PL179695B1 - Method of obtaining substituted gem-diflurocyclopropanes - Google Patents

Abstract

1. The method of producing substituted gem-difluorocyclopropanes of general formula I, wherein R1 and R2 are hydrogen, alkyl, or the aryl group and are the same or different, or R1 and R2 together represent hydrocarbon portions a chain of 3 to 7 atoms carbon and Z is an electron withdrawing group alkoxycarbonyl or acyl or sulfone or thioethers, characterized in that gem-dichlorocyclopropanes of general formula 2, wherein R1, R2 and Z are as defined above reaction with a fluoride anion-containing salt and optionally with tetraalkylammonium salt at temperature 0-150 ° C, in a polar aprotic solvent or dipolar or in an ethereal solvent or in a mixture of these solvents with water, the salt containing the fluoride anion it is used at least twice the mole excess.

Description

The subject of the invention is a process for the preparation of gem-difluorocyclopropanes of the general formula I, in which R and R2 represent hydrogen atoms, an alkyl group or an aryl group and may be the same or different, or R1 together with R2 represent parts of a hydrocarbon chain containing from 3 to 7 carbon atoms and Z is an electron withdrawing group.

There are known methods of obtaining gem-difluorocyclopropanes which do not contain electron-withdrawing groups marked with the letter Z in the formula.

Also described is a method for the preparation of one of the compounds described by the general formula 1, namely 1,1-difluoro-2-cyanocyclopropane (D. Seyferth, S. Hopper; J. Org. Chem., 37, 4070, 1972). It was obtained by heating acrylonitrile with phenyltrifluoromethylmercury and sodium iodide in absolute toluene under an inert gas atmosphere and isolated by preparative gas chromatography in low yield.

This reaction uses an expensive, hardly available and toxic organomercuric compound, it is conducted in a strictly anhydrous environment, and moreover, it has not been shown to be generally applicable to the preparation of the derivatives of formula 1.

The aim of the invention was to develop a process of general nature, based on the available raw materials and technologically simple.

A method for the preparation of substituted gem-difluorocyclopropanes of general formula I, wherein IR and R2 are hydrogen or alkyl or aryl are the same or different, or R1 and R2 collectively represent parts of a hydrocarbon chain containing from 3 to 7 carbon atoms, and Z is an electron withdrawing group, characterized in that gem-dichlorocyclopropanes of general formula 2, where R _b, R ₂ and Z are as defined above, are reacted with a salt containing a fluoride anion, at a temperature of 0-150 ° C, in a polar aprotic or dipolamic solvent, or in an ethereal solvent or in a mixture of these solvents with water. A salt containing a fluoride anion is used at least

179 695 two-fold molar excess. As an electron withdrawing group, an alkoxycarbonyl, acyl, sulfonate, thioether group is used. As salts containing the fluoride anion, alkali metal fluorides or tetraalkylammonium fluorides are preferably used. When using an alkali metal fluoride, a tetraalkylammonium salt is additionally used, preferably tetran-butylammonium sulfate.

The reaction products are usually isolated by extraction of the water-diluted reaction mixture with a nonpolar solvent and distillation, or column chromatography and / or crystallization.

The compounds of general formula II are obtained according to known methods, e.g. by reaction of acrylic acid esters with chloroform under conditions of phase transfer catalysis (M. Fedoryński, W. Żółtowska, A. Jończyk; J. Org. Chem., 58, 6120, 1993 ).

The compounds according to the invention can be used for the preparation of biologically active compounds and for the production of fragrances.

The method according to the invention is presented in more detail in the application examples.

Example 1: 1,1-Dichloro-2- (t-butoxycarbonyl) cyclopropane (1.9 g, 9 mmol), potassium fluoride (10.5 g, 180 mmol), tetran-butylammonium bisulfate TBAHS (9 , 2 g, 27 mmol), acetonitrile (50 ml), water (7.5 ml) and the mixture was stirred and heated at 80-85 ° C for 8 hours. The mixture was diluted with water (ca 250 ml), extracted with pentane (3 x 60 ml), the combined organic phases were washed with water (3 x 150 ml) and dried over anhydrous MgSO ₄ . After stripping the solvent, the residue was distilled to give 1.0 g (66% yield) of 1,1-difluoro-2- (t-butoxycarbonyl) cyclopropane, bp 42 ° C / 4 kPa.

