CN103694157B - 一种制备手性α-氯代氮杂环丙烷的方法 - Google Patents
一种制备手性α-氯代氮杂环丙烷的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 150000002466 imines Chemical class 0.000 claims abstract description 24
- XJTUNBKAWATELL-UHFFFAOYSA-N dichloromethyl(trimethyl)silane Chemical compound C[Si](C)(C)C(Cl)Cl XJTUNBKAWATELL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- -1 nitrogen-containing compound Chemical class 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 4
- 150000001408 amides Chemical class 0.000 claims 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
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- 230000015572 biosynthetic process Effects 0.000 abstract description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
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- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- XPGZPOKAMBELJD-UHFFFAOYSA-N C=CC.N1C=CC=CC=C1 Chemical group C=CC.N1C=CC=CC=C1 XPGZPOKAMBELJD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
- C07D203/24—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/02—Preparation by ring-closure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及一种制备手性α-氯代氮杂环丙烷的方法,在有机溶剂中,手性(Rs)-N-(叔丁基亚磺酰)亚胺、三甲基(二氯甲基)硅烷以及碱在-80℃~30℃温度下,反应0.5~10个小时,得到手性α-氯代氮杂环丙烷。与现有技术相比,本发明制备的手性α-氯代氮杂环丙烷,为一种潜在的生物活性分子合成砌块,可以作为重要的中间体用来合成手性的含氮化合物,比如氮杂环丙烷。本发明的制备手性α-氯代氮杂环丙烷的方法,制备用到的原料经济易得,制备的工艺条件温和、方法高效且制备得到的α-氯代氮杂环丙烷光学纯度高。本发明制备得到的手性α-氯代氮杂环丙烷,有望在不对称合成以及医药研发领域得到应用。
Description
技术领域
本发明涉及一种氮杂环丙烷的制备方法,尤其是涉及一种制备手性α-氯代氮杂环丙烷的方法。
背景技术
氮杂环丙烷是一类重要的有机化合物,由于三元环的张力,氮杂环丙烷易于发生选择性的开环反应,因而经常被用于合成各种各样的含氮化合物。α-氯代氮杂环丙烷是一类重要的C-杂代氮杂环丙烷(Singh,G.S.;D’hooghe,M.;DeKimpe,N.Chem.Rev.,2007,107,2080),它可以发生开环反应转化为其他的含氮化合物,也可以发生取代反应转化为其它重要的氮杂环丙烷的衍生物((a)Deyrup,J.A.;Greenwald,R.B.J.Am.Chem.Soc.1965,87,4538;(b)Hassner,A.;Burke,S.S.;Cheng-fanI,J.J.Am.Chem.Soc.1975,97,4692)。
制备α-氯代氮杂环丙烷类化合物的方法,有报道利用一氯卡宾与N-(苯基)亚胺的反应进行制备(Deyrup,J.A.;Greenwald,R.B.TetrahedronLett.1965,5,321)。另外,利用含有活泼二氯甲基的化合物与亚胺发生Darzens类型的反应((a)Coutrot,P.;Gadi,A.E.J.Organomet.Chem.1985,280,C-11;(b)Giubellina,N.;Mangelinckx,S.;K.W.;DeKimpe,N.J.Org.Chem.2006,71,5881.)、氮宾对氯代烯烃的加成反应(Pellacani,L.;Persia,F.;Tardella,P.TetrahedronLett.1980,21,4967),以及氮杂丙烯啶与酰氯的加成反应(Fowler,F.W.;Hassner,A.J.Am.Chem.Soc.1968,90,2875)进行制备此类化合物,也都有一定的应用,虽然这几种方法一般不具有较高的普适性和选择性。但是对于α-氯代氮杂环丙烷的高效手性合成方法却未见诸报道。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种工艺条件温和、方法高效的制备手性α-氯代氮杂环丙烷的方法。
