HU203520B - Process for producing disubstituted cyclopropane derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of geminal disubstituted cyclopropane derivatives of formula (I) wherein X is halogen or methyl, Y and Z are the same or different, and cyano, COOR, wherein R1 is C1-4 alkyl; or aminocarbonyl, while Me is methyl. According to the present invention, a diene of the formula (II) in the formula (X): X and Me in the above inert organic solvent, in the presence of an elemental halogen, an inorganic base and, if desired, a phase transfer catalyst, is between room temperature and the boiling point of the reaction mixture. with a compound of formula (I), wherein Y and Z are as defined above in formula (ΠΙ). > = \ = /. Me Me Me. (II) H2C (I) (III) 203520 B Scope of the description: 6 pages (Figure 1) -1-

Description

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

Pyrethroid insecticides are known to have high specific activity and, at the same time, have low toxicity to mammals. [Nádasy M .: Journal of Hungarian Chemists 10,534-537. (1979); Elliot M. and James N. F., Chem. Soc. Rev. 4.473. (1978)].

The most effective representatives of pyrethroids are the 2,2-dimethyl-3- (2,2-dihalo-vinyl) -cyclopropanecarboxylic acid esters of formula (IV). In the formula, X 'is chlorine or bromine (in pyrethrin, permethrin, decamethrin (deltamethrin)); Y 'and Z' represent one hydrogen atom and the other alkoxycarbonyl group, and Me represents a methyl group.

Particularly preferred for specific activity are the 2,2-dimethyl-3- (2,2-dihalo-vinyl) -cyclopropanecarboxylic acid esters wherein the substituents 1 and 3 are in the formula (TV) and X ' denotes bromine (decamethrin; Tessier, J. Chem. and Ind. 1984, 1999).

The synthesis of the above compounds has been the subject of numerous publications and patents. Reference is made to Arit, D., Jautelot, M., Lantzsch., R. (1981), Angew Chem. 93, 719 (1981). From an economical point of view, one of the most important routes is the reaction of the dienes of the formula etben in which X is a halogen or methyl group and Me is a methyl group with alkoxycarbonylcarbenes of the formula V in which R is lower alkyl. The reaction yields a mixture of cis and trans cyclopropane derivatives in a ratio of about 1: 1 (Staudinger, H. Muntwyler, O., Ruzicka, L. Seibt, S. Helv. Chim. Acta 7,390. (1924)].

The disadvantage of the process is that the reaction is not stereo- and enantioselective, which results in a mixture of isomers. A further disadvantage is that the process is expensive and the diazoacetic acid ester used is explosive.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the drawbacks of the known process and to provide a process for the stereo and enantioselective preparation of compounds of formula (TV).

The present invention relates to a process for the preparation of geminal disubstituted cyclopropane derivatives of formula (I):

X is halogen or methyl,

Y and Z may be the same or different and are cyano, - COOR, wherein R is C 1-4 alkyl, or aminocarbonyl,

Me is a methyl group such that a diene of formula (Π) in formula (Π) X and Me is as defined above, in an inert organic solvent in the presence of an elemental halogen inorganic base and optionally a phase transfer catalyst between room temperature and the boiling point of the reaction mixture at a temperature, with a compound of formula (H1) wherein Y and Z are as defined above.

The present invention is based on the discovery that compounds containing an active methylene group of the formula (ΠΙ), in the presence of an elemental halogen and a base, react with the dienes of the formula (Π) to yield the geminal cyclopropane derivatives of the formula (I). Based on the knowledge available in the literature, this recognition is unexpected and even surprising. Indeed, there are only two methods known in the literature for assembling a malonester unit and an olefin unit to a cyclopropane derivative. One method involves reacting the bromo malonic ester with olefins in the presence of a base (U.S. Patent No. 4,334,091). According to the patent, the process can be performed only with olefins which are good Michael acceptors. Alternatively, the dibromo malonic ester is reacted with mono-olefin in the presence of copper (I) bromide (Julia, M., Guy-Renault, A .: Bull. Soc. Chim. Francé 7967, 1411). According to the authors, only in a few cases could an identifiable product be isolated.

The above procedures as well as Torii, S., Tanaka, H. Nagai, Y .: Bull. Chem. Soc. Japan, 50,2825 (1977), on the one hand, is lengthy and uneconomical, and, on the other hand, results in the formation of the desired product only with olefins considered to be good Michael acceptors.

According to our own experiments, the reaction of the diene (Π) with the bromomalonic or dibromo-malonic ester did not result in a trace amount of the compound (I). Otherwise, this type of reaction has not been reported in the literature.

From the foregoing, it is particularly unexpected to discover that compounds of formula (ΙΠ) containing the active methylene group do not undergo reaction cycloaddition under the conditions of reaction with Michael dienes of formula (Π) to provide the desired compounds of formula (I).