For formula C ₈ H _I2 F ₂ O ₂ (178.18): obi. C 53.93% H 6.79% equation C 53.71% H 6.78%

Example II. 1,1-Dichloro-2- (isopropoxy carbonyl) -3-methylolopropcin, mixture of diastereoisomers (3.4 g, 16 mmol) was dissolved in DMF (20 ml), cooled to 0 ° C and with stirring A solution of tetra-n-butylammonium fluoride TBAF x 3H ₂ O (15.2 g, 48 mol) in DMF (30 ml) was added dropwise over 2 hours, maintaining the temperature at 5 ° C. After the dropwise addition, the mixture was stirred at 5 ° C for 4 hours, diluted with water (ca. 500 ml) and extracted with pentane (3 x 120 ml). The combined organic extracts were washed with water (3 x 400 mL), dried with anhydrous MgSO ₄ , the solvent stripped and the residue distilled. 1,1-Difluoro-2- (isopropoxycarbonyl) -3-methyl-cyclopropane (mixture of diastereoisomers), boiling point 159 ° C / 101.3 kPa, was kept at 2.0 g, 70% of theory.

For formula C ₈ H ₁₂ F ₂ O2 (178.18): obi. C 53.99% H 6.79% Eq. C 54.20% H 6.86%

Example III. To a stirred solution of TBAF x 3 H ₂ O (38.0 g, 120 mmol) in DMSO (70 ml) was added dropwise over 3 hours a solution of 1,1-dichloro-2,2-dimethyl-3- (isopropoxycarbonyl) cyclopropane (9, 0 g, 40 mmol) in DMSO (40 mL) while maintaining the temperature at 5-10 ° C. After the dropwise addition, stirring was continued at 5-10 ° C for 2 hours, diluted with water (ca. 800 ml), extracted with pentane, the organic extracts washed with water and dried over MgSO4. The solvent was stripped on a vacuum evaporator and the residue was chromatographed on a silica gel column (Merck Silica gel 60), eluting with hexane / ethyl acetate -1: 1. 4.2 g (55% yield) 1,1-difluoro-2,2-dimethyl-3- (isopropoxycarbonyl) cyclopropane are obtained in the form of a colorless oil.

For the formula C ₉ H _I4 F2O ₂ (192.20): c ^ t> l. C 56.24% H equivalent C 56.29% H 7.45%

Example IV. 1,1-dichloro-2- (phenylsulfonyl) cyclopropane (4.5 g, 18 mmol), potassium fluoride (15.7 g, 270 mmol), tetra-n-butyl ammonium chloride (7.5 g, 27 mmol) dioxane (100 mL) and water (10 mL) were stirred at ca. 100 ° C for 10 hours, cooled to room temperature, and diluted with water (400 mL). The organic products were extracted with methylene chloride (3 x 100 ml), the combined extracts were washed with water (2 x 200 ml) and dried (MgSO ₄ ). Dissolve 4

The solvent was stripped and the residue was crystallized from hexane to give 2.7 g (69% yield) of 1,1-difluoro-2- (phenylsulfonyl) cyclopropane, mp 91 ° C.

For formula C ₉ H ₈ F ₂ O ₂ S (218.22): obi. C 49.54% H 3.70% S 14.69% equation C 49.73% H 3.72% S 14o57%

Example 5 1,1-Dichloro-2-benzoylcyclopropane (1.7 g, 8 mmol) and HMPT hexamethylamide (6 mL) were charged to a round bottom flask. Stirring was started, the contents of the flask were cooled to 10 ° C and a solution of TBAF x 3H ₂ O (7.9 g, 25 mmol) in HMPT (10 ml) was added dropwise over 1 hour maintaining the temperature at 15-20 ° C. After the dropwise addition, the reaction was run at 15-20 ° C for 2 hours, diluted with water (ca. 300 ml) and extracted with pentane (3 x 60 ml). The organic extracts were washed sequentially with 1% hydrochloric acid (50 ml), water until neutral and dried over _MgSO4 The residue after evaporation of solvent was distilled in vacuo, collecting the 1,1-difluoro-2-be7zoilocyklopropa7 b.p. 120 ° C / 3.6 kPa in the amount of 0.8 g (55% yield).