本发明的目的可以通过以下技术方案来实现:
一种制备手性α-氯代氮杂环丙烷的方法,在有机溶剂中,手性(Rs)-N-(叔丁基亚磺酰)亚胺、三甲基(二氯甲基)硅烷以及碱在-80℃~30℃温度下,反应0.5~10个小时,得到手性α-氯代氮杂环丙烷;
所述的(Rs)-N-(叔丁基亚磺酰)亚胺具有如下结构式:
其中:R为C1-9的烷基、C2-10的烯基、C4-12的芳基或C4-12的取代芳基;
所述的取代芳基为C1-6的烷基取代的芳基、C1-8的烷氧基取代的芳基、卤代芳基、氰基取代的芳基、酯基取代的芳基或硝基取代的芳基;
所述的芳基为苯基、萘基、呋喃基或吡啶基。
所述的碱为叔丁醇钠、叔丁醇钾、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钠或二(三甲基硅基)氨基钾。
所述的(Rs)-N-(叔丁基亚磺酰)亚胺、三甲基(二氯甲基)硅烷以及碱的摩尔比为1:(1~3):(1~4)。
所述的有机溶剂为乙醚、四氢呋喃、甲苯、二氯甲烷、N,N-二甲基甲酰胺或二甲基亚砜。
本发明的典型反应如下
所述式(1)中所示的亚磺酰亚胺可采用文献Liu,G.;Cogan,D.A.;Owens,T.D.;Tang,T.P.;Ellman,J.A.J.Org.Chem.1999,64,1278报道的方法制备。
所述式(1)中所示的TMSCCl2H(三甲基(二氯甲基)硅烷),是商品化的试剂,也可采用文献Yoon,K.;Son,D.Y.J.Organomet.Chem.1997,545–546,185报道的方法进行制备。
与现有技术相比,本发明制备的手性α-氯代氮杂环丙烷,为一种潜在的生物活性分子合成砌块,可以作为重要的中间体用来合成手性的含氮化合物,比如氮杂环丙烷。
本发明的制备手性α-氯代氮杂环丙烷的方法,制备用到的原料经济易得,制备的工艺条件温和、方法高效且制备得到的α-氯代氮杂环丙烷光学纯度高。本发明制备得到的手性α-氯代氮杂环丙烷,有望在不对称合成以及医药研发领域得到应用。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
以下实施例中,反应的产率指的是分离收率;dr指的是反应的对映异构体比例。
实施例1
在-70℃的温度下,将叔丁醇钠(0.96克,10mmol,溶解于1.0ml四氢呋喃中)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(1.57克,10mmol),式(2a)所示的亚胺(2.1克,10mmol),以及15ml四氢呋喃的反应瓶中。反应1小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(体积比1:5)快速柱层析,得到1.62克产品3a,产率为62%,dr为99:1。
化合物3a的表征数据:
淡黄色液体;mp71.1-71.8℃;[α]D 25+54.4(c0.51,CHCl3);IR(film)2917,1450,1285,1078,918,699cm-1;1HNMR(CDCl3)δ7.39(ddd,J=7.3,4.2,1.5Hz,5H),4.57(d,J=5.6Hz,1H),3.93(d,J=5.6Hz,1H),1.20(s,9H);13CNMR(CDCl3)δ131.4,128.8,128.5,128.2,57.6,53.3,37.5,22.5;MS(ESI)m/z:280.1[M+Na]+;HRMS(ESI)m/z:[M+Na]+calcdforC12H16ClNOSNa280.0533;Found280.0535。
实施例2
在-20℃的温度下,将叔丁醇钠(1.92克,20mmol,溶解于1.0mlN,N-二甲基甲酰胺中)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(3.14克,20mmol),式(2b)所示的亚胺(2.23克,10mmol),以及15mlN,N-二甲基甲酰胺的反应瓶中。反应3小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(体积比1:4)快速柱层析,得到2.30克产品3b,产率为85%,dr为98:2。
化合物3b的表征数据:
淡黄色液体;[α]D 25+69.6(c0.59,CHCl3);IR(film)2924,1459,1290,1086,927,707cm-1;1HNMR(CDCl3)δ7.31(d,J=8.1Hz,2H),7.20(d,J=7.9Hz,2H),4.56(d,J=5.6Hz,1H),3.90(d,J=5.5Hz,1H),2.37(s,3H),1.20(s,9H);13CNMR(CDCl3)δ138.4,128.9,128.7,128.5,57.6,53.4,37.5,22.6,21.2;MS(ESI)m/z:294.1[M+Na]+;HRMS(ESI)m/z:[M+H]+calcdforC13H19ClNOS272.0870;Found272.0875.
