SI7811927A8 - Process for preparation of pyridine compounds - Google Patents

Description

The present invention relates to a process for the preparation of novel pyridine derivatives having herbicidal properties.

A technical problem

There was a need for a new, technologically advanced process for the preparation of pyridine compounds with herbicidal effect in good yield and in satisfactory purity.

The state of the art

The compounds of formula (I) listed below are novel and the process for their preparation has not yet been described.

Description of solution to a technical problem with implementation examples

We have now found that in a technically convenient manner, novel, herbicidally highly effective, pyridine compounds of formula I are obtained

\

CH, '2 O-CH-R (I) in which Z is trifluoromethyl, difluoromethyl or chlorodifluoromethyl, Y is hydrogen or chlorine, R is carboxy, (C1-6-alkoxy) carbonyl, a group of the formula COOCHgCH ^ OR ^, where S is alkyl of 1 to 4 carbon atoms, cyclohexyloxycarbonyl or (C1-6-alkenyl) oxycarbonyl, or in the case where p is R carboxy, their salts as the sodium salts, by the proposed process in which the compound of formula (II) is reacted

--OH (II) in which Z and Y have the above meanings, or a metal thereof, as a sodium salt, with a compound of formula (III)

CHHal ·

CH (III) ο

wherein R has the above meaning and is Hal halogen, in the presence of an inorganic base such as potassium carbonate, an inert solvent, as methylethylketone, and at a temperature between room temperature and reflux temperature.

If R is an alkoxycarbonyl group, the alkoxy group is e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec.butoxy and octyloxy.

Salts of the compounds of formula (I) in which R is carboxyl can be prepared by conventional methods known for the preparation of carboxylic acid salts. Typical salts include metal salts and ammonium salts. Metallic salts include salts composed of alkali metal cations, e.g. sodium, potassium, lithium, and cationic alloys, e.g. calcium, strontium and magnesium. Ammonium salts include salts consisting of an amine cation or a mono-, di-, tri- or tetrasubstituted ammonium cation in which the substituents may be e.g. aliphatic residues of 1 to 6 carbon atoms; these can be e.g. alkyl radicals having 1 to 6 carbon atoms.

One group of compounds of formula (I) includes those in which Z is a CF3 radical, Y is a hydrogen atom, a residue

2 R is defined above. Within this group, R may e.g. a carboxyl group of ssma per se or in the form of its salt, or it may be an alkoxycarbonyl residue in which the alkoxy group contains from 1 to 6 carbon atoms.

Another group of compounds of formula (I) of the invention includes those in which Z is a CF3 moiety, Y is a chlorine atom, a moiety o

R is defined above. Within this group, R may e.g.

the carboxyl group itself or as such is in the form of its salt, or it may be an alkoxycarbonyl residue in which the alkoxy group contains from 1 to 6 carbon atoms.

A further group of compounds of formula (I) includes those in which group Z is difluoromethyl or chlorodifluoromethyl o a residue, Y is hydrogen or chlorine and a residue R is defined above, p

Within this group of compounds, R may e.g. the carboxyl group alone or in the form of its salt, or it may be an alkoxycarbonyl residue in which the alkoxy group contains 1 to 6 carbon atoms.

The compounds obtained by the process of the invention contain an asymmetric carbon atom and are therefore able to exist in two optically isomeric forms. The present invention includes right and left rotary isomers of each compound (I) and mixtures thereof in all ratios.

Specific examples of compounds (I) of the present invention include those listed in Table I below.

TABLE I

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(continued)

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(0 + »a t «D Φ P Al (9> O-rl ΛΗ CO., LTD (0 0 Φ H> t) / ~, aj »oa φ Λ4-ΗΚ / -HtMX0 K «-H • H -P, r- ~ Oh rH 1 Φ Φ Φ Φ φφφφ O Ό Ό Ό Γ3 f-} tj τ \) · (“□ M rH h oooo oooo • r4 CO., LTD -P σ ' K o ci 5 ai aj o m Λ ® N rti ~ - χ - r- w · Η V O O (N m 3 -4 _ (A <J> Γ ® 8 O if 8 ΐ V « ° 8 8 8 . < > 1 »—4 rH · - <<Ή r-4 H H U o (J O U O o o o o N n n n n m fA K \ κλ t <\ CufcCutufc. »Pq pq pq u u u u u o o o o o CD a * • H-P τοχη 0 0> CD CO cr »o v CM tf? 4 LA <0 V in OJ Ol CM Λ) (\ J (\ J

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Φ Φ T3 Φ Φ T3 H Oh T3 (—1 OJ Oh r-1 rH o <0 Oh Oh

f ^- 1 ro p

α d

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IO 4- what IO to it

In the case of many of the compounds in the above table, a physical constant in the form of boiling point or melting point is not available because the compounds are often isolated by thin layer chromatography and the majority are viscous oils. The structure of the compounds, however, was confirmed by investigation of their NMR spectra, which corresponded to the structure set out in Table I.

Compounds (I) are herbicides that are generally significantly more effective against grass species than against broad-leaved plant species. They can be used to control unwanted species of grasses growing on their own, or we can use a suitable application dose to control grass weeds growing among broad-leaved crop plants. The compounds are applied to the soil, either before the emergence of undesirable grass species (pre-emergence application) or above-ground parts of growing grasses (postemergence application).

For the compounds of formula (I), the herbicidal toxifier p

supposedly free acid (i.e., R is carboxy), but the compound usually refers to ester-shaped plants. The exact nature of this ester has no significant effect on herbicide efficacy.

