CH649524A5 - METHOD FOR PRODUCING CYCLOPROPAN DERIVATIVES. - Google Patents

Description

The invention relates to a process for the preparation of cyclopropane derivatives.

DE-OS 2 639 777 describes a multistage process for the preparation of 2- (2,2-dihalogenvinyl) -3,3-dimethylcy-clopropane-carboxylic acid. This acid, especially in the cis form, is a valuable intermediate for the production of insecticidal compounds. The process specified there is based on a compound of the formula

'0

CH-z - C

in which R1 and R2 have the meaning given above, and R3 is an optionally substituted alkyl group with which hypochlorite or hypobromite of an alkali or alkaline earth metal is reacted in the presence of water.

2. The method according to claim 1, characterized in that R1 and R2 each represent an alkyl group having 1 to 4 carbon atoms.

3. The method according to claim 2, characterized in that R1 and R2 each represent a methyl group.

4. The method according to any one of claims 1 to 3, characterized in that R3 is an unsubstituted alkyl group having up to 6 carbon atoms.

5. The method according to any one of claims 1 to 4, characterized in that the hypochlorite or hypobromite is formed in situ.

6. The method according to any one of claims 1 to 5, characterized in that sodium hypochlorite is used.

7. The method according to any one of claims 1 to 6, characterized in that one works at a temperature in the range of -10 to 80 ° C.

8. The method according to any one of claims 1 to 7, characterized in that the molar ratio of hypochlorite ions or hypobromite ions to the compound of general formula II is in the range from 3: 1 to 7: 1.

9. Process for the preparation of cyclopropane derivatives of the general formula

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in which R1 and R2 have the meaning given in claim 1, characterized in that a compound of the formula (I) according to claim 1 is prepared by the process according to claim 1, and the compound formed is converted into the corresponding anhydride.

in which X has different meanings. Trans-ethyl-2-acetyl-3,3-dimethylcyclopropane-carboxy-lat is given as an example of this, and the geometry of this compound is retained in the process described therein unless a special isomerization step is introduced. In fact, the isomerization of either the starting material or any intermediate in the process is extremely difficult, as can be seen from the isomerization exemplified in the OS, in which the trans compound could only be converted to a 70:30 trans: cis mixture. This is obviously a very unsatisfactory way to make the cis compound.

It has now been shown that starting materials of the type specified in DE-OS 2 639 777 can be implemented in such a way that either ice or trans compounds are formed, as desired.

The present invention relates to a process for the preparation of a compound of the general formula

40

45

(I)

in which R1 and R2 each independently represent a hydrogen atom or an alkyl group having up to 10 carbon-50 atoms, or R1 and R2 together represent an alkylene group having 2 to 5 carbon atoms, or an alkali or alkaline earth metal salt thereof. The process is characterized in that an ester of the general formula

CH, -

cu)

65

in which R1 and R2 have the meaning given for the general formula I and R3 denotes an optionally substituted alkyl group, with a hypochlorite or hypo-

3rd

649 524

reacted with an alkali or alkaline earth metal in the presence of water.

R1 and R2 can be the same or different, but are preferably the same. R1 and R2 are preferably each an alkyl group having 1 to 4, in particular 1 or 2, carbon atoms. R1 and R2 are each particularly preferably methyl groups.

The group R3 preferably has up to 6, in particular up to 4, carbon atoms in the alkyl group and the substituents optionally present on the alkyl group can e.g. be selected from halogen atoms, alkoxy groups and phenyl groups. R3 preferably denotes an unsubstituted alkyl group, in particular a primary or secondary group, especially a methyl or ethyl group.

In the method according to the invention, a hypochlorite or hypobromite of an alkali or alkaline earth metal, e.g. of sodium, potassium, calcium, magnesium or barium. A hypochlorite, in particular sodium hypochlorite, is preferably used.

The hypochlorite or hypobromite, where appropriate, may be added to the reaction mixture in the form of a solid (e.g. calcium hypochlorite) or as an aqueous solution or may be formed in situ, conveniently by adding elemental chlorine or bromine to an aqueous one Solution or suspension of an alkali or alkaline earth hydroxide. Thus, in a preferred embodiment of the process according to the invention, the compound of the general formula II is mixed with an alkali metal or alkaline earth metal hydroxide in the presence of water and, if appropriate, one or more additional solvents or diluents, and elemental chlorine or bromine is added in metered amounts to the reaction mixture formed .

