CS272527B1 - Process for preparing optically active cis-cyclobutanones - Google Patents

Abstract

A method for preparing optically active cyclobutanone of general formula I, where X represents a halogen atom and Y represents a halogen atom or a trifluoromethyl group, wherein 0.3 to 0.7 molar equivalents of the salt of an optically active base of general formula IV, a-,h+b (IV), are gradually added to a solution of a racemic salt of cyclobutanesulfonic acid of general formula III, in which X and Y have the same meaning as in formula I and M+ represents an alkali cation, in an inert solvent. in which A" means the anion of an optically inactive inorganic or organic acid and H+B means the protonated form of an organic optically active base, which preferentially reacts with one enantiomer of the racemic salt of the general formula III to form one diastereoisomer of the cyclobutanesulfonic acid salt of the general formula II, in which X and Y have the previously indicated meaning and H+B has the previously indicated meaning for the general formula IV, which is precipitated from the solution in the form of crystals and separated by filtration, decantation or centrifugation from the other enantiomer of the substance of the general formula III, which remained dissolved in the solution, chemically unchanged, after which the separated salts of the general formula II and III are optionally purified by known methods and decomposed by hydrolysis into optically active antipodes of cis-cyclobutanone of the general formula I, with the meaning of X and Y as previously indicated.

Description

The invention relates to a process for the preparation of optically active cis-cyclobutanones. of general formula I, in which X represents a halogen atom and Y represents a halogen atom or a trifluoromethyl group. Said ketones are useful for the preparation of cyclopropanecarboxylic acid derivatives with significant insecticidal activity.

It is known in the art that optically active cyclobutanones of this type can be prepared from the corresponding racemic cyclobutanones by reaction with an optically active base sulfite to give a diastereolsomeric mixture of cyclobutanesulfonic acid salts of formula II, wherein X and Y are as previously defined and H ⁺ B is an organic optically active base in protonated form, followed by fractional crystallization of a diastereoisomeric mixture of salts of formula II and then decomposition of the separated diastereoisomers of formula II into optically active cyclobutanones of formula I, see for example Greuter H., Dingwall J., Martin P. and Belus D. . Ghlm. Acta 64, 2812, 1981. The prior art process for the preparation of optically active cyclobutanones is laborious and time consuming.

These disadvantages are substantially reduced by the process for the preparation of optically active cyclobutanones of the general formula I, in which X represents a halogen atom and Y represents a halogen atom or a trifluoromethyl group, according to the invention. It consists in a stereoselective precipitation reaction induced in a solution of a racemic alkaline sulfonic acid salt of formula III, in which X and Y are as defined above and an alkaline cation, by adding an optically active organic base salt of formula IV 'A, BH ⁺ (IV) wherein a ^ '^ is an anion optically inactive organic or inorganic acids, preferably selected from the group consisting of hydrohalic acid, sulfuric acid or a lower fatty acid and BH ⁺ ^ ^ is as previously defined for formula II, in a total amount exceeding 0.7 molar equivalent of the starting racemic salt of formula III, wherein X and Y are as previously defined.

The essence of the discovered reaction is the preferential transformation of one enantiomer of the racemic salt of formula III into one diastereoisomer of the salt of formula II, which precipitates from solution as crystals, while the other enantiomer of the salt of formula III remains predominantly in solution, chemically unchanged and separated by filtration, decantation and decantation. or by centrifugation. The crystalline diastereoisomer of the salts of the formula III obtained is then optionally purified by customary methods known per se, for example by crystallization or chromatography. By hydrolysis of the optically active sulfone salts of the formulas II and III thus obtained, both optically active cis-cyclobutanones of the formula I are prepared in opposite absolute configurations.

The reaction of the racemic alkali salt of formula III with the optically active salt of formula IV is carried out in an inert polar solvent, expediently selected from the group of hydroxyl solvents, ethers, amides, nitriles, sulfoxides and water, at -10 ° C to + 70 ° C. . .

