More specifically, the present invention re- lates to a process for the preparation of N-acyl derivatives of methyl N- (2,6-dimethylphenyl)-D- alaninate with high yields and a high optical pu- rity.

N-Acyl derivatives of methyl N- (2,6- dimethylphenyl)-DL-alaninate having a fungicidal activity have been commercially developed, in par- ticular for controlling phytopathogen fungi belong- ing to the group of oomycetes. Among these, the most important commercial compounds are methyl N- (2,6-dimethylphenyl)-N- (2-methoxyacetyl)-DL-

alaninate (known as metalaxyl), methyl N- (2,6- <BR> <BR> dimethylphenyl)-N- (2-furanyl-carbonyl)-DL-alaninate (known as furalaxyl) and methyl N- (2,6- dimethylphenyl)-N- (phenylacetyl)-DL-alaninate (known as benalaxyl).

It has been demonstrated that the fungicidal activity of these compounds is essentially associ- ated with the D optical isomer.

The Applicant has now identified a. productive process which allows the preparation of the single D isomers of metalaxyl, furalaxyl and benalaxyl with a high optical purity and high overall yields.

The object of the present invention therefore relates to a process for the synthesis of compounds having general formula I consisting in reacting methyl (S)-2- (hydroxy)- propanoate having formula II with a sulfonyl chlo- ride having general formula III to give a sulfonate derivative of methyl (S)-2- (hydroxy)-propanoate

having formula IV (step 1); step 1: in condensing the sulfonate derivative having gen- eral formula IV with 2,6-xylidine having formula V to give methyl N- (2,6-dimethylphenyl)-D-alaninate having formula VI (step 2); step 2: COOCH3 NH,it ( H NHz , COACH CH3xA CH3 NH CH3 I Hh..... OSOZRL- O > CH3 CH cil3 IV V VI in reacting methyl N- (2,6-dimethylphenyl)-D- alaninate having formula VI with an acyl chloride having general formula VII to give compounds having general formula I (step 3);

in said formulae I, III, IV and VII: R represents a 2-methoxymethyl group, a 2-furanyl group or a phenylmethyl group; Ri represents a Cl-C. alkyl group, a trifluoromethyl group or a phenyl group optionally substituted by methyl, methoxy, nitro groups.

Step 1 of the process object of the present invention is carried out by feeding the sulfonyl chloride having general formula III, wherein R has the meanings defined above, into a mixture consist- ing of methyl (S)-2- (hydroxy)-propanoate having formula II, an inert organic solvent, an organic base and/or an inorganic base, at a temperature ranging from-10° to +25°C.

Preferred solvents for conducting the above reaction are aromatic hydrocarbons such as toluene, xylene, chlorobenzene.

Preferred organic bases for effecting the above reaction are triethylamine, diisopropyleth- ylamine, pyridine, etc.

Preferred inorganic bases are sodium or potas- sium carbonate.

The methyl (S)-2- (hydroxy)-propanoate having formula II and the sulfonyl chloride having general

formula III are reacted in stoichiometric ratios or using a slight excess (up to 10%) of sulfonyl chlo- ride.

The base, or mixture of bases, is used in a ratio varying from 1: 1 to 1.5: 1 with respect to the sulfonyl chloride.

Operating as described, very high yields of the compounds having general formula IV are ob- tained. For example, using methanesulfonyl chloride (Rl = methyl) as compound having formula III, tolu- ene as solvent, triethylamine and/or sodium carbon- ate as base, methyl (S)-2- [ (methylsulfonyl) oxy]- propanoate is obtained with yields ranging from 90- 95%, decisively higher than the best yield cited so far in literature for the same product (DE 4,131,242: 72% using tert-butyl-methylether as sol- vent and a mixture of triethylamine and N, N- dimethyl-aminopyridine as base). The product ob- tained under these conditions moreover has no methyl (R)-2-chloro-propanoate which may be formed due to the nucleophilic substitution of the meth- ylsulfonyloxy groups on the part of the Cl ions present in the reaction environment; this parasite reaction, often observe in methanesulfonation re- actions, takes place with configuration inversion

and, apart from a lower absolute yield to methyl (S)-2-[(methylsulfonyl) oxy]-propanoate, would pro- duce a certain quantity of the undesired isomer in subsequent step 2.

At the end of step 1, the salts formed are eliminated from the reaction mixture which is con- centrated to give the sulfonate having general for- mula IV which is used as raw product in the subse- quent step; alternatively, the sulfonate solution is only partially concentrated and used directly in the subsequent reaction.

Step 2 of the process is carried out by react- ing 2,6-xylidine having formula V with the sul- fonate having general formula IV without a solvent or in the presence of an inert organic solvent, at a temperature ranging from 60°C to the boiling point of the reaction mixture, preferably in the presence of an inorganic base.

The reaction proceeds with configuration in- version of the asymmetric carbon atom and methyl N- (2,6-dimethyl-phenyl)-alaninate having D configura- tion (or R according to the Cahn, Ingold and Prelog classification) is obtained from the sulfonate hav- ing L configuration (or S according to the above classification).

Preferred solvents for effecting the reaction are those used in the previous step of the process, for example aromatic hydrocarbons such as toluene, xylene, chlorobenzene.

Preferred inorganic bases for carrying out the reaction are sodium or potassium bicarbonate, so- dium or potassium carbonate, sodium or potassium monohydrogen phosphate.

The sulfonate having general formula IV and xylidine are used in ratios varying from 1: 1 to 1: 5. The base is used in a ratio varying from 1: 1 to 1,5: 1 with respect to the sulfonate having for- mula IV.

At the end of the reaction the possible excess of xylidine is removed by distillation or washing with an aqueous solution of a mineral acid.

This alternative allows reaction product VI to be obtained already dissolved in an suitable sol- vent for carrying out the subsequent step 3, ena- bling the whole process to be conducted in a single solvent and without isolating the intermediates having formulae IV and VI.

In any case, operating as described, it is possible to obtain methyl N- (2,6-dimethylphenyl)-D- alaninate having formula VI with a high optical pu-

rity (higher than 97%) and with high yields (>90%).

Considering the cost of the starting reagents and yields obtained, preferred intermediates having formulae III and IV for carrying out the reactions described in steps 1 and 2 are those wherein Ri = methyl, i. e.-respectively-methanesulfonyl chlo- ride and methyl (S)-2-[(methylsulfonyl) oxy]- propanoate.

Step 3 of the process is conveniently carried out by reacting methyl N- (2, 6-dimethylphenyl)-D- alaninate having formula VI with an acyl chloride having general formula VII in the presence of an inert organic solvent and an inorganic or organic base, at a temperature ranging from-20 to + 40°C, preferably from-5 to + 20°C.

Preferred solvents for effecting the reaction are aromatic hydrocarbons (for example toluene, xl, - lene, chlorobenzene), chlorinated hydrocarbons (for example methylene chloride, dichloroethane), esters (for example ethyl acetate).

Examples of inorganic bases which can be used for the reaction are sodium or potassium bicarbon- ates and carbonates.

Examples of organic bases which can be used for the reaction are triethylamine, pyridine, etc.

Operating as described, there is no racemiza- tion of the asymmetrical carbon and products having general formula I are obtained with a D/L ratio corresponding to that of the intermediate having formula VI (higher than 97: 3) and with a chemical yield higher than 950. If a product with an even higher optical purity is desired, the end-product can be crystallized from a suitable solvent or mix- ture of solvents (preferably aliphatic hydrocar- bons) with a reduced weight loss (5°O at the most).

Following the procedure object of the present invention, it is therefore possible, starting from methanesulfonyl chloride and methyl (S)-2- (hydroxy)-propanoate, to obtain the optical D iso- mers of metalaxyl, furalaxyl and benalaxyl with op- tical purities higher than 97o and with chemical yields higher than 80% in the three passages.

Considering the limited cost of methanesulfo- nyl chloride and methyl (S)-2- (hydroxy)-propanoate, this process is therefore economically extremely advantageous for an industrial production of single optical D isomers of the above phyto-drugs.

The following examples are provided for a bet- ter illustration of the invention.

EXAMPLE 1

Preparation of methyl (S)-2-[(methylsulfonyl) oxy]- propan-oate.

521 g of methyl (S)-2- (hydroxy)-propanoate (5.0 moles) and 660 g of triethylamine (6.5 moles) are dissolved in 3.0 liters of toluene. The mixture is cooled to 5°C and 590 g of methanesulfonyl chlo- ride (5.15 moles) are added dropwise over a period of 2 hours, the internal temperature being main- tained below 12°C. The resulting light yellow sus- pension is stirred for 3 hours at room temperature.

The precipitate is filtered by squeezing it on the filter, and is washed twice with 0.8 liters of toluene. The overall organic solution is washed in succession with 1 liter of a solution at 5eÓ of hy- drochloric acid, 1 liter of a solution at 1'6 of so- dium bicarbonate, and 1 liter of water.

The resulting solution is concentrated at re- duced pressure, until the suitable concentration of the product in toluene is obtained for use in the subsequent passage. The quantity of product ob- tained is estimated by eliminating the solvent from a sample of the solution.

The concentrated solution obtained weighs 1543 g and contains 850 g of methyl (S)-2- [(methylsulfonyl) oxy] pro-panoate (yield 93%).

EXAMPLE 2 Preparation of methyl N- (2,6-dimethylphenyl)-D- alaninate.

Part of the toluene solution obtained from the reaction described in Example 1, containing 770 g of methyl (S)-2-[(methylsulfonyl) oxy]-propanoate (4.22 moles) and 0.70 liters of toluene, is added to 1690 g of 2,6-xylidine (13.9 moles). 390 g of sodium bicarbonate (4.64 moles) are suspended and the mixture is heated under vigorous stirring to 135°C for 14 hours.

The mixture is cooled and 1.2 liters of water are added to dissolve the solid present together with about 0.2 liters of toluene. The aqueous phase is separated and the organic phase is washed three times with water. The resulting organic solution (3470 g) is subjected to fractionated distillation at reduced pressure, which allows the solvent to be eliminated, the excess of 2,6-xylidine to be recov- ered and the product collected, as a liquid which boils at about 98°C/0.4 mmHg.

789 g of methyl N- (2,6-dimethylphenyl)-D- alaninate are obtained (yield 90%), with an enan- tiomorphic composition R/S = 97.5/2,5.

EXAMPLE 3

Preparation of methyl N- (2,6-dimethylphenyl)-N- (phenyl-acetyl)-D-alaninate.

415 g of methyl N- (2,6-dimethylphenyl)-D- alaninate (2.0 moles) obtained from the reaction described in Example 2 are dissolved in 1.3 liters of toluene, 176 g of sodium bicarbonate (2.1 moles) are suspended and the mixture is cooled to 10°C.

316 g of phenylacetyl chloride (2.04 moles) are added dropwise over a period of 1 hour, the in- ternal temperature being maintained below 20°C. At the end, the mixture is stirred for 4 hours at room temperature.

1 liter of water is added to dissolve the sus- pended solid, the phases are separated, and the or- ganic solution is washed twice with 0.5 liters of water, and with 0.25 liters of deionized water.

The toluene solution is concentrated at re- duced pressure, by heating to 55°C, until a liquid raw product of about 670 g is obtained. 1.8 liters of hexane are added and the mixture is kept under stirring at 55°C obtaining a limpid solution from which the product precipitates on cooling to 5°C.

The product is filtered and is then washed on the filter with hexane, and dried.

625 g of methyl N- (2,6-dimethylphenyl)-N-

(phenyl-acetyl)-D-alaninate are obtained (yield 9690) as a white crystalline solid, with an enantio- morphic composition R/S = 97.5/2.5.

EXAMPLE 4 Preparation of methyl N- (2, 6-dimethylphenyl)-N- (2- methoxy-acetyl)-D-alaninate.

Analogously to the procedure described in Ex- ample 3, from 208 g of methyl N- (2,6- dimethylphenyl)-D-alaninate (1.0 mole), 88 g of so- dium bicarbonate in 0. 7 liters of toluene, treating with 112 g of methoxyacetyl chloride (1.02 moles), 262 g of methyl N- (2, 6-dimethylphenyl)-N- (2- methoxy-acetyl)-D-alaninate are obtained (yield 940) with an enantiomorphic composition correspond- ing to the starting product (97.5/2.5).