,使用羧酸作为亲核试剂更符合绿色化学的原子经济性要求,且催化剂价格低廉,催化活性高。
Description
技术领域
本发明属于有机合成技术领域,涉及一种氮杂环丙烷类化合物的开环方法。
背景技术
氮杂环丙烷是一种用途广泛的有机合成中间体,其具有的环丙烷结构可以进行一系列亲核开环反应,用于合成β-取代的氨基化合物,进而合成许多具有生物活性及在医药化工行业极具应用前景的氨基醇、氨基酸、生物碱以及β-内酞胺等各种生物活性化合物,这一性质使得氮杂环丙烷受到研究者的广泛重视。
虽然已有若干研究者报道了氮杂环丙烷与各种亲核试剂进行的开环反应,但羧酸与氮杂环丙烷的开环反应令人意外地少见报道。探索廉价、高效的羧酸与氮杂环丙烷的开环反应方法对于有机合成工作者仍是一个相当大的挑战。
事实上,较强的有机酸,例如苯磺酸,可以直接与活性氮杂环丙烷发生反应。此类反应往往在极性溶剂中进行,产率通常很高。
为取得羧酸对氮杂环的开环产物,化学工作者通常采用相应的酸酐来进行反应(Fan R. H., Hou
X. L. Efficient ring-opening reaction of epoxides and aziridines promoted by
tributylphosphine in water[J]. J. Org. Chem. 2003, 68: 726–730.),当氮杂环上的取代基为脂肪链时,反应结果以酸酐进攻低位阻位点得到的产物居多,而氮杂环上的取代基为芳环时,产物的区域选择性不明显。
Cardillo小组(Cardillo G., Gentilucci L, Tolomelli A., et al. Formation
of Aziridine-2-amides through 5-Halo-6-methylperhydropyrimidin-4-ones. A Route
to Enantiopure l- and d-Threonine and allo-Threonine[J]. J. Org. Chem. 1998,
63(10): 3458–3462.)在严格无水的环境下,用嘧啶催化乙酸酐进攻特定底物氮杂环,产物的立体选择性和区域选择性都很高。缺点是这个方法仅针对个别氮杂环体系有较好的效果,并没有广泛的适用范围。
直接催化羧酸对氮杂环丙烷进行开环反应的方法由Yadav等人于2002年提出(Yadav J. S., Reddy B. V. S., Sadashiv K., et al.
Indium Triflate-Catalyzed Ring Opening of Aziridines with Carboxylic Acids[J].
Tetrahedron Letters, 2002, 43(11): 2099-2101.),他们采用In(OTf)3作催化剂,以二氯甲烷为溶剂,室温条件下反应,收率在85-92%之间,而且有较好的对应选择性。该反应反应时间短,条件温和,收率高,缺点在于催化剂In(OTf)3比较昂贵。
Compernolle小组曾报道过一种氮杂环丙烷的开环反应方法(Cho S. J., Jensen N. H., Kurome T. et
al. Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the
Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like
Action[J].J. Med. Chem., 2009, 52:1885-1902.),使用醋酸钾代替醋酸作为亲核试剂进行开环反应。为得到较高的立体选择性,他们采用了特定的高位阻氮杂环丙烷与醋酸钾在四氢呋喃中回流。该方法不需要催化剂就能取得高于90%的产率。但是,为了阻止副反应,醋酸钾的投入是较大过量的。
综上所述,氮杂环丙烷与羧酸的亲核开环反应已取得了一定成果,但围绕更廉价高效的催化剂,更简便的反应操作,更环保和更高原子经济性等方面进行研究仍有重要的理论意义和实际意义。
发明内容
本发明的目的是提供一种利用羧酸对环己基氮杂环丙烷开环的方法。
本发明利用羧酸对环己烷氮杂环丙烷开环的方法是:以甲苯磺酰基活化的环己烷氮杂环丙烷为起始原料,以碱金属类无机碱为催化剂,在极性非质子溶剂体系中,使用一元羧酸作为亲核试剂,对环己烷氮杂环丙烷进行开环反应。其具体反应式如下:
式中的通式RCOOH表示脂肪族或芳香族一元取代羧酸,其取代基R为H,或者脂肪族取代基甲基、乙基、乙烯基、乙炔基、丙基、正丁基,或者芳香族取代基苯基、氯苯基、邻甲苯基、间甲苯基、对甲苯基、邻硝基苯基、间硝基苯基、对硝基苯基、吡啶基。