The amount of the compound to be administered depends on many factors, e.g. of the individual plant species whose growth we would like to suppress is generally generally sufficient from about 0.025 to 5 kg per hectare and preferably from 0.1 to 1 kg per hectare. One skilled in the art will readily be able to determine the appropriate amount to use in terms of standardized plant tests without undue experimentation.

The compounds (I) are preferably administered in the form of compositions in which the active ingredient is mixed with a carrier which, with a solid or liquid diluent, is present. Preferably, the composition further comprises a surfactant.

Solid extrusion compositions may be e.g. in the form of dusts, or may take the form of granules. Suitable solid diluents include e.g. kaolin, bentonite, quartz, dolomite, calcium carbonate, talc, powdered magnesium and Puller's soil.

Solid compositions may also be in the form of dispersible powders or grains, additionally incorporated into the active ingredient, a moisturizing agent to facilitate the dispersion of powders in liquids. Such powders or grains may include fillers, suspending agents and the like.

Liquid compositions include aqueous solutions, dispersions and emulsions containing the active ingredients, preferably in the presence of one or more surfactants. Water or organic solvents can be used to prepare solutions, dispersions or emulsions of the active ingredient. The liquid compositions of the invention may also contain one or more corrosion inhibitors, e.g. laurylisoquinoline bromide.

Surfactants can be cationic, anionic, or nonionic. Suitable cationic type agents include e.g. quaternary ammonium compounds, e.g. cetyltrimethyl-ammonium bromide. Suitable anion-type agents include e.g. soaps, salts of aliphatic sulfuric acid monoesters, e.g. sodium lauryl sulfate; and salts of sulfonated aro11 mat compounds, e.g. dodecylbenzenesulfonate, sodium, calcium and ammonium lignosulfonate, butylnaphthalenesulfonate and a mixture of sodium salts of diisopropyl and triisopropylnaphthalenesulfonic acid. Suitable non-ionic type agents include e.g. the condensation products of ethylene oxide with fatty alcohols, such as · · · olelyl alcohol and cetyl alcohol, or with alkylphenols such as octylphenol, ncynphenolor and octyl cresol. Other non-ionic agents are partial esters derived from long-chain fatty acids and hexitol-anhydrides e.g. sorbitol monolaurate; condensation products of the foregoing ethylene oxide partial esters, and lecithins.

The ingredients to be used in the form of aqueous solutions, dispersions or emulsions are generally commercially available as a concentrate containing a large proportion of the active ingredient, a concentrate that is diluted with water before use. These concentrates are required to withstand storage for extended periods and, after such storage, can be diluted with water to form aqueous preparations that remain homogeneous for sufficient time to be applied with conventional spraying equipment. For convenience, the concentrates may generally contain from 10 to 85% and preferably from 25 to 60% by weight of the active ingredient. Diluted ready-made preparations may contain different amounts of the active ingredient depending on the intended use, and diluted preparations suitable for different uses contain between 0.01% and 10% by weight, and preferably between 0.1% and 1% by weight. % by weight of active ingredient.

Compounds (I) can be prepared from suitably substituted 2-halogenopyridines of formula II

N

Y (IT) in which X represents a fluorine, chlorine, bromine or iodine atom and Y and Z are as defined above in formula (i). There are, however, two routes for the conversion of halogenopyridines (II) to the compounds of the invention. They are described below as routes A and B.

Route A is described in the following scheme:

'Oh

OCH.

(III) (

Demethylating agent (lil) e.g. pyridine hydrochloride

(IV)

- 13 CH_ | ⁵ (IV) + hal-CH-R ² base (V) (I)

In path A, the symbols R, Z and Y have previously defined meanings, hal is halogen, preferably chlorine or chromium, and M is a cation, e.g. sodium.

In route A, the appropriately substituted halogenopyridine (II) is reacted with a metal salt of p-methoxyphenol, e.g. p-methoxyphenol sodium salt. The metabolism is preferably carried out in a solvent or diluent, e.g. methylethylketone, tetrahydrofuran, dimethylsulfoxide or dimethylacetamide. The 2-p-methoxy phenoxy compound (III) thus obtained is then demethylated in the usual manner, e.g. by heating with pyridine hydrochloride or hydrobromic acid in acetic acid to give the corresponding p-hydroxy compound (IV). It is reacted in the form of its metal salt (e.g. sodium or potassium salt) with the corresponding halogenalkane saliva derivative (V) to give the required compound (I). This metabolism is preferably carried out in a solvent or diluent, e.g. methylethylketone.

Route B is described in the following scheme:

k (II) base (iv) base

> (I) (IV)

-Ά In the sense of route B, the suitably substituted 2-halogenopyr din (II) is reacted with hydroquinone in the presence of a base to give the mo p-hydroxy-phenoxy compound (IV) already mentioned in route A The reaction is preferably carried out in a solvent or diluent for reagen te. Examples of suitable solvents include aprotic solvents, e.g. dimethylformamide. The metabolism is preferably accelerated by heating e.g. to a temperature in the range of 5θ to 150 ° C. The metabolite used may be e.g. inorganic base, e.g. sodium or potassium carbonate.

The second stage of Route B is identical to the last stage of Route A and requires no further description.

Starting substances (II) used in routes. A and B can be prepared by different methods. Compounds containing a fluorinated alkyl group may be prepared e.g. by metabolizing the appropriate chlorinated compound with a fluorinating agent to replace some or all of the chlorine atoms with fluorine atoms. Thus, 2-chloro-5-trifluoromethyl-pyridine can be obtained by metabolizing 2-chloro-5-trichloromethyl-pyridyl with a fluorinating agent, e.g.

