CN102603566B - 一种手性化合物的合成方法 - Google Patents
一种手性化合物的合成方法 Download PDFInfo
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- CN102603566B CN102603566B CN2012100432078A CN201210043207A CN102603566B CN 102603566 B CN102603566 B CN 102603566B CN 2012100432078 A CN2012100432078 A CN 2012100432078A CN 201210043207 A CN201210043207 A CN 201210043207A CN 102603566 B CN102603566 B CN 102603566B
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- bromine
- phenyl
- phenylacetonitrile
- ethylamino
- phenylethylamine
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- 150000001875 compounds Chemical class 0.000 title abstract description 7
- 238000000034 method Methods 0.000 title abstract description 5
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract 2
- -1 silicane nitrile Chemical class 0.000 claims description 9
- 238000010189 synthetic method Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 claims description 5
- 241000545067 Venus Species 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 abstract 2
- 238000013375 chromatographic separation Methods 0.000 abstract 1
- 229940076286 cupric acetate Drugs 0.000 abstract 1
- 239000003208 petroleum Substances 0.000 abstract 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 abstract 1
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- XUHFBOUSHUEAQZ-UHFFFAOYSA-N bromobenzyl cyanide Chemical group N#CC(Br)C1=CC=CC=C1 XUHFBOUSHUEAQZ-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical group C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AAPLIUHOKVUFCC-UHFFFAOYSA-N trimethylsilanol Chemical compound C[Si](C)(C)O AAPLIUHOKVUFCC-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
一种手性（S,R）-1-乙氨基苯基-（2-溴)苯基乙腈的合成方法，所述的合成用15mol%（R）α-苯乙胺乙酸铜做催化剂，2-溴苯甲醛1mmol，三甲基硅腈3mmol，用2mL无水甲醇做溶剂，室温搅拌反应3天后，柱层析分离，用石油醚/二氯甲烷=7/3洗脱，将收集的第三组分点自然挥发，得单晶(S,R)-1-乙氨基苯基-（2-溴)苯基乙腈。
Description
一、技术领域
本发明涉及一种手性化合物的合成方法，确切地说是一种含氮的腈类化合物的合成方法。
二、背景技术
1-乙氨基苯基-(2-溴)苯基乙腈是重要的医药中间体，可用来合成杂环类药物芳基吡嗪【1】,手性1-乙氨基苯基-(2-溴)苯基乙腈的合成方法已有许多文献报道。【2】
参考文献：
1. Novel Asymmetric Synthesis of Atropisomeric 6-Aryl Pyrazinones via an Unusual Chirality Transfer Process, Tulinsky, John; Cheney, B. Vernon; Mizsak, Stephen A.; Watt, William; Han, Fusan; Dolak, Lester A.; Judge, Thomas; Gammill, Ronald B. Journal of Organic Chemistry (1999), 64(1), 93-100.
2. Product subclass 3: sodium halides and sodium cyanide , Krapcho, A. Paul , From Science of
Synthesis (2006), Volume Date2005, 8b, 925-1010.
申请人在用配合物(R)-α-苯乙胺乙酸铜配合物不对称催化2-溴苯甲醛腈硅化反应过程中，得到了一种手性化合物(S, R)-1-乙氨基苯基-(2-溴)苯基乙腈。
三、发明内容
本发明旨在提供手性化合物(S, R) -1-乙氨基苯基-(2-溴)苯基乙腈。所要解决的技术问题是一步合成得到目标产物。
本合成方法包括合成和分离，所述的合成用15mol%（R-α-苯乙胺乙酸铜做催化剂，2-溴苯甲醛1mmol，三甲基硅腈3mmol，用2mL无水甲醇做溶剂，室温反应3天后，柱层析分离，用石油醚/二氯甲烷（7/3）洗脱，将收集的第3组分点自然挥发，得单晶(S, R)-1-乙氨基苯基-(2-溴)苯基乙腈。
合成反应如下：
本合成方法一步得到目标产物，工艺简单，操作方便。
其反应机理可推测如下：
2-溴苯甲醛与三甲基硅腈，在催化剂15mol%（R）-α-苯乙胺乙酸铜的作用下，首先生成产物S-(-)-(α-三甲基硅氧基）邻溴苯乙腈，产物又与催化剂作用，苯乙胺中的氢质子与三甲基硅醚形成三甲基硅醇脱去，然形成手性化合物(S, R)-1-乙氨基苯基-(2-溴)苯基乙腈。
四、附图说明
图1是的X-衍射分析图。
五、具体实施方式
在25mL两口瓶中,无水无氧条件下,加入2mL无水甲醇, 2-溴苯甲醛1mmol, 三甲基硅腈3mmol，催化剂（R）-α-苯乙胺乙酸铜0.667g（0.15mmol），将反应物在室温下搅拌3天,停止反应,柱层析分离，用石油醚/二氯甲烷（7/3）洗脱，将收集的第三组分点自然挥发，得单晶(S, R)-1-乙氨基苯基-(2-溴)苯基乙腈。产率25%；[a]5 D=-100.44o (c=0.0448 CH2Cl2): 1HNMR (300MHz, CDCl3, 27℃), δ (ppm) = 7.55～7.59(m, 2H), 7.33～7.47(m, 5H), 7.20～7.23 (m, 2H), 4.67(s, 1H), 4.18～4.22 (m, 1H), 1.50 (s, 1H), 1.43(d, J=6.3Hz, 1H), 13CNMR(100MHz, CDCl3, 27℃) 144.02, 136.55, 134.96 131.92, 130.57, 129.93, 129.48, 129.22, 128.66, 124.56, 120.26, 58.19, 53.74, 25.67. IR (KBr) : 3435, 3308, 3064, 3025, 2981, 2965, 2927, 2866, 2223, 1592, 1570, 1494, 1472, 1452, 1436, 1370, 1360, 1342 1310, 1291, 1275, 1210, 1189, 1114, 1085, 1059, 1050, 1027, 1003, 986, 967, 929, 836, 772, 751, 716, 705, 686, 633, 623, 592, 553, 463, 437; 元素分析结果：C：60.97%；H：4.80%；N：8.89%;实测值C：59.47%；H：4.69%；N：8.46%。
Claims (1)
1.一种手性（S,R）-1-乙氨基苯基-（2-溴)苯基乙腈的合成方法，包括合成和分离，其特征在于：所述的合成用15mol%（R）-α-苯乙胺乙酸铜做催化剂，2-溴苯甲醛1mmol，三甲基硅腈3mmol，用2mL无水甲醇做溶剂，室温搅拌反应3天后，柱层析分离，用石油醚/二氯甲烷=7/3洗脱，将收集的第三组分点自然挥发，得单晶(S,R)-1-乙氨基苯基-（2-溴)苯基乙腈。
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