CN117209457A - 一种α-手性脒化合物的合成 - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
本文公开了一种制备α‑手性脒的方法。通过现场制备手性烯丙基胺和烯基亚胺的方式,利用不对称N‑杂克莱森重排方法成功构建α‑手性脒。反应有以下优点:(1)反应条件十分温和,室温反应,并且不需要当量的强碱,更加环保。(2)一锅两步法,可以除去制作手性底物的中间处理步骤,节省人力物力,减少消耗。(3)能够同时构手性中心和脒官能团,具有原子经济性和步骤经济性。(4)反应的收率高,能以两步总收率94%获得模板产物。烯丙基胺的手性也能够立体专一性的转移到脒中,模板产物具有95%的ee值。(5)底物普适性和官能团容忍良好,如氰基、叔丁基、酯基、甲氧基、硝基、三氟甲基均能发生反应,邻位取代和二取代都有活性,杂芳环化合物也能获得目标产物。
Description
技术领域
本发明涉及医药、有机化工合成技术领域,具体涉及到一种α-手性脒化合物的合成方法。
背景技术
脒是一类重要的含氮化合物,在各个领域都有非常广泛的应用。长期以来,合成脒类化合物的方法已经得到很好的发展,所使用的原料种类繁多,方法也不尽相同。2005年以来,利用铜催化炔烃与叠氮化物环加成是制备脒化合物的重要方法,能够温和高效合成各种取代的脒( I. Bae, H. Han, and S. Chang.J. Am. Chem. Soc.2005,127, 2038-2039)。目前构建脒化合物大多是消旋的(Ref.(a)K. D. Veeranna, K. K. Das, and S.Baskaran. (b)H. D. Xu, Z. H. Jia, K. Xu, M. Han, S. N. Jiang, J. Cao, J. C.Wang, and M.H. Shen.Angew. Chem. Int. Ed.2014, 53, 9284–9288.(c)C. G. Wang,R. Wu, T. P. Li, T. Jia, Y. Li, D. M. Fang, X. Z. Chen, Y. J. Gao, Hai-LiangNi, P. Hu, B. Q. Wang, andP. Cao.Org. Lett.2020,22, 3234−3238.(d)Y. Huang, W.Y. Yi, Q. H. Sun, F. P. Yi.Adv. Synth. Catal.,2018,360, 3074-3082.),构建手性脒的方法非常少,Cu催化的端炔-叠氮化物环加成(CuAAC)/N-杂克莱森重排串联反应能够快速高效构建α-手性高烯丙基脒化合物,但是不对称合成方法仍未报道。尽管α-手性脒化合物可以通过不对称取代反应实现(T. Kochi and J. A. Ellman.J. Am. Chem. Soc.2004,126, 15652-15653),但是这样需要分步构建官能团和手性中心,并且因为会用到当量的强碱,既不环保也不高效,本发明提供了一种较为简便、高效的合成α-手性脒的方法。通过现场制备手性烯丙基胺和烯基亚胺的方式,利用不对称N-杂克莱森重排方法一步构建α-手性中心和脒官能团,具有更好的步骤济性。
发明内容
本发明的目的在于提供一种合成α-手性脒的方法。通过现场制备手性烯丙基胺和烯基亚胺的方式,利用不对称N-杂克莱森重排方法一步构建α-手性中心和脒官能团。
本发明是采用以下具体方案实现的:通过一锅两步的手段,使用烯丙基碳酸酯,仲胺,铱催化剂先行反应生成手性的三级烯丙基胺,之后再通过Cu催化的端炔-叠氮化物环加成(CuAAC)反应产生烯基亚胺,烯基亚胺再被烯丙基胺捕获后发生不对称两性离子N-杂克莱森重排生成相应的α-手性脒。反应过程如下反应式(I)所示:
反应式I