{antimony trifluoride or liquid fluorodes. By regulating the amount of fluorinating agent used in the metabolism, compounds with alkyl groups containing both fluorine atoms and chlorine can be obtained; 2-chloro-5-trichlororaethylethylpyridine may e.g. is reacted with a limited amount of antimony trifluoride to give 2-chloro-5-chlorodifluoromethyl-pyridine.

In these halogen exchange metabolites, part of the halogen substituent at position 2 of the pyridine can also be exchanged so that part of the 2-fluorinated compound can be obtained. This is not a practical disadvantage, the halogen ηβ of position 2 is displaced in the subsequent conversion of halogenopyridine to the compound of the invention. Certain chlorinated compounds required as starting materials are considered new compounds, e.g. 2-chloro-5-trichloromethyl pyridine and 2,5-dichloro-5-trichloromethyl pyridine. Their preparation is described in the south. patent application P-2670/82.

-1ύ

In addition to their usefulness as intermediates for the preparation of compounds of the invention, they are somewhat biologically active as insecticides.

In an alternative process for the preparation of 2-halogen

3- or -5-trifluoromethyl-pyridines, 2-halogen-3 or -5-carboxy-pyridine can be reacted with sulfur tetrafluoride in the presence of hydrogen fluoride, as shown below for 2-chloro-5-trifluoromethyl-pyridine:

-1?

J

Compounds containing a difluoromethyl group can be prepared by treating the corresponding pyridinaldebide with sulfur tetrafluoridor as shown below:

The invention is illustrated by the following examples, in which all parts are mass and all temperatures are in degrees Celsius, unless otherwise stated.

- 18 EXAMPLE 1

This example illustrates the preparation of ethyl a-4 (5-trifluoromethyl-2-pyridyloxy) phenoxypropionate (compound No. 3).

(a) Preparation of 2-chloro-5-trichloromethyl · -pyridine

2-Bromo-5-ethylethylpyridine (55 g) in dry carbon tetrachloride (600 ml) was filtered and then treated with dry hydrogen chloride to give a salt. The separated solid is crushed and the mixture is heated under reflux. Dry chlorine for 6 1/2 hours is passed through a boiling mixture, irradiated with an ultraviolet lamp placed in a reaction flask. The mixture was then cooled, filtered and evaporated to a pale yellow liquid, which solidified upon cooling. It is identified as the required chloro compound by its NMR spectrum.

(b) Preparation of 2-chloro-5-trifluoromethyl-pyridine and 2-chloro-5-difluorochloromethyl-pyridine

2-chloro-5-trichloromethyl-pyridine (13 g) and antimony trifluoride (50 g) were heated at 140 to 145 ° C for 1 hour. The mixture was cooled, mixed with ice and concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried with magnesium sulfate and evaporated. The products of several liquid preparations are combined and distilled at atmospheric pressure through a short column filled with Fenske jivas.

The product boiling at 124 ° C to 194 ° C is collected and identified as 2-chloro-5-trifluoromethyl-pyridine. The higher boiling fractions were again distilled at a pressure of 26.6 mbar to give 2-chloro-5-difluorochloromethyl-pyridine, which boils at 82 to 90 ° C.

(c) Preparations of 2-p-methoxy-phenoxy-5-trifluoromethyl-pyridine

Sodium hydride (4.2 g of 5θ% dispersion in oil, washed with petroleum ether) was stirred in dry dimethyl sulfoxide (100 ml) and a solution of p-methoxy-phenol (10.4 g) in dimethyl sulfoxide (100 ml) was added within minutes. The mixture was stirred for 30 minutes to give the sodium salt. To the solution, 2-chloro-5-trifluoromethyl-pyridine (15.0 g) in dimethylsulfoxide (80 ml) was added in a few minutes. The mixture was then heated to 70 to 75 ° C for 3 hours and allowed to cool overnight. Thin layer chromatography shows that only one compound is present. Dilute the mixture with water to

1.5 liters and extracted with ether (3 x 600 ml). The ethereal extract is washed several times with water and then with molar sodium hydroxide solution and finally with water (2 x 200 ml). The ether extract was dried and evaporated to give the required pyridine compound as a brown oil.

(d) Preparation of 2-p-hydroxy-phenoxy-5-trifluoromethyl-pyridine

2-p-methoxy-phenoxy-5-trifluoromethyl-pyridine (10.5

g) in glacial acetic acid (100 ml) and 48% hydrobromic acid (50 ml)

- 20 stirred and heated for 7.5 hours under reflux. The solution was then evaporated and the remaining oil treated with a bicarbonate solution and shaken with ether (2 x 100 ml). The ether extract was shaken with 2m sodium hydroxide solution (200 ml) and then with water (15 ° ml). The aqueous layers were combined, acidified with 2m hydrochloric acid and extracted with ether (2 x 100 per acre). The ether extracts were dried and evaporated to give a brown oil identified as 2-phidroxy-phenoxy-5-trifluoromethyl-pyridine.

(e) Preparation of compound no. 3 of Table I

2-p-hydroxyphenoxy-5-trifluoromethylpyridine (0.22 g), ethyl a-bromopropionate (0.24 g) and potassium carbonate (0.18 g) in methyl ethyl ketone (5 ml) were stirred and refluxed. We heat for 2 hours. The mixture was left overnight, then filtered and the residue was washed with methyl ethyl ketone. The filtrate and the washing liquids were evaporated and traces of solvent were removed from the oil remaining under high vacuum. The NMR spectrum of the oil is in accordance with a particular structure and the compound is identified as compound no. 5.

