CN109879829B - Synthesis method of trans-4-hydroxy-5-amino-1, 2-oxazinane compounds - Google Patents
Synthesis method of trans-4-hydroxy-5-amino-1, 2-oxazinane compounds Download PDFInfo
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- -1 trans-4-hydroxy-5-amino-1, 2-oxazinane compounds Chemical class 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000003480 eluent Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 14
- 150000003973 alkyl amines Chemical class 0.000 claims description 7
- 150000004982 aromatic amines Chemical class 0.000 claims description 7
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 claims description 4
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 3
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- GEQNZVKIDIPGCO-UHFFFAOYSA-N 2,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C(OC)=C1 GEQNZVKIDIPGCO-UHFFFAOYSA-N 0.000 claims description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims description 2
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 claims description 2
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 claims description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 2
- 238000004809 thin layer chromatography Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- OZQGLZFAWYKKLQ-UHFFFAOYSA-N oxazinane Chemical compound C1CCONC1 OZQGLZFAWYKKLQ-UHFFFAOYSA-N 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 150000001412 amines Chemical class 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000004894 1,2-oxazines Chemical class 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 1
- BHXSRLKYVPSYMQ-UHFFFAOYSA-N C=CC=C.C=CC=C Chemical compound C=CC=C.C=CC=C BHXSRLKYVPSYMQ-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 241000187180 Streptomyces sp. Species 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 150000001500 aryl chlorides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- CTFXYMMZXWWOFY-UHFFFAOYSA-N ent-phyllanthidine Natural products O1N2CCCCC2C23OC(=O)C=C3C=CC1C2 CTFXYMMZXWWOFY-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical class ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- CTFXYMMZXWWOFY-MDZLAQPJSA-N phyllantidine Chemical group O1N2CCCC[C@H]2[C@]23OC(=O)C=C3C=C[C@@H]1C2 CTFXYMMZXWWOFY-MDZLAQPJSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
Classifications
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于化学制药和精细化工制备技术领域，具体涉及一种反式‑4‑羟基‑5‑氨基‑1,2‑恶嗪烷类化合物的合成方法，以N‑芳酰基‑3,6‑二氢‑1,2‑恶嗪环氧化物和有机胺为原料，以Salen‑Cr(III)为催化剂，于乙二醇二甲醚中40℃下反应，得到最终产物。本发明的反应原料制备方法简单，合成反式‑4‑羟基‑5‑氨基‑1,2‑恶嗪烷类化合物的反应条件温和，反应操作简单，合成产物为高度官能团化的1,2‑恶嗪烷，是潜在的医药合成结构单元，可用于多种化学转化，具有重要的应用价值。The invention belongs to the technical field of chemical pharmacy and fine chemical preparation, and in particular relates to a method for synthesizing trans-4-hydroxy-5-amino-1,2-oxazinane compounds, comprising N-aroyl-3,6- Dihydro-1,2-oxazine epoxide and organic amine are used as raw materials, and Salen-Cr(III) is used as a catalyst to react in ethylene glycol dimethyl ether at 40° C. to obtain the final product. The preparation method of the reaction raw materials of the invention is simple, the reaction conditions for synthesizing trans-4-hydroxy-5-amino-1,2-oxazinane compounds are mild, the reaction operation is simple, and the synthesized product is a highly functionalized 1,2- Oxazinane is a potential structural unit for pharmaceutical synthesis, which can be used for various chemical transformations and has important application value.
Description
技术领域technical field
本发明属于化学制药和精细化工制备技术领域，涉及一种反式-4-羟基-5-氨基-1,2-恶嗪烷类化合物的合成方法。The invention belongs to the technical field of chemical pharmacy and fine chemical preparation, and relates to a method for synthesizing trans-4-hydroxy-5-amino-1,2-oxazinane compounds.
背景技术Background technique
1,2-恶嗪烷是一类重要的六元氮氧杂环，其作为一种结构单元见于很多具有生物活性的天然产物分子。例如化学式(a)所示的FR900482是从一种链霉菌分离得到的天然产物，包含1,2-恶嗪烷结构，具有很强的抗菌和抗癌活性。又如化学式(b)所示的Phyllantidine，是从油柑属类植物中提取的天然生物碱，同样具有核心1,2-恶嗪烷骨架。另外，1,2-恶嗪烷中的氮氧键容易断开给出1,4-氨基醇类化合物，使得该类恶嗪同时是一类非常多功能的有机合成中间体。因此发展新的合成1,2-恶嗪烷的方法具有重要的应用价值和现实意义。1,2-oxazinane is an important class of six-membered nitrogen-oxo-heterocycles as a building block found in many biologically active natural product molecules. For example, FR900482 represented by chemical formula (a) is a natural product isolated from a Streptomyces sp., which contains a 1,2-oxazinane structure and has strong antibacterial and anticancer activities. Another example is Phyllantidine represented by chemical formula (b), which is a natural alkaloid extracted from plants of the genus Oleum, and also has a core 1,2-oxazinane skeleton. In addition, the nitrogen-oxygen bond in 1,2-oxazine is easily cleaved to give 1,4-amino alcohol compounds, which makes the oxazines also a kind of very versatile organic synthesis intermediates. Therefore, the development of new methods for synthesizing 1,2-oxazinane has important application value and practical significance.