The process according to the invention is preferably carried out at a temperature in the range from -10 to +80 ° C. In general, it is preferred to start the reaction at a temperature in the range of -10 to + 20 ° C to avoid the formation of undesirable halogen compounds. In particular, if the hypochlorite or hypobromite is formed in situ, as described above, it is preferred that the reaction mixture is initially at a low temperature, e.g. B. - 10 to + 20 ° C, preferably - 5 to 15 ° C and in particular - 5 to 5 ° C to keep the formation of chlorate or bromate instead of hypochlorite or hypobromite as low as possible. It may be beneficial to raise the temperature of the reaction mixture after an initial reaction time to accelerate the completion of the reaction.

The process according to the invention is carried out in the presence of water. In general, it is preferred that an inert organic solvent is also present to aid in the solution of the starting materials. This additional solvent can be wholly or partly miscible with water, e.g. an alcohol such as ethanol or it may be immiscible with water e.g. a hydrocarbon such as toluene or benzene. In the latter case it is possible that a phase transfer catalyst e.g. Tetrabutylammonium chloride is applied.

The molar ratio of the reactants is not critical. In general, however, it is preferred to use an excess of hypochlorite or hypobromite over the compound of general formula II. The molar ratio of hypochlorite ions or hypobromite ions to the compound of the general formula II is preferably in the range from 3: 1 to 7: 1, in particular from 3.5: 1 to 5: 1.

Depending on the precise reaction conditions, a mono- or dialkali or alkaline earth metal salt of the acid of the general formula I is formed. If the free acid is to be produced, it can be obtained by customary work-up procedures under acidic conditions.

The starting material of the general formula II occurs in the form of isomers in which the CH3CO and the -C02R3 group can be ice or trans to one another. The relative proportion of these eis and trans isomers in the starting material depends on how the starting substance was made. For example, in the process of DE-OS 2 639 777 for the preparation of a compound of the formula II in which R1 and R2 both mean methyl groups, in which a sulfur ylide of the formula (CH3) 2S + - CH-C02R3 with the mesityl oxide (CH3 ) 2C = CH-CO-CH3 is implemented, almost exclusively the trans isomer obtained. Within the scope of this description and the claims, the terms eis and trans refer exclusively to the relative positions of the CH3CO and the C02R3 groups or the groups into which they have been converted. Other isomers can of course occur, e.g. if R1 and R2 have different meanings.

The process according to the invention can be carried out using an eis or trans starting material or a mixture thereof and in general the configuration is retained in the acid obtained. The resulting acid or salt, whatever its configuration, can then be easily converted to the corresponding cis-anhydride of the formula

0

in which R1 and R2 have the meaning given above.

Thus, a preferred embodiment of the process according to the invention also comprises the additional step of converting the resulting acid of the formula I or its alkali metal or alkaline earth metal salt into the corresponding cis-anhydride of the formula III.

A cis acid of formula I or an alkali or alkaline earth salt thereof can be easily converted to the cis anhydride of formula III by known methods, e.g. By gentle heating or by treatment with a dewatering agent, e.g. Phosphorus trichloride or acetic anhydride.

The trans acid or its salt must be treated with somewhat harsher procedures to enable isomerization to the cis anhydride of Formula III, e.g. by converting at least one of the carboxy groups into an acyl halide group or into an anhydride group and then thermally initiating the isomerization to form the cis anhydride of the formula III.

An anhydride group may be one with another molecule of the cyclopropanedioic acid itself, e.g. by heating or by reaction with a dehydrating agent. However, it is preferably a mixed anhydride because the thermal isomerization of a mixed anhydride generally takes place at a lower temperature than that required for an anhydride of the cyclopropanoic acid itself.

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The conversion (functionalization) of the carboxy group (s) into an acyl halide group or an anhydride group can be carried out by known methods, e.g. by reaction with a phosphorus halide or oxyhalide or sulfur oxyhalide or the acyl halide or anhydride of an alkanoic acid, advantageously one having up to 4 carbon atoms in or in each alkyl group. Suitable reagents include PC13, PC15, POCI3, SOCl2, CH3COCI and (CH3C0) 20. The use of acetic anhydride or acetyl chloride is preferred. The functionalization can in some cases be carried out under conditions in which it is not necessary to isolate the acyl halide or anhydride which occurs as an intermediate.