(f) Preparation of compound no. 8

The product of (e) (0.5 g) was dissolved in n-pentanol (15 ml) containing concentrated sulfuric acid (2 drops). The mixture was heated under reflux for 5 1/2 hours. The solvent was removed and the residue was taken up in ether and washed with saturated solution

-21 Sodium bicarbonate. The ether solution was dried and evaporated to a colorless oil, which was purified by preparative thin-layer chromatography on silica gel with a mixture of petroleum ether (60 to 80 ° C) and ether (80:20) as solvent. The NMR spectrum identifies the product as the required pentyl ester.

(g) Preparation of Compound No, 1

Product of (e) (0.14 g) in isopropanol (2 ml)

1.75 w at room temperature was stirred with aqueous sodium hydroxide solution (1.6 ml of a solution containing 1 g of NaOH per 100 ml of water). The mixture was evaporated in vacuo and the residue taken up in water, acidified and extracted with ether (2 x 50 ml). The ether extract gives an oil that is identified as the required carboxylic acid.

(h) Preparation of compounds 2, 4 to 7 and 14

In the manner described in paragraph (e) above, in each case using the appropriate α-bromo-propionester instead of ethyl-α-bromopropionate, compounds 2, 4 to 7 inclusive, but 14 are not prepared.

(i) Preparation of 2 [4 (5-trifluoromethylpyridyl-2-oxy) phenoxy] propionyl chloride

The carboxylic acid prepared as described in paragraph (g) above (1.2 g) is heated under reflux for 1 hour with thionyl chloride (20 ml) and then the excess of thionyl chloride from 22 is removed under reduced pressure. The residue was mixed with tolnene and the toluene was evaporated under reduced pressure to remove traces of thionyl chloride. The propionyl chloride derivative is obtained as an oil.

(J) Preparation of compound 17

The acid chloride as prepared above in (i) (0.87 ε) is dissolved in allyl alcohol and heated to 100 ° C for 1 hour. The excess alcohol is removed under reduced pressure and the residual oil is washed with water and 2m hydrochloric acid and dissolved in ether. The ether solution was dried and evaporated and the residual oil was purified by flash chromatography on silica gel using a mixture of the same volumes of ether and light petroleum (boiling point 60 to 80 ° C) as the eluent. Allylester (compound et. 17) is obtained as a colorless oil.

PBIHER 2

This illustrates the preparation of 2-chloro-5-trichloromethyl-pyridine by chlorination of 3-methyl-pyridine under the influence of ultraviolet light.

Dissolve 5-methyl-pyridine (10 ml) in dry carbon tetrachloride (500 ml). The solution was heated to reflux (about 80 ° C) and the dry chlorine gas was bubbled through the boiling mixture for 5 hours, while simultaneously irradiated with a 100 watt ultraviolet lamp from the inside, which gave light with a wavelength of 185 nm. Preparative thin layer chromatography (silica, chloroform / cyclohexane) of a sample of a solution which is thus obtained to identify the 3 major products in a total yield of 10 to 15%, of which the predominant is identified by its NMR spectrum as desirable 2-chloro-5- trichloromethyl pyridine. This is confirmed by mass spectrographic analysis of the solution obtained. The other two major products are 2-chloro-3-trichloromethyl-pyridine and di (trichloromethyl) pyridine, which is present in an amount of about 1/2 oz. 1/10 main products.

- EXAMPLE 5

K

This example illustrates the preparation of 2-chloro-5-trichloromethyl · pyridine from aoli 3-methyl-pyridine.

3-Methyl-pyridine (15 g) in dry carbon tetrachloride (200 ml) was treated with dry HCl gas to give the hydrochloride. The oil mixture thus obtained was mixed and heated under reflux. Dry gas chlorine was bubbled into the refluxing mixture for 4 hours while irradiated with ultraviolet light from the one used in Example 1. The reaction mixture was then cooled and separated by decantation into a solution and an oil solid. The latter is purified and proved to contain an unrefined salt of 3-methyl-pyridine. The former is subjected to an oil semi-solid which is demonstrated by thin-layer chromatography to have the properties of 2-chloro-5-trichloromethyl-pyridine.

EXAMPLE 4

This example describes the preparation of 2-chloro-5-trifluoromethylpyridine by a method alternative to the method of Example 1.

The 6-chloronicotin kialino (23.6 g), sulfur tetra24 fluoride (57.4 g) and anhydrous hydrogen fluoride (18.7 e) were heated in an autoclave during stirring at 120 ° C for 8 hours. The mixture was cooled, poured onto ice and neutralized with concentrated sodium hydroxide at 0 ° C, the mixture extracted with ether and the extracts washed with water, dried and evaporated. The residue is distilled off and the fraction boiling at 140 to 150 ° C is collected. · Analysis shows that it consists of 2-chloro-5-trifluoromethyl-pyridine with some 2-fluoro-5-trifluoromethyl-pyridine.

(

EXAMPLE 5

This example describes the preparation of 2-chloro-5-trifluoromethylpyridine by a method alternative to the methods of Examples 1 and 4.

2-Chloro-5-trichloromethyl-pyridine (50.8 g) and anhydrous hydrogen fluoride (80 g) were heated to 200 ° C for 10 hours while stirring in the autoclave. The mixture was cooled, poured onto ice and neutralized at 0 ° C. The mixture was filtered and the residue and the filtrate extracted with ether. The ether extracts were baked with water, dried and evaporated (to give an oil. This was distilled and collected at a boiling point at 140 to 154 ° C. Analyzes showed that it was composed of 2chloro-5-trifluoromethyl-pyridine with some 2-Fluoro-5-trifluoromethyl-pyridine.