目前，合成1,2-恶嗪烷的方法可大致分为两种,一种是利用硝酮化合物的环加成反应。如方程式(1)所示，硝酮化合物与α-甲苯磺酰基氧代酮发生[3+3]环加成反应，可得到官能团化的1,2-恶嗪烷。该反应底物范围较窄，产率较低。At present, the methods for synthesizing 1,2-oxazinane can be roughly divided into two types, one is the cycloaddition reaction of nitrone compounds. As shown in equation (1), a [3+3] cycloaddition reaction between a nitrone compound and a-toluenesulfonyl oxoketone can give a functionalized 1,2-oxazinane. The reaction substrate range is narrow and the yield is low.
另一种合成1,2-恶嗪烷的方法是利用芳基亚硝基化合物与醛类化合物的反应。如方程式(2)所示，链状烯醛与芳基亚硝基化合物在L-脯氨酸催化下，可获得手性1,2-恶嗪烷。该反应同样底物范围较窄，且氮上的芳基不易脱除，不利于后期官能团转化。Another method for synthesizing 1,2-oxazinane utilizes the reaction of arylnitroso compounds with aldehydes. As shown in equation (2), a chiral 1,2-oxazinane can be obtained under the catalysis of L-proline with a chain alkenal and an arylnitroso compound. This reaction also has a narrow substrate range, and the aryl group on the nitrogen is not easy to remove, which is not conducive to the conversion of functional groups in the later stage.
发明内容SUMMARY OF THE INVENTION
本发明要解决的技术问题是：基于背景技术部分指出的1,2-恶嗪烷类化合物的重要性和目前合成方法的有限性，本发明提供一种新的高度官能团化1,2-恶嗪烷类化合物的合成方法，即一种反式-4-羟基-5-氨基-1,2-恶嗪烷类化合物的合成方法。The technical problem to be solved by the present invention is: based on the importance of the 1,2-oxazine compounds pointed out in the background section and the limitation of the current synthesis methods, the present invention provides a novel highly functionalized 1,2-oxazine compound. A method for synthesizing oxazinane compounds, namely a method for synthesizing trans-4-hydroxy-5-amino-1,2-oxazinane compounds.
本发明提供的反式-4-羟基-5-氨基-1,2-恶嗪烷类化合物的合成方法如下：在氮气保护下，向无水乙二醇二甲醚中加入N-芳酰基-3,6-二氢-1,2-恶嗪环氧化物1、芳基胺或烷基胺、催化剂Salen-Cr(III)，搅拌条件下加热至40℃反应，薄层色谱跟踪反应，待反应结束后减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到N-芳酰基-反式-4-羟基-5-氨基-1,2-恶嗪烷类化合物2。The synthesis method of the trans-4-hydroxy-5-amino-1,2-oxazinane compound provided by the invention is as follows: under nitrogen protection, add N-aroyl- 3,6-Dihydro-1,2-oxazine epoxide 1, arylamine or alkylamine, catalyst Salen-Cr(III), heated to 40°C under stirring conditions to react, followed by thin layer chromatography, wait for After the reaction, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain N-aroyl-trans-4-hydroxy-5-amino-1,2- Oxazinane compounds 2.
上述反应过程概括为如下反应方程式(3)：Above-mentioned reaction process is summarized as following reaction equation (3):
N-芳酰基-3,6-二氢-1,2-恶嗪环氧化物1结构通式为：The general structure of N-aroyl-3,6-dihydro-1,2-oxazine epoxide 1 is:
其中，R1为氢、甲氧基、硝基中任一种。Wherein, R 1 is any one of hydrogen, methoxy and nitro.
N-芳酰基-3,6-二氢-1,2-恶嗪环氧化物1可以方便地从相应的芳基甲酸S1经四步反应获得，如反应方程式(4)所示，芳基甲酸S1与草酰氯反应生成对应的芳基酰氯S2，然后与盐酸羟胺反应得到对应的羟胺化合物S3，接着用高碘酸钠氧化S3得到亚硝基中间体，与1,3-丁二烯(Butadiene)发生Diels-Alder反应得到N-芳酰基-3,6-二氢-1,2-恶嗪S4(参考文献Duangduan Chaiyaveij,Andrei S.Batsanov,Mark A.Fox,Todd B.Marder,AndrewWhiting.J.Org.Chem.2015,80,9518-9534.)，最后用间氯过氧苯甲酸(m-CPBA)氧化得到N-芳酰基-3,6-二氢-1,2-恶嗪环氧化物1。N-aroyl-3,6-dihydro-1,2-oxazine epoxide 1 can be conveniently obtained from the corresponding arylcarboxylic acid S1 through a four-step reaction, as shown in reaction equation (4), arylcarboxylic acid S1 reacts with oxalyl chloride to generate the corresponding aryl chloride S2, then reacts with hydroxylamine hydrochloride to obtain the corresponding hydroxylamine compound S3, and then oxidizes S3 with sodium periodate to obtain a nitroso intermediate, which is combined with 1,3-butadiene (Butadiene ) Diels-Alder reaction occurs to obtain N-aroyl-3,6-dihydro-1,2-oxazine S4 (references Duangduan Chaiyaveij, Andrei S.Batsanov, Mark A.Fox, Todd B.Marder, AndrewWhiting.J .Org.Chem.2015,80,9518-9534.), and finally oxidized with m-chloroperoxybenzoic acid (m-CPBA) to obtain N-aroyl-3,6-dihydro-1,2-oxazine epoxy Compound 1.