用于促进上述反应进行的碱金属类无机碱催化剂包括碱金属氢氧化物或碱金属碳酸盐,比如LiOH、NaOH、KOH、CsOH、Na2CO3、K2CO3或Cs2CO3等。其中优选的碱金属类无机碱催化剂是NaOH、KOH或CsOH。
优选地,所述的极性非质子溶剂可以是二甲基亚砜或N-甲基吡咯烷酮,更优选地,所述极性非质子溶剂为二甲基亚砜。
进一步地,在本发明的开环方法中,反应原料环己基氮杂环丙烷与一元羧酸的用量摩尔比为1︰1~3,而碱金属类无机碱催化剂的摩尔数用量则是环己基氮杂环丙烷摩尔数的10~50%,极性非质子溶剂的用量以环己基氮杂环丙烷计为2.5~10mL/mmol。
一般地,本发明的开环反应是在25~65℃下进行的,优选的反应温度为25~45℃。
本发明是以甲苯磺酰基活化的环己烷氮杂环丙烷为起始原料的,甲苯磺酰基作为吸电子取代基,可以降低氮杂环上的电子云密度,使其容易被亲核试剂进攻。开环反应后产物上的甲苯磺酰基采用常规方法即可去除,并不是本发明描述的重点,故本发明对其并未予以说明。
本发明提供了一种以一元羧酸为亲核试剂,碱金属类无机碱为催化剂的环己烷氮杂环丙烷开环方法,该方法反应过程简单,反应条件温和,采用溶剂对环境友好。使用羧酸作为亲核试剂,较之采用酸酐更符合绿色化学的原子经济性要求。采用的催化剂价格低廉,催化活性高,与In(OTf)3比较,不仅价格大为降低,而且收率高达98%。
具体实施方式
实施例1
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,KOH4.5mg,乙酸14μL,二甲基亚砜1.0mL,加热至35℃搅拌反应12h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。将粗产品经硅胶层析柱纯化后,得到开环产物A,收率98%。
核磁共振波谱仪:Bruker AVANCE III 600MHz,溶剂CDCl3,内标TMS。1H NMR数据在600MHz条件下采集,化学位移单位ppm,其中CDCl3化学位移(δ)7.27,耦合常数单位Hz;13C NMR数据采集在150MHz完全去耦条件下,其中CDCl3化学位移(δ)77.0。以下实施例条件相同。
1H NMR
(600MHz, CDCl3): δ 1.14-1.30 (m,
4H), 1.57-1.64 (m, 2H), 1.76 (s, 3H), 1.88-1.92 (m, 1H), 2.02-2.04 (m, 1H),
2.37 (s, 3H), 3.10-3.16 (m, 1H), 4.54-4.58 (td, J=10.2, 4.2Hz, 1H), 5.36-5.37
(d, J=7.8Hz, 1H), 7.24-7.26 (d, J=8.4Hz, 2H), 7.71-7.72 (d, J=8.4Hz, 2H)ppm。
实施例2
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,KOH4.5mg,甲酸9μL,N-甲基吡咯烷酮1.5mL,加热至45℃搅拌反应4h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物B,收率64%。
1H NMR
(600MHz, CDCl3): δ 1.11-1.24 (m,
4H), 1.66-1.70 (m, 2H), 2.00-2.02 (m, 2H), 2.42 (s, 3H), 3.23-3.28 (m, 1H),
4.64-4.68 (td, J=10.2, 5.4Hz, 1H), 4.90 (m, 1H), 7.28-7.29 (d, J=8.4Hz, 2H),
7.53 (s, 1H), 7.73-7.74 (d, J=7.8Hz, 2H )ppm。
实施例3
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,NaOH4mg,苯甲酸36.6mg,二甲基亚砜1.2mL,加热至55℃搅拌反应2h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物C,收率98%。
1H NMR
(600MHz, CDCl3): δ 1.28-1.48 (m,
4H), 1.69-1.76 (m, 3H), 2.00-2.04 (m, 1H), 2.18 (s, 3H), 2.22-2.24 (m, 1H),