The temperature required to initiate isomerization depends on which functional derivative of the acid has been formed. In general, however, a temperature of at least 130 ° C, preferably at least 160 ° C is used. This temperature can be reached e.g. by heating the functional derivative in the presence of a low-boiling solvent under pressure, by heating the functional derivative in the presence of a high-boiling solvent or by evaporating the functional derivative. For example, the trans acid I or an alkali or alkaline earth salt thereof are dissolved in an alkanoic acid halide or anhydride which serves both as a reagent and as a solvent, e.g. As acetyl chloride or acetic anhydride, and the mixture can be heated under pressure in a sealed tube or an autoclave to prevent evaporation of the solvent. Optionally, the functional derivative can either be formed beforehand or formed in situ, dissolved in a solvent with a boiling point at or above the desired temperature, and heated to the desired temperature under atmospheric pressure. Any aprotic, still boiling solvent that is inert to the reaction products,

can be used for this purpose. For example, N-methylpyrrolidone has been found to be suitable.

Another means of initiating the thermal isomerization comprises introducing the functionalized trans compound, optionally in the presence of an inert solvent, into a hot reaction zone, which preferably contains an inert contact material. Evaporation and isomerization occur under these conditions. The functional starting material, optionally in an inert solvent, e.g. Toluene, xylene or petroleum ether can be pumped into the reaction zone or passed with the aid of a carrier gas which can be one of the above-mentioned solvents in gaseous form or which can be an inert gas such as nitrogen. The reaction zone, which is preferably heated to a temperature between 250 and 350 ° C., is advantageously packed with an inert contact material, which is preferably a mechanically solid material with good thermal conductivity. Suitable for this include Glass, a-aluminum and carborundum.

By a suitable choice of the reaction conditions, it is possible to carry out the reaction starting from the compound of the general formula II to form the cis anhydride of the formula III, without the acid I or a salt thereof occurring as an intermediate having to be isolated and / or purified.

The resulting compound of general formula III can be converted into a corresponding cis-2- (2,2-dihalogen-vinyl) cyclopropanecarboxylic acid in many ways. A number of reactions are given below by way of example. For the sake of simplicity, only the preparation of 2- (2,2-dichlorovinyl) -3,3-dimethyl-cyclopropanecarboxylic acid is described. However, similar methods can also be used to prepare other compounds.

(a) The anhydride of formula III is reacted with sodium tri-chloroacetate, preferably at a temperature in the range of -60 to 60 ° C, in the presence of a solvent such as acetonitrile to form an equilibrium mixture of cis-2-trichloroacetyl-3,3- dimethylcyclopropane carboxylic acid and its lactol tautomer.

(b) The mixture of the tautomers is reacted with sodium borohydride in an aprotic solvent such as dimethylformamide at elevated temperature to form a lactone of the formula:

0

'CH

(c) The lactone is mixed with a strong base, e.g. Potassium tert-butoxide in dimethyl sulfoxide reacted to form the desired cis-2- (2,2-dichlorovinyl) -3,3-dimethyl-cyclo-propane carboxylic acid.

The trans connection can be established as follows:

(a) The mixture of tautomers obtained in step (a) above is reacted with phosphorus trichloride and zinc in the presence of an inert polar solvent such as dimethylformamide to form a lactone of the formula:

Cl

.CH

(b) The lactone is hydrolyzed under alkaline conditions in the presence of methanol to form trans-2-dichloroacetyI-3,3-dimethyl-cyclopropanecarboxylic acid re-methyl ester.

(c) This is reduced to the corresponding alcohol trans-2- (2,2-dichloro-l-hydroxyethyl) -3,3-dimethyl-cyclopropanecarboxylic acid methyl ester.

(d) The alcohol is reacted with tris (dimethylamino) -phosphine (N (CH3) 2) 3P and carbon tetrachloride to form the trans-ester trans-2- (2,2-dichlorovinyl) -3,3-dimethylcyclopropanecarboxylic acid- methyl ester, which can be hydrolyzed under known conditions to form the corresponding trans acid.

It can also be a compound of the general formula:

Hal "C = C;

in the shark a fluorine,

Chlorine or bromine means to be produced. In these processes, a compound of the general formula II is converted into a compound of the general formula I or a salt thereof using Ver4 according to the invention

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driving. The anhydride of the formula III, insofar as it has been produced by the process according to the invention, is used to produce a dihalovinyl-cyclopropanecarboxylic acid, in particular such an acid in cis form.