芳基胺为苯胺、邻甲氧基苯胺、间甲氧基苯胺、对甲氧基苯胺、2、4-二甲氧基苯胺、邻甲苯胺、间甲苯胺、对甲苯胺、对碘苯胺、对溴苯胺、对氯苯胺、对氟苯胺中任一种；Arylamines are aniline, o-methoxyaniline, m-methoxyaniline, p-methoxyaniline, 2,4-dimethoxyaniline, o-toluidine, m-toluidine, p-toluidine, p-iodoaniline, Any of p-bromoaniline, p-chloroaniline and p-fluoroaniline;
烷基胺为苄胺、烯丙胺、炔丙胺、甘氨酸乙酯、哌啶、吗啉、1-(叔丁氧羰基)哌嗪、异喹啉、吡咯烷中任一种。The alkylamine is any of benzylamine, allylamine, propargylamine, ethyl glycine, piperidine, morpholine, 1-(tert-butoxycarbonyl)piperazine, isoquinoline, and pyrrolidine.
Salen-Cr(III)的结构式为：
N-芳酰基-3,6-二氢-1,2-恶嗪环氧化物1、芳基胺或烷基胺、Salen-Cr(III)摩尔比为1:1.2～2:0.05～0.1。The molar ratio of N-aroyl-3,6-dihydro-1,2-oxazine epoxide 1, arylamine or alkylamine, and Salen-Cr(III) is 1:1.2-2:0.05-0.1.
反应时间为3～10天。The reaction time is 3 to 10 days.
合成的N-芳酰基-反式-4-羟基-5-氨基-1,2-恶嗪烷类化合物2的结构通式为：
其中R1为氢、甲氧基、硝基中任一种；Wherein R 1 is any one of hydrogen, methoxy, nitro;
R2为如下所示结构中任一种：R 2 is any one of the structures shown below:
本发明方法合成了一种全新结构的N-芳酰基-反式-4-羟基-5-氨基-1,2-恶嗪烷类化合物，环上的羟基和氨基丰富了现有1,2-恶嗪烷的结构，可以进一步官能团化，有利于制备相关结构药物中间体。其用途很广泛，将其作为药物合成中间体，可以用于很多种药物的合成。其中的N-芳酰基是个易离去的基团，离去之后裸露出的氮原子又可发生各种反应，便于药物化学的构效关系研究。The method of the invention has synthesized a new structure of N-aroyl-trans-4-hydroxy-5-amino-1,2-oxazinane compounds, and the hydroxyl and amino groups on the ring enrich the existing 1,2- The structure of oxazinane can be further functionalized, which is beneficial to the preparation of drug intermediates with related structures. It has a wide range of uses. It can be used as a drug synthesis intermediate and can be used in the synthesis of many kinds of drugs. The N-aroyl group is an easily leaving group, and the exposed nitrogen atom can undergo various reactions after leaving, which is convenient for the study of the structure-activity relationship of medicinal chemistry.
本发明的有益效果是：以包含1,2-恶嗪环的N-芳酰环氧化合物和有机胺为原料，以Salen-Cr(III)为催化剂，在40℃下，有机胺作为亲核试剂，进攻环氧开环，胺进攻后同时在1,2-恶嗪烷环上引入羟基和氨基两个重要的官能团，高区域选择性地制得反式双官能团化的N-芳酰基-1,2-恶嗪烷，而官能团化的1,2-恶嗪烷在药物合成反应中更受欢迎。该反应原料制备简单，反应条件温和，反应操作简单，合成的产物是潜在的医药合成结构单元，可用于多种化学转化，具有重要的应用价值。The beneficial effects of the present invention are: using N-aroyl epoxy compound containing 1,2-oxazine ring and organic amine as raw material, using Salen-Cr(III) as catalyst, at 40° C., organic amine as nucleophile Reagent, attacking epoxy ring-opening, after the attack of amine, two important functional groups, hydroxyl and amino, are introduced into the 1,2-oxazinane ring at the same time, and the trans-bifunctionalized N-aroyl- 1,2-oxazinane, and functionalized 1,2-oxazinane are more popular in drug synthesis reactions. The reaction raw material is simple to prepare, the reaction conditions are mild, the reaction operation is simple, and the synthesized product is a potential pharmaceutical synthesis structural unit, which can be used for various chemical transformations and has important application value.
具体实施方式Detailed ways
现在结合具体实施例对本发明作进一步说明，以下实施例旨在说明本发明而不是对本发明的进一步限定。The present invention will now be further described with reference to specific embodiments, and the following embodiments are intended to illustrate the present invention rather than further limit the present invention.
本发明使用的N-芳酰基-3,6-二氢-1,2-恶嗪环氧化物1是参考相关文献制备(参考文献Duangduan Chaiyaveij,Andrei S.Batsanov,Mark A.Fox,Todd B.Marder,AndrewWhiting.J.Org.Chem.2015,80,9518-9534.)。各种芳基胺或烷基胺为市场购得后直接使用。催化剂Salen-Cr(III)参考相关文献制备(参考文献Donald.J.Darensbourg,RyanM.Mackiewicz,Jody L.Rodgers,Cindy C.Fang,Damon R.Billodeaux,JosephH.Reibenspies.Inor.Chem.2004,43,6024-6034.)。溶剂乙二醇二甲醚经过纯化和精制。The N-aroyl-3,6-dihydro-1,2-oxazine epoxide 1 used in the present invention is prepared with reference to relevant literature (references Duangduan Chaiyaveij, Andrei S. Batsanov, Mark A. Fox, Todd B. Marder, Andrew Whiting. J. Org. Chem. 2015, 80, 9518-9534.). Various arylamines or alkylamines are purchased directly from the market. The catalyst Salen-Cr(III) was prepared with reference to relevant literature (Reference Donald. J. Darensbourg, Ryan M. Mackiewicz, Jody L. Rodgers, Cindy C. Fang, Damon R. Billodeaux, Joseph H. Reibenspies. Inor. Chem. 2004, 43 , 6024-6034.). The solvent ethylene glycol dimethyl ether is purified and refined.