3.31-3.32 (m, 1H), 4.79-4.84 (td, J=10.2, 4.2 Hz, 1H), 5.04-5.05 (d, J=7.2,
1H), 6.90-6.92 (d, J=7.8, 2H), 7.35-7.38 (t, J=7.8 Hz, 2H), 7.53-7.58 (m, 3H),
7.75-7.76 (m, 2H)ppm。
实施例4
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,CsOH6mg,间硝基苯甲酸36.8mg,二甲基亚砜1.5mL,加热至45℃搅拌反应6h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物D,收率49%。
1H NMR
(600MHz, CDCl3): δ 1.29-1.39 (m,
3H), 1.51 (m, 1H), 1.70-1.75 (m, 2H), 2.04-2.07 (m, 2H), 2.17 (s, 3H),
3.34-3.40 (m, 1H),4.86-4.90 (td, J=10.8, 4.8Hz, 1H), 5.07-5.08 (d, J=7.8Hz,
1H), 6.97-6.99 (d, J=7.8Hz, 2H), 7.59-7.61 (m, 3H), 8.19-8.20 (m, 1H),
8.38-8.40 (m, 1H),8.56 (m, 1H)ppm;13C NMR
(150MHz, CDCl3): δ 21.3, 23.7,
24.2, 31.1, 33.5, 56.9, 75.8, 124.6, 126.6, 127.2, 129.4, 131.7, 135.5, 138.4,
142.8, 148.1, 164.4ppm;MS (ESI): Calcd
for C20H22N2O6S+Na 441.1096,found
441.1096。
实施例5
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,CsOH11.5mg,对硝基苯甲酸40.5mg,二甲基亚砜1.0mL,加热至45℃搅拌反应3h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物E,收率95%。
1H NMR
(600MHz, CDCl3): δ 1.27-1.37 (m,
3H), 1.45-1.52 (m, 1H), 1.68-1.78 (m, 2H), 2.03-2.09 (m, 2H), 2.23 (s, 3H),
3.37-3.42 (m, 1H), 4.82-4.86 (td, J=10.2, 4.8Hz, 1H), 5.05-5.06 (d, J=8.4Hz,
1H), 7.02-7.04 (d, J=7.8Hz, 2H), 7.61-7.62 (d, J=8.4Hz, 2H), 7.98-8.00 (m, 2H),
8.19-8.21 (m, 2H)ppm;13C NMR
(150MHz, CDCl3): δ 21.4, 23.7,
24.3, 31.1, 33.6, 56.9, 75.8, 123.2, 126.6, 129.5, 130.9, 135.2, 138.5, 142.9,
150.5, 164.7ppm;MS (ESI): Calcd
for C20H22N2O6S+Na 441.1096, found
441.1093。
实施例6
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,NaOH3.2mg,邻甲基苯甲酸38.2mg,二甲基亚砜1.2mL,加热至55℃搅拌反应1.5h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物F,收率94%。
1H NMR
(600MHz, CDCl3): δ 1.25-1.50 (m,
4H), 1.69-1.79 (m, 2H), 1.99-2.02 (m, 1H), 2.19 (s, 3H), 2.21 (m, 1H), 2.45 (s,
3H), 3.29-3.31(m, 1H), 4.79-4.83 (td, J=10.2, 4.2Hz, 1H), 5.08-5.10 (d,
J=7.2Hz, 1H), 6.89-6.92 (d, J=7.8Hz, 2H), 7.15-7.20 (m, 2H), 7.38-7.40 (m, 1H),