EXAMPLE 6

This example illustrates the preparation of compound no. 20 from Table I along Route A.

(a) Preparation of 2-amino-5-broao-5-methyl-pyrrolidine

The 2-amino-5-methyl-pyridine (108 g) in ice (JOO ml) was warmed to 90-100 ° C while bromine (160 g) in acetic acid (55 ml) was added slowly while stirring. When the addition is complete, the mixture is stirred and heated for a further 30 minutes and then allowed to cool overnight. The separating solid was filtered off and mixed with ice and the mixture was neutralized with concentrated ammonia while maintaining the temperature from 0 to (5 ° C. The solid was collected, washed with water and dried to give the bromo compound.

(b) Preparation of 3-bromo-2-chloro-5-methyl-pyrrolidine

The product of (a) (145 g) was dissolved in concentrated hydrochloric acid (750 al) and water (450 ml) and the solution cooled to -10 ° C. Sodium nitrite (54 g) was added dropwise over 90 minutes while stirring with cold water (450 ml) while keeping the solution at -5 ° C. The solution was stirred nadeljni 2 hours, and then basified with concentrated ammonia, whereby _<o keeping the temperature below 20 ° C. The separable solid was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1 m, 1 liter). The ether solution was washed twice with water (1 liter delsr), dried and calibrated to give the required 3-bromo-2-chloro-5-methyl-pyridine.

(c) Preparation of 2 '3-dichloro-5-trichloromethyl-pyrrolidine

The product of (b) (64 g) was treated with dry hydrochloride in dry carbon tetrachloride (650 ml). The precipitate is broken down and the suspension is heated under reflux, while auh chlorine is introduced into the mixture during irradiation with a source of ultraviolet light. After 4 1/2 hours, the mixture was cooled, filtered and the filtrate evaporated to give the required 2,3-dichloro-5-trichloromethyl-pyridine. The mass spectrum is consistent with the structure specified for this compound.

(d) Preparation of 2,3-dichloro-5-trifluoromethyl-pyridine

The product of (c) (1.0 g) and antimony trifluoride (3.0 g) were heated at 1 ° 0 to 180 ° C for 3θ minutes. The mixture was cooled, mixed with ice and water and extracted with ether.

The ether extracts gave a brown oil containing a mixture of 2,3-dichloro 5-trifluoromethyl-pyridine and 3-chloro-2-fluoro-5-trifluoromethyl-pyridine with a smaller amount of 2,3-dichloro-5-chlorodifluoromethyl-pyridine.

(e) Preparation of ^{3-chloro-2-p-methoxy-phenoxy-5-t} trlfluoi ometllplridina p-metokeifenol (1.5 g) was added to a suspension of sodium hydride (0.6 g 50% oil dispersion, washed with petroleum ether) in of dry dimethyl sulfoxide (30 ml) and the mixture was stirred for 15 minutes. The combined products solution (1.5 g) of several preparations, '27, as described in paragraph (d), in dimethylsulfoxide (20 ml) was added to the reaction mixture and heated to 60 ° C for 4 hours. A further amount of sodium hydride (0.3 g, 50% oil dispersion, washed with petroleum ether) and potassium carbonate (1.38 g) was added. Continue heating for a further 4 hours.

The mixture was poured into ice and water and extracted with ether (400 ml). The ether extracts were washed with water, dilute sodium hydroxide and water, dried and evaporated to give the product.

((f) Preparation of 3-chloro-2-p-hydroxy-phenoxy-5-trifluoromethylpyridine

The product of (e) (2 g) was heated for 6 hours with pyridine hydrochloride (20 g) at 170 to 180 ° C. The mixture was cooled, diluted with dilute hydrochloric acid and extracted with ether. The ether extracts give an oily solid which is purified by preparative thin layer chromatography using silica as an adsorbent and 6% ethanol-chloroform as solvent.

f (g) Preparation of compound no. 20 from Table I

The product of (f) (0.16 g), ethyl a-bromopropionate (0.3 g) and potassium carbonate (0.25 g) was heated and stirred under reflux in methyl ethyl ketone (10 ml) for 2 hours. The mixture was cooled and filtered. Evaporation of the filtrate gives us the oil which is heated in vacuo to remove traces of solvent. The oil is identified as compound no. 20 by examination of its mass spectrum and its purity confirmed by gas-liquid chromatography.

2,3-Dichloro-5-trichloromethyl-pyridine is prepared by the alternative route as follows:

(h) Preparation of 2-amino-3-chloro-5-methyl-pyridine

2-Amino-5-methyl-pyridine (10.8 g) in concentrated hydrochloric acid (100 ni) was kept at 10 to 15 ° θ 'while hydrogen peroxide (30%, 21 ml) was added dropwise while stirring. When the addition is complete, the mixture is stirred for 1 1/4 hours (without cooling and poured onto ice (about 200 g). The mixture is brought to pH 8 to 9 by adding concentrated ammonia dropwise while maintaining the temperature at 0 ° C with the addition of The solution was extracted with chloroform (2 x 300 ml) and the chloroform extracts gave the required chloroform as yellow »

solid.