实施例1Example 1
取干燥过的10mL封管，称取1a(61.0mg,0.3mmol)、苯胺(56.0mg,0.6mmol)和Salen-Cr(III)(22.0mg，30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌3天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到64mg黄色粘稠状液体2a，产率为72％。2a:1H NMR(400MHz,CDCl3)δ7.69(t,J＝9.3Hz,2H),7.48(t,J＝7.0Hz,1H),7.40(t,J＝7.3Hz,2H),7.17(t,J＝7.4Hz,2H),6.74(t,J＝7.2Hz,1H),6.65(d,J＝7.5Hz,2H),4.40(d,J＝10.0Hz,1H),4.25–4.08(m,1H),4.05–3.87(m,2H),3.68–3.55(m,2H).13C NMR(75MHz,CDCl3)δ170.79,146.14,133.01,131.38,129.68,128.79,128.18,118.61,113.40,72.95,65.76,53.15,47.96.HRMS(ESI)m/z理论值C17H19N2O3 +[M+H]+ 299.1390,实测值299.1386.Take the dried 10 mL sealed tube, weigh 1a (61.0 mg, 0.3 mmol), aniline (56.0 mg, 0.6 mmol) and Salen-Cr(III) (22.0 mg, 30 μmol), and after evacuating and changing nitrogen, add 1 mL of dried of ethylene glycol dimethyl ether, heated to 40 °C and stirred for 3 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 64 mg of yellow viscous liquid 2a with a yield of 72%. 2a: 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (t, J=9.3 Hz, 2H), 7.48 (t, J=7.0 Hz, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.17 (t, J＝7.4Hz, 2H), 6.74 (t, J＝7.2Hz, 1H), 6.65 (d, J＝7.5Hz, 2H), 4.40 (d, J＝10.0Hz, 1H), 4.25–4.08 (m, 1H), 4.05–3.87 (m, 2H), 3.68–3.55 (m, 2H). 13 C NMR (75MHz, CDCl 3 ) δ 170.79, 146.14, 133.01, 131.38, 129.68, 128.79, 128.18, 118.61, 113.40 ,72.95,65.76,53.15,47.96.HRMS(ESI) m/z theoretical value C 17 H 19 N 2 O 3 + [M+H] + 299.1390, found 299.1386.
实施例2Example 2
取干燥过的10mL封管，称取1a(61.0mg,0.3mmol)、苯胺(33.6mg,0.36mmol)和Salen-Cr(III)(22.0mg，30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌4天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到65mg黄色粘稠状液体2a，产率为73％。Take a dried 10 mL sealed tube, weigh 1a (61.0 mg, 0.3 mmol), aniline (33.6 mg, 0.36 mmol) and Salen-Cr(III) (22.0 mg, 30 μmol), and after changing nitrogen, add 1 mL of dried of ethylene glycol dimethyl ether, heated to 40 °C and stirred for 4 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 65 mg of yellow viscous liquid 2a with a yield of 73%.
实施例3Example 3
取干燥过的10mL封管，称取1a(61.0mg,0.3mmol)、苯胺(56.0mg,0.6mmol)和Salen-Cr(III)(11.0mg，15μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌5天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到59mg黄色粘稠状液体2a，产率为66％。Take the dried 10 mL sealed tube, weigh 1a (61.0 mg, 0.3 mmol), aniline (56.0 mg, 0.6 mmol) and Salen-Cr(III) (11.0 mg, 15 μmol), after evacuating and changing nitrogen, add 1 mL of dried of ethylene glycol dimethyl ether, heated to 40 °C and stirred for 5 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 59 mg of yellow viscous liquid 2a with a yield of 66%.
实施例4Example 4
取干燥过的10mL封管，称取1a(61.0mg,0.3mmol)、对甲氧基苯胺(74.0mg,0.6mmol)、Salen-Cr(III)(22.0mg,30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌3天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到79mg黄色粘稠状液体2b，产率为80％。2b:1H NMR(400MHz,CDCl3)δ7.71–7.63(m,1H),7.53–7.43(m,1H),7.43–7.34(m,1H),6.76(d,J＝8.8Hz,1H),6.62(d,J＝8.7Hz,1H),4.35(d,J＝9.1Hz,1H),4.27–4.17(m,1H),3.94–3.83(m,1H),3.73(s,2H),3.63–3.55(m,1H),3.52–3.46(m,1H).13C NMR(75MHz,CDCl3)δ170.59,152.95,140.06,133.03,131.31,128.74,128.14,115.22,115.19,73.05,66.01,55.85,54.51,48.06.HRMS(ESI)m/z理论值C18H21N2O4 +[M+H]+ 329.1496,实测值329.1492.Take a dried 10 mL sealed tube, weigh 1a (61.0 mg, 0.3 mmol), p-methoxyaniline (74.0 mg, 0.6 mmol), and Salen-Cr(III) (22.0 mg, 30 μmol), and after evacuating and changing nitrogen, 1 mL of dried ethylene glycol dimethyl ether was added, and the mixture was heated to 40°C and stirred for 3 days. Then, the organic solvent was removed by distillation under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 79 mg of yellow viscous liquid 2b with a yield of 80%. 2b: 1 H NMR (400 MHz, CDCl 3 ) δ 7.71–7.63 (m, 1H), 7.53–7.43 (m, 1H), 7.43–7.34 (m, 1H), 6.76 (d, J=8.8 Hz, 1H) ),6.62(d,J=8.7Hz,1H),4.35(d,J=9.1Hz,1H),4.27–4.17(m,1H),3.94–3.83(m,1H),3.73(s,2H) ,3.63–3.55(m,1H),3.52–3.46(m,1H). 13 C NMR(75MHz, CDCl 3 )δ170.59,152.95,140.06,133.03,131.31,128.74,128.14,115.22,115.19,73.05,66.01, 55.85, 54.51, 48.06. HRMS(ESI) m/z theoretical value C 18 H 21 N 2 O 4 + [M+H] + 329.1496, found value 329.1492.