The process of the present invention also provides an industrially significant method and the preparation of novel compounds. The advantages of our procedure are as follows:

1. Compounds of formula (I), by partial or total hydrolysis and subsequent partial decarboxylation, provide cyclopropane derivatives (TV) of formula (I) for the production of permethrin or decamethrin, by a new method which is economically feasible on an industrial scale.

2. The fact that theoretical considerations (Schneider, M. Engel, N .: Chemistry and Biotechnology of Biologically Active Natural Products, 2nd Int. Conf. Proceedings Ed., By Cs. Szántay, Academic Publisher Budapest, p. 203) is particularly significant. ) and our experiments have shown that the hydrolysis and subsequent partial decarboxylation of the geminal carboxylic acid esters or nitriles of formula (I) can be performed stereo- and enantioselectively, and thus the optics containing substituents 1 and 3 in the cis position 21

The compounds of the general formula (TV) (Y 'and Z' represent a hydrogen atom and the other a carboxyl group) can be prepared. Synthetic synthesis of optically active cis compounds of formula (IV) is not known in the literature.

3. The vast majority of the compounds of formula (I) produced by the process of the present invention are novel, only two compounds of formula (I) are known [those derivatives of formula (I) wherein X-CH ₃ , Y = COOCH ₃ , Z- COOK (Tedeschi, RJ: Air Products and Chemicals Inc. U.S. Pat. No. 4334091, 1982); X-CH ₃ , YZ-COOCH ₃ (Julia, M., Guy-Renault, A: Bull. Soc. Chim. Francé 1967 1411)] ·

This represents a potential opportunity for the synthesis of new pyrethroid analogs or for the preparation of new compounds (e.g., hormonal derivatives) that can be used for other purposes.

The reaction of the compounds of formula (Π) and (ΙΠ) according to the invention can be carried out in the presence of elemental halogen and a base. The use of iodine has proved particularly advantageous for this purpose. If desired, iodine may be formed from an alkali metal iodide, preferably sodium or potassium iodide, with a weak oxidizing agent in situ.

Preferred bases are alkali metal carbonates (e.g., sodium or potassium carbonate), alkali metal bicarbonates (e.g., sodium or potassium bicarbonate), alkali metal hydroxides (e.g., sodium or potassium hydroxide). the use of alkali metal carbonates, particularly potassium carbonate, has proven to be advantageous.

The reaction is preferably carried out in the presence of a phase transfer catalyst. For this purpose, e.g. the following may be used: salts of lipophilic cations (e.g. Aliquat ^R , trioctylmethylammonium chloride, tetrabutylammonium bromide, triethylbenzylammonium chloride, etc.), complexing agents (e.g., 18-crown-o, benzo-15- crown-5, polyethylene glycol, etc.), amines (e.g., tetramethylethylenediamine, etc.).

The process according to the invention is preferably carried out in an inert organic solvent medium. Suitable reaction media are solvents which are inert to the components involved and have a boiling point corresponding to the reaction temperature, preferably aliphatic or aromatic hydrocarbons (e.g. hexane, benzene, toluene, xylene) or ethers (e.g. tetrahydrofuran or dioxane). The compounds of formula (II) and (ΙΠ) may generally be used in equimolar amounts, but one component may also be added in small amounts. The reaction may be carried out at room temperature to the reflux temperature of the reaction mixture, preferably under reflux.

The compound of formula (I) may be isolated from the reaction mixture by methods known per se, e.g. evaporation of the organic phase followed by vacuum fractionation of the residue.

In the process of the present invention, it is preferable to use starting materials wherein Y and Z in formula (H1) may be the same or different and represent a cyano group or a carboxy group or an electron withdrawing derivative thereof, preferably a cyano group, carbamoyl group or -COOR group C 1-4 alkyl.

The alkyl group R represents a linear or branched alkyl group (e.g., methyl, ethyl or isopropyl). Preferably, the starting materials used are those wherein Y and Z are methoxycarbonyl, ethoxycarbonyl or cyano.

Preferably the starting compound of formula (Π) is 1,1-dichloro-4-methylpenta-1,3-diene, 1,1-dibromo-4-methylpenta-1,3-diene or 2,5-dimethyl-. hexa-2,4-diene may be used.

The process of the present invention can be performed with about 100% regioselectivity using asymmetric diolefins of formula (Π). The malonate moiety is based on a double bond farther from the olefin bound to the halogen atoms. The reaction is illustrated in Scheme A for the example of 1,1-dichloro-4-methylpenta-1,3-diene and malonic acid diethyl ester.

In the reaction type of the process of the present invention, there is a novel method, which is unparalleled in the literature, by which it is possible to prepare predominantly new compounds. The yields obtained are excellent compared to normal values in this field of chemistry. On the one hand, the process may be the basis for new pyrethroid productions, and not just ldassi- <

can be said to produce permethrin and tetramethrin; decamethrin for new types of diastereospecific and enantiospecific synthesis.