其中R1为C1-C10的烷基、末端带有官能团的烷基、苯基、芳基或者杂环基。R2为C1-C10的烷基、末端带有官能团的烷基、苯基、芳基、杂环基。R3为烷基、末端带有官能团的烷基。R4为烷基、末端带有官能团的烷基。其中末端带有官能团的烷基选自碳碳双键,碳碳三键,烃氧基、硅醚基、酯基、酰基、酰氧基、酰胺基、磺酸基、卤素、磺酰基、氰基、硝基、烃基取代的氨基、酰基取代的氨基;所述芳基是邻、间、对位具有吸电子或给电子取代基的苯基,所述杂环是噻吩、呋喃、吡啶或者具有给电子或吸电子取代基的噻吩、呋喃或者吡啶。所述吸电子取代基包括卤素、硝基、酯基、酰基、酰胺基、磺酸基、氰基,所述给电子取代基包括、烷基、烯基、炔基、苯基、烃氧基、氨基酰氧基、烃基取代的氨基、酰基取代的氨基。
优选地,R1为苯基、芳基或者杂环基。R2为C1-C10的烷基、末端带有官能团的烷基、苯基、芳基、杂环基。R3为烷基、末端带有官能团的烷基。R4为烷基、末端带有官能团的烷基。其中末端带有官能团的烷基选自碳碳双键,碳碳三键,烃氧基、硅醚基、酯基、酰基、酰氧基、酰胺基、磺酸基、卤素、磺酰基、氰基、硝基、烃基取代的氨基、酰基取代的氨基;所述芳基是邻、间、对位具有吸电子或给电子取代基的苯基,所述杂环是噻吩、呋喃、吡啶或者具有给电子或吸电子取代基的噻吩、呋喃或者吡啶。所述吸电子取代基包括卤素、硝基、酯基、酰基、酰胺基、磺酸基、氰基,所述给电子取代基包括、烷基、烯基、炔基、苯基、烃氧基、氨基酰氧基、烃基取代的氨基、酰基取代的氨基。
进一步优选地,R1为苯基或具有给电子基团的芳基。R2为C1-C10的烷基、末端带有官能团的烷基、苯基、芳基、杂环基。R3R4NH选自四氢吡咯、六氢吡啶、哌嗪、4-甲基哌啶。
本发明的具体操作如下:
在手套箱中,向干燥的反应管中称取铱催化剂,配体和溶剂A,再依次加入1和2,室温搅拌反应至原料完全消耗后,在手套箱中再加入铜催化剂和溶剂B。然后再依次加入TsN3(对甲苯磺酰叠氮)和3,并室温反应至烯丙基胺消耗完全, 处理纯化后得到脒4。反应方程式如反应式II所示:
反应式II
所述的铱催化剂为[Ir(COD)Cl]2。[Ir(COD)Cl]2与1的摩
尔比为0.01:1。所述的配体为,配体L与1的摩尔比为0.02:1。
所述的溶剂A为0.5 mL四氢呋喃,溶剂B为0.5 mL乙腈。
所述的铜催化剂与1的摩尔比为0.1:1。
所述的铜催化剂选自六氟磷酸(四乙腈)亚铜、四氟硼酸(四乙腈)亚铜、醋酸亚铜、三氟甲磺酸亚铜甲苯联合体、氯化亚铜、溴化亚铜、碘化亚铜、噻吩-2-甲酸亚铜其中的一种。优选地,为醋酸亚铜。
作为进一步改进,1与2与对甲苯酰叠氮及3的摩尔比为1:1.1:1.5:1.5。
附图说明
图1,2是实施例1所得产物液相谱图;图13,14是实施例1所得产物核磁氢谱和碳谱谱图;
图3,4是实施例2所得产物液相谱图;图15,16是实施例2所得产物核磁氢谱和碳谱谱图;
图5,6是实施例3所得产物液相谱图;图17,18是实施例3所得产物核磁氢谱和碳谱谱图;
图7,8是实施例4所得产物液相谱图;图19,20是实施例4所得产物核磁氢谱和碳谱谱图;
图9,10,是实施例5所得产物液相谱图;图21,22,23是实施例5所得产物核磁氢谱和碳谱及氟谱谱图;
图11,12是实施例6所得产物液相谱图;图24,25是实施例6所得产物核磁氢谱和碳谱谱图;
具体实施方式
下面结合具体实施例对本发明作进一步详细地描述,但本发明的实施方式不限于此。
在手套箱中,向干燥的反应管中称取铱催化剂[Ir(COD)Cl]2(1.3mg, 1 mol%),配体(R,R,R)-L(2.2mg, 2 mol%)和THF (0.5 mL),再依次加入烯丙基碳酸酯1a(0.2 mmol)和仲胺2a(0.22 mmol),室温搅拌反应至原料完全消耗后(大约10 h),在手套箱中再加入CuOAc (2.5 mg, 10 mol%)和MeCN (0.5 mL)。然后再依次加入TsN3(0.3 mmol)和端炔3(0.3 mmol),并反应24 h, TLC监测反应,当烯丙基胺反应完全后,过硅藻土抽滤除去金属,旋蒸除去溶剂后,利用柱层析法获得脒。