(i) Preparation of 2-bromo-3-chloro-5-methyl-pyridine

The product of paragraph (h) (5.7 g) in hydrobromic (acid (48%, 50 ml) was cooled to -15 ° C to -10 ° C and bromine (2.6 ml) was added dropwise while stirring. at -5 ° C to 0 ° C, while sodium nitrite (5.53 g) in water (12 ml) is added dropwise over 45 minutes, and the mixture is stirred at 0 ° C for a further 30 minutes and then poured over The mixture is slightly alkaline by adding concentrated ammonia dropwise while keeping the temperature at 0 ° C. with ice.The mixture is extracted with ether (15 ° ml). · The ether extract is washed with water, sodium bisulfite solution and water and then dried. The residue was taken up in petroleum ether (boiling point 40 to 60 [deg.] C.), the solution filtered and evaporated The residue was identified as 2-bromo-5-chloro-5-methyl-pyridine.

(j) Preparation of 2,3-dichloro-5-trichloromethyl-plridine

Treat the product referred to in paragraph (i) (2.9 g) in dry carbon tetrachloride (25θ) with dry hydrogen chloride, to be converted? ¹ * hydrochloride. Chlorine is passed through the suspension, kept at 80 ° 0 and irradiated with an ultraviolet lamp inside the reaction flask. After 5 hours, the solvent was removed leaving 2,3-dichloro-5-trichloromethyl-pyridine.

EXAMPLE 7

This example illustrates the preparation of 2,5-dichloro-5-trifluoromethylpyridine by fluorination of 2,5-dichloro-5-trichloromethylpyridine using a fluorinating agent alternative to the fluorinating agent of Example 6.

2,3-Dichloro-5-trichloromethyl-pyridine (55 g) was heated ^{in an} autoclave for 10 hours with anhydrous hydrogen fluoride (100 g) at 200 ° C. The cooled reaction mixture was poured onto ice and neutralized with sodium hydroxide at 0 ° C. The mixture was extracted with methylene chloride (750 ml). The extracts were washed with water (5OO ml), sodium carbonate solution (500 ml) and water (5θθ), dried and washed. The remaining oil is distilled off and the fraction boiling at 77 to 83 ° / 333 mbar is collected and identified as the required pyridine derivative.

PRIMES 8

This example further illustrates the preparation of 2,3-dichloro-5-trifluoromethyl-pyridine.

Aatimon-trifluoride (61 g) was evaporated in vacuo to remove moisture. The cooled material was broken down and heated to 65 to 70 ° C, while antimony pentachloride (6.6 g) was added dropwise while stirring. The mixture is then added dropwise

2,3-dichloro-5-trichloromethyl-pyridine (40 g) was heated to 160 ° C in 45 minutes. The mixture was cooled and distilled in steam. The pre-distillating oil was extracted with ether (2 x 100 ml). The ether extract was washed with tartaric acid solution, then with water, sodium bicarbonate and water, and dried. Distill the remaining oil. The fraction boiling at 71 to 80 ° / 24 mbar is identified as the required pyridine derivative.

EXAMPLE 9

This example illustrates the preparation of 3-chloro-5-trifluoromethyl-2-p-hydroxy-phenoxy-pyridine by route B.

Dry dimethylformamide (50 ml) was removed by refluxing in argon for 3θ minutes. Hydroquinone (4.95 g) and anhydrous potassium carbonate (6.84 g) were added and heated to reflux for 90 minutes. To the above mixture, 2,3-dichloro-5-trifluoromethyl-pyridine (6.48 g) in dry dimethylformamide was removed over 4 hours to remove air (30 ml). The mixture was allowed to cool and diluted with water (500 ml) overnight. The mixture was acidified with dilute hydrochloric acid and extracted with ether (2 x 400 ml). The ether extract was washed with water (2 χ 5θθ ml) and extracted with dilute sodium hydroxide solution (3θθ ml). The ether extract was washed with water and the aqueous fractions were combined and re-acidified with hydrochloric acid. The acidified aqueous solution was extracted with chloroform (2 x 400 ml). Chloroform extract gives light oil, which, when rubbed with petroleum ether (boiling point 3θ to 40 ° C), gives a colorless solid which is identified as the required 3-fluoro-5-trifluoromethyl-2-p-hydroxy-phenoxy-pyridine.

EXAMPLE 10

This example illustrates the preparation of ethyl-2 [4 (3-chloro-5-trifluoromethylpyridyl-2-oxy) phenoxy] propionate (compound No. 20 of Table I).

The product of Example 7 (1 * 0 g) was stirred and refluxed for 4 hours with potassium carbonate Jv methyl ethyl ethyl ketone (25 ml) and ethyl 2-bromo-propionate (1.0 g). The mixture was cooled, filtered and the filtrate evaporated to give an oil which was purified by thin layer chromatography on 2 mm thick plates, each 20 x 20 cm large, using a mixture of 20 volumes of ether and 100 volumes of hexane as eluent. The product is extracted with ethanol. Evaporation of ethanol yields a colorless oil which is identified as compound no. 20 with its NMR spectrum.

EXAMPLE 11

According to the method described in Example 10, compounds No. 19, 21 to 3 ^ from Table I, each using the corresponding 2-bromopropionic acid esters.

\ EXAMPLE 12

This example illustrates the preparation of 2 [4 (3-chloro-5-trifluoromethylpyridyl-2-octa) phenocai] propionic acid (Compound No. 18 in Table I).

Compound no. 21 from Table I (2.19 g) in isopropanol (20 ml) was treated dropwise at room temperature with a solution of sodium hydroxide (0.23 g) in water (20 ml). The mixture was stirred at room temperature for 4 hours, diluted to 3θθ ml with water. The solution was extracted with methylenedichloride (2 x 50 ml) and acidified with 2m hydrochloric acid. The acidified solution was extracted with methylenedichloride (2 x 150 ml), the extract was dried and evaporated to give an oil. It solidifies under condition and is vacuum dried at 85 ° C to give us compound no. 18 with a melting point at 104 to 107 ° C.