The invention is illustrated by the following examples.

example 1

Preparation of trans-3,3-dimethylcyclopropane-1,2-dicarboxylic acid

1.5 g of a mixture obtained by reacting the ylide:

C2H50 • CO • CH-S (CH3) 2

with mesityl oxide:

(CH3) 2C = CH-CO-CH3

in toluene and containing 65% by weight of trans-2-acetyl-3,3-dimethyl-cyclopropanecarboxylic acid ethyl ester (5.3 mmol) was dissolved in 3 ml of ethanol and cooled in an ice-water bath. A solution of 0.5 g (12.5 mmol) of sodium hydroxide in 7 ml of water and 21 g of a cold aqueous solution of sodium hypochlorite containing 1.55 mmol of hypochlorite per gram was then added dropwise with stirring. The mixture was stirred for a further hour and the temperature was then slowly increased to 60 ° C. and held at this value for one hour. The mixture was then cooled, extracted with dichloromethane, acidified to pH 1 with concentrated hydrochloric acid, saturated with sodium chloride and extracted with diethyl ether. The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue contained 0.60 g of trans-3,3-dimethylcyclopropane-l, 2-dicarboxylic acid, corresponding to a yield of 72%.

Example 2

The procedure described in Example 1 was repeated with the following changes: No sodium hydroxide solution was added, but instead 7 ml of water, and the mixture was heated to 60 ° C. for 2 hours instead of 1 hour.

0.62 g of trans-3,3-dimethylcyclopropane-1,2-dicarboxylic acid was obtained, corresponding to a yield of 74%.

Example 3

Preparation of the anhydride of cis-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid 1.2 g (7.6 mmol) of trans-3,3-dimethylcyclopropane-1,2-dicarboxylic acid, which had been obtained according to Example 1 , were mixed with 3.5 g (45 mmol) of acetyl chloride at room temperature. After the mixture obtained had been boiled for 2 hours with stirring, excess acetyl chloride was distilled off under reduced pressure (26.6 mbar). 4 ml of N-methylpyrrolodon were added to the residue and the mixture obtained was heated to 200 ° C. for 30 minutes with stirring in a nitrogen atmosphere and this temperature was maintained for 1 hour. After cooling to room temperature, most of the solvent was distilled off under reduced pressure (1.33 mbar) in a rotating band column. The residue contained 0.95 g of the anhydride of cis-3,3-dimethylcyclopropane-l, 2-dicarboxylic acid.

Example 4

Preparation of the anhydride of cis-3,3-dimethylcyclo-

propane-1,2-dicarboxylic acid 1.5 g of trans-3,3-dimethylcyclopropane-l, 2-dicarboxylic acid, which had been obtained according to Example 1, were dissolved in 4 ml of acetyl chloride at 60 ° C. After heating for a further 1 hour at 60 ° C., the volatile constituents were evaporated off under reduced pressure. The residue was dissolved in toluene to obtain 10 ml of solution. This solution was pumped through a glass tube filled with small pieces of glass at a temperature of 300 ° C. (3.2 ml / h). A nitrogen flow was maintained through the tube during the experiment. The product stream was condensed. It was found that it contained the anhydride of cis-3,3-dimethylcyclopropane-1,2-dicarboxylic acid as the main product. Yield 25%.

Example 5

Preparation of the anhydride of cis-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid 3 glass ampoules, each containing 40 ml of trans-3,3-dimethylcyclopropane-l, 2-dicarboxylic acid and 0.15 g of acetic anhydride were placed in an oil bath of Given 220 ° C. The ampoules were then removed from the oil bath after Vi, 1 or 2 hours.

The NMR spectrum of the content showed that all three ampoules contained the anhydride of cis-3,3-dimethylcyclopropane-1,2-dicarboxylic acid as the only cyclopropane derivative and that no decomposition products were formed.

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Claims (2)

649 524 2nd PATENT CLAIMS 1. Process for the preparation of cyclopropane derivatives of the general formula (I) in which R1 and R2 each independently represent a hydrogen atom or an alkyl group having up to 10 carbon atoms or R1 and R2 together represent an alkylene group having 2 to 5 carbon atoms, or an alkali or alkaline earth metal salt thereof, characterized in that an ester of the general formula CH. m) jC (in)