实施例1
端炔3为苯乙炔,通过柱层析分离纯化,得到目标产物4a,所用的柱层析洗脱液为体积比(先100 mL5:1的石油醚:乙酸乙酯混合溶剂,再3:1的石油醚:乙酸乙酯混合溶剂)溶剂,产率94%, 95%ee。实施例1所得产物的结构表征数据如下(液相谱图如图1和图2所示)(核磁谱图如图13(氢-谱图)和图14(碳-谱图)所示):
the amidine4awas isolated (eluent solvent,EtOAc/ petroleum=1/5→1/3)as the yellow solid (86.4 mg, 0.188 mmol, 94% yield), m.p. 80oC .
1H NMR(600 MHz, CDCl3) δ 7.89 (d,J= 8.1 Hz, 2H), 7.32 – 7.27 (m, 8H),7.26 – 7.19 (m, 4H), 6.43 (d,J= 15.8 Hz, 1H), 6.34 – 6.26 (m, 1H), 5.31 (s,1H), 3.75-3.60 (m, 2H), 3.29 – 3.27(m, 1H), 3.05 – 2.93 (m, 2H), 2.92 – 2.84(m, 1H), 2.38 (s, 3H), 1.81 – 1.60 (m, 4H).
13C NMR(151 MHz, CDCl3) δ 165.7, 142.1, 141.7, 137.6, 137.3,132.1,129.2, 128.9, 128.5, 127.5, 127.3, 127.2, 126.3, 126.3, 50.9, 48.3, 47.8,33.6, 26.1, 23.6, 21.5.
HRMS (ESI)m/z: C28H30N2O2S [M+H]+Calcd. For 459.2101; found: 459.2130.HPLC analysis: (Daicel Chiralcel AD-H, eluent,60/40 hexane/i-propanol , 1.0mL/min, 25oC, 254 nm, tmajor: 35.4 min and tminor: 24.7 min).ee= 95%. [α]D 20= +94.0 (c =0.2, CHCl3).
根据以上数据确定化合物的结构如下
实施例2
端炔3为2-噻吩乙炔,通过柱层析分离纯化,得到目标产物4b,所用的柱层析洗脱液为二氯甲烷,产率98%, 96%ee。实施例2所得产物的结构表征数据如下(液相谱图如图3和图4所示)(核磁谱图如图15(氢-谱图)和图16(碳-谱图)所示):
the amidine4bwas isolated (DCM as the eluent solvent) as the redsolid (91 mg, 0.196 mmol, 98% yield), m.p. 153.4oC
1H NMR(600 MHz, CDCl3) δ 7.85 (d,J= 8.2 Hz, 2H), 7.35 – 7.13 (m, 9H),6.93 – 6.87 (m, 2H), 6.45 (d,J= 15.8 Hz, 1H), 6.29 – 6.20 (m, 1H), 5.48 (br,1H), 3.68 – 3.55 (m, 2H),3.39 – 3.29 (m, 1H), 3.18 – 3.09 (m, 1H), 3.04 –2.94 (m, 1H), 2.94 – 2.87 (m, 1H), 2.33 (s, 3H), 1.81 – 1.60 (m, 4H).
13C NMR(151 MHz, CDCl3) δ 164.7, 141.9, 141.8, 140.7, 137.1,132.7,129.2, 128.5, 127.4, 127.0, 126.4, 126.3, 126.3, 125.3, 124.7, 50.9, 48.3,44.1, 35.3, 26.2, 23.4, 21.5.