As optically active salts of the general formula IV, salts of an optically inactive inorganic or organic acid with an optically active organic base selected from the group of substituted amines are used in the reaction. Examples of suitable optically active bases are certain alkaloids with optically active centers, for example / - / - ephedrine, / + / - e-. fedrine, / + / pseudoephedrine, / - / - N-methylephedrine, brucine, some esters of optically active amino acids, for example I-phenylalanine t-butyl ester, 1-valine benzyl ester, and also some synthetic amines, for example S - / - / - phenylethylamine, R - (+) - 1-phenylethylamine, (+) - 1-naphthylethylamine, (+) - threo- (p-nitrophenyl) -2-N, N-dimethylaminopropane-1,3-diol and R - / - N-amino-1-butanol.

CS 272527 Bl 2

The stereoselectivity of the precipitation reaction according to the invention can be controlled, inter alia, by the choice of the salt of the optically active base of the formula IV, by the choice of the solvent, by the reaction temperature. Preferably, seeding of the solution by adding crystals of the desired diastereoisomer of formula II is used.

The separation of the reaction mixture is carried out by methods known per se. The precipitated solid diastereoisomer of the salts of formula II, optionally with coprecipitated salts, is separated from the dissolved salt of formula III, for example by filtration, decantation or centrifugation, and optionally further purified by crystallization, chromatography and the like. The dissolved salt of formula III may be isolated, for example, by concentrating the solution and optionally further purified by crystallization or precipitation reaction with a suitable salt of an optically active base of formula IV.

The decomposition of the optically active salts into the formula II is carried out by methods known per se, as described, for example, in the above-mentioned work of the Swiss authors. The decomposition of the optically active salts of the general formula III is carried out analogously. The undesired enantiomer of cis-cyclobutanone of the formula I which is obtained can be easily converted back into the starting racemic salt of the formula III by methods known per se.

The advantage of the new process is the easy availability of the starting racemic alkali salt of formula III. Another advantage is that it replaces the laborious and lengthy fractional crystallization of the diastereoisomeric mixture of salts of formula II with a faster and more efficient precipitation process. The fact that the optically active base is used in the new process in an amount not exceeding 0.7 molar equivalent of the resolved salt of the general formula III also represents an advantage in comparison with the prior art process.

The process for the preparation of optically active cis-cyclobutanones of the formula I is illustrated in the following examples, which do not limit the scope of the invention in any way. Example 1

Racemic 2-chloro-4- (2,2,2-trichloroethyl) -1-hydroxy-3,3-dimethylcyclobutane-1-sulfonic acid sodium salt (14.4 g; 39.3 mmol) and (-) - hydrochloride 1-Phenylethylamine (3.08 g; 19.6 mmol) was dissolved in hot 50% undenatured ethanol (100 mL). -After cooling, the crystals were filtered off with suction, washed with cold 50% ethanol (4 ml), ether and dried. The salt obtained (6.05 g) corresponded to a ketone with an optical rotation of + 75.0 ° (c 0.8;

Two crystallizations from 25 ml of 50% ethanol gave 4.5 g (49% of theory) of pure salt, from which the ketone released had [.alpha.] D @ 20 +122.9 DEG (c 0.8; Literature (Helv, Chim. Acta 64, 2819, 1981) reports W ₃₆₅ + 105.5 °.

Example 2

Racemic 2-chloro-4- (2 ', 2', 2''-trichloroethyl] -1-hydroxy-N-dimethylcyclobutane-1-sulfonic acid sodium salt (6.7 g; 18.3 mmol) and N-ephedrine hydrochloride (1.82 g; 9.0 mmol) were dissolved in 25 mol of hot 50% undenatured ethanol, and the precipitated crystals (4.15 g) corresponding to a ketone of C ^ gg -59.6 ° were recrystallized twice from 15 ml of 50% ethanol, yield 1.9 g (41% of theory) of the salt from which the ketone released had a C18 H-gb of -106.3 ° (c 0.8; CCl ₄ ).

Example 3, '

Racemic 2-chloro-4- (3 ', 3', 3'-trifluoro-2'-chloropropyl) -1-hydroxy-3,3-dimethyl-cyclobutane-1-sulfonic acid potassium salt (4.2 g; 10 mmol) in 25 ml of 60% ethanol was mixed hot with 1.2 g (5.9 mmol) of / - / - ephedrine hydrochloride in 5 ml of 60% ethanol. After seeding and slow cooling to 20 [deg.] C., the precipitated salt is filtered off with suction, washed with 1 ml of 60% ethanol and dried, weighing 1.6 g (58% of theory).

