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Synthetic method for aza-bicyclo octane[3.3.0] derivatives

An azabicycle technology and a synthesis method, which are applied in the field of organic compound technology applications, can solve problems such as harsh method conditions and difficult realization, and achieve the effects of simple synthesis route, easily available raw materials, low price, and high yield.

Inactive Publication Date: 2012-12-19
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method has harsh conditions and is difficult to realize in industrial scale-up production

Method used

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  • Synthetic method for aza-bicyclo octane[3.3.0] derivatives
  • Synthetic method for aza-bicyclo octane[3.3.0] derivatives
  • Synthetic method for aza-bicyclo octane[3.3.0] derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Weigh tetrahydrophthalic anhydride XI (152.2mg, 1.0mmol) and p-toluenesulfonic acid (9.5mg, 0.05mmol) in 5.0mL of methanol, and heat to reflux for 5 hours. TLC monitors that the raw material is basically completed, and the solvent is evaporated to dryness by rotary evaporation, diluted by adding 10.0 mL of ethyl acetate, and then washed twice with saturated aqueous sodium bicarbonate solution. After drying over anhydrous sodium sulfate, 188.3 mg of the title compound was obtained. Yield: 95.0%, colorless liquid. Mass spectrometry MS (ESI, m / s): 188.

[0034] 1 H-NMR (CDCl 3 / TMS, 400MHz): δ(ppm) 5.65(s, 2H), 3.66(s, 6H), 3.09~3.01(m, 2H), 2.55~2.50(m , 2H), 2.36 ~ 2.3 (m, 2H).

Embodiment 2

[0036]

[0037] 120.0 mL of compound X (8.4 g, 42.0 mmol) in acetone was slowly added dropwise to 200.0 mL of KMnO 4 (20.3g, 126.0mmol) in aqueous solution, stirred and reacted at room temperature for 3 hours, TLC monitored the disappearance of the starting material. Sodium sulfite and concentrated hydrochloric acid were added, and dichloromethane obtained from the reaction liquid was rotatably evaporated, and then extracted 4 times with ethyl acetate. The ethyl acetates were combined and dried over anhydrous sodium sulfate to obtain 10.3 g of crude product as a white solid. directly into the next reaction.

[0038] Weigh sodium acetate (4.9 g) into the above crude product, add 50.0 mL of acetic anhydride, and then heat to 120° C. for 3 hours to complete the reaction. Drain the acetic anhydride, cool to room temperature, add 50.0 mL of water, and add solid sodium carbonate several times to make the pH value about 9. Extract with ethyl acetate, combine the organic layers,...

Embodiment 3

[0042]

[0043] Weigh compound VIII (1001.0 mg), ethylene glycol (931.5 mg) and p-toluenesulfonic acid (95.1 mg) into a 50.0 mL single-port reaction flask with a water separator, and add 30.0 mL of benzene. Be heated to 90 DEG C of water, about 6 hours reaction finishes substantially. Drain the remaining solvent, add 30.0 mL of ethyl acetate to dilute, wash the organic layer with 10.0 mL of saturated aqueous sodium bicarbonate solution, and then wash the organic layer with 10.0 mL of saturated brine. After drying with anhydrous sodium sulfate, column chromatography gave 1184.4 mg of the target compound. Yield: 97.0%, white solid. Mass spectrometry MS (ESI, m / s): 245 (M+H).

[0044] 1 H-NMR (CDCl 3 / TMS, 400MHz): δ(ppm) 3.89(s, 4H), 3.65(s, 6H), 3.22~3.15(m, 2H), 2.34~2.29(m, 2H), 2.15~2.09(m, 2H) .

[0045] 13 C-NMR (CDCl 3 , 75MHz): δ (ppm) 173.5, 115.5, 64.8, 64.1, 51.9, 43.8, 38.5.

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Abstract

The invention discloses a synthetic method for aza-bicyclo octane[3.3.0] derivatives as represented by formula (I). According to the invention, 1,2,3,6-tetrahydrophthalic anhydride as represented by formula (XI) is used as a raw material and successively undergoes esterification, oxidation, cyclodecarboxylation, a ketal protection reaction for carbonyl groups, reduction, an easily-leaving cyclization group reaction on the carbonyl groups, a cyclization reaction for removal of easily-leaving groups, removal of substituted benzyl groups, a PG reaction on N atoms and removal of ketal protective groups so as to prepare the aza-bicyclo octane[3.3.0] derivatives as represented by formula (I). The invention has the following advantages: reaction conditions are mild; the raw material is easily available and cheap; synthetic route is simple; high yield is obtained; the products, i.e., the aza-bicyclo octane[3.3.0] derivatives can be extensively applied in industrial mass production as important medical intermediates.

Description

technical field [0001] The invention belongs to the technical field of organic compound technology application, and specifically relates to a synthesis method of azabicyclo[3.3.0]octane derivatives. Background technique [0002] Aza-bicyclo octane [3.3.0] derivatives (aza-bicyclo octane [3.3.0] derivatives) is a very important class of chemical intermediates, with very high pharmaceutical application value. In some new drugs reported in recent years, such as serine protease dipeptidase peptidase (DDP-4) inhibitors for the treatment of diabetes (Bioorganic and Medicinal Chemistry Letters, 2010, 20, 3565-3568), are azabicyclic [3.3.0] Octane structure. The synthetic methods of azabicyclo[3.3.0]octane derivatives in the prior art mainly include: one of the methods, as shown in equation (a), is to combine (7S, 8R)-1,4-dioxaspiro[4.4] Nonane-7, 8-dicarboxylic acid dimethyl ester reacted with secondary amine at 190°C for 16 hours with locking (J.Org.Chem.1989, 54, 5115-5122 and ...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 姜雪峰谭忠飞姜卫华
Owner EAST CHINA NORMAL UNIV
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