实施例3
在0℃的温度下,将叔丁醇钾(2.8克,25mmol,溶解于2.0ml二甲基亚砜)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(3.92克,25mmol),式(2c)所示的亚胺(2.23克,10mmol),以及15ml二甲基亚砜的反应瓶中。反应3小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:4)快速柱层析,得到2.44克产品3c,产率为90%,dr为99:1。
化合物3c的表征数据:
无色液体;[α]D 25+155.9(c0.95,CHCl3);IR(film)2923,1477,1293,1082,948,810,698cm-1;1HNMR(CDCl3)δ7.29–7.15(m,4H),4.55(d,J=5.6Hz,1H),3.90(d,J=5.6Hz,1H),2.37(s,3H),1.20(s,9H);13CNMR(CDCl3)δ137.9,131.4,129.5,129.4,128.1,125.9,57.6,53.3,37.6,22.6,21.5;MS(ESI)m/z:294.1[M+Na]+;HRMS(ESI)m/z:[M+H]+calcdforC13H19ClNOS272.0870;Found272.0880。
实施例4
在20℃的温度下,将二(三甲基硅基)氨基钾(5ml,2.0N的甲苯溶液)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(1.57克,10mmol),式(2d)所示的亚胺(2.59克,10mmol),以及15ml甲苯的反应瓶中。反应7小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:4)快速柱层析,得到2.55克产品3d,产率为83%,dr为99:1。
化合物3d的表征数据:
白色固体;mp121.2-121.9℃;[α]D 25+45.3(c0.60,CHCl3);IR(film)2974,1463,1286,1059,927,770,722cm-1;1HNMR(CDCl3)δ8.16(d,J=8.2Hz,1H),7.89(dd,J=18.6,7.9Hz,2H),7.56(ddd,J=21.1,12.0,7.2Hz,4H),4.79(d,J=5.5Hz,1H),4.62(d,J=5.5Hz,1H),1.29(s,9H);13CNMR(CDCl3)δ133.4,132.4,128.9,127.3,126.7,126.2,126.1,124.9,122.7,57.7,53.5,35.7,22.5;MS(ESI)m/z:307.9[M+H]+;HRMS(ESI)m/z:[M+H]+calcdforC16H19ClNOS308.0870;Found308.0878。
实施例5
在-20℃的温度下,将二(三甲基硅基)氨基钠(10ml,2.0N的四氢呋喃溶液)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(3.14克,20mmol),式(2d)所示的亚胺(2.43克,10mmol),以及15ml四氢呋喃的反应瓶中。反应0.5小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:4)快速柱层析,得到2.04克产品3e,产率为70%,dr为97:3。
采用的亚胺为2e:产率为89%,dr为99:1。
化合物3e的表征数据:
浅黄色液体;[α]D 25-36.9(c0.53,CHCl3);1HNMR(CDCl3)δ7.44–7.41(m,2H),7.33–7.29(m,2H),4.66(d,J=5.6Hz,1H),4.32(d,J=5.6Hz,1H),1.24(s,9H);13CNMR(CDCl3)δ135.2,129.8,129.7,129.6,129.5,126.4,57.7,52.9,35.9,22.5;MS(ESI)m/z:314.0[M+Na]+;HRMS(ESI)m/z:[M+Na]+calcdforC12H15Cl2NOSNa314.0144;Found314.0143.