实施例5Example 5
取干燥过的10mL封管，称取1a(61.0mg，0.3mmol)、对甲苯胺(64.0mg，0.6mmol)、Salen-Cr(III)(22.0mg，30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌5天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到76mg黄色粘稠状液体2c，产率为81％。2c:1H NMR(400MHz,CDCl3)δ7.73–7.64(m,2H),7.51–7.45(m,1H),7.43–7.37(m,2H),6.98(d,J＝8.2Hz,2H),6.66–6.54(m,2H),4.38(d,J＝9.2Hz,1H),4.26–4.11(m,1H),3.98–3.82(m,2H),3.81–3.65(m,2H),3.64–3.58(m,1H),3.58–3.53(m,1H),2.24(s,3H).13C NMR(75MHz,CDCl3)δ170.66,143.78,133.05,131.32,130.11,128.76,128.15,113.69,73.00,65.87,53.64,48.04,20.46.HRMS(ESI)m/z理论值C18H20N2NaO3 +[M+Na]+ 335.1366,实测值335.1376.Take the dried 10 mL sealed tube, weigh 1a (61.0 mg, 0.3 mmol), p-toluidine (64.0 mg, 0.6 mmol), and Salen-Cr(III) (22.0 mg, 30 μmol), and add 1 mL of nitrogen after evacuating and changing nitrogen. The dried ethylene glycol dimethyl ether was heated to 40°C and stirred for 5 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 76 mg of yellow viscous liquid 2c with a yield of 81%. 2c: 1 H NMR (400 MHz, CDCl 3 ) δ 7.73–7.64 (m, 2H), 7.51–7.45 (m, 1H), 7.43–7.37 (m, 2H), 6.98 (d, J=8.2 Hz, 2H ), 6.66–6.54 (m, 2H), 4.38 (d, J=9.2Hz, 1H), 4.26–4.11 (m, 1H), 3.98–3.82 (m, 2H), 3.81–3.65 (m, 2H), 3.64–3.58(m,1H), 3.58–3.53(m,1H), 2.24(s,3H). 13 C NMR (75MHz, CDCl 3 )δ170.66,143.78,133.05,131.32,130.11,128.76,128.15,113.69, 73.00, 65.87, 53.64, 48.04, 20.46. HRMS(ESI) m/z theoretical value C 18 H 20 N 2 NaO 3 + [M+Na] + 335.1366, found 335.1376.
实施例6Example 6
取干燥过的10mL封管，称取1b(75.0mg，0.3mmol)、苯胺(56.0mg，0.6mmol)、Salen-Cr(III)(22.0mg，30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌10天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到85mg黄色粘稠状液体2d，产率为82％。2d:1H NMR(300MHz,CDCl3)δ8.22(d,J＝8.7Hz,2H),7.81(d,J＝8.3Hz,2H),7.17(t,J＝7.7Hz,2H),6.75(t,J＝7.3Hz,1H),6.64(d,J＝7.9Hz,2H),4.39(d,J＝9.6Hz,1H),4.26–4.12(m,1H),4.07–3.93(m,2H),3.71–3.55(m,2H).13C NMR(75MHz,CDCl3)δ168.09,149.10,145.97,138.97,129.68,129.65,123.31,118.64,113.22,73.24,65.27,52.71,47.38.HRMS(ESI)m/z理论值C17H17N3NaO5 +[M+H]+366.1060,实测值366.1059.Take the dried 10 mL sealed tube, weigh 1b (75.0 mg, 0.3 mmol), aniline (56.0 mg, 0.6 mmol), and Salen-Cr(III) (22.0 mg, 30 μmol), and after evacuating and changing nitrogen, add 1 mL of dried of ethylene glycol dimethyl ether, heated to 40 °C and stirred for 10 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 85 mg of yellow viscous liquid 2d with a yield of 82%. 2d: 1 H NMR (300 MHz, CDCl 3 ) δ 8.22 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H), 7.17 (t, J=7.7 Hz, 2H), 6.75 (t, J=7.3Hz, 1H), 6.64 (d, J=7.9Hz, 2H), 4.39 (d, J=9.6Hz, 1H), 4.26–4.12 (m, 1H), 4.07–3.93 (m, 2H), 3.71–3.55(m, 2H). 13 C NMR(75MHz, CDCl 3 )δ168.09,149.10,145.97,138.97,129.68,129.65,123.31,118.64,113.22,73.24,65.27,52.71,47.38.HRMS(SI ) m/z theoretical value C 17 H 17 N 3 NaO 5 + [M+H] + 366.1060, found 366.1059.