HRMS (ESI) m/z: C26H28N2O2S2[M+H]+Calcd. For 465.1665; found: 465.1673.HPLC analysis: (Daicel Chiralcel AD-H, 60/40 hexane/i-propanol, 0.7 mL/min,25oC, 254 nm, tmajor:87.0 min and tminor:56.0 min).ee= 96%. [α]D 20= -96.5 (c =0.8, CHCl3).
根据以上数据确定化合物的结构如下
实施例3
端炔3为丙炔酸乙酯,通过柱层析分离纯化,得到目标产物4c,所用的柱层析洗脱液为体积比(先100 mL5:1的石油醚:乙酸乙酯混合溶剂,再3:1的石油醚:乙酸乙酯混合溶剂)溶剂,产率87%, 89%ee。实施例2所得产物的结构表征数据如下(液相谱图如图5和图6所示)(核磁谱图如图17(氢-谱图)和图18(碳-谱图)所示):
the amidine4cwas isolated (1:3 EtOAc/ petroleum ether as the eluentsolvent) as the colorless oil (79 mg, 0.175 mmol, 87% yield, 89%ee).
1H NMR(600 MHz, CDCl3) δ 7.84 – 7.79(m, 2H), 7.31 – 7.26 (m, 4H), 7.22– 7.18 (m, 3H), 6.45 (d,J= 15.8 Hz, 1H), 6.26 – 6.20 (m, 1H), 4.90 (s, 1H),4.22 – 4.16 (m, 2H), 3.65 – 3.59 (m, 1H), 3.56 – 3.49 (m, 2H), 3.34 – 3.28(m, 1H), 3.10 – 3.03(m, 1H), 2.88 – 2.79 (m, 1H), 2.37 (s, 3H), 1.94 – 1.78(m, 4H), 1.23 (t,J= 7.1 Hz, 3H).
13C NMR(151 MHz, CDCl3) δ 169.1, 161.2, 141.8, 141.6, 137.1,133.1,129.1, 128.6, 127.5, 126.4, 126.3, 125.7, 61.9, 50.0, 48.2, 48.1, 32.0, 26.2,23.7, 21.5, 14.2.
HRMS (ESI) m/z: C25H30N2O4S [M+H]+Calcd. For 455.1999; found: 455.2022.HPLC analysis: (Daicel Chiralcel AD-H, 70/30 hexane/i-propanol, 0.8 mL/min,25oC, 254 nm, tmajor:27.7 min and tminor:22.1min).ee =89%. [α]D 20= +67.4 (c = 0.1,CHCl3).
根据以上数据确定化合物的结构如下
实施例4
烯丙基碳酸酯1为4-甲氧基肉桂醇碳酸甲酯,通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比(先100 mL 5:1的石油醚:乙酸乙酯混合溶剂,再3:1的石油醚:乙酸乙酯混合溶剂)溶剂,产率87%, 89%ee。实施例2所得产物的结构表征数据如下(液相谱图如图7和图8所示)(核磁谱图如图19(氢-谱图)和图20(碳-谱图)所示):
the amidine4dwas isolated (1:3 EtOAc/ petroleum ether as the eluentsolvent) as the white solid (73.3 mg, 0.15 mmol, 75% yield), m.p. 170.0oC
1H NMR(600 MHz, CDCl3) δ 7.87 (d,J= 8.1 Hz, 2H), 7.31 (d,J= 4.4 Hz,4H), 7.25 – 7.20 (m, 5H), 6.82 (d,J= 8.6 Hz, 2H), 6.36 (d,J= 15.8 Hz, 1H),6.17 – 6.09 (m, 1H), 5.27 (br, 1H), 3.80 (s,3H), 3.74 – 3.60 (m, 1H), 3.30 –3.24 (m, 1H), 3.01 – 2.91 (m, 2H), 2.88 – 2.81 (m, 1H), 2.38 (s, 3H), 1.79 –1.62 (m, 4H).
