HU217185B - Halogenated 1r,cis-2,2-dimethyl-cyclopropane-1-carboxylic acid lactone derivatives and preparation thereof - Google Patents

Abstract

The present invention relates to novel compounds of the general formula (III1), (III2) or (III3), from which X is a genes of the gene, and to the production of compounds having a ring of 2,2-dimethyl-3- (2-oxo-propyl) cyclopentane-1-carbamic acid at least Treated with 2 equivalents of fish gene, preferably chlorine, bromine or iodine, and treating the crude reaction mixture with a base, in the case of an acidic addition, the genesis of the general compound (III1) or (III2) obtained is melted with an excess of gene (III3) to produce a compound of the general formula. ŕ

Description

The present invention relates to halogenated 1R, cis-2,2-dimethylcyclopropane-1-carboxylic acid lactone derivatives and their preparation.

According to the present invention, an IR, cis-configurated compound of formula (II) is reacted with at least 2 equivalents of halogen, preferably chlorine, bromine or iodine, to give a compound of formula (III i), (III ₂ ) or (III ₃ ) which may be generated with a compound (IV) of the formula, and optionally after treating the crude reaction mixture with a base can be further halogenation of the resulting (III _t) or (III ₂₎ wherein the compound of formula is carried out in an excess of the halogen mentioned above (III ₃₎ of the formula compound.

Accordingly, the invention is a compound, cis configuration (II) is treated with at least 4 equivalents of a halogen (III ₃₎ A compound of formula (IV) formed of a mixture of a compound of formula for the preparation.

More particularly, the process of the invention is characterized in that the halogen is chlorine or bromine.

Preferably, the halogenation is carried out at room temperature in a halogenated organic solvent such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or a mixture of these solvents, or in an organic ester such as ethyl acetate.

The crude reaction mixture from the halogenation is treated with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate before isolating the halogenated compound.

The starting material of the process of the present invention may be a compound of formula (II) which is, for example, Agr. Biol. Chem., Vol. 29, No. 8, p. 784 (1965).

Reaction of the compound of formula II with a halogen directly results in the open form of the lactone of formula III, III ₂ or III ₃ , from which the lactone is reacted with an alkaline agent in an aqueous medium. A certain amount of the acid actin of formula (IV) may also be produced simultaneously per lactone, and more particularly the lactone of formula (III ₂ ) and (III ₃ ).

Thus, the reaction is illustrated by the following general scheme.

The compounds of formula III, III ₂ and III ₃ are novel compounds.

Further details of the invention are illustrated by the following examples.

Example 1 (1R- (1alpha, 4beta, 5alpha)) -6,6-dimethyl-4- (tribromoacetyl) -3-oxabicyclo [3.1.0] hexan-2-one and (1S- (1alpha, 2beta) (5 alpha)) - 6,6-dimethyl-4-oxo-3-oxabicyclo [3.1.0] hexane-2-carboxylic acid 0.51 g of 1R, cis-2,2-dimethyl-3- (2-oxopropyl) A mixture of cyclopropane-1-carboxylic acid, 10 cm ^{3 of} chloroform and 10 cm ^{3 of} carbon tetrachloride was stirred under an inert gas atmosphere, cooled to 5 ° C, and 0.7 cm ³ of 4.5 equivalents of bromine was added slowly. After stirring at room temperature for 18 hours, 15 cm ^{3 of} ice-cooled water was added, stirring was continued for 1 hour, potassium carbonate (2.12 g) was added and stirring was continued for 1 hour. The whole was poured into 15 cm ^{3 of} water and extracted with methylene chloride. The organic phase is dried and evaporated to dryness. The crude product was recrystallized from a mixture of methylene chloride and isopropyl ether to give 0.222 g of the expected tribrominated derivative, m.p. 188-190 ° C. Thin layer chromatography of the reaction mixture revealed the presence of the dibrominated derivative along with the tri-brominated derivative.

The aqueous phase was acidified to pH 1 by addition of 2N hydrochloric acid and extracted with ethyl acetate: methanol (9: 1). The organic phase is dried and the solvent is evaporated. The residue was chromatographed on silica, eluting with a 75:25 by volume mixture of ethyl acetate and methanol. 0.2 g of 2,2-dimethyl-3- (hydroxycarboxymethyl) -cyclopropane-1-carboxylic acid lactone or (1S (1alpha, 2beta, 5alpha)) - 6,6-dimethyl-4-oxo-3 oxa-bicyclo [3.1.0] hexane-2-carboxylic acid is obtained.

1 H NMR (CDCl ₃ -250 MHz): 1.24 and 1.30; CH ₃ twin; 2.17 (d, J = 6) and 2.31 (d, J = 6); H, and H ₃ 5.56 (s) -O-CH-CO-.

Example 2 (1R- (1alpha, 4beta, 5alpha)) -6,6-dimethyl-4- (dibromoacetyl) -3-oxabicyclo [3.1.0] hexan-2-one and (1S- (1alpha, 2beta) (5 alpha)) - 6,6-Dimethyl-4-oxo-3-oxabicyclo [3.1.0] hexane-2-carboxylic acid 0.34 g of 1R, cis-2,2-dimethyl-3- (2-oxopropyl) ) -cyclopropane-1-carboxylic acid 6 cm ³ of chloroform, and 6 cm ³ of carbon tetrachloride in an inert gas atmosphere were mixed, and the mixture was cooled to 5 ° C and then slowly added 0.4 cm ³ of 4 equivalents of bromine. Stir at 5 ° C for 6 hours and then at room temperature for 16 hours. After cooling to 5 [deg.] C., 10 cm <^{3> of} ice-water are added and the mixture is stirred for another hour, and then 1.5 g of potassium carbonate are added and the mixture is stirred again for 1 hour. The mixture was poured into 15 cm ^{3 of} water and extracted with methylene chloride. The organic phase is dried and the solvent is evaporated. 0.22 g of the desired product is obtained with traces of the corresponding tribrominated derivative.

