Substituted methyl-n-amidooxamoyl-n-phenyl-d,l-alaninates and a method for preparation thereof

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted methyl-N-amidooxamoyl-N-phenyl-D,L-alaninates having general formula I:

where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

EFFECT: increased choice of fungicides.

5 cl, 1 tbl, 11 ex

 

The invention relates to derivatives of phenylalanine, namely the substituted methyl-N-aminooctanoic-N-phenyl-D,L-alaninate General formula I

where R1and R2independently of one another denote alkyl with the number of carbon atoms one to four, R3and R4independently of one another denote unbranched or branched alkyl with a number of carbon atoms of from one to six or R3and R4together form a group -(CH2)2-X-(CH2)2-where X is an atom or group Of CH2which possess fungicidal activity and can be used for the prevention and treatment of plant diseases in agriculture.

For fungi of the class Oomycetes, which include pathogens such an important economic plant diseases as late blight of potato (Phytophthora infestans) and mildew grape (Plasmopara viticola), a long time could not find enough effective drugs for systemic effects. Only in 1973 was obtained now widely known representative of the class of acylalanines - methyl-N-(2,6-dimetilfenil)-N-methoxyacetyl-D, L-alaninate (metalaxyl) [LNC. The pesticides. Chemistry, technology and application. -M.: Chemistry, 1987. - S. 149-157].

Known oxamate General formula II

where R is H, HE,-OR, -COR, -COOR, -NR'r R", CONR'R"; R1and R2mean H, HE, -OR, -COR, -COOR, -R NR'r", -SR, -CH2OR'; R3means COOR4where R4means H or a linear, cyclic, substituted or unsubstituted alkyl, C1-C30; X means OR4, SR4, NR5R6that can be used for depigmentation and skin whitening and hair man [U.S. Pat. U.S. No. 6159482, class a 61 K 7/00, 2000]. They get treatment of substituted aniline with diethyloxalate with subsequent aminolysis product Amin NR'r R":

The most similar in structure to the compounds of the present application N-oxalyl-N-phenyl-α-amino acids and their esters [U.S. Pat. U.S. No. 4248886, class a 01 N 37/46, 1981] General formula III

where R1means H, alkyl, or halogen; R2and R3denote H or alkyl; R4means H, alkyl or substituted phenyl; R5means H, alkyl, cianelli, alkenyl, quinil, halogenoalkane, cycloalkyl, cycloalkenyl, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, dialkylaminoalkyl, substituted aryl or substituted arylalkyl; R6means alkyl, cianelli, alkenyl, quinil, halogenoalkane, cycloalkyl, cycloalkenyl, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylthiomethyl, the alkyl is offinally, alkylsulfonates, dialkylaminoalkyl, substituted aryl, substituted aralkyl, substituted amoxiillin, abaxially or a group of formula IV or V

where R7, R8and R9independently of one another denote alkyl; X means alkylen or alkylidene; Y represents O or S; Z denotes the anion of an organic or inorganic acid, which have high fungicidal activity. They are obtained by interaction of substituted N-phenyl-α-amino acids or their esters with harpiocephalus acid or its esters or oxalylamino, and in the case of oxalicacid product is treated with an alcohol or thiol R6YH:

The known method of synthesis of metalaxyl, including acylation of 2,6-dimethylaniline by methoxyacetanilide with subsequent alkylation of the resulting product is the methyl ester of D,L-α-bromopropionic acid in the presence of alkali metals, their alcoholate, amides or complex hydrides [U.S. Pat. Of the Russian Federation No. 2051144, class C 07 C 235/16, 1995, bull. No. 36].

Object of the invention is to provide new compounds with fungicidal activity. To solve the task, synthesize methyl-N-aminooctanoic-N-phenyl-D,L-alaninate General formula I, having fungicidal activity.

According to the invention, the compounds of formula I poluchaets known methyl-N-phenyl-D,L-alaninato structure VI [U.S. Pat. The USSR №639445, class C 07 C 103/46, bull. No. 47, 1979], where R1and R2have the same meanings as in formula I, their interaction with compounds of General formula VII, where M stands for a chlorine atom or alkoxygroup, Q means a group NR3R4where R3and R4have the same meaning as in the formula I, in the presence of kislorodsvyazyvayushchei agent, such as tertiary amines or inorganic bases and/or in the presence of a catalyst such as dimethylformamide, in a neutral solvent under heating or without him:

Otherwise, the compounds of formula I is produced by interaction of the known products VIII, where Q denotes a chlorine atom or alkoxygroup, R1and R2have the same meanings as in formula I, with an amine HNR3R4where R3and R4have the same meaning as in the formula I, in an environment of neutral solvent with an excess of amine and/or in the presence of kislorodsvyazyvayushchei agent, which can be tertiary amines or inorganic bases:

The known compounds of formula VIII is obtained by interaction of esters of substituted N-phenyl-α-amino acids with harpiocephalus acid or its esters or oxalylamino, and in the case of oxalicacid product is treated with alcohol [U.S. Pat. U.S. No. 4248886, class a 01 N 37/46, 1981].

Otherwise with the organisations of the formula VIII is produced by interaction of the known N-phenylacetate formula IX [Leibigs Annalen der Chimie, 184, 66] methyl-α-kalogeropoulos when heated in the neutral solvent in the presence of a base, which can serve as alkali metals, alkoxides, amides or hydrides.

where Hal means a halogen atom.

Otherwise, the compounds of formula I obtained by processing the known N-phenylacetamido General formula X [U.S. Pat. U.S. No. 6159482, class a 61 K 7/00, 2000], where R1, R2, R3and R4have the same meanings as in formula I, methyl-α-kalogeropoulos when heated in a neutral solvent in the presence of bases, which can serve as alkali metals, alkoxides, amides or hydrides:

where Hal means a halogen atom.

Example 1. 24.3 g (0.2 mol) of 2,6-dimethylaniline, 55.8 g (0.33 mol) of methyl-D,L-α-bromopropionate, a catalytic amount of potassium iodide and 21 g (0.2 mol) of sodium bicarbonate is stirred for 17 h at 140°, then cooled, diluted with 74 ml of water and extracted with diethyl ether. The extract is washed with water, dried over sodium sulfate, the solvent is distilled off and the residue is distilled in vacuum, collecting the fraction with TKIP-139°C/ 11 mmHg Receive 60.3 g (93%) of methyl-N-2,6-dimetilfenil-D,L-alaninate.

Example 2. The mixture contains 0.946 g (4.57 mmol) of methyl-N-2,6-dimetilfenil-D,L-alaninate, 0.802 g (4.57 mmol) of 2-oxo-2-piperidineacetate and 1 ml of dimethyl who formamide in 100 ml of toluene is refluxed 6 hours The solvent is distilled off, the residue is recrystallized from a mixture of isopropanol and hexane. Obtain 1.05 g (75%) of methyl 2-[2,6-dimethyl(2-oxo-2-piperidineacetic)aniline]-D,L-propanoate. TPL 117-118°C. an NMR Spectrum1N (δ, ppm): 0.93 (d, 3 H, CH3CH), 1.32, 1.48 (both m, 6 H, 3 CH2) 2.22, 2.39 (both s, 6 H, (CH3)2AG), 2.97, 3.49 (both t, 4 H, 2 CH2N), 3.72 (s, 3 H, CH3O), 4.52 (K, 1 H, CHN), 7.05-7.22 (m, 3 H, C6H3).

Example 3. A mixture of 6.05 g (0.05 mol) of 2,6-dimethylaniline and 7.45 g (0.051 mol) of diethyloxalate incubated 4 hours at a temperature of 120°C. the Reaction mass is repeatedly washed on the filter with hot ethanol, alcohol extract evaporated and the residue recrystallized from aqueous ethanol. Obtain 8.3 g (75%) of the ethyl ester of 2,6-dimethylphenylimino acid. TPL 57-59°C.

Example 4. A solution of 5 g (0.02 mol) of ethyl ester of 2,6-dimethylphenylimino acid and 1.55 g (0.021 mol) of diethylamine in 50 ml of ethanol is boiled for 4 hours under reflux. Then the reaction mass is then cooled to 0°C, the precipitate is filtered off and dried in air. Obtain 3.22 g (65%) of N-(2,6-dimetilfenil)-N',N'-diethylacetamide.

Example 5. A solution of 5 g (0.02 mol) of ethyl ester of 2,6-dimethylphenylimino acid and 5.5 g (0.033 mol) of methyl ester of D,L-α-bromopropionic acid in 50 ml of xylene is heated to 120°and add to it dropwise 8 ml of 30%solution methylate is the atrium in methanol, driving while continuously methanol. Then the reaction mixture is stirred for 30 minutes, then evaporated. The residue is cooled, filtered, the obtained crystals and wash them with cold isopropyl alcohol solution with hexane. Obtain 4.1 g (67%) of ethyl ester of D,L-N-(2,6-dimetilfenil)-N-(1-methoxycarbonylethyl)examinados acid.

Example 6. 4.1 g (13.3 mmol) of the ethyl ester of D,L-N-(2,6-dimetilfenil)-N-(1-methoxycarbonylethyl)examinados acid are dissolved in 30 ml of toluene, and thereto is added dropwise to 2 g (27.4 mmol) of diethylamine in 5 ml of toluene at 25°C. the Mixture is stirred for 5 h at 50°C, after which the solvent is distilled off. The residue is recrystallized from a mixture of isopropanol and hexane. Obtain 3.24 g (73%) of D,L-N-(2,6-dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-diethylacetamide. TPL 84-86°C. an NMR Spectrum1N (δ, ppm): 0.63, and 1.06 (both t, 6 H, 2CH3CH2), 0.97 (d, 3 H, CH3CH), 2.22 and 2.40 (both s, 6 H, (CH3)2AG), 2.87, 3.22 (both K, 4 H, 2CH2), 3.72 (s, 3 H, CH3Oh), 4.51 (K, 1 N, SSN3), 7.07-7.19 (m, 3 H, C6H3).

Example 7. To a solution of 6.05 g (0.05 mol) of 2,6-dimethylaniline and 5.6 g (0.055 mol) of triethylamine in 70 ml of xylene is added dropwise 7.5 g (0.055 mol) of acid chloride of N,N-dimethylarsino acid. The reaction mass is stirred for 30 minutes, then mixed with 16.7 g (0.1 mol) of methyl ester of D,L-α-bromopropyne the Oh of the acid, heated to 120°C. and add dropwise within 1 h, 20 ml of 30%solution of sodium methylate in methanol, driving while continuously methanol. Then the reaction mixture is stirred for 30 minutes, cooled to room temperature and mixed with 100 ml of water. The organic layer is separated, the aqueous layer was extracted three times with xylene. The combined organic phases, dried over sodium sulfate and the solvent is distilled off. After recrystallization allocate 11.8 g (80%) of D,L-N-(2,6-dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-dimethylacetamide.

Example 8. A solution of 10.5 g (0.05 mol) of methyl-N-2,6-dimetilfenil-D,L-alaninate and a few drops of dimethylformamide in 25 ml of toluene is added dropwise over 10 min to a solution of 12.7 g (0.1 mol) of oxalicacid in 50 ml of toluene at 20-25°and stirred at room temperature for another 30 minutes, the Solvent is distilled off, again add toluene, again distilled off, and repeat these operations until complete removal of oxalicacid. The residue is dissolved in 40 ml of toluene, and thereto is added dropwise 7.3 g (0.1 mol) of diethylamine in 20 ml of toluene at 25°C. the Mixture is stirred for 3 h at 50°C, then washed with 10%aqueous pyridine, 20%hydrochloric acid, 10%sodium hydrogen carbonate solution and water. The organic layer is separated, dried over sodium sulfate, the solvent is distilled off. The residue is recrystallized from a mixture of the propanol and hexane. Get 9.85 g (59%) of D,L-N-(2,6-dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-diethylacetamide.

Example 9. Methyl 2-[2,6-dimethyl(2-oxo-2-morpholinoethyl)aniline]-D,L-propanoate. TPL 112-113°C. an NMR Spectrum1N (δ, ppm): 0.97 (d, 3 H, CH3CH), 2.20, 2.40 (both s, 6 H, (CH3)2AG), 3.30-3.50 (m, 8 H, 4 CH2), 3.75 (s, 3 H, CH3O), 4.52 (K, 1 H, CHN), 7.10-7.20 (m, 3 H, C6H3).

Example 10. N-(2,6-Dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-Diisopropylamine. TPL 92-93°C. an NMR Spectrum1N (δ, ppm): 1.00 (d, 3 H, CH3CH), 1.05-1.15 (both d, 12 H, N(CH(CH3)2)2), 2.25, 2.45 (both s, 6 H, (CH3)2AG), 3.25, 4.02 (both m, 2 H, N(CH(CH3)2)2), 3.75 (s, 3 H, CH3Oh), 4.43 (K, 1 H, CHN), 6.98-7.15(m, 3H,C6H3).

Example 11. Test compounds on the biological activity was conducted at the research Institute of Chemical plant protection products on the causative agent of downy mildew potato Phytophthora infestans. To create a composition by the method of successive dilutions were prepared aqueous solutions of the compounds at concentrations of 0.1 and 0.005%. This environment was sprayed sliced potatoes, pre-artificially infected with a spore suspension of Phytophthora infestans. As a reference used metalaxyl-gold. The results are given in the table.

Table

The results of the s test for fungicidal activity against Phytophthora infestans substituted methyl-N-aminooctanoic-N-phenyl-N-alaninato
ConnectionThe degree of suppression of the development of the fungus, %
 concentration under current substance 0.1%concentration on the current matter 0.005%
D, L-N-(2,6-dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-diethylacetamide100100
D, L-N-(1,6-dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-dimethyloctane3020
Methyl 2-[2,6-dimethyl(2-oxo-2-morpholinoethyl)aniline]-D,L-propanoate10080
Methyl 2-[2,6-dimethyl(2-oxo-2-piperidineacetic)aniline]-D,L-propanoate100100
N-(2,6-Dimetilfenil)-N-(1-methoxycarbonylethyl)-N',N'-Diisopropylamine10060
Standard: Metalaxyl-gold100100

1. Substituted methyl-N-aminooctanoic-N-phenyl-D,L-alaninate General formula I

where R1and R2independently of one another denote alkyl with the number of carbon atoms one to four, R3and R4independently from each other mean a hydrogen atom, an unbranched or branched alkyl with a number of carbon atoms of from one to six or R3and R4compatible with the local form the group -(CH 2)2-X-(CH2)2-where X is an atom or group Of CH2.

2. The method of obtaining substituted methyl-N-aminooctanoic-N-phenyl-D,L-alaninate according to claim 1, which consists in the interaction of substituted methyl-N-phenyl-D,L-alaninato General formula II

where R1and R2independently of one another denote alkyl with the number of carbon atoms one to four,

with a derivative of oxalic acid of General formula III

where M denotes a chlorine atom or an unbranched alkoxygroup with the number of carbon atoms one to four, R3and R4independently of one another denote unbranched or branched alkyl with a number of carbon atoms of from one to six or R3and R4together form a group -(CH2)2-X-(CH2)2-where X is an atom or group Of CH2,

in the presence of kislorodsvyazyvayushchei agent and/or in the presence of a catalyst in a neutral solvent under heating or without it.

3. The method of obtaining substituted methyl-N-aminooctanoic-N-phenyl-D,L-alaninate according to claim 1, which consists in the interaction of substituted acylated methyl-N-phenyl-D,L-alaninato General formula IV,

where R1and R2regardless of others is g from each other, means alkyl with the number of carbon atoms one to four, Q denotes a halogen atom or an unbranched alkoxygroup with the number of atoms from one to four,

with the amine HNR3R4where R3and R4independently of one another denote unbranched or branched alkyl with a number of carbon atoms of from one to six or R3and R4together form a group -(CH2)2-X-(CH2)2-where X is an atom or group Of CH2in the presence of kislorodsvyazyvayushchei agent and/or in the presence of a catalyst in a neutral solvent under heating or without it.

4. The method of obtaining substituted methyl-N-aminooctanoic-N-phenyl-D,L-alaninate according to claim 1, which consists in the interaction of N-phenylacetamido General formula V

where R1and R2independently of one another denote alkyl with the number of carbon atoms one to four, R3and R4independently of one another denote unbranched or branched alkyl with a number of carbon atoms of from one to six or R3and R4together form a group -(CH2)2-X-(CH2)2-where X is an atom or group Of CH2,

with methyl-α-kalogeropoulos in neutral solvent at 110-140°C in the presence of a base selected from a number of alkaline metal, its amide, alkoxide or hydride.

5. The way p the receipt of substituted methyl-N-aminooctanoic-N-phenyl-D,L-alaninate according to claim 1, which consists in the interaction of N-phenylacetate General formula VI,

where Q denotes unbranched alkoxygroup with the number of atoms from one to four, R1and R2independently of one another denote alkyl with the number of carbon atoms one to four,

with methyl-α-kalogeropoulos when heated to 110-140°C in a neutral solvent in the presence of a base selected from a number of alkaline metal, its amide, alkoxide or hydride, and subsequent treatment of the product with the amine HNR3R4where R3and R4independently of one another denote unbranched or branched alkyl with a number of carbon atoms of from one to six or R3and R4together form a group -(CH2)2-X-(CH2)2-where X is an atom or group Of CH2neutral solvent under heating or without it.



 

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FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes a synergistic composition of herbicides comprising components (A) and (B) wherein (A) represents herbicide taken among the group of the formula (I):

wherein R1 means (C1-C4)-alkyl; R2 means (C1-C4)-alkyl; R3 means hydrogen atom; X and Y mean (C1-C4)-alkoxy-group; (B) represents one or two herbicides taken among the group of compounds or their acceptable forms: alachlor, metolachlor, acetochlor, dimetenamide, atrazine, cyanasin, metribusin, fluthiamide, nicosulfuron, rimsulfuron, primisulfuron, pendimetalin, sulcotrion, dicamba, mesotrion, isoxachlortol, metosulam, anilofos, fenoxaprop-ethyl, setoxydim, diclofop-methyl, MCPA, bromoxynil, pyridat, clopyralid, iodosulfuron-methyl, ethoxysulfuron, amidosulfuron, gluphosinat-amminium, isopropylammonium-glyphosate, imasetapir wherein components (A) and (B) are taken in the effective doses. Also, invention describes a method for control of weeds by using above indicated herbicide composition. Invention provides the development of the synergistic herbicide composition eliciting high activity.

EFFECT: improved method for control, valuable properties of composition.

6 cl, 26 tbl, 3 ex

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