7.57-7.58 (d, J=7.2Hz, 2H), 7.64-7.66 (m, 1H)ppm;13C NMR
(150MHz, CDCl3): δ 21.4, 22.0,
23.8, 24.2, 31.3, 34.0, 57.3, 74.3, 125.5, 126.5, 128.8, 129.3, 131.0, 131.6,
132.2, 138.2, 140.6, 142.7, 167.6ppm;MS
(ESI): Calcd for C21H25NO4S+Na 410.1402, found
410.1403。
实施例7
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,K2CO311.1mg,邻硝基苯甲酸50.1mg,二甲基亚砜2.0mL,加热至25℃搅拌反应24h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物G,收率23%。
1H NMR
(600MHz, CDCl3): δ 1.30-1.37 (m,
3H), 1.47-1.53 (m, 1H), 1.70-1.72 (m, 1H), 1.77-1.79 (m, 1H), 2.04-2.09 (m,
2H), 2.23 (s, 3H), 3.38-3.40 (m, 1H), 4.82-4.86 (td, J=10.2, 4.2Hz, 1H),
4.90-5.92 (d, J=8.4Hz, 1H), 7.02-7.03 (d, J=7.8Hz, 2H), 7.60-7.62 (m, 2H),
7.79-7.80 (d, J=7.8Hz, 2H), 8.20-8.22 (m, 2H)ppm;13C NMR
(150MHz, CDCl3): δ 21.5, 23.4,
24.1, 30.2, 32.8, 56.3, 76.2, 123.6, 126.7, 127.4, 129.4, 130.2, 131.6, 132.9,
138.4, 142.8, 147.9, 165.2ppm;MS (ESI): Calcd
for C20H22N2O6S+Na 441.1096, found
441.1088。
实施例8
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,KOH4.5mg,对甲基苯甲酸32.6mg,二甲基亚砜1.0mL,加热至45℃搅拌反应2h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物H,收率98%。
1H NMR
(600MHz, CDCl3): δ 1.28-1.47 (m,
4H), 1.69-1.79 (m, 2H), 2.00-2.02 (m, 1H), 2.10 (s, 3H), 2.14 (m, 1H), 2.34 (s,
3H), 3.19-3.24 (m, 1H), 4.70-4.74 (td, J=10.2, 4.2Hz, 1H), 5.11-5.13 (d,
J=6.6Hz, 1H), 6.82-6.84 (d, J=8.4Hz, 2H), 7.06-7.08 (d, J=8.4Hz , 2H),
7.49-7.50 (m, 2H), 7.56-7.57 (d, J=8.4Hz, 2H)ppm;13C NMR
(150MHz, CDCl3): δ 21.3, 21.6,
23.8, 24.2, 31.3, 34.1, 57.3, 74.4, 126.6, 127.0, 128.8, 129.3, 129.8, 138.1,
142.6, 143.6, 166.9ppm;MS (ESI): Calcd
for C21H25NO4S+Na 410.1402, found 410.1402。
实施例9
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,KOH3.9mg,2-吡啶甲酸31.9mg,二甲基亚砜1.5mL,加热至45℃搅拌反应5h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物I,收率82%。
1H NMR
(600MHz, CDCl3): δ 1.26-1.42 (m,
4H), 1.56-1.57 (m, 1H), 1.71-1.76 (m, 2H), 2.05-2.07 (m, 1H), 2.19 (s, 3H),