实施例7Example 7
取干燥过的10mL封管，称取1c(70.5mg，0.3mmol)、苯胺(56.0mg，0.6mmol)、Salen-Cr(III)(22.0mg，30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌7天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到80mg黄色粘稠状液体2e，产率为80％。2e:1H NMR(400MHz,CDCl3)δ7.78–7.69(m,2H),7.16(t,J＝7.8Hz,2H),6.93–6.85(m,2H),6.73(t,J＝7.3Hz,1H),6.78–6.59(m,2H),4.39(d,J＝7.8Hz,1H),4.26–4.16(m,1H),4.13–3.98(m,1H),3.97–3.87(m,2H),3.84–3.81(m,3H),3.65–3.55(m,2H).13C NMR(75MHz,CDCl3)δ170.33,162.15,146.33,131.21,129.59,124.80,118.38,113.39,113.32,72.86,65.82,55.43,53.27,48.15.HRMS(ESI)m/z理论值C18H20N2NaO4 +[M+Na]+ 351.1315,实测值351.1322.Take the dried 10 mL sealed tube, weigh 1c (70.5 mg, 0.3 mmol), aniline (56.0 mg, 0.6 mmol), and Salen-Cr(III) (22.0 mg, 30 μmol), and after changing nitrogen, add 1 mL of dried of ethylene glycol dimethyl ether, heated to 40 °C and stirred for 7 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 80 mg of yellow viscous liquid 2e with a yield of 80%. 2e: 1 H NMR (400 MHz, CDCl 3 ) δ 7.78-7.69 (m, 2H), 7.16 (t, J=7.8 Hz, 2H), 6.93-6.85 (m, 2H), 6.73 (t, J=7.3 Hz, 1H), 6.78–6.59 (m, 2H), 4.39 (d, J=7.8Hz, 1H), 4.26–4.16 (m, 1H), 4.13–3.98 (m, 1H), 3.97–3.87 (m, 2H), 3.84–3.81 (m, 3H), 3.65–3.55 (m, 2H). 13 C NMR (75MHz, CDCl 3 )δ170.33, 162.15, 146.33, 131.21, 129.59, 124.80, 118.38, 113.39, 113.32, 72.86, 65.82, 55.43, 53.27, 48.15. HRMS(ESI) m/z theoretical value C 18 H 20 N 2 NaO 4 + [M+Na] + 351.1315, found value 351.1322.
实施例8Example 8
取干燥过的10mL封管，称取1c(70.5mg，0.3mmol)、苄胺(91.0mg，0.6mmol)、Salen-Cr(III)(22.0mg，30μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌4天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到60mg黄色粘稠状液体2f，产率为58％。2f:1H NMR(300MHz,CDCl3)δ7.66(d,J＝8.7Hz,2H),7.33–7.17(m,5H),6.89–6.80(m,2H),4.41(d,J＝12.7Hz,1H),4.17–3.99(m,1H),3.84–3.70(m,5H),3.70–3.62(m,1H),3.49–3.29(m,2H),2.86–2.78(m,1H).13C NMR(75MHz,CDCl3)δ170.02,162.08,139.89,131.25,128.71,128.13,127.43,124.92,113.32,73.51,67.79,58.65,55.46,51.73,48.68.HRMS(ESI)m/z理论值C19H22N2NaO4 +[M+Na]+365.1472,实测值365.1467.Take the dried 10 mL sealed tube, weigh 1c (70.5 mg, 0.3 mmol), benzylamine (91.0 mg, 0.6 mmol), and Salen-Cr(III) (22.0 mg, 30 μmol). ethylene glycol dimethyl ether, heated to 40 °C and stirred for 4 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 60 mg of yellow viscous liquid 2f with a yield of 58%. 2f: 1 H NMR (300 MHz, CDCl 3 ) δ 7.66 (d, J=8.7 Hz, 2H), 7.33-7.17 (m, 5H), 6.89-6.80 (m, 2H), 4.41 (d, J=12.7 Hz, 1H), 4.17–3.99 (m, 1H), 3.84–3.70 (m, 5H), 3.70–3.62 (m, 1H), 3.49–3.29 (m, 2H), 2.86–2.78 (m, 1H). 13 C NMR (75MHz, CDCl 3 ) δ 170.02, 162.08, 139.89, 131.25, 128.71, 128.13, 127.43, 124.92, 113.32, 73.51, 67.79, 58.65, 55.46, 51.73, 48.68. HRMS (ESI) m/z theoretical value C 19 H 22 N 2 NaO 4 + [M+Na] + 365.1472, found 365.1467.
实施例9Example 9
取干燥过的10mL封管，称取1c(59.0mg,0.25mmol)、烯丙胺(29.0mg，0.5mmol)、Salen-Cr(III)(18.0mg，25μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌8天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到48mg黄色粘稠状液体2g，产率为66％。2g:1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),6.87(d,J＝8.5Hz,2H),5.88–5.75(m,1H),5.23–5.05(m,2H),4.46(d,J＝11.2Hz,1H),4.23–4.03(m,1H),3.81(s,3H),3.68(s,1H),3.54–3.33(m,2H),3.33–3.05(m,2H),2.99–2.69(m,1H).13C NMR(75MHz,CDCl3)δ169.89,162.04,136.43,131.17,124.88,116.65,113.29,73.47,67.57,58.43,55.40,50.14,48.77.HRMS(ESI)m/z理论值C15H21N2O4 +[M+H]+ 293.1496,实测值293.1497.Take the dried 10 mL sealed tube, weigh 1c (59.0 mg, 0.25 mmol), allylamine (29.0 mg, 0.5 mmol), Salen-Cr(III) (18.0 mg, 25 μmol), evacuate and change nitrogen, add 1 mL of dry ethylene glycol dimethyl ether, heated to 40 °C and stirred for 8 days. Then, the organic solvent was removed by distillation under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 48 mg of yellow viscous liquid 2g, with a yield of 66%. 2g: 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.88–5.75 (m, 1H), 5.23–5.05 ( m, 2H), 4.46 (d, J=11.2Hz, 1H), 4.23–4.03 (m, 1H), 3.81 (s, 3H), 3.68 (s, 1H), 3.54–3.33 (m, 2H), 3.33 –3.05(m,2H),2.99–2.69(m,1H). 13 C NMR(75MHz, CDCl 3 )δ169.89,162.04,136.43,131.17,124.88,116.65,113.29,73.47,67.57,58.43,55.40,50.14, 48.77.HRMS(ESI) m/z theoretical value C 15 H 21 N 2 O 4 + [M+H] + 293.1496, found 293.1497.
