CS255176B1 - Substituted (E) -3-mathylene-hoxahydro-2 (3H) -benzofuranones and their method of preparation - Google Patents

Abstract

The newly discovered (E)-3-methylene-substituted hexahydro-2(3H)-benzofuranones of the general formula I, where X represents a morpholino-, piperidino-, pyrrolidino-, (E ,-hexahydro-2(3H)- -benzofuranone-3-methyleneoxy- or (Z)-hexahydro-2(3H)-benzofuranone-3-methyleneoxy group, which have potential antitumor activity and can be used as precursors for the preparation of substances with similar properties, are prepared by reacting a solution of 3-(4- -toluenesulfonyloxymethylene)hexahydro-2-(3H)-benzofuranone in aqueous acetone with morpholine, piperidine, pyrrolidine or with a solution of the sodium salt of 3-(hydroxymethylene)-hexahydro-2(3H)-benzofuranone in the same solvent.

Description

The invention relates to 3-methylenesubstituted hexahydro-2 (3H) -benzofuranones and to a process for their preparation.

Natural sesquiterpenes containing the alpha-methylenlactone moiety exhibit antitumor activity in some cases, but are also highly toxic. Some synthetically prepared alpha-methylenlactone derivatives, such as 3-methylenedihydro-2 (3H) -furanone, also have similar properties (Stang P.J., Treptow W.L. S. J. Med. Chem. 24, 469, 1981).

The compounds prepared according to the invention may be expected to exhibit some antitumor activity on account of their structural similarity to the compounds, and may also serve as precursors for the preparation of other compounds with similar activity (Grieco P. A., Synthesis 1975, 67).

Substituted 3-methylenehexahydro-2 (3H) -benzofuranones of the formula I have been found according to the invention

X wherein X is morpholino-, piperidino-, pyrrolidino, (E) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy of formula cxé or (Z) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy of formula

UČ

These compounds can be prepared by reacting a 1% to saturated solution of 3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in an oetone-water ratio of 1: 5 to 5: 1 with 2- to 3-fold molar amounts of morpholine or piperidine; pyrrolidine or with a 1% to saturated solution of 1- to 2-fold molar amount of 3- (hydroxymethylene) hexahydro-2 (3H) -benzofuranone sodium in the same solvent. When the (E) -isomer of 3- (4) -toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone is used as the starting material in the last reaction, the product is a compound of formula I wherein X is (E) -hexahydro-2 ( 3H) -benzofuranone-3-methyleneoxy.

When the (Z) -isomer is used, the reaction product is a mixture of compounds of formula I wherein X is (E) - or (Z) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy which can be separated by chromatography.

Example 1

To a solution of 6 g of 3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in 100 ml of 3: 2 acetone-water was added 3.6 ml of morpholine and the mixture was stirred at room temperature for 10 hours. After working up the reaction mixture, 3.6 g of (E) -3- (morpholinomethylene) hexahydro-2 (3H) -benzofuranone (compound of formula I wherein X is morpholino) are obtained, i.e. 74% of theory, m.p. Mp 5-130 ° C.

Example 2

To a solution of 9 g of 3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in 150 ml of 2: 1 acetone-water was added 6 ml of piperidine. The reaction mixture was stirred at room temperature for 6 hours. Workup of the reaction mixture gave 6.3 g (95%) of (E) -3- (piperidinomethylene) hexahydro-2 (3H) -benzofuranone (compound of formula I wherein X is piperidino), m.p. 88-89 ° C.

Example 3

To a solution of 12 g of 3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in 250 ml of 4: 1 acetone-water was added 7 ml of pyrrolidine and stirred at room temperature for 10 hours. Further work-up of the mixture afforded 7.1 g (81%) of (E) -3- (pyrrolidinomethylene) hexahydro-2- (3H) -benzofuranone (compound of formula I wherein X is pyrrolidino), mp 89-90 ° C.

Example')

To a solution of 3 g of (E) -3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in 50 ml of 3: 1 acetone-water was added a solution of 2 g of 3- (hydroxymethylene) hexahydro-2 sodium salt. Of (3H) -benzofuranone in 50 ml of the same solvent. After stirring at room temperature for 10 hours, the reaction mixture was worked up to give 2.7 g (91%) of (E, E) -3,3 '- (oxydimethylidin) bis (hexahydro-2 (3H) -benzofuranone) (compound of formula Where X is (E) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy, mp 250-252 ° C.

Example 5

To a solution of 6 g of (Z) -3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in 100 ml of 3: 1 acetone-water was added a solution of 5 g of 3- (hydroxymethylene) hexahydro-2 sodium salt. (3H) -benzofuranone in 100 ml of the same solvent. After stirring at room temperature for 8 hours, the reaction mixture was worked up and chromatographed to afford 2.9 g (49%) of (E, Z) -3,3 '- (oxydimethylidin) bis (hexahydro-2 (3H) -benzofuranone) ( compound of formula I wherein X is (Z) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy), mp 256.5-257 ° C, and 1.4 g (24%) (E, E) -3,3 '- (oxydimethylidin) bis (hexahydro-2 (3H) -benzofuranone).

. SUBJECT OF THE INVENTION

Claims (2)

. SUBJECT OF THE INVENTION 1. Substituted (E) -3-methylenehexahydro-2 (3H) -benzofuranones of the general formula I X wherein X is morpholino-, piperidino-, pyrrolidino-, (E) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy- or (Z) -hexahydro-2 (3H) -benzofuranone-3-methyleneoxy. 2. A process for the preparation of compounds according to claim 1, wherein a solution of 3- (4-toluenesulfonyloxymethylene) hexahydro-2 (3H) -benzofuranone in aqueous acetone is treated with 2-3 times molar amounts of morpholine, piperidine or pyrrolidine or 1-2 times molar amounts. 3- (hydroxymethylene) hexahydro-2 (3H) -benzofuranone sodium salt.