SU731731A1 - 6-acetoxymethylene-3-oxa-2-bicyclo-(3,3,0)-oct-7-ene as intermediate compound in full synthesis of prostaglandines and method of obtaining same - Google Patents

Abstract

1. 6-Atsvtoksimetilen-3-oxo-2-oxa-bicyclo

Description

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: o 1 The invention of olHocHTCH to new derivatives of bicyclo-octene, specifically, to 6-acetoxymethylene-3-oxo-2-oxabicyclo- (3.3.0) -oct-7-ene formula (1): g (3 - СН -0-С СНз and to the method of its preparation.

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(1P)

H

RL pieces aOH at HC1

(OR)

A significant disadvantage of this method is its multistage nature, which is associated with the need to introduce protective groups. The analogue of the claimed compound is also 6-methoxymethyl-3-oxo-2-oxabicyclo- (3,3,0) -oct-7-ene (V) 2. It is obtained from 5-nitro-7-methoxymech1CH (OR ),

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bicyclo- (2,2,1) -hept-2-ene CIV) according to the scheme, which includes treatment (IV) with alkali and hydrochloric acid. This produces a mixture of (V) and 7-methoxymetch-1-4-oxo-3-aza-2-oxabicyclo- (4,3,0) -non-8-ene (VI), and from (VI) it is then transferred to (V) reaction with sodium nitrite: 1 her compound is intermediate in the complete synthesis of prostaglandins (PG) - biologically active natural compounds. Known are the bicyclic precursors of PG - 6-dialkoxymethyl-3-oxo-2-oxabicyclo- (3,3,0) -oct-7-ene of general formula (II) and the method for their preparation, starting from 5-nitro-7 acetoxymethylene bicyclo- ( 2,2,1) -hept-2-ene (III). in four stages according to the scheme:

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A significant disadvantage of 6-methoxymethyl-3-oxo- -oxabicyclo- (3,3,0) -oct-2-ene (V) as an intermediate in the synthesis of PG is the difficulty of re373

move from it to the universal predecessor of NG - Corey aldehydolactone (VII). This transition can theoretically be carried out in two stages (saponification and oxidation), but it requires special experimental conditions for the preservation of two labile elements of the structure — the double bond and the lactone moiety.

The purpose of this invention is to expand the range of GHG precursors, using a number of

simplifies the transition to final products.

This goal is achieved by the method of obtaining 6-acetoxymethylene-3-oxo-2-oxa-bicyclo- (3,3,0) -oct-7-ene by sequential treatment with 7-acetoxymeththene-5-nitrobicyclo- (2,2,1 ) -hept-2-ena base and acid in the environment of aliphatic alcohol at a temperature of 0-10 ° С „

The process proceeds according to the scheme:

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H (Sha)

ABOUT

0- SNOAc

U.P.

The present method of producing 6-acetoxymethylene-3-oxo-2-oxabicyclo- (3,3,0).-Oct-7-ene (1) is based on the known ability of nitro compounds to interact with bases and acids. A method of obtaining analog (V) is also based on this reaction. However, despite the fact that the interaction of nitro compounds with. Bases and acids are known; in the number and in the row of nitrobicycloheptanes, the ambiguity of this reaction is noted depending on the structure of nitrobicyclohepthene. The presence of a double bond in the seventh position of the starting (III) presupposes the possibility of a different direction of cyclization of the intermediate hydroxamic acid (III a) with the formation of a product different from the claimed one. Therefore, the use of this reaction as a method of the claimed compound (I) is not obvious.

The process is carried out in a polar solvent. As

the solvent is used alcohol, mainly methanol, the reaction temperature is maintained in the range of 0 - (- 10 ° C). The optimum time of the process is 4 hours. Then the reaction mixture is processed and the target product is separated by chromatography on silica gel.

Example 1. To an ice-cooled solution () of 0.52 g (0.25 mmol) of 5-nitro-7-acetoxymethylenebicyclo- (2.2.1) -hept-2-ene in 4 ml of methanol is added dropwise 10 ml of a 20% sodium hydroxide solution and stirred for 3.5 hours. The resulting solution was added dropwise to 10 ml of concentrated hydrochloric acid at a temperature of -10 ° C. The reaction mixture was stirred for 45 minutes and extracted with chloroform, the organic phase was washed with water, the solvent was removed in vacuo, the residue was chromatographed on silica gel 100/160 (and eluting the product with a mixture of benzene: ethyl acetate 6: 4i) Oj15 g (3.0%) chromium was obtained of tographically pure b-acetoximethien-3-oxo-2-oxabicyclo- (3.3.0) oct-7-ene (1) Rf 0.44 (Silufol plates, benzyl ethyl acetate 9: 1). IR spectrum, cm - : 1740 (-С-СНа), -, О 1775 (С О lactone). Mol. Weight (mass spectrometrically) 194, Calculated for C, 04 194. Example 2. To cooled with ice and salt (-10 s) 20 ml of sodium hydroxide solution are added dropwise to a solution of 1.04 g (0.5 mmol of 5-nitro-7-acetoxymethylenebicyclo- (2.2.1) -hept-2-ene in 15 MP of isopropyl alcohol and stirred for 3 hours The crawled solution is added dropwise to 20 MP of concentrated hydrochloric acid at a temperature and the mixture is continued mixing is half an hour. Next, the reaction mixture is processed as described in Example 1. 0.32-g (32%) of chromatographically pure 6-acetoxymethylene 3-oxo-2-oxabicyclo (3.3.0) oct-7-ene (1) is obtained, identical to the above obz I Example. To a cooled solution of 1.2 g (0.6 mmol) of 5-nitro-7-acetoxymethylene bicyclo- (2,2,1) -hept-2-ene in 40 ml of methanol at a temperature O - a cooled solution is dropped to 0 ° С sodium methoxide, prepared from 0.33 g of sodium by dissolving in 10 ml of methanol. The reaction mixture is stirred for 3 hours. The pollen solution is cooled before and with vigorous stirring, 1.7 M hydrochloric acid and 20 MP of methanol are added to the mixture, keeping the temperature of the reaction mixture within -10 -. The stirring is continued for 1 hour at 0 ° C and 1 h at ksmnatnoy temperature, Next, the reaction mixture is treated as described in example 1. Obtain 0.4 g (32%) of b-acetoxymeter-3-oxo-2-oxabicyclo- (3,3,0) -oct-7-ene (T), identical to the above sample. Use of the claimed 6-ace; toxymethylene-3-oxo-2-oxabicyclo- (3,3,0) -oct-7-ene ") as a precursor of aldehydolactone Cory (VII) allows a short one-step transition from (f) to the universal precursor (VIII) This transition is accomplished by the stereospecific mint of the 6-acetoxymethylene group in the compound (O under mild conditions.

Claims (2)

1. 6-Acetoxymethylene-3-oxo-2-oxa-bicyclo- (3,3,0) -οκτ-7-ene formulas as an intermediate in the complete synthesis of prostaglandins. 2. The method of obtaining the compound according to claim 1, characterized in that 7-acetoxymethylene-5-nitrobicyclo- (2,2,1) -hept-2-ene is sequentially treated with base and acid in a C ₄ -C * aliphatic alcohol medium at temperature 0 (-10 ° С).