实施例6
采用与实施例1相同的方法,其中:
采用的亚胺为2f:产率为67%,dr为99:1
化合物3f的表征数据:
淡黄色液体;[α]D 25+88.1(c0.56,CHCl3);IR(film)2925,1491,1289,1085,861,743cm-1;1HNMR(CDCl3)δ7.36(s,4H),4.56(d,J=5.6Hz,1H),3.89(d,J=5.6Hz,1H),1.19(s,9H);13CNMR(CDCl3)δ129.8,129.5,129.4,126.3,57.7,52.9,36.9,22.5;MS(ESI)m/z:314.0[M+Na]+;HRMS(ESI)m/z:[M+Na]+calcdforC12H15Cl2NOSNa314.0144;Found314.0157.
实施例7
采用与实施例2相同的方法,其中:
采用的亚胺为2g:产率为63%,dr为99:1。
化合物3g的表征数据:
淡黄色液体[α]25–28.6(c=0.92,CHCl3);IR(film)2930,1455,1326,1170,787,779cm-1;1HNMRδ7.65(d,J=5.6Hz,1H),6.43-6.46(m,2H),4.0(d,J=5.6Hz,1H),3.43(d,J=5.6Hz,1H),1.31(s,9H);13CNMRδ151.0,141.5,110.0,109.2,59.6,57.1,48.1,27.2;ESI(m/z)247(M+);HRMS(ESI)calcd.ForC10H14ClNO2S(M+):247.0434,Found247.0431.
实施例8
采用与实施例3相同的方法,其中:
采用的亚胺为2h:产率为53%,dr为99:1。
化合物3h的表征数据:
[α]25–31.0(c=1.21,CHCl3);IR(film)2938,1350,1043,859,718cm-1;1HNMRδ8.21(d,J=8.1Hz,1H),7.55(d,J=8.1Hz,1H),3.92(d,J=5.6Hz,1H),3.47(d,J=5.6Hz,1H),1.35(s,9H);13CNMRδ146.2,144.4,124.4,123.7,61.4,57.7,52.9,23.7;ESI(m/z)302(M+);HRMS(ESI)calcd.ForC12H15ClNO3S(M+):302.0492,Found302.0489.
实施例9
采用与实施例4相同的方法,其中:
采用的亚胺为2i:产率为87%,dr为99:1。
化合物3i的表征数据:
油状液体;[α]D 25-57.7(c0.55,CHCl3);IR(film)2923,2852,1464,1081,964,683cm-1;1HNMR(CDCl3)δ4.36(d,J=5.7Hz,1H),2.55(dd,J=8.9,5.7Hz,1H),1.97–1.88(m,1H),1.28(s,9H),1.14(d,J=6.8Hz,3H),1.08(d,J=6.8Hz,3H);13CNMR(CDCl3)δ57.0,54.2,43.1,27.4,22.3,20.4,19.7;MS(EI)m/z:223[M]+;HRMS(EI)m/z:[M]+calcdforC9H18ClNOS223.0798;Found223.0795.
实施例10
采用与实施例5相同的方法,其中:
采用的亚胺为2j:产率为82%,dr为99:1。
化合物3j的表征数据:
[α]25–20.4(c=0.90,CHCl3);IR(film)3320,1770,1519,1035,975,932cm-1;1HNMRδ7.33-7.40(m,3H),7.24(d,J=8.0Hz,2H),6.58(d,J=15.8Hz,1H),6.42(dd,J=15.8,2.6Hz,1H),3.63(m,1H),2.65(d,J=5.8Hz,1H),1.32(s,9H);13CNMRδ137.4,135.5,128.66,128.64,127.0,123.4,59.6,57.3,48.2,22.8;ESI(m/z)284(M++1);HRMS(ESI)calcd.ForC14H19ClNOS(M++1):284.0876,Found284.0873.