CS 272527 Bl

Example. 4- ·

The precipitated optically active salt from Example 3 was heated with stirring for 1 h in 10 ml of ethanol and 2 ml of conc. hydrochloric acid (1: 1). After partial evaporation, the reaction mixture was partitioned between pentane and water, the organic phase washed with water, dried and evaporated. The yield of crystalline ketone was 0.74 g (86%); (50% calculated on the starting potassium salt from Example 3)? “5 ° .9 ° (c 0.5? CCl ^).

Example 5

A solution of 26.2 g (0.1 mol) of 2- (2 ', 2', 2 ^, -trichloroethyl) -3,3-dimethyl-4-chloro-1-cyclobutanone in 35 ml of ethanol was added to a vigorously stirred solution of 13 .0 g (0.068 mol) of sodium metabisulfite in 35 ml of water. After stirring at 45 [deg.] C. for 4 h, the mixture was cooled to 15 [deg.] C. The precipitated product was filtered off with suction, dried and recrystallized from 50% ethanol at 60 [deg.] C. Yield 36.6 g (99% of theory)? melts with gradual decomposition without a sharp melting point. For C 9 E 12 Cl 2 NaO 2 S (368.0) calculated 26.11% C? 3.01% H? 38.53% Cl? 8.71% S; found 26.97% C? 3.39% H? 38.35% Cl; 8., 49% S.

Example 6

5.3 g (50 mmol) / -f - / - 2-chloro-3,3-dimethyl-4- / ^2, 2 \ ² -trichlorethyl / cyclobutane-l-one with a specific rotation = + 59 ° ( CCl 2) was heated in a melt with 1.5 g (5 mmol) of tetrabutylammonium chloride at 120 ° C for 4 h with magnetic stirring. After cooling, the reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. 5.2 g of racemic cyclobutanone were obtained, which according to vpc represents a mixture of cis and trans isomers in a ratio of 92: 8.

Example 7

The procedure of Example 3 was followed, except that 5.9 mmol of acetate was used instead of / - / - ephedrine hydrochloride. / - / - ephedrine. The yield of optically active salt was 1.6 g (58% of theory).

Example 8

The procedure of Example 1 was followed using N-l-phenylethylamine sulfate instead of the corresponding hydrochloride. 6.0 g of the desired optically active salt were obtained.

Example 9

The procedure of Example 3 was followed except that aqueous acetonitrile was used in the reaction instead of aqueous ethanol.

Claims (4)

OBJECT OF THE INVENTION 1. Process for the preparation of optically active cis-cyclobutanones of the general formula I in which X represents a chlorine atom and Y represents a chlorine atom or a trifluoromethyl group, characterized in that a racemic cyclobutanesulfonic acid salt of the general formula III in which X and Y have the same meaning as in formula I and M * is an alkaline cation, 0.3 to 0.7 molar equivalents of the salt of the optically active base of formula IV are gradually added in an inert solvent A, H ⁺ B (IV), in which A represents an anion of optically inactive inorganic or organic acid, preferably selected from the group consisting of hydrohalic, sulfuric or lower fatty acid And H ⁺ B represents a protonated form of an organic optical active base and preferably selected from the group of amines which preferentially reacts with one enantiomer of the racemic salt of formula III to form one diastereoisomer of the cyclobutanesulfonic acid salt of formula II, wherein X and Y have the foregoing meaning and H ⁺ B is as previously defined for formula IV, which precipitates from solution in the form of crystals and is separated from the second enantiomer of the compound of formula III which remains dissolved in solution by filtration, decantation or centrifugation, then chemically unchanged, then the separated salts of the formulas II and III are optionally purified by methods known per se and decomposed by hydrolysis into optically active cis-cyclobutanone antipodes of the formula I, with the meanings X and Y as previously indicated, 2, Preparation process according to claim 1, characterized in that S - / - / - 1-phenylethylamine hydrochloride, R - / + / - 1-phenylethylamine, / - / - ephedrine or / + is used as the salt of the optically active base of general formula IV / -ephedrine. 3. ' Process according to items 1 and 2, characterized in that aqueous ethanol or aqueous acetonitrile is used as solvent. 4. The process according to items 1 to 3, characterized in that the reaction mixture is seeded with crystals of the desired diastereoisomer of the cyclobutenesulfonic acid salt of the general formula II,