13C NMR(151 MHz, CDCl3) δ 159.1, 142.2, 141.7, 137.7, 131.5,130.2,129.2, 128.9, 127.6, 127.5, 127.2, 126.4, 125.0, 114.0, 55.4, 50.9, 48.3,48.0, 33.7, 26.2, 23.6, 21.6.
HRMS (ESI) m/z: C29H33N2O3S [M+H]+Calcd. For 489.2206; found: 489.2235.HPLC analysis: (Daicel Chiralcel IA, 65/35 hexane/i-propanol, 0.7 mL/min,25oC, 254 nm, tmajor: 39.4 min and tminor:30.6 min). ee = 92% [α]D 20= +86.2 (c =0.3, CHCl3).
根据以上数据确定化合物的结构如下
实施例5
烯丙基碳酸酯1为3-氟肉桂醇碳酸甲酯,通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比(先100 mL5:1的石油醚:乙酸乙酯混合溶剂,再3:1的石油醚:乙酸乙酯混合溶剂)溶剂,产率87%,89%ee。实施例2所得产物的结构表征数据如下(液相谱图如图9和图10所示)(核磁谱图如图20(氢-谱图)和图21(碳-谱图)所示及图22(氟-谱图)所示):
the amidine4ewas isolated (1:3 EtOAc/ petroleum ether as the eluentsolvent) as the white solid (58.1 mg, 0.122 mmol, 61% yield),
1H NMR(600 MHz, CDCl3) δ 7.87 (d,J= 8.2 Hz, 2H), 7.34 – 7.29 (m, 4H),7.26 – 7.19 (m, 4H), 7.06 (d,J= 7.7 Hz, 1H), 7.00 – 6.96 (m, 1H), 6.89 (dt,J=8.4, 2.4 Hz, 1H), 6.37 (d,J= 15.9 Hz, 1H), 6.34 – 6.24 (m, 1H), 5.28 (s, 1H),3.74 – 3.59 (m, 2H), 3.29 – 3.22(m, 1H), 3.04 – 2.92 (m, 2H), 2.90 – 2.82 (m,1H), 2.37 (s, 3H), 1.81 – 1.60 (m, 4H).
13C NMR(151 MHz, CDCl3) δ 165.5, 163.1 (d,J= 244.62 Hz), 142.1, 141.7,139.6, 139.6, 137.4, 131.0, 131.0, 129.9, 129.9, 129.1, 128.9,128.6, 127.4,127.2, 126.3, 122.1, 122.1, 114.1, 113.9, 112.8, 112.7, 50.9, 48.2, 47.7,33.4, 26.1, 23.5, 21.4.
19F NMR(565 MHz, CDCl3) δ -113.65 –-113.70 (m).
HRMS (ESI) m/z: C28H29FN2O2S [M+H]+Calcd. For 477.2007; found:477.2045. HPLC analysis: (Daicel Chiralcel OD-H, 80/20 hexane/i-propanol, 0.7mL/min, 25oC, 254 nm, tmajor:28.7 min and tminor:25.4 min).ee =95%. [α]D 20= +87.2(c = 0.9, CHCl3).
根据以上数据确定化合物的结构如下
实施例6
仲胺2为哌啶,通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比(5:1的石油醚:乙酸乙酯混合溶剂),产率62%,96%ee。实施例2所得产物的结构表征数据如下(液相谱图如图11和图12所示)(核磁谱图如图24(氢-谱图)和图25(碳-谱图)所示):
the amidine4fwas isolated (1:5 EtOAc/ petroleum ether as the eluentsolvent) as the yellow oil (60 mg, 0.124 mmol, 62% yield) .m.p. 134.5oC
1H NMR(600 MHz, CDCl3) δ 7.84 (d,J= 8.2 Hz, 2H), 7.37 – 7.17 (m, 13H),6.47 (d,J= 15.9 Hz, 1H), 6.40 – 6.33 (m, 1H), 5.67 (br, 1H), 4.00 – 3.00 (m,5H), 2.86 – 2.76 (m, 1H), 2.36 (s, 3H), 1.59 – 1.15 (m, 5H).
13C NMR(151 MHz, CDCl3) δ 167.0, 141.8, 141.7, 138.2, 137.2,132.2,129.1, 128.9, 128.5, 127.3, 127.2, 126.9, 126.7, 126.3, 126.3, 48.3, 47.5,46.5, 33.7, 25.3, 23.9, 21.5.
HRMS (ESI) m/z: C29H32N2O2S [M+H]+Calcd. For 473.2257; found: 473.2269.HPLC analysis: (Daicel Chiralcel IB, 90/10 hexane/i-propanol, 0.8 mL/min,25oC, 254 nm, tmajor:34.3 min and tminor:31.7 min).ee= 96%. [α]D 20= +136.3 (c =0.1, CHCl3).
根据以上数据确定化合物的结构如下
Claims (4)
1.本发明提供了一种较为简便、高效的合成α-手性脒的方法。通过现场制备手性烯丙基胺和烯基亚胺的方式,利用不对称N-杂克莱森重排方法成功构建α-手性脒。通过一锅两步的手段,使用烯丙基碳酸酯,仲胺,铱催化剂先行反应生成手性的三级烯丙基胺,之后再通过Cu催化的端炔-叠氮化物环加成(CuAAC)反应产生烯基亚胺,烯基亚胺再被烯丙基胺捕获后发生不对称两性离子N-杂克莱森重排生成相应的α-手性脒。反应方程式如下(反应式1)所示:
反应式1
其中R1为烷基、带有官能团的烷基、苯基、芳基、杂环基。R2为烷基、带有官能团的烷基、苯基、芳基、杂环基。R3为烷基、带有官能团的烷基。R4为烷基、带有官能团的烷基。所述的芳基为邻位、对位或间位具有给电子或者吸电子的芳基。所述的杂环基为噻吩、呋喃、吡啶或具有给电子或吸电子取代基的噻吩、呋喃或者吡啶。
2.根据权利要求1所示的合成手性脒的方法,其主要特征在于其中R1为C1-C10的烷基、末端带有官能团的烷基、苯基、芳基或者杂环基。R2为C1-C10的烷基、末端带有官能团的烷基、苯基、芳基、杂环基。R3为烷基、末端带有官能团的烷基。R4为烷基、末端带有官能团的烷基。其中末端带有官能团的烷基选自碳碳双键,碳碳三键,烃氧基、硅醚基、酯基、酰基、酰氧基、酰胺基、磺酸基、卤素、磺酰基、氰基、硝基、烃基取代的氨基、酰基取代的氨基;所述芳基是邻间对为具有吸电子或给电子取代基的苯基,所述杂环是噻吩、呋喃、吡啶或者具有给电子或吸电子取代基的噻吩、呋喃或者吡啶。所述吸电子取代基包括卤素、硝基、酯基、酰基、酰胺基、磺酸基、氰基,所述给电子取代基包括、烷基、烯基、炔基、苯基、烃氧基、氨基酰氧基、烃基取代的氨基、酰基取代的氨基。
3.一种权利要求1所述的通式(I)其合成方法为:在手套箱中,向干燥的反应管中称取铱催化剂,配体和溶剂A,再依次加入1和2,搅拌反应至原料完全消耗后,在手套箱中再加入铜催化剂和溶剂B。然后再依次加入TsN3(对甲苯磺酰叠氮)和3,并反应至烯丙基胺消耗完全, 处理纯化后得到脒4。
所述的铱催化剂为[Ir(COD)Cl]2。[Ir(COD)Cl]2与1的摩尔比为0.01:1。所述的配体为,
配体L与1的摩尔比为0.02:1。
所述的溶剂A为0.5 mL四氢呋喃,溶剂B为0.5 mL乙腈。所述的铜催化剂与1的摩尔比为0.1:1。
4.一种权利要求1所示的合成手性脒的方法,其主要特征在于所述的铜催化剂为六氟磷酸(四乙腈)亚铜、四氟硼酸(四乙腈)亚铜、醋酸亚铜、三氟甲磺酸亚铜甲苯联合体、氯化亚铜、溴化亚铜、碘化亚铜、噻吩-2-甲酸亚铜其中的一种。
所述的处理纯化过程为硅藻土过滤、浓缩后以柱层析提纯(石油醚:乙酸乙酯体积比=5:1~1:1)。
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