实施例11
在-80℃的温度下,将二(三甲基硅基)氨基钾(20ml,2.0N的四氢呋喃溶液,40mmol)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(3.14克,20mmol),式(2k)所示的亚胺(2.43克,10mmol),以及15ml四氢呋喃的反应瓶中。反应10小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:1)快速柱层析,得到2.17克产品3k,产率为75%,dr为97:3。
采用的亚胺为2k:
化合物3k的表征数据:
1HNMRδ7.76(m,1H),7.24(d,J=8.0Hz,2H),7.61(m1H),6.58(m,1H),4.03(d,J=5.6Hz,1H),3.28(d,J=5.6Hz,1H),3.80(s,3H),1.32(s,9H).
实施例12
在30℃的温度下,将二(三甲基硅基)氨基钾(20ml,2.0N的四氢呋喃溶液,40mmol)缓慢滴加入含有三甲基(二氯甲基)硅烷(TMSCCl2H)(3.14克,20mmol),式(2l)所示的亚胺(2.24克,10mmol),以及15ml四氢呋喃的反应瓶中。反应10小时后,加入10ml水终止反应。然后将反应液转移到分液漏斗中,用乙酸乙酯萃取(50ml×2)。有机相用无水硫酸钠干燥后,减压下除去溶剂。用乙酸乙酯/石油醚(1:1)快速柱层析,得到2.19克产品3l,产率为81%,dr为97:3。
采用的亚胺为2l:
化合物3l的表征数据:
1HNMRδ7.09(d,J=7.2Hz,1H),6.58(d,J=7.2Hz,2H),3.82(d,J=5.6Hz,1H),3.43(d,J=5.6Hz,1H),3.80(s,3H),1.36(s,9H).
实施例13
本发明制备的手性α-氯代氮杂环丙烷类化合物,可以用来合成氮杂环丙烷,具体的合成方法如下:
在90℃的温度下,将式(3a)所示的α-氯代氮杂环丙烷(1.28克,5mmol)溶解在甲苯中(5ml)。然后将三丁基锡氢(0.4克)加入至上述反应体系中。在90℃的温度下反应8小时后,降温至室温。用乙酸乙酯/石油醚(体积比1:6)快速柱层析,得到1.03克产品4,产率为92%。
化合物4的表征数据:
1HNMRδ7.26-7.37(5H,m),3.61(dd,J=6.9Hz,4.1Hz,1H),2.45(d,J=6.9Hz,1H),2.17(d,J=4.1Hz,1H),1.18(9H,s);13CNMRδ137.3,128.8,128.0,127.0,57.0,32.0,31.5,22.9.
Claims (3)
1.一种制备手性α-氯代氮杂环丙烷的方法,其特征在于,在有机溶剂中,手性(Rs)-N-(叔丁基亚磺酰)亚胺、三甲基(二氯甲基)硅烷以及碱在-80℃~30℃温度下,反应0.5~10个小时,得到手性α-氯代氮杂环丙烷;
其中,(Rs)-N-(叔丁基亚磺酰)亚胺具有如下结构式:
其中:R为C1-9的烷基、C2-10的烯基、C4-12的芳基或C4-12的取代芳基,以及C4-C6的取代杂芳基;
所述的取代芳基为C1-6的烷基取代的芳基、C1-8的烷氧基取代的芳基、卤代芳基、氰基取代的芳基或硝基取代的芳基;
所述的芳基为苯基或萘基;
所述的取代杂芳基为甲氧基或氰基取代的杂芳基;
所述的杂芳基为呋喃基或吡啶基;
所述的碱为叔丁醇钠、叔丁醇钾、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钠或二(三甲基硅基)氨基钾。
2.根据权利要求1所述的一种制备手性α-氯代氮杂环丙烷的方法,其特征在于,(Rs)-N-(叔丁基亚磺酰)亚胺、三甲基(二氯甲基)硅烷以及碱的摩尔比为1:(1~3):(1~4)。
3.根据权利要求1所述的一种制备手性α-氯代氮杂环丙烷的方法,其特征在于,所述的有机溶剂为乙醚、四氢呋喃、甲苯、二氯甲烷、N,N-二甲基甲酰胺或二甲基亚砜。
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