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WO2000076960A1 - Process for the preparation of optically active n-acyl derivatives of methyl n-(2,6-dimethylphenyl)-d-alaninate - Google Patents

Process for the preparation of optically active n-acyl derivatives of methyl n-(2,6-dimethylphenyl)-d-alaninate Download PDF

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Publication number
WO2000076960A1
WO2000076960A1 PCT/EP2000/005460 EP0005460W WO0076960A1 WO 2000076960 A1 WO2000076960 A1 WO 2000076960A1 EP 0005460 W EP0005460 W EP 0005460W WO 0076960 A1 WO0076960 A1 WO 0076960A1
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group
methyl
formula
process according
general formula
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PCT/EP2000/005460
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French (fr)
Inventor
Giampaolo Zanardi
Giovanni Confalonieri
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Isagro S.P.A.
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Priority to AU54048/00A priority Critical patent/AU5404800A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for the preparation of optically active fungicidal products .
  • the object of the present invention therefore relates to a process for the synthesis of compounds having general formula I
  • step 1 consisting in reacting methyl (S) -2- (hydroxy) - propanoate having formula II with a sulfonyl chloride having general formula III to give a sulfonate derivative of methyl (S) -2- (hydroxy) -propanoate having formula IV (step 1) ; step 1:
  • step 2 in condensing the sulfonate derivative having general formula IV with 2,6-xylidine having formula V to give methyl N- (2, 6-dimethylphenyl) -D-alaninate having formula VI (step 2) ;
  • R represents a 2-methoxymethyl group, a 2-furanyl group or a phenylmethyl group
  • Ri represents a Ci-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 consisting 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 potassium carbonate.
  • 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.
  • the product obtained 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 observed in methanesulfonation re- actions, takes place with configuration inversion and, apart from a lower absolute yield to methyl (S) -2- [ (methylsulfonyl) oxy] -propanoate, would produce a certain quantity of the undesired isomer in subsequent step 2.
  • step 1 the salts formed are eliminated from the reaction mixture which is concentrated to give the sulfonate having general formula IV which is used as raw product in the subsequent 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 reacting 2,6-xylidine having formula V with the sulfonate 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 configuration (or R according to the Cahn, Ingold and Prelog classification) is obtained from the sulfonate having 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, sodium 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 formula IV.
  • 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.
  • Step 3 of the process is conveniently carried out by reacting methyl N- (2, 6-dimethylphenyl) -D- alanmate having formula VI with an acyl chloride having general formula VII m 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, x ⁇ - lene, chlorobenzene), chlorinated hydrocarbons (for example methylene chloride, dichloroethane) , esters (for example ethyl acetate) .
  • aromatic hydrocarbons for example toluene, x ⁇ - lene, chlorobenzene
  • chlorinated hydrocarbons for example methylene chloride, dichloroethane
  • esters for example ethyl acetate
  • inorganic bases which can be used for the reaction are sodium or potassium bicarbon- ates and carbonates.
  • organic bases which can be used for the reaction are triethylamine, py ⁇ dme, 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 95%. If a product with an even higher optical purity is desired, the end-product can be crystallized from a suitable solvent or mixture of solvents (preferably aliphatic hydrocar- bons) with a reduced weight loss (5% at the most) .
  • a suitable solvent or mixture of solvents preferably aliphatic hydrocar- bons
  • 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 5% of hy- drochloric acid, 1 liter of a solution at 1% of sodium bicarbonate, and 1 liter of water.
  • the resulting solution is concentrated at reduced pressure, until the suitable concentration of the product m toluene s obtained for use m the subsequent passage.
  • the quantity of product obtained is estimated by eliminating the solvent from a sample of the solution.
  • 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 mHg.
  • the toluene solution is concentrated at reduced 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention relates to a process for the preparation of fungicides consisting of N-acyl derivatives of methyl N-(2,6-dimethylphenyl)D-alaninate having formula (I) with high yields and with a high optical purity.