1 HNMR (COCl ₃ ): 1.78 - 1.84 (m., 1H, CHCO), 2.34 - 2.45 and 3.32 - 3.47 (dm, 2H, CH2), 7.47 - 8.03 (m, 5H, ArH).

Example VI. Cesium fluoride (76.0 g, 500 mmol), 1,1-dichloro-2-phenyl-3- (methylthio) cyclopropane as a mixture of diastereoisomers (11.65 g, 50 mmol), DMF (400 ml) 1 tetra chloride -n-butylammonium (41.6 g, 150 mmol) was stirred and heated at 120-130 ° C for 8 hours. The mixture was cooled to ca. 20 ° C, diluted with water (1500 ml) and extracted with hexane (5 x 100 ml). The combined organic extracts were washed with ca 0.5% hydrochloric acid (300 ml), water (3 x 200 ml), dried over MgSO ₄ and the solvent was evaporated. The residue was separated by column chromatography (Merck Silica gel 60, eluent hexane / ethyl acetate gradient) to give a mixture of 1,1-difluoro-phenylG4-methylthio-cyclopropane diastereoisomers in 4.8 g, 48% of theory.

For the formula C ₁₀ H ₁₀ F2S (200.25): < RTI ID = 0.0 > S 16.01% equivalent S 16.22%

Example VIII. To a suspension of potassium fluoride (23.2 g, 400 mmol) in DMF (100 ml) was added 1,1-dichloro-2-acetylspiro [2.5] octane (4.4 g, 20 mmol), TBAHS (23.7 g, 70 mmol) and the mixture was vigorously stirred and heated to ca. 110 ° C for 4 hours. The mixture was cooled to 5-10 ° C, the solids were filtered off, washed with hexane (3 x 50 ml), the filtrate was diluted with water (400 ml) and the organic phase was separated. The aqueous phase was extracted with hexane (3 x 50 ml), the organic extracts were washed with water (2 x 100 ml), dried with MgSO 4, the solvent was evaporated and the residue was distilled. 1.9 g (51% yield) of 1,1-difluoro-2-acetylspiro [2.5] octane were obtained, boiling point 70 ° C / 40 kPa.

For the formula C | ₀ H ₁₄ F ₂ O (188.22): cal. C 63.81% H 7.50% Eq. C 63.99% H 7.52%

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Claims (5)

Patent claims A method for the preparation of substituted gem-difluorocyclopropanes of general formula I, wherein R 1 and R ₂ represent a hydrogen atom, an alkyl group or an aryl group and are the same or different, or R and R ₂ together represent parts of a hydrocarbon chain containing from 3 up to 7 carbon atoms, and Z is an electron-withdrawing alkoxycarbonyl or acyl or sulfone or thioether group, characterized in that gem-dichlorocyclopropanes of the general formula 2, in which R1, R2 and Z are as defined above are reacted with a salt containing a fluoride anion and optionally with a tetraalkylammonium salt at a temperature of 0-150 ° C, in a polar or dipolar aprotic solvent or in an ethereal solvent or in a mixture of these solvents with water, the salt containing the fluoride anion being used in at least a 2-fold molar excess. 2. The method according to p. The process of claim 1, wherein the salt containing the fluoride anion is tetraalkylammonium fluorides. 3. The method according to p. The process of claim 1, wherein the ammonium fluoride-containing salt is alkali metal fluorides. 4. The method according to p. The process of claim 1, wherein the tetraalkylammonium salt is added when alkali metal fluorides are used as the salt containing the fluoride anion. 5. The method according to p. The process of claim 1, wherein the tetraalkylammonium salt is tetra-n-butylammonium sulfate.