This invention relates to organic compounds having biological activity and in particular to organic compounds having herbicidal properties and plant growth regulating properties, to processes for the preparation of such compounds, to intermediates useful in the preparation of such compounds and to herbicidal compositions and processes utilising such compounds. The use of certain sulfonylurea derivatives as herbicides is known in the art. Thus, for example, the "Pesticide Manual" (C R Worthing Editor, The British Crop Protection Council, 7th Edition 1983) describes the sulfonylurea derivative known commercially as chlorsulfuron [l-(2-chloro- phenylsulfonyl)-3-(4-methoxy-6-methyl-l,3,5-triazin- -2-yl) urea] and its use as a broadleaf weed herbicide in cereals. This compound is described in Australian Patent No. 510,056.

whilst chlorsulfuron has proved to be a useful herbicide for the control of many broadleaf weeds in cereal crops, the compound does have shortcomings such as low activity on many grass weeds and a high soil persistence.

European Patent Application 0 096 004 (published November 1983) discloses herbicidal sulfonylureas of the general formula

QS0 ₂ NHCN-Het

^R l

wherein

R- is hydrogen or C.-C ₅ alkyl;

Z is oxygen or sulfur; Het is a pyrimidyl or triazinyl ring; and Q is an unsubstituted or substituted 6-membered heterocyciic radical containing 2 or 3 nitrogen atoms and bound through a carbon atom.

It has now been found that a small group of 5-pyrimidyl sulfonylurea derivatives which have strongly electron donating substituents in both the 4 - and - 6 positions of the pyrimidyl ring, which have not previously been disclosed and which are not readily accessible by established synthetic methods, exhibit particularly useful herbicidal activity.

According to the present invention there are provided compounds of formula I and salts thereof:

^R 3 wherein X is selected from the groups NR 4R5, OR6 and S(0) R ⁷ ;

Y is selected from the groups R , NR R , S(°) _m ^R ,

NR ⁴ NR ⁸ R ⁹ , ONR ⁸ R ⁹ , ON=CR ⁸ R ⁹ and NR ⁴ OR ⁶ ; R 4, R5 , R6, R7 R8 and R9 are independently selected from C. to C _g alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, azido, amino, (C, to Cg alkyl)amino, di(C. to C _g alkyl)amino, cyano, nitro, thiocyanato, C, to C _g alkoxy, C, to C _g alkythio, (C, to C _g alkoxy) carbonyl, acyloxy, C. to C _g dialkoxyphosphoryl, C. to C _g dialkoxythiophosphoiryl, tri(C. to C _g alkoxy) silyl and phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, C. to C _β alkoxy, cyano, amino, carboxyl, carbamoyl and (C. to C _β alkoxy) carbamyl; C ₃ to C _g alkenyl; C, to C _β haloalkenyl; C, to Cg alkynyl; phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, C. to Cg alkyl, C. to C _g alkoxy, amino, (C, to Cg alkyl) amino, di(C.-Cg alkoxy)amino, carboxyl, (C,-Cg alkoxy)carbonyl and carbamoyl; cyano; or, where they are bound to nitrogen, R 4 and R5 together or R 8 and R9 together may form a saturated or

SUBSTITUTESHEET

unsaturated 5 - to 7 - membered heterocyciic ring system which may contain oxygen, sulfur or an NR group wherein R is hydrogen or C.-Cg alkyl; m is selected from zero and the integers 1 and 2; subject to the provisos that if X and Y are both NR 4R5 then R4 and R5 are not all hydrogen and if X is OR 6 and Y is R4 then R6 and R4 are not both methyl;

W is oxygen or sulphur; E is a methine group or nitrogen;

R is hydrogen or C, to C _g alkyl;

R is methyl, methoxy, ethoxy, halogen, trifluoro- methyl or difluoromethoxy;

R-, is hydrogen, methyl, ethyl, methoxy, ethoxy, methoxymethyl, amino, methylamino, dimethylamino, trifluoromethyl, methylthio, allyloxy, 2,2,2,- trifluoroethoxy, difluoromethoxy, ethoxymethyl or dimethoxymethyl.

In one preferred embodiment of the invention X is selected from the groups NR 4R5 and

OR and Y is the group NR R .