Description

PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE N-ACYL DERIVATES OF METHYL N-( 2 , 6-DIMETHYLPHENYL )-D-ALANINATE
1 0
The present invention relates to a process for the preparation of optically active fungicidal products .
More specifically, the present invention re-
15 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 purity.
N-Acyl derivatives of methyl N-(2,6-
20 dimethylphenyl) -DL-alaninate having a fungicidal activity have been commercially developed, in particular for controlling phytopathogen fungi belonging to the group of oomycetes. Among these, the most important commercial compounds are methyl N-
25 (2, 6-dimethylphenyl) -N- (2-methoxyacetyl) -DL- alaninate (known as metalaxyl) , methyl N-(2,6- dimethylphenyl) -N- (2-furanyl-carbonyl) -DL-alaninate (known as furalaxyl) and methyl N-(2,6- dimethylphenyi) -N- (phenylacetyl) -DL-alaninate (known as benalaxyl) .
It has been demonstrated that the fungicidal activity of these compounds is essentially associated 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
Figure imgf000003_0001
consisting in reacting methyl (S) -2- (hydroxy) - propanoate having formula II with a sulfonyl chloride having general formula III to give a sulfonate derivative of methyl (S) -2- (hydroxy) -propanoate having formula IV (step 1) ; step 1:
Figure imgf000004_0001
II III IV in condensing the sulfonate derivative having general formula IV with 2,6-xylidine having formula V to give methyl N- (2, 6-dimethylphenyl) -D-alaninate having formula VI (step 2) ;
Figure imgf000004_0002
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) ;
Figure imgf000004_0003
VI VII 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 Ci-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 consisting 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 potassium carbonate.
The methyl (S) -2- (hydroxy) -propanoate having formula II and the sulfonyl chloride having general
- A - formula III are reacted in stoichiometric ratios or using a slight excess (up to 10%) of sulfonyl chloride .
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 obtained. For example, using methanesulfonyl chloride (Ri = methyl) as compound having formula III, toluene as solvent, triethylamine and/or sodium carbonate 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 solvent and a mixture of triethylamine and N,N- dimethyl-aminopyridine as base) . The product obtained 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 observed in methanesulfonation re- actions, takes place with configuration inversion and, apart from a lower absolute yield to methyl (S) -2- [ (methylsulfonyl) oxy] -propanoate, would produce 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 concentrated to give the sulfonate having general formula IV which is used as raw product in the subsequent 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 reacting 2,6-xylidine having formula V with the sulfonate 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 configuration (or R according to the Cahn, Ingold and Prelog classification) is obtained from the sulfonate having 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, sodium 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 formula 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- πty (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 m steps 1 and 2 are those wherein R = methyl, i.e. - respectively - methanesulfonyl chloride and methyl (S) -2- [ (methylsulfonyl) oxy] - propanoate .
Step 3 of the process is conveniently carried out by reacting methyl N- (2, 6-dimethylphenyl) -D- alanmate having formula VI with an acyl chloride having general formula VII m 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, x^ - 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, pyπdme, 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 95%. If a product with an even higher optical purity is desired, the end-product can be crystallized from a suitable solvent or mixture of solvents (preferably aliphatic hydrocar- bons) with a reduced weight loss (5% 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 optical purities higher than 97% and with chemical yields higher than 80% in the three passages.
Considering the limited cost of methanesulfonyl 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 better illustration of the invention. EXAMPLE 1 Preparation of methyl (S) -2- [ ( ethylsulfonyl) oxy] - propan-oate .
521 g of methyl ( S) -2- (hydroxy) -propanoate (5.0 moles) and 660 g of triethylamine (6.5 moles) are dissolved m 3.0 liters of toluene. The mixture is cooled to 5°C and 590 g of methanesulfonyl chloride (5.15 moles) are added dropwise over a period of 2 hours, the internal temperature being maintained 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 5% of hy- drochloric acid, 1 liter of a solution at 1% of sodium bicarbonate, and 1 liter of water.
The resulting solution is concentrated at reduced pressure, until the suitable concentration of the product m toluene s obtained for use m the subsequent passage. The quantity of product obtained 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 mHg.
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 m- 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 suspended 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 reduced 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 96%) as a white crystalline solid, with an enantiomorphic 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 Example 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 94%) with an enantiomorphic composition correspond- ing to the starting product (97.5/2.5).