- 33 PRIMES 13

This example illustrates the preparation of ethyl alpha-4 (5-difluorochloro-2-pyridyloxy) phenoxy propionate. (St. 32 compounds along Route A.

(a) Preparation of 5-flufluorochloromethyl-2-p-methoxy-phenoxy pyrrolidine.

2 »chloro-5-difluorochloromethylpyridine, prepare one for example 1 (h) (1.0 g) in dimethylsulfoxide. (10 ml) was added to a solution of p-methoxyphenol (0.62 g) previously digested with Na-hydride (0.24 g of a 50% oil dispersion, washed with petroleum ether) in dimethylsulfoxide (15 ml). The mixture was stirred and heated to 60-65 ° C for 5 hours, poured onto ice and extracted with ether. The etme extracts were washed with water, dilute sodium hydroxide and water, dried and evaporated to give an oil that was identified as the required p-methoxy compound.

(b) Preparation of 3-difluorochloromethyl-2-p-hydroxy-phenoxypyridine

The product of (a) (1.0) was dissolved in ice (12 ml) and aqueous hydrochloric acid (48%, 5 ml) was added. The reaction mixture was stirred and refluxed for 3 1/2 hours. The mixture was cooled and evaporated under reduced pressure. The residue was taken up in ether and washed with sodium bicarbonate solution and water. The ethereal solution is dried and evaporated to give a partially solidified oil. This is purified with preparations

- 54 silica gel thin layer chromatography using a mixture of 6% ethanol in chloroform as solvents.

(c) Preparation of Compound No.52

The product of (b) (0.18 g) was heated under reflux for 2 1/2 hours in methylethylketone (10 ml), with ethyl a-bromopropionate (0.5 g) and potassium carbonate (0.25 g) - The mixture was cooled , the solids are filtered off and washed with methylethylketone. The filtrate and washing liquids were evaporated in vacuo to give an oil. j

EXAMPLE 14

This example illustrates the herbicidal properties of compounds (I). Each test compound is prepared by mixing it with 5 ml of emulsion, which is prepared by 100 ml of a solution containing 21.8 g per liter of Span 80 and 78.2 g per liter of Tween 20 in methyl cyclohexanonn, dilute to 500 ml with water. Spanish 80 is a trademark for a surfactant containing sorbitan monolaurate. Tween 20 is a trademark for a surfactant containing the condensate of 20 molar parts of ethylene oxide with sorbitan mono-oleate. Shake the mixture of the compound and emulsion with glass beads and dilute to 12 ml with water.

- 35 The spray composition thus prepared should be sprayed on young pot plants (post-emergence test) of the species mentioned in Table II below in a ratio equivalent to 1000 liters per hectare. The damage to the plants is estimated 14 days after spraying, comparing it with the untreated plants, in a scale from 0 to 3, where 0 means no effect and 3 represents 75 to 100% destruction. In the pre-emergence herbicide activity test, place the seeds of the tested species on the surface of the trays of soil-filled fibers and spray 1000 liters per hectare with the compositions. Then cover the seed with a further layer of soil 3 weeks after spraying the seedlings in the sprayed trays of fibers and compare the seedlings in the unsprayed, control trays, the damage being evaluated on the same scale from 0 to 3. The dash (-) in the results table indicates that the test is not performed. The results are presented in Table II below.

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TABLE II

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KA KA

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The names of the test plants are as follows:

Lt = lettuce

It = tomatoes

Ot / av = cultured oats and wild oats (Avena fatua).

Wild oats are used in the postemergence test and the cultivated in the preemergence test.

Ll = Lolium perenne (permanent feeding grass)

0n = Cyperus rotundus

St = Setaria viridis

The results in Table II clearly illustrate the selectivity of compounds (X), with the grass species in the test being severely damaged or destroyed, while the two-pointed plants were essentially intact.

EXAMPLE 15

This example illustrates the herbicidal properties of the compounds of Table I. The tests are performed as described in Example 14. The compound is formulated by mixing an appropriate amount of compound with 5 ml of emulsion, which is prepared by 160 ml of a solution containing 21.8 grams per liter of Span -a 80 and 78.2 grams per liter of Tween 20 in methylcyclohexanone, diluted to 500 ml with water. Shake the mixture of the compound and emulsion with glass beads and dilute to 40 ml with water. Damage to plants is estimated on a scale from 0 to 5, where 0 is damage from 0 to 20% and complete destruction. In the result table, a dash (-) indicates that we did not perform the test. The results are presented in Table III below.

TABLE III

According to Xs 0 0 0 0 m Oh 0 0 Oh o Oh rH o rH o o o o 1 Oh o —1 Oh CM 0 0 C CM Ca o o Oh Oh m o Oh o o Oh o o rH rH • H Ex o o Oh o o o rH o o Oh o o Oh Oh w s 1 o o rH o b o m o o Oh rH o m m H A EH W S H o o rH o o o Oh o <n rH o o o o Sn 1 o rH o 1 o 1 rH Oh CN 1 rH o rH A . H CQ A Rc m n m m m m and m n m m ž and co m M * and 'T and m n m M * and CH N S m m m and m m and ' m τη and m Ν ' m > 1 W Oh Oh Oh Oh rH Oh Oh Oh o Oh o Oh rH Oh ct Oh Oh rH Oh o rH rH rH o Oh o CN Oh rH Rp Oh r — 1 Oh Oh o (N o o o Oh o rH o o Сб r — t <n . Oh Oh o CM o rH CN CN o Oh m rH PRE- (A) OR POST- (B) EMERGENCY APPLICATION m < ffl « < m < m < CQ o RATIO APPLICATIONS .______ SN / ⁹ M :. · * Oh and Oh e » Oh 'Φ Oh 1 80 * 0 1.0 m o rH COMPOUND NO. rH m cO 20 In ¹ CM , <M ic, C, rc,

Names

Сб

RP

Ct

Mz

Ww

Rc

Sn

Ip

Am

Pi t

Ga

Po

Xs

Ab

Cv

Ot / Av

Dg

Pu

The 100 test plants are as follows:

Sugar beet oilseed rape cotton soy corn winter wheat rice

Senecio vulgaris čIpomoea purpurea

Amaranthus retroflexus, Polygonum aviculare

Chenopodium album

Portulaca oleracea

Xanthium spinosum

Abutilon theophrastii

Convolvulus arvensis

Cultivated oves and wild oats (Avena fatua)

Wild oats are used in the postemergence test and the cultivated in the preemergence test. Digitaria sanguinalis

Poa annua

Setaria viridis

Ec Echinochloa crus-galli Sh Sorghum halepense Ag Agropyron repens He Cyperus rotundus EXAMPLE 16

_; This example further illustrates the selective herbieid activity of compounds (I). The tests are carried out in the field of cultivated plants and weeds, applying the compounds to the crops in 10 times the ratio as weeds. The test procedure is similar to the procedure described in Example 14. Damage is assessed 20 days after spraying, on a scale of 0 to 10, where 0 means no effect and 10 complete destruction. Each result given in the table below is an average picture of the damage to the three plants. The selective nature of herbicidal compounds (I) will

I can easily see from the results table, that despite the fact that we applied 10 times the amount of compounds to the crops, such as the amount that caused serious damage to the grass species in the test, the damage caused to the crops was small, or there was none.

I

44 The meaning of the abbreviations for the names of the test plants has already been given in the case Expressed for Al, which means Alopecurus m.yosuroides.

EXAMPLE 17

This example illustrates the herbicidal activity of compounds (I) with respect to perennial grass species, compared to a known herbicidal compound of a similar type. A previously known compound is compound A below.

Compounds no. 5 and 21 of Table I are compared with Compound A. In the cut test, the Sorghum halepense rhizome, 5 to 8 cm long containing 2 to 3 knees ^ is buried in compost on a plastic tray in the greenhouse. Form the test compounds as described in Example 15- In the pre-emergence test 3 days after the root segments have been buried, spray the compounds over the compost. Then cover the surface with more compost and pour. In the postemergency test, the segments of the carrots are allowed 20 days to sprout shoots with two to four straight leaves and spray. Herbicide damage is assessed 3 weeks after treatment. In the test, three replicates are used for each treatment. The results are expressed as percentage damage to plants and are the averages of two separate tests. The figures for the percentage injury are listed in the tables below:

Preemergence results

Compound Application ratio, kg / ha ^st * 0.125 0.25 0.5 1.0

A 11 55 69 100 5 58 98 100 98 21 85 88 100 100

Postemergence results Compound no. Application Ratio, kg / ha 1.0 0,125 th most common 0.25 0.5 A 58 85 94 100 5 66 88 100 100 21 96 100 100 100

From the tables above, it can be seen that Compounds (I) are more herbicidally effective than Compound A at lower ratios.

EXAMPLE 18

This example illustrates the herbicidal properties of the further compounds (I) · The compounds are tested by the procedure shown above in Example 14 and the results are expressed in the same way. The results are given in the following table, which can be considered as a continuation of Table II.

- 46 3 repetitions are made for each treatment in the test. The results are expressed as a percentage of damage to plants, and is the average of two separate tests. The values for the percentage of injury are given in the tables below.

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An indication of the best known applicant for the economic exploitation of the invention

This example illustrates the preparation of 2 [4 (3-chloro-5-trifluoromethylpyridyl-2-oxy) phenoxy] propionic acid (epoxy fit 18 of Table I).

Compound no. 21 from Table I (2, 19, g) in isopropanol (20 ml) was treated dropwise with a dropwise solution of sodium hydroxide (0.23 g) in water (20 ml). It was stirred at room temperature for 4 hours, then it was not diluted with water until 3θθ. The solution was extracted with methylenedichloride (2 × 5θ mL) and acidified with 2m hydrochloric acid. The acidified solution was extracted with methylenedichloride (2 x 150 ml), the extract was dried and evaporated to give an oil. It solidifies under condition and is dried in vacuo at 85 ° C to give compound no. 18 with a melting point at 104 to 107 ° C.

For

IMPERIAL CHEMICAL INDUSTRIES LIMITED:

Claims (1)

PATENT APPLICATION The process for the preparation of the pyridine compounds of formula (I) z. Oh 7 \ CH, ^{1 3} 2 O-CH-R (I) in which Z is trifluoromethyl, difluoromethyl or chlorodifluoromethyl, Y is hydrogen or chlorine, R4 is carboxy, (C1-8-alkoxy) carbonyl, a group of the formula COOC ^ C ^ OR®, wherein R is alkyl of 1 to 4 carbon atoms, cyclohexyloxycarbonyl or (C 1-6 alkenyl) oxycarbonyl, or in the case of R is carboxy, a salt thereof, characterized in that the compound of the formula wherein Z and Pomen the above meaning, or a salt thereof, as the sodium salt, with a compound of the formula CH, I Hal-CH-R (1H) ~ 5Ο2 wherein R has the above meaning and is Hal halogen, in the presence of an inorganic base as potassium carbonate and in the presence of an inert solvent such as methylethylketone and at room temperature and reflux temperature.