实施例10Example 10
取干燥过的10mL封管，称取1c(59.0mg，0.25mmol)、甘氨酸乙酯(52.0mg,0.5mmol)、Salen-Cr(III)(18.0mg,25μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌6天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到69mg黄色粘稠状液体2h，产率为83％。2h:1H NMR(300MHz,CDCl3)δ7.77–7.58(m,2H),6.87(d,J＝8.7Hz,2H),4.53(d,J＝10.6Hz,1H),4.23–4.04(m,3H),3.82(s,3H),3.73–3.62(m,1H),3.57–3.26(m,4H),2.79–2.67(m,1H),1.25(t,J＝7.1Hz,3H).13C NMR(75MHz,CDCl3)δ173.28,169.84,162.04,131.18,124.97,113.31,73.34,68.00,61.37,59.52,55.43,49.01,48.47,14.24.HRMS(ESI)m/z理论值C16H22N2NaO6 +[M+Na]+ 361.1370,实测值361.1364.Take a dried 10 mL sealed tube, weigh 1c (59.0 mg, 0.25 mmol), glycine ethyl ester (52.0 mg, 0.5 mmol), and Salen-Cr(III) (18.0 mg, 25 μmol), evacuate and change nitrogen, add 1 mL The dried ethylene glycol dimethyl ether was heated to 40°C and stirred for 6 days. Then, the organic solvent was removed by distillation under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 69 mg of a yellow viscous liquid for 2 h with a yield of 83%. 2h: 1 H NMR (300 MHz, CDCl 3 ) δ 7.77–7.58 (m, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.53 (d, J=10.6 Hz, 1H), 4.23–4.04 ( m, 3H), 3.82 (s, 3H), 3.73–3.62 (m, 1H), 3.57–3.26 (m, 4H), 2.79–2.67 (m, 1H), 1.25 (t, J=7.1Hz, 3H) . 13 C NMR (75MHz, CDCl 3 ) δ 173.28, 169.84, 162.04, 131.18, 124.97, 113.31, 73.34, 68.00, 61.37, 59.52, 55.43, 49.01, 48.47, 14.24. HRMS(ESI) m/z Theoretical value C 16 HRMS 22 N 2 NaO 6 + [M+Na] + 361.1370, found 361.1364.
实施例11Example 11
取干燥过的10mL封管，称取1c(59.0mg，0.25mmol)、吗啉(43.5mg，0.5mmol)、Salen-Cr(III)(18.0mg，25μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌4天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到68mg黄色粘稠状液体2i，产率为84％。2i:1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.7Hz,2H),6.89(d,J＝8.8Hz,2H),4.75(dd,J＝12.8,4.6Hz,1H),4.15(dd,J＝11.2,4.2Hz,1H),3.91–3.81(m,4H),3.76–3.64(m,6H),3.27-3.19(m,1H),2.96(s,1H),2.84–2.75(m,2H),2.72-2.65(m,1H),2.57-2.47(m,2H).13C NMR(75MHz,CDCl3)δ169.52,162.07,131.20,124.84,113.29,74.97,69.56,67.42,66.11,64.31,63.66,55.41,49.89,41.78.HRMS(ESI)m/z理论值C16H23N2HO5 +[M+H]+ 323.1601,实测值323.1601.Take the dried 10 mL sealed tube, weigh 1c (59.0 mg, 0.25 mmol), morpholine (43.5 mg, 0.5 mmol), and Salen-Cr(III) (18.0 mg, 25 μmol), evacuate and change nitrogen, add 1 mL of dry ethylene glycol dimethyl ether, heated to 40 °C and stirred for 4 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 68 mg of yellow viscous liquid 2i with a yield of 84%. 2i: 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.75 (dd, J=12.8, 4.6 Hz, 1H) ,4.15(dd,J=11.2,4.2Hz,1H),3.91-3.81(m,4H),3.76-3.64(m,6H),3.27-3.19(m,1H),2.96(s,1H),2.84 -2.75(m, 2H), 2.72-2.65(m, 1H), 2.57-2.47(m, 2H). 13 C NMR (75MHz, CDCl 3 ) δ 169.52, 162.07, 131.20, 124.84, 113.29, 74.97, 69.56, 67.42 , 66.11, 64.31, 63.66, 55.41, 49.89, 41.78.HRMS(ESI) m/z theoretical value C 16 H 23 N 2 HO 5 + [M+H] + 323.1601, found 323.1601.
实施例12Example 12
取干燥过的10mL封管，称取1c(59.0mg，0.25mmol)，四氢异喹啉(67.1mg，0.5mmol)、Salen-Cr(III)(18.0mg，25μmol)，抽空换氮后，加入1mL干燥过的乙二醇二甲醚，加热至40℃搅拌6天。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到59mg黄色粘稠状液体2j，产率为64％。2j:1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.8Hz,2H),7.10–7.03(m,1H),6.97(d,J＝7.1Hz,1H),6.90(d,J＝8.8Hz,2H),6.82(d,J＝8.3Hz,1H),6.65(t,J＝7.3Hz,1H),4.75(dd,J＝13.0,4.5Hz,1H),4.19–4.04(m,2H),4.04–3.97(m,1H),3.84(s,3H),3.77–3.69(m,1H),3.43–3.32(m,2H),3.16–3.09(m,1H),2.75(t,J＝6.3Hz,2H),1.99–1.77(m,2H).13C NMR(75MHz,CDCl3)δ169.65,162.21,145.11,131.35,129.81,127.36,124.71,123.89,117.40,113.38,111.48,70.21,64.45,59.56,55.48,49.63,43.02,28.13,22.58.HRMS(ESI)m/z理论值C21H24N2NaO5 +[M+Na]+ 391.1628,实测值391.1632.Take a dried 10 mL sealed tube, weigh 1c (59.0 mg, 0.25 mmol), tetrahydroisoquinoline (67.1 mg, 0.5 mmol), and Salen-Cr(III) (18.0 mg, 25 μmol), and after evacuating and changing nitrogen, 1 mL of dried ethylene glycol dimethyl ether was added, and the mixture was heated to 40°C and stirred for 6 days. Then, the organic solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 59 mg of yellow viscous liquid 2j with a yield of 64%. 2j: 1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J=8.8 Hz, 2H), 7.10-7.03 (m, 1H), 6.97 (d, J=7.1 Hz, 1H), 6.90 (d, J＝8.8Hz, 2H), 6.82(d, J＝8.3Hz, 1H), 6.65(t, J＝7.3Hz, 1H), 4.75(dd, J＝13.0, 4.5Hz, 1H), 4.19–4.04( m, 2H), 4.04–3.97 (m, 1H), 3.84 (s, 3H), 3.77–3.69 (m, 1H), 3.43–3.32 (m, 2H), 3.16–3.09 (m, 1H), 2.75 ( t, J=6.3Hz, 2H), 1.99–1.77 (m, 2H). 13 C NMR (75MHz, CDCl 3 )δ169.65, 162.21, 145.11, 131.35, 129.81, 127.36, 124.71, 123.89, 117.40, 113.38, 111.48, 70.21, 64.45, 59.56, 55.48, 49.63, 43.02, 28.13, 22.58. HRMS(ESI) m/z theoretical value C 21 H 24 N 2 NaO 5 + [M+Na] + 391.1628, found 391.1632.
实施例13Example 13
取干燥过的10mL封管,称取2e(131.0mg，0.4mmol)，NaOH(64.0mg,1.6mmol),加入2mL甲醇，置于室温搅拌36小时。然后将其减压蒸馏除去有机溶剂，残留物以二氯甲烷和甲醇为洗脱剂，经硅胶色谱柱分离，得到62.3mg白色固体3，产率80％。1H NMR(400MHz,DMSO)δ7.01(t,J＝7.9Hz,2H),6.59(d,J＝7.8Hz,2H),6.46(t,J＝7.2Hz,1H),6.36–6.29(m,1H),5.48(d,J＝7.4Hz,1H),4.99(s,1H),4.00(dd,J＝11.3,4.0Hz,1H),3.49–3.41(m,1H),3.26(dd,J＝11.2,8.3Hz,1H),3.22–3.11(m,2H),2.75–2.65(m,1H).13C NMR(75MHz,DMSO)δ153.47,134.13,120.79,117.36,76.21,72.24,59.89,58.95.HRMS(ESI)m/z理论值C4H9N4O2 +[M+H]+ 145.0720,实测值145.0727.Take the dried 10 mL sealed tube, weigh 2e (131.0 mg, 0.4 mmol), NaOH (64.0 mg, 1.6 mmol), add 2 mL of methanol, and stir at room temperature for 36 hours. Then, the organic solvent was removed by distillation under reduced pressure, and the residue was separated by silica gel chromatography using dichloromethane and methanol as eluents to obtain 62.3 mg of white solid 3 with a yield of 80%. 1 H NMR(400MHz,DMSO)δ7.01(t,J=7.9Hz,2H),6.59(d,J=7.8Hz,2H),6.46(t,J=7.2Hz,1H),6.36-6.29( m, 1H), 5.48 (d, J=7.4Hz, 1H), 4.99 (s, 1H), 4.00 (dd, J=11.3, 4.0Hz, 1H), 3.49–3.41 (m, 1H), 3.26 (dd , J=11.2, 8.3Hz, 1H), 3.22–3.11 (m, 2H), 2.75–2.65 (m, 1H). 13 C NMR (75MHz, DMSO) δ153.47, 134.13, 120.79, 117.36, 76.21, 72.24, 59.89 , 58.95.HRMS(ESI) m/z theoretical value C 4 H 9 N 4 O 2 + [M+H] + 145.0720, found 145.0727.
以上述依据本发明的理想实施例为启示，通过上述的说明内容，相关工作人员完全可以在不偏离本项发明技术思想的范围内，进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容，必须要根据权利要求范围来确定其技术性范围。Taking the above ideal embodiments according to the present invention as inspiration, and through the above description, relevant personnel can make various changes and modifications without departing from the technical idea of the present invention. The technical scope of the present invention is not limited to the contents in the specification, and the technical scope must be determined according to the scope of the claims.
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| Enantioselective Addition of Nitrones to Activated Cyclopropanes;Mukund P. Sibi 等;《J.AM.CHEM.SOC.》;20050329;第127卷;第5764-5765页 * |
| Highly Enantioselective and Diastereoselective Cycloaddition of Cyclopropanes with Nitrones and Its Application in the Kinetic Resolution of 2-Substituted Cyclopropane-1,1-dicarboxylates;Yan-Biao Kang 等;《Angew.Chem.Int.Ed. 》;20070417;第46卷;第3918-3921页 * |
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