Claims

1. A process for the synthesis of compounds having formula IV consisting in reacting methyl (S) -2- (hydroxy) -propanoate having formula II with a sulfonyl chloride having formula III, in an inert organic solvent and in the presence of an organic base and/or an inorganic base or their mixtures, at a temperature ranging from -10° to + 25°C, to give a sulfonate derivative of methyl (S) -2- (hydroxy) - propanoate having general formula (IV), according to the following scheme:
Figure imgf000015_0001
CH3
II III IV wherein
Ri represents a Cι~C4 alkyl group, a tri- fluoromethyl group or a phenyl group optionally substituted by methyl, methoxy, nitro groups .
2. The process according to claim 1, wherein the solvent is an aromatic hydrocarbon selected from the group consisting of toluene, xylene, chlorobenzene .
3. The process according to claim 1, wherein the base, or the mixture of bases, is used m a ratio varying from 1:1 to 1.5:1 with respect to the sulfonyl chloride.
4. The process according to claim 1, wherein the organic base is selected from the group consisting of triethylamine, dnsopropylethyla- mme, pyπdme and the inorganic base is so- dium or potassium carbonate.
5. The process according to claim 1, wherein the substituent Rx is methyl.
6. A process for the preparation of compounds having general formula VI which consists m condensing the sulfonate derivative having general formula IV, obtained according to the process of claim 1, with 2,6-xylιdme having formula V, m the absence of a solvent or m the presence of an inert organic solvent, at a temperature ranging from 60°C to the boiling point of the reaction mixture to give methyl N- (2, 6-dιmethyl-phenyl) -D-alanmate having formula VI, according to the following scheme:
Figure imgf000017_0001
IV V VI wherein:
Ri has the meaning defined in claim 1.
7. The process according to claim 6, wherein the reaction is carried out in the presence of an inorganic base.
8. The process according to claim 7, wherein the inorganic base is selected from the group consisting of sodium or potassium bicarbonate, sodium or potassium carbonate, sodium or potassium monohydrogen phosphate.
9. The process according to claim 6, wherein the solvent is selected from the group of aromatic hydrocarbons consisting of toluene, xylene, chlorobenzene .
10. The process according to claim 6 and 7, wherein the sulfonate having general formula IV and the xylidine are used in a ratio varying from 1:1 to 1:5 and the base is used in a ratio varying from 1:1 to 1.5:1 with respect to the sulfonate having formula IV. 11. A process for the preparation of compounds
- 16 -
SUBSTITUTE SHEET (P.U π 2G) having general formula I which consists in reacting methyl N- (2, 6-dimethylphenyl) -D- alaninate having formula VI obtained according to the process of claim 6, 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, to give the compounds having general formula I, according to the following scheme:
Figure imgf000018_0001
wherein:
R represents a 2-methoxymethyl group, a 2-furanyl group or a phenylmethyl group. The process according to claim 11, wherein the solvent is selected from the group consisting of aromatic hydrocarbons, chlorinated hydro- carbons, esters.
13. The process according to claim 12, wherein the solvent is selected from the group consisting of toluene, xylene, chlorobenzene, methylene chloride, dichloroethane, ethyl acetate.
14. The process according to claim 11, wherein the inorganic base is selected from the group consisting of sodium or potassium bicarbonates and carbonates .
PCT/EP2000/005460 1999-06-15 2000-06-13 Process for the preparation of optically active n-acyl derivatives of methyl n-(2,6-dimethylphenyl)-d-alaninate WO2000076960A1 (en)

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EP2514311A1 (en) 2005-09-13 2012-10-24 ISAGRO S.p.A. Method for protecting against phytopathogens with kiralaxyl, usage and means for same
US8664160B2 (en) 2005-11-10 2014-03-04 Basf Se Fungicidal mixtures
CN110804034A (en) * 2019-11-29 2020-02-18 江苏宝灵化工股份有限公司 Synthetic method of furalaxyl-M
KR20210030636A (en) 2019-09-10 2021-03-18 주식회사 엘지화학 Method for synthesizing compound
WO2022055267A1 (en) * 2020-09-09 2022-03-17 주식회사 엘지화학 Method for preparing alkyl-d-alaninate
KR20220035680A (en) 2020-09-14 2022-03-22 주식회사 엘지화학 Methods for preparing compounds
CN114213266A (en) * 2021-12-07 2022-03-22 浙江禾本科技股份有限公司 Synthesis process of high-purity D-N- (2, 6-xylyl) alanine methyl ester
KR20220035678A (en) 2020-09-14 2022-03-22 주식회사 엘지화학 Method for preparing compound
WO2023277587A1 (en) * 2021-06-29 2023-01-05 주식회사 엘지화학 Method for preparing n-acyl derivative, composition, and pharmaceutical or agricultural product containing same
WO2023277590A1 (en) * 2021-06-29 2023-01-05 주식회사 엘지화학 Method for preparing alkyl-d-alaninate, alkyl-d-alaninate, alkyl-d-alaninate derivative, and pharmaceutical or agricultural product including same
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CN114213266A (en) * 2021-12-07 2022-03-22 浙江禾本科技股份有限公司 Synthesis process of high-purity D-N- (2, 6-xylyl) alanine methyl ester
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