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Method for preparing 7-Azabicyclo[2.2.1]heptane

An azabicyclo and heptane technology, which is applied in the field of preparing 7-azabicyclo[2.2.1]heptane, can solve the problems of many reaction steps and long routes, and achieves simple steps, simple reaction operation and short synthesis route. Effect

Inactive Publication Date: 2014-09-24
CENT SOUTH UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Horacio F. Olivo (Olivo, H.F.; Peeples, T.L.; Rios, M.Y.; Velazquez, F.; Kim, J.W.; Narang, S. Microbial C-hydroxylation and 4-O-methylglucosidation of Methylbenzamide 7-azanorbornane ethers with Beauveria bassiana[ J] Journal of Molecular Catalysis B: Enzymatic, 2003, 21, 97-105) and other synthetic methods designed in the reaction steps are many, the route is long

Method used

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  • Method for preparing 7-Azabicyclo[2.2.1]heptane
  • Method for preparing 7-Azabicyclo[2.2.1]heptane
  • Method for preparing 7-Azabicyclo[2.2.1]heptane

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Experimental program
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Effect test

Embodiment 1

[0033] Example 1: Preparation of trans-4-trifluoroacetylaminocyclohexanol

[0034] At room temperature, 4.6g (0.04mol) trans-4-aminocyclohexanol was added to a 100mL three-necked flask, dissolved in 35mL acetonitrile, and 6.2g (0.05mol) methyl trifluoroacetate was slowly added dropwise. After the dropwise addition, a white precipitate was formed, the liquid was stirred, filtered with suction, and the solid was dried to obtain 8.4 g of almost quantitative white product with a yield of 100%.

[0035] 1 H NMR (DMSO-d 6 , 400MHz, ppm) δ9.23(d, J=7.6Hz, 1H), 4.60(d, J=4.4Hz, 1H), 3.60-3.52(m, 1H), 3.39-3.32(m, 1H), 1.84 -1.73(m, 4H), 1.40-1.16(m, 4H);

Embodiment 2

[0036] Example 2: Preparation of trans-4-(2,2,2-trifluoroacetylamino)cyclohexyl methanesulfonate

[0037] Under ice bath, dissolve 8.4g (0.04mol) of the amino-protected product in 100mL of dichloromethane solution, add 8.5mL (0.106mol) of pyridine, and dropwise add the dichloromethane solution in which 5.04g (0.044mol) of methanesulfonyl chloride is dissolved . After the dropwise addition was complete, stirring was continued at this temperature for 1 hour. Suction filtration, pour the filtrate into 80mL of dichloromethane, wash with 80mL of water and 80mL of 1mol / L hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 11.5 g of almost quantitative white solid with a yield of 100%.

[0038] 1 H NMR (DMSO-d 6 , 400MHz, ppm) δ9.33(t, J=7.6Hz, 1H), 4.59-4.52(m, 1H), 3.68-3.32(m, 1H), 3.18(d, J=9.6Hz, 3H), 2.08 -2.05(m, 2H), 1.85-1.82(m, 2H), 1.63-1.43(m, 4H);

Embodiment 3

[0039] Embodiment 3: the preparation of 7-azabicyclo [2.2.1] heptane

[0040] At room temperature, add 2.89g (0.01mol) of the product from the previous step and 2.65g of sodium carbonate into a 250mL single-necked bottle, and mix with 120mL of a 50% (V / V) methanol / water mixed solution, and stir for 48 hours. The solid was removed by filtration, the filtrate was adjusted to pH 4 with 37% hydrochloric acid, and the solvent was removed under reduced pressure to obtain a white solid. The white solid was dissolved in 20 mL of water and adjusted to pH 12 with sodium hydroxide solution. The solution was extracted with 100mL ether, and dried over anhydrous sodium sulfate. Ether was removed under normal pressure to obtain a light yellow liquid, and 6N hydrochloric acid was added slowly. The solvent was removed under reduced pressure to obtain 1.2 g of white solid as the product with a yield of 90%.

[0041] 1 H NMR (D 2 (0, 400 MHz, ppm) δ 4.21-4.19 (m, 2H), 1.93-1.90 (m, 4H), 1.7...

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Abstract

The invention relates to a method for preparing 7-Azabicyclo[2.2.1]heptane as important intermediate in organic chemistry such as a biological fluorescent probe and a biological medicine. The method comprises the following steps of: firstly, reacting trans-4-amino cyclohexanol serving as a raw material with trifluoroacetic acid ester in acetonitrile so that amino is completely acylated and protected, but hydroxyl is not affected, wherein the yield is about 100%; secondly, reacting a protection product of amino with sulfonyl chloride to obtain a protection product of hydroxyl, wherein the yield of the protective product of hydroxyl is about 100%; and simultaneously carrying out deprotection and cyclization reaction in an alcoholic water solution in the presence of weak alkalis to obtain 7-Azabicyclo[2.2.1]heptanes with high purity, wherein the yield of 7-Azabicyclo[2.2.1]heptanes with high purity is 90%. A protecting group of amino adopted in the method is easily removed trifluoroacetyl; and meanwhile, the amino is protected by the trifluoroacetic acid ester instead of acid anhydride in the first step, thus, amino can be selectively protected, but hydroxyl is not affected. In the three-step synthesis process, quantitative high-purity products with the total yield of about 90% are almost obtained in the first two steps, and meanwhile, the reaction in the first step and the reaction in the third step are carried out at room temperature, the reaction condition is mild, and the reactions are simple and convenient to operate.

Description

technical field [0001] The present invention relates to a method for preparing 7-azabicyclo[2.2.1]heptane, in particular, relates to an important intermediate 7-azabicyclo[ 2.2.1] Heptane method. Background technique [0002] In recent years, a series of nitrogen-containing derivatives containing 7-azabicyclo[2.2.1]heptane have attracted great research interest. There are endless reports on the synthesis and reaction of nitrogen-containing bicyclo[2.2.1]heptane derivatives. For the organic compound 7-azabicyclo[2.2.1]heptane, it has been widely used as a special and effective dialkylamine auxochrome in the research of fluorescent probes (Song, X. ; Johnson, A.; Foley, J.7-Azabicyclo[2.2.1]heptane as a Unique and Effective Dialkylamino Auxochrome Moiety: Demonstration in a Fluorescent Rhodamine Dye[J]J.Am.Chem.Soc., 2008, 130, 17652-17653). Using it to replace the traditional dialkylamine group in fluorescent dyes as an electron donor auxochrome has many excellent propert...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/08
CPCY02P20/55
Inventor 宋相志陈颂刘晓忠王建秀
Owner CENT SOUTH UNIV
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