The following non-limiting examples of the present invention are set forth in the following non-limiting Examples.

Example 1

To a 100 ml flask with stirring, addition funnel and reflux condenser add 10 ml toluene, 0.1 g Aliqat ^R , (lipophilic cation salt) 2 g (13.2 mmol) 1,1-dichloro-4-methylpenta -1.3-diene, 3.3 g (23 mmol) of potassium carbonate and 3 g (12 mmol) of iodine are added.

1.6 g (10 mmol) of malonic acid diethyl ester is added under reflux and vigorous stirring. After the addition was complete, the reaction mixture was stirred for an additional 15 minutes, cooled and water (10 mL) was added. The phases were separated and the organic layer was washed with 10% sodium thiosulfate solution (10 mL) followed by water (10 mL), dried over sodium sulfate, and the toluene solution was concentrated in vacuo to 90 ° C. The distillate was collected at a pressure of 66 Pa. 1.59 g of diethyl ether of 2- (2,2-dichloro-vinyl) -3,3-dimethyl-cyclopropane-1,1-dicarboxylic acid are obtained in the form of an oil. Yield: 52%.

HU 203 520 Β

Example 2

The procedure described in Example 1 was carried out by replacing the diethyl malonic acid dimethyl ester with 1.32 g (10 mmol) of dimethyl ester of malonic acid in the form of an oil of 1.4 g of 2- (2,2-dichlorovinyl). 49% yield of -3,3-dimethylcyclopropane-11-dicarboxylic acid dimethyl ester.

Example 3

The procedure described in Example 1 was carried out with the modification that 0.66 g (10 mmol) of malonic acid dinitrile was replaced by tetrahydrofuran instead of toluene as the solvent.

The reaction mixture was worked up by distilling off the tetrahydrofuran in vacuo, adding 10 ml of benzene, and following the procedure of Example 1. Concentration gave 1.52 g (55%) of crystalline 2- (2,2-dichloro-vinyl) -3,3-dimethyl-cyclopropane-1,1-dinitrile, m.p. 104-106 ° C.

Example 4

The procedure described in Example 3 was carried out with the change of 1.1 g (10 mmol) of 2,5-dimethylhexa-2,4diene instead of 1,1-dichloro-4-methylpenta-1,3-diene. The residue was evaporated at a pressure of 2.66 Pa and the boiling point 80 ° C was collected. 0.31 g of crystalline 2- (2-methylprop-1-ene) -1-yl-3,3-dimethylcyclopropane-1,1-dinitrile are obtained in a yield of 18%, m.p.

Example 5

The procedure described in Example 1 is carried out with the change that 3.2 g of 1,2-dichloro-4-methylpenta-1,3-diene is replaced by 3.2 g of 1-dibromo-4-methylpenta-1,3-diene. 1 g of 2- (2,2-dibromovinyl) -3,3-dimethylcyclopropane-1,1-dicarboxylic acid ester (25%) are obtained as an oil.

Example 6

The procedure described in Example 1 was performed except that the reaction was carried out in the absence of Aliquat ^R catalyst. 0.62 g (20%) of [2,2-dichloro-vinyl] -3,3-dimethyl-cyclopropane-1,1-dicarboxylic acid diethyl ester are obtained.

Fp.:90'C/3Pa

Example 7

Example 3 except that 0.94 g (10 mmol) of cyanoacetamide was used in place of malonic acid dinitrile. After working up the reaction mixture, 0.43 g (18%) of 1-cyano-1-aminocarbonyl-2- (2 2-dichlorovinyl) -3,3-dimethylcyclopropane was obtained

160-162'C-are.

IR (KBr): 3480, 3170, 2260, 1680, 1615 cm ^-1 .

Claims (5)

PATENT CLAIMS 1. A process for the preparation of geminal disubstituted cyclopropane derivatives of the formula I: X is halogen or methyl, Y and Z may be the same or different, and Cyano, -COOR, wherein R is C 1-4 alkyl, or aminocarbonyl, Me denotes methylene group to denote a diene of formula (Π) - in formula (Π), X and Me in the above inert organic solvent in the presence of an elemental halogen, inorganic base and optionally a phase transfer catalyst at a temperature between room temperature and the reflux temperature of the reaction mixture, Compound 30 is reacted with Y and Z are as defined above 2. The process of claim 1 wherein the halogen is elemental iodine. 3. The l.or2. The process according to claim 1, wherein the inorganic base is an alkali metal carbonate, an alkali metal hydroxide or an alkali metal bicarbonate. 4. A process according to claim 1, wherein the inert organic solvent is an aromatic hydrocarbon, an aliphatic hydrocarbon or an ether. 5. A process according to claim 1, wherein the inert solvent is benzene, xylene or tetrahydrofuran.