In another preferred embodiment of the invention X is selected from the groups OR and

S(0) _m R ⁷ and Y is the group S(0) _m R ⁷ . In a further preferred embodiment of the invention X is selected from the groups OR ,

4 5 7

NR R and S(O) R and Y is selected from the groups

R ⁴ , NR ⁴ NR ⁸ R ⁹ , ONR ⁸ R ⁹ , ON=CR ⁸ R ⁹ and NR ⁴ OR ⁶ .

In a preferred group of compounds of the invention X is the group OR and Y is the group

In another preferred group of compounds of the invention X is the group OR and Y is the group ^s (0) _m R ⁷ . In a further preferred group of compounds of

the invention X is the group OR and Y is selected from the groups R ⁴ , NR ⁴ NR ⁸ R ⁹ and NR ⁴ OR ⁶ .

Preferred values for R include C.-C ₄ alkyl, C,-C ₄ haloalkyl, C-,-Cg alkenyl, C-,-Cg haloalkenyl, C-,-Cg alkynyl, C.-C ₄ alkylthio

( ^C 1~ 4 ^allcv1 )' ^c ι~ ^c 4 alkoxy(C _χ -C ₄ alkyl), C ₁ -C ₃ alkylamino(C ₁ -C ₃ alkyl), difC _j -C- _j alkyl) amino (C- _j -C ₃ alkyl), phenyl and phenyl substituted with one or more substituents selected from chloro, methyl, nitro and methoxy.

Preferred values for R , R , R and R include hydrogen, C. -C. alkyl, C--C. haloalkyl, C- _j -C ₄ alkenyl, C- _j -C ₄ alkynyl, C,-C, alkoxy (C ₁ -C ₃ alkyl), C^-C _j alkylthio(C ₁ ~C ₃ alkyl), (C ₁ -C ₃ alkylamino(C ₁ -C ₃ alkyl), di(C ₁ -C ₃ alkyl) amino (C^-C- _j ^a - ¹ *~f--) ι ^c χ~ ^C 4 cyanoalkyl, phenyl and phenyl substituted with one or more substituents selected from chloro, nitro, methyl and methoxy or

R 4 and R5 together or R8 and R9 together may form a saturated 5 - to 7 - membered heterocyciic ring system which may contain oxygen, sulfur or the group

NR wherein R is hydrogen or C.-C ₄ alkyl.

Preferred values for R include C,-C ₄ alkyl,

C ₃ ~C ₄ alkenyl, (C* _j -C ₃ alkoxy)carbonyl(C,-C ₄ alkyl), and phenyl and phenyl substituted with one or more substituents selected from chloro, nitro, methyl and methoxy.

In a further embodiment the invention encompasses the salts which the compounds of formula I are able to form with amines, alkali metal bases and alkaline earth metal bases, or with quaternary amine bases.

In the definitions given above, the term

"alkyl" used either alone or in compound words such as "alkoxy" or "haloalkyl" denotes straight chain or

branched alkyl, eg. methyl, ethyl, fl-propyl, isopropyl or the different butyl isomers.

Preferred compounds of the invention include those compounds of formula I in which: X is selected from methoxy, ethoxy, propoxy, difluor¬ omethoxy and 2,2,2,-trifluoroethoxy and Y is selected from amino, methylamino, ethylamino, propylamino, alkylamino, 2,2,2-trifuloroethylamino, 2-methoxyeth- ylamino, ethoxycarbonylmethylamino, 2-tetrahydrofur- ylmethylmino, dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, N-methylanilino, pyrrolidino, morpholino and thiamorpholino; X is selected from methoxy, ethoxy, and 2,2,2-trif- luroethoxy and Y is selected from methylthio, ethylthio and 4-methylphenylthio; X is selected from methoxy, ethoxy and 2,2,2-triflu- roethoxy and Y is selected from hydrazino, 2-methyl- hydrazino, 2,2-dimethylhydrazino, methoxyamino and ethoxya ino; W is oxygen; R. is hydrogen or methyl; E is -CS.- or -N=; and R ₂ and R ₃ are independently selected from methyl, methoxy, chloro, 2,2,2-trifluoroethoxy, difluoromethoxy. Particularly preferred individual compounds are:

N-[(4-Methoxy-6-methyl-1,3,5-triazin-2-yl)amino- carbonyl]-4-ethoxy-6-propylaminopyrimidine-5- sulfonamide; N-[(4-Methoxy-6-methyl-l,3,5-triazin-2-yl)amino - carbonyl]-4-pyