CS209528B2 - Method of making the (pyrimidyloxy) phenoxyalcancarboxyll acids derivatives - Google Patents

Description

The invention relates to a process for the preparation of (pyrimidyloxy) phenoxyalkanecarboxylic acid derivatives having herbicidal properties.

Certain novel (pyrimidyloxy) phenoxyalkanecarboxylic acids and their derivatives have been found to exhibit biological activity, particularly herbicidal activity.

Accordingly, the invention provides compounds of Formula I, (wherein n

A and D are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkoxycarbonyl or halogen,

B is hydrogen, halogen, cyano, (2-6C) alkoxycarbonyl, (1-6C) alkyl, (1-6C) haloalkyl or (1-6C) alkoxy,

Each of a hydrogen atom, a halogen atom, a nitro group or an alkyl group having 1 to 6 carbon atoms,

R ¹ and R ² are each independently hydrogen or C 1 -C 6 alkyl,

W represents a hydroxymethyl group or a radical of formula

O — C — G where

G is hydroxyl, C1-C10 alkoxy optionally substituted by halogen, cyano, phenyl or C1-C6 alkoxy, C1-C10 alkylthio optionally substituted by phenyl, C2-C10 alkenyloxy C 2 -C 10 alkenylthio, C 2 -C 10 alkynyloxy, phenoxy optionally substituted by nitro, cyclohexyloxy, amino optionally substituted by one or two substituents selected from C 1 -C 6 alkyl, phenyl, optionally substituted with halogen or haloalkyl of 1 to 6 carbon atoms, and thienylmethyl, further denotes a morpholino or OM moiety, wherein M is an alaskal metal or alkaline earth metal ion, and X and Y are each independently oxygen or sulfur, and their optical is omers and salts thereof.

Compounds of formula (I) wherein:

R ¹ and R ² do not represent the same radicals, are optically active and the invention also encompasses the individual stereoisomers of such compounds and mixtures of these stereoisomers as well as racemic mixtures of stereoisomers.

Preferred residues in the meaning of the symbols A,

B and D are hydrogen, alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, halogen atoms, alkoxy of 1 to 6 carbon atoms, and haloalkyl of 1 to 6 carbon atoms.

A preferred residue within the meaning of the symbol

R @ ¹ is hydrogen or C1 -C6 alkyl, a preferred radical for R @ ² is hydrogen or methyl.

Preferably W represents the remainder of the formula

O — C — G

N ^CH i zy ° ^ o ~ ° ~ c ~ ^{c h} ° ^F · I ^CH and ^{C 0} C ~ ^H ~ ^{H CH2-} ° "Θ © '/ AO-CH-CO _of Na.

^F i ^C

in which

G is liydroxyl, C1-C10 alkoxy optionally substituted by halogen or C1-C6 alkoxy, C2-C10 alkenyloxy, C2-C10 alkynyloxy or cyclohexyloxy.

Preferred radicals X and Y are oxygen atoms.

The following compounds are exemplified by the compounds of the invention:

Specific examples of the compounds of the invention are:

compounds of formula XX,

Br

ca

AND

O-CH-CO? H?

(XX)

CH,

in which

W represents a radical of the formula —C — G,

0 listed in Table 1, compounds of formula XXb,

NO _from CHi O-CH ~

CO ^ H?

209328 in which

W represents the CH 2 OH group shown in Table 1b of the compound of formula XXI,

in which

W represents a radical of the formula --C - G,

0 listed in Table 2, compounds of formula XXII,

(XXII) wherein

W is the radical of formula -C-G listed in Table 3 of the compound of formula XXIII,

A p

A, A

O-xO-c- * '

· R ² (wherein xxun

W represents a radical of the formula —C — G110

listed in Table 4, and compounds of formula XXIV,

AND'

and

IN

N and -x / ^X y-x

D

Y-C ~ W (XXIV) wherein

W represents a radical of the formula —C — G110

listed in Table 5.

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WHAT

The compounds of formula (I), as well as their optical isomers or salts, can be prepared by a number of methods.

In accordance with the invention, the compounds of formula (I) above are produced by condensing a phenoxy- or phenylthiopyrimidine of formula (IX),

wherein each general symbol is as defined above, with a compound of formula X,

R1 hal — C — W (X)

R ² in which Hal represents chlorine, bromine or iodine and the other symbols are as hereinbefore defined, in the presence of an alkali.

The condensation described above is preferably carried out in the presence of an alkaline reagent and preferably in the presence of a solvent. Suitable alkaline agents include, for example, alkali metal and alkaline earth metal hydroxides and carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Suitable solvents include ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphosphoramide and sulfonate.

The reaction conditions required to carry out the condensation reaction vary depending on the nature of the reactants, the alkaline reagent used and the solvent. Generally, the reaction is accelerated by heating, usually with a reaction temperature in the range of 40 ° C to 150 ° C and a reaction time of 0.5 to 20 hours. However, higher or lower reaction temperatures and / or shorter or longer reaction times may be used if desired.

Compounds of formula (Ia) below (I; W = C-G),

II o

in which

G is not a hydroxyl group, it can be prepared from the acid of formula 1b (I; W - CO 2 H) by any of the conventional methods known in the art for converting carboxylic acids to salts, esters or acid amides. Such a procedure can be illustrated by the following Reaction Scheme A.

Scheme A

Compounds of Formula 1c below (I; W = -CH 2 OH) may be prepared from an acid or acid ester of Formula Id (I; W = C-G,

II o

where

G = OH or O-alkyl is any of the conventional methods known in the art for converting an acid to an acid ester or an alcohol (e.g., lithium aluminum hydride reduction). Such a process can be illustrated by the following Reaction Scheme B.

Scheme B:

f / c)

The compounds of the invention exhibit herbicidal activity against a wide variety of plants, both monocotyledonous and dicotyledonous, but are nevertheless selectively effective so that when applied to certain useful plants, including cereals, and in particular dicotyledonous crops, relative to these useful plants plants when administering those doses of the compounds of the invention that are lethal or severely damaging to other plant species.

The disclosed compounds are effective both in direct application to plants (post-emergence application) and in soil application before emergence of plants (pre-emergence application). However, the compounds of the invention are generally more effective in post-emergence application to plants.

The application rates of the compounds according to the invention depend on various factors, such as the nature of the weeds and / or crop plants to which the active compounds are applied and the nature of the compound used. In general, doses ranging from 0.01 to 20 kg per hectare are preferred, preferably from 0.1 to 2 kg per hectare. It will not be difficult for those skilled in the art to determine appropriate application rates using standard conventional methods without carrying out any extensive experimental verification.

Compounds No. 1, 14, 15, 16, 28, 67, 73, 74 and 75 of Table 1 exhibit particularly good selectivity in weed control in dicotyledonous crops such as sunflower, cotton, soybean, sugar beet and peanut.

The compounds of the present invention may be used as such to inhibit growth, severe damage or control of plants, but are preferably used in the form of compositions comprising the compounds of the present invention in admixture with a solid or liquid diluent carrier.

Methods for the preparation of compositions containing the compounds of the invention as active ingredients, as well as a description of the application of these compositions and the results of the efficacy tests are disclosed in our co-pending Czechoslovak patent specification No. 203,527.

The invention is illustrated by the following non-limiting examples.

These examples also illustrate the preparation of the starting materials required for the process of the invention.

He did

Preparation of ethyl 2- (4- (5-bromo-2-pyrimidoyloxy) phenoxy) propionate (1)

(a) Mixture of 3,0 g of 5-bromo-2-chloropyrimidine,

2.5 g of p-methoxyphenol, 50 ml of methyl ethyl ketone dried over anhydrous potassium carbonate and 2.5 g of anhydrous potassium carbonate were stirred and refluxed for 6 hours. The solvent was evaporated under reduced pressure, water was added to the residue and the precipitated compound was filtered off. A 5% aqueous sodium hydroxide solution was added to the product, and the mixture was stirred for about 30 minutes. The solid material was filtered off, washed with water and recrystallized from methanol-water to give 3.4 g of 5-bromo-2- (4-methoxyphenoxy) pyrimidine, m.p. 92 ° C.

(b) 2.4 g of 5-bromo-2- (4-methoxyphenoxy) pyrimidine are dissolved in 50 ml of methylene chloride, cooled to -70 ° C and 12.7 g of boron tribromide are added dropwise while stirring. The reaction mixture was stirred at -65 to -75 ° C for an additional hour, then allowed to warm slowly to room temperature and carefully added water and methylene chloride in small portions. The aqueous suspension was cooled to 20 ° C, the solid material was filtered off, washed with water and recrystallized from a mixture of methanol and water to give 2.1 g of 4- (5-bromo-2-). 178 DEG C. (pyrimidyloxy) phenol.

c) A mixture of 1.45 g of 4- (5-bromo-2-pyrimidyloxyphenol), 1.1 g of ethyl 2-bromopropionate, 201 ml of methyl ethyl ketone dried over anhydrous potassium carbonate and 1.0 g of anhydrous potassium carbonate was stirred with 8 The solvent was evaporated under reduced pressure, water was added to the residue, the mixture was extracted with methylene chloride, the methylene chloride extract was dried over anhydrous sodium sulfate, and the methylene chloride was evaporated under reduced pressure. 0.9 g of liquid product is obtained, identified by proton magnetic resonance spectroscopy and mass spectrometry as expected with ethyl 2- [4- (5-bromo-2-pyrimidyloxy) phenoxy] propionate.

Example 2

In accordance with the procedure described in Example 1 for the preparation of Compound No. 1 of Table 1, Compounds No. 3, 11, 12, 13, 14, 24, 25 are prepared from the corresponding 2-chloropyrimidine, p-methoxyphenol and the corresponding alkyl esters of 2-bromoalkyl acids. 26, 27, 28, 29 and 32 of Table 1 and compounds No. 76, 78 and 79 of Table 2.

Example 3

Preparation of ethyl 2- [4- (5-chloro-2-pyrimidylthio) phenoxy] -propionate (42)

a) 30 g of 5-chloro-2-methylthio-4-pyrimidinecarboxylic acid was heated to 180-200 ° C until all solid material melted and carbon dioxide evolution ceased (5 minutes). The residue was allowed to cool and then washed several times with chloroform. The chloroform washes were freed of dark insoluble material by filtration and the filtrate was concentrated to give 21 g (89%) of 5-chloro-2-methylthiopyrimidine as a light brown crystalline solid, m.p. 55 ° C.

b) To a solution of 19 g of 5-chloro-2-methylthiopyrimidine in 45 ml of acetic acid at 20 ° C was added 45 ml of 30% hydrogen peroxide. First, a suspension is formed which is cleared after 24 hours to give a colorless solution, from which 15 g (67%) of 5-chloro-2-methylsulfonylpyrimidine precipitates in the form of large colorless crystals, m.p. 124 DEG C., over 5 days.

c) To a solution of 6.7 g of 5-chloro-2-methylsulfonylpyrimidine and 5.0 g of 4-methoxythiophenol in 50 ml of methyl ethyl ketone was added 5.8 g of potassium carbonate, and the mixture was refluxed under stirring for 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and 5% aqueous sodium hydroxide solution. The chloroform extracts were dried over magnesium sulphate and evaporated under reduced pressure to give 8.5 grams of 5-chloro-2- (4-methoxyphenylthio) pyrimidine as a colorless solid, m.p. 75 ° C.

d) 7.5 g of 5-chloro-2- (4-methoxyphenylthio) pyrridine are dissolved in 60 ml of methylene chloride, cooled to -78 ° C and stirred while maintaining the temperature at -65 to -75 ° C. 18 g of boron tribromide are added dropwise, after the addition is complete, the reaction mixture is stirred at -78 [deg.] C. for a further hour and then allowed to slowly rise to 20 [deg.] C. The reaction is quenched with 50 ml of water. to give 5 g of 4- (5-chloro-2-pyrimidylthio) phenol as an almost colorless solid.

A mixture of 4- (5-chloro-2-pyrimidylthio) -phenol (2.36 g), ethyl 2-bromopropionate (1.81 g), methyl ethyl ketone (20 ml) and anhydrous potassium carbonate (1.55 g) was refluxed for 16 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and water. The chloroform layer was dried over magnesium sulfate and the chloroform was evaporated. 4.0 g of a liquid residue are obtained which, after chromatography on 30 g of silica gel using chloroform as eluent, gives an almost colorless liquid product, formed by identification of PMR by spectroscopy ethyl 2- [4- (5-chloro-2-pyrimidylthio) phenoxy propionate.

Example 4

Compounds No. 33 and 48 of Table 1 and Compounds No. 82 and 83 of Table 3 were also prepared from the corresponding 2- (methylsulfonyl) pyrimidine, the appropriate methoxyphenol, and the corresponding bromoalkanoic ester by the procedure described in Example 3. The products were identified by Proton Magnetic Resonance Spectroscopy (PMR) or Mass Spectrometry, and their characteristics are given in Table 6 below.

Example 5

Preparation of ethyl 2- [2-nitro-4- (5-chloropyrrolidine-2-oxy) phenoxy] propionate (45)

a) To a solution of 1.4 g of 4- (5-chloro-2-pyrimidyloxy phenol in 20 ml of acetic acid) was added 0.5 g of fuming nitric acid at 25 DEG C. After 4 hours, the mixture was poured into water and extracted with ethyl acetate. Chloroform extracts were dried over magnesium sulphate and evaporated to a yellow solid which was chromatographed on 40 g of silica gel to give 0.9 g of 4- (5-chloro-2-pyrimidyloxy) -2- nitrophenol in the form of pale yellow crystals.

b) A mixture of 0.9 g of 4- (5-chloro-2-pyrimidyloxy) -2-nitrophenol, 0.7 g of ethyl 2-bromopropionate and 0.5 g of potassium carbonate in 30 ml of methyl ethyl ketone is refluxed for 16 hours under stirring. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and water, the chloroform extracts were dried over magnesium sulfate and evaporated to a colorless solid residue which, after recrystallization from ethanol, yielded 0.66 g of ethyl 2- [2-nitro- 4- (5-chloropyrimides 1-2-oxy) phenoxy] propionate as colorless needle crystals, m.p. 82 ° C.

Example 6

In essentially the same manner as described in Example 5 for the preparation of compound 6. 45, with nitration of 3- (5-chloro-2-pyrimidinyloxy) phenol followed by the reaction thus obtained

3- (5-chloro-2-pyrimidyloxy) -6-nitrophenol with ethyl 2-bromopropionate prepared by Compound No. 77 from Table 2.

Example 7

Preparation of methyl 2- [4- (pyrimidyl-5-oxyphenoxy) propionate (93)

(a) 22.4 g of potassium hydroxide in pellets and 50 g of molten p-methoxyphenol are heated to 90 to 100 ° C with stirring until a clear solution is obtained, at a rate which maintains the temperature between 90 and 100 ° C. 100 ° C, add 120 grams of chloroacetaldehyde diethyl acetal. After stirring for 15 minutes, the water from the reaction vessel was removed as an azeotropic mixture with chloroacetaldehyde diethyl acetal, the water was separated from the acetal and the acetal returned to the reaction mixture. The azeotropic distillation is continued until the vapor temperature rises to 140-150 ° C and the reaction mixture is then refluxed for 6 hours.

Water (200 ml) was added to the cooled reaction mixture and the resulting mixture was extracted with chloroform (2 x 200 ml). The chloroform extracts were washed with 100 ml of 2 N aqueous sodium hydroxide to remove unreacted phenols, the chloroform layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was distilled under reduced pressure as the third fraction to give 45.6 g of p-methoxyphenoxyacetaldehyde diethyl acetal, b.p. 180-190 ° C / 50 mbar. The product was characterized by PMR spectroscopy.

b) To a solution of 18 ml of phosphorus oxychloride, while maintaining the temperature at 0 ° C, 20 ml of dry dimethylformamide are added dropwise, the reaction mixture is allowed to warm to room temperature and 16 g of p-methoxyphenoxyacetaldehyde diethyl acetal are added.

The resulting mixture was gently heated to 90 ° C with stirring, maintained at this temperature for 6 hours, then cooled and poured slowly over about 1 kg of crushed ice. The pH of the solution was adjusted to 10 by adding solid potassium carbonate while stirring, 500 ml of a mixture of 95% benzene and 5% alcohol was added, the mixture was heated to just under boiling for 2 hours, cooled, the organic layer was separated and dried. The solvent was distilled off under reduced pressure and the black oily residue was crystallized from ethanol (after charcoal clarification) to give 6.4 g of the product formed by PMR spectroscopy of 2- (p-methoxyphenoxy) -3- (dimethylamino) acrolein.

(c) 4.1 g of sodium metal are dissolved in 90 ml of absolute ethanol and 18.4 g of formamidine acetate, and to the resulting ethanolic solution of sodium ethoxide is added 13.0 g of 2- (p-methoxyphenoxy) -3- (dimethylamino) acre olein. The mixture was heated to reflux with stirring for 40 hours, after which the solvent was distilled off under reduced pressure. The residue is stirred with 200 ml of water and 200 ml of chloroform, the chloroform layer is separated and the chloroform is evaporated under reduced pressure. Purification of the residue by silica gel column chromatography using chloroform as eluent gave 7.7 g of an oily product formed by 5- (p-methoxyphenoxy) pyrimidine according to PMR spetroscopy.

dj 7.7 g of 5- (p-methoxyphenoxy) pyrimidine are dissolved in dichloromethane and 7 ml of boron tribromide are added dropwise while maintaining the temperature at -70 to -7 ° C. The solution is allowed to warm to room temperature while stirring, then allowed to warm to room temperature. After standing overnight, washed with 100 ml of cold saturated aqueous sodium bicarbonate solution, dried, clarified with charcoal and the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to give 0.4 g of product, m.p. by PMR spectroscopy with 5- (p-hydroxyphenoxy) pyrimidine.

e) A mixture of 0.4 g of 5- (p-hydroxyphenoxy) pyrimidine, 0.43 g of methyl 2-bromopropionate, 0.29 g of anhydrous potassium carbonate and 20 ml of methyl ethyl ketone was heated under reflux for 4 hours with stirring. The solvent was evaporated under reduced pressure, the residue was stirred with water, extracted with chloroform, the chloroform extracts were dried over sodium sulfate, and the chloroform was distilled off under reduced pressure. 4 g of an oily product identified by PMR spectroscopy and mass spectrometry as methyl 2- [4- (pyrimidyl-5-oxy) phenoxy] propionate.

Example 8

The mass spectra, PMR spectra and, if appropriate, melting and boiling points were detected for the compounds prepared according to the invention. These data are summarized in Table 6 below.

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a) mass spectrum: m / e 288 (M ^& lt ^{; +} & gt ^; ), 215, 187 bj comprising a proton of the residue R &lt; ²⁰ &^gt; j protons of the ethoxy group on the pyrimidyl ring

d) includes protons of a thienyl residue

(e) Mass spectrum: m / e 407 (M ⁺ ) fj Mass spectrum: m / e 415 (H ⁺ )

g) includes allyl protons

h) comprises one proton of the pyrimidyl residue

j) includes protons of the group

3 — C1 — CeH-d — O—

Abbreviations of PMR spectra:

s - singlet šs - broad singlet d = doublet d — d - doublet of doublets t triplet q - quartet m = multiplet

Claims (3)

Process for the preparation of (pyrimidyloxy) phenoxyalkanecarboxylic acids of the general formula I, in which: A and D are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkoxycarbonyl or halogen, B is hydrogen, halogen, cyano, (2-6C) alkoxycarbonyl, (1-6C) alkyl, (1-6C) haloalkyl or (1-6C) alkoxy, E and V each independently represent a hydrogen atom, a halogen atom, a nitro group or an alkyl group having 1 to 6 carbon atoms, R ¹ and R ² are each independently hydrogen or C 1 -C 6 alkyl, W represents a hydroxymethyl group or a radical of formula O — C — G where G is hydroxyl, C1-C10 alkoxy optionally substituted by halogen, cyano, phenyl or C1-C6 alkoxy, C1-C10 alkylthio optionally substituted by phenyl, C2-C10 alkenyloxy , alkenylthio having 2 In the present invention there are up to 10 carbon atoms, alkynyloxy of 2 to 10 carbon atoms, phenoxy, optionally substituted by nitro, cyclohexyloxy, amino, and the like. substituted with one or two substituents selected from the group consisting of C 1 -C 6 alkyl, phenyl optionally substituted with halo or C 1 -C 6 haloalkyl, and thienylmethyl, further denotes a morpholino group or an OM moiety wherein M is an alkali metal ion or an alkaline earth metal ion, and X and Y are each independently oxygen or sulfur, their optical isomers or salts, characterized in that the phenoxy- or phenylthiopyrimidine of the formula IX, in which the individual symbols are as defined above, is condensed with a compound of the formula X, R ¹ Hal-W-C R 2 wherein hal is chlorine, bromine or iodine and the remaining general symbols are as defined above, in the presence of an alkaline reagent. 2. A process according to claim 1, wherein the alkali and alkaline earth metal hydroxides and carbonates are used. 3. A process according to claim 1 or 2, wherein the alkali is potassium carbonate.