The aqueous phase was acidified to pH 1 by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. The residue is chromatographed on silica. The eluent was a 9: 1 mixture of methylene chloride and acetic acid. 0.1 g of lactone of 2,2-dimethyl-3- (hydroxycarboxymethyl) -cyclopropane-1-carboxylic acid or (1S- (1?, 2?, 5?, 5?)) - 6,6-dimethyl-4-oxo-3-oxa bicyclo [3.1.0] hexane-2-carboxylic acid is obtained.

1 H NMR (CDCl ₃ -250 MHz) of the dibrominated derivative: 1.24 and 1.25; CH ₃ twin; 2.07 (d, J = 6) and 2.41 (d, J = 6); H, and H ₃ ; 4.90 (s): -CO-CH-O-, 6.38 (s): = C-CHX ₂ .

Example 3 (1R- (1alpha, 4beta, 5alpha)) -4- (bromoacetyl) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexan-2-one

0.54 g of 1R, cis-2,2-dimethyl-3- (2-oxopropyl) cyclopropane-1-carboxylic acid, 5 cm ^{3 of} carbon tetrachloride and 10 cm ^{3 of} methylene chloride are mixed with inert gas.

185 ° C, cool to +2 and 5 ° C, then slowly add 0.32 cm ^{3 of} 2 equivalents of bromine. After stirring at room temperature for 1 hour 30 minutes, water (10 cm ³ ) is added and the mixture is stirred for another 15 minutes. After cooling to + 5 ° C, 1.32 g of potassium carbonate are added and the mixture is stirred at + 5 ° C for 1 hour. The mixture was poured into 20 cm ^{3 of} water and extracted with methylene chloride. The organic phase is dried, the solvent is evaporated off and the residue is chromatographed on silica. Elute with a 7: 3 (v / v) mixture of ethyl acetate and cyclohexane. 0.51 g of the expected product is obtained. 1 H NMR (CDCl ₃ -25O MHz):

1.23 (s): CH ₃ twin; 2.05 (d, J = 6) and 2.34 (d, J = 6); H _t and H ₃ (cis cyclopropyls; 4.09 (d, J 1 = 12.5) and 4.23 (d, Jab = 12.5): -CO-CH ₂ X; 4.68 (s) - CO-CH-O-CO-.

Example 4 (1R- (1alpha, 4beta, 5alpha)) -4- (dibromoacetyl) -6,6-dimethyl-3-oxabicyclo [3.1.1] hexan-2-one

0.125 g of Example 3 (1R- (alpha, 4beta,

5 alpha) -4- (bromoacetyl) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexan-2-one is mixed with 1 cm ^{3 of} methylene chloride and 1 cm ^{3 of} chloroform under an inert gas atmosphere. Add 50 μ 50 of bromine slowly at 25-30 ° C and stir at room temperature for 48 hours. Water was added, then decanted and extracted with methylene chloride. The organic phase is dried, the solvent is evaporated off under reduced pressure and 0.199 g of the desired product is obtained in the form of an oil. 1 H NMR (CDCl ₃ -25O MHz):

1.24 (s): CH ₃ twin; 2.08 (d) and 2.41 (d): H and H ₃ ; 4.90 (s): -CO-CH-O-; 6.38 (s): CO-CHX _second

Claims (7)

PATENT CLAIMS A process for the preparation of a mixture of a compound of formula (III), (III ₂ ) or (III ₃ ) wherein X is halogen optionally with a compound of formula (IV), characterized in that Compound III is treated with at least 2 equivalents of halogen, preferably chlorine, bromine or iodine, and after treatment of the crude reaction mixture with a base, optionally halogenation of the resultant compound (IIIj) or (III ₂ ) to give compound (III ₃ ). 2. The method of claim 1, wherein the compound of formula (II) R, cis configuration is used, and this is treated with at least 4 equivalents of a halogen (III ₃₎ and compound (IV) is a mixture of compound represented by formula. The process according to claim 1 or 2, wherein the halogen is chlorine or bromine. 4. A process according to any one of claims 1 to 3, wherein the process is carried out in a halogenated organic solvent or an organic ester. 5. Process according to any one of claims 1 to 3, characterized in that the crude reaction product obtained from the halogenation is treated with a basic agent, preferably an alkali metal, alkaline earth metal hydroxide or carbonate, before the halogenated compound is isolated. 6. A process according to claim 1 wherein the basic agent is an alkali metal or alkaline earth metal hydroxide or carbonate in the presence of water. 7. Compounds of formula (III), (III ₂ ) and (III ₃ ) wherein X is halogen.