3.38-3.44 (m, 1H), 4.89-4.93 (td, J=10.2, 4.8 Hz, 1H), 5.04-5.06 (d, J=7.2Hz,
1H), 6.93-6.94 (d, J=7.8Hz, 2H), 7.45-7.47 (m, 1H), 7.60-7.62 (d, J=7.8Hz, 2H),
7.75-7.78 (m, 1H), 7.88-7.90 (d, J=7.8Hz, 1H), 8.71-8.72 (m, 1H) ppm;13C NMR (150MHz, CDCl3): δ 21.4, 23.8, 24.2, 31.1, 34.0, 57.1, 75.6, 125.3, 126.7,
129.3, 136.7, 138.3, 142.5, 147.6, 149.8, 165.1ppm;MS (ESI): Calcd for C19H22N2O4S+Na
397.1198, found 397.1192。
实施例10
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,NaOH3.6mg,丙烯酸20μL,N-甲基吡咯烷酮2.0mL,加热至25℃搅拌反应24h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物J,收率59%。
1H NMR
(600MHz, CDCl3): δ 1.23-1.38 (m, 4H),
1.67-1.73 (m, 2H), 1.95-1.96 (m, 1H), 2.06-2.08 (m, 1H), 2.40 (s, 3H),
3.20-3.24 (m, 1H), 4.61-4.65 (td, 10.2, 4.2Hz, 1H), 5.00-5.02 (d, J=7.2Hz, 1H),
5.70-5.72 (m, 1H), 5.75-5.80 (m, 1H), 6.21-6.24 (dd, J=16.8, 1.2Hz, 1H),
7.24-7.27 (d, J=7.8 Hz, 2H), 7.69-7.71 (d, J=8.4 Hz, 2H) ppm。
实施例11
在试管中加入甲苯磺酰基活化的环己烷氮杂环丙烷50mg,Na2CO310.6mg,对氯苯甲酸31.2mg,二甲基亚砜2.0mL,加热至35℃搅拌反应12h。反应结束后,以5%K2CO3溶液除去余酸,二氯甲烷萃取三次。合并有机相,以饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压蒸干溶剂,得到粗产品。粗产品经硅胶层析柱纯化后,得到开环产物K,收率21%。
1H NMR
(600MHz, CDCl3): δ 1.27-1.37(m,
3H), 1.45-1.50 (m, 1H), 1.66-1.74 (m, 2H), 2.07-2.10 (m, 2H), 2.23 (s, 3H),
3.32-3.37 (m, 1H), 4.83-4.87 (td, J=10.2, 4.2Hz, 1H), 5.10-5.12 (d, J=7.8Hz,
1H), 7.00-7.02 (d, J=7.8Hz, 2H), 7.24-7.27 (m, 1H), 7.41-7.42 (m, 2H), 7.65-7.69
(m, 3H) ppm。
Claims (4)
1.一种利用羧酸对环己烷氮杂环丙烷开环的方法,是以甲苯磺酰基活化的环己烷氮杂环丙烷为起始原料,以NaOH或KOH为催化剂,在极性非质子溶剂体系中,使用一元羧酸作为亲核试剂,在25~45℃下对环己烷氮杂环丙烷进行开环反应,其中,所述环己基氮杂环丙烷与一元羧酸的用量摩尔比是1︰1~3,碱金属类无机碱催化剂的摩尔数用量是环己基氮杂环丙烷摩尔数的10~50%,所述极性非质子溶剂为二甲基亚砜或N-甲基吡咯烷酮。
2.根据权利要求1所述的开环方法,其特征是所述的一元羧酸是通式为RCOOH的脂肪族或芳香族取代羧酸,其中,所述的取代基R为:
H,或脂肪族取代基甲基、乙基、乙烯基、乙炔基、丙基、正丁基,或芳香族取代基苯基、氯苯基、邻甲苯基、间甲苯基、对甲苯基、邻硝基苯基、间硝基苯基、对硝基苯基、吡啶基。
3.根据权利要求1所述的开环方法,其特征是所述的极性非质子溶剂为二甲基亚砜。
4.根据权利要求1所述的开环方法,其特征是所述极性非质子溶剂的用量为2.5~10mL/mmol环己基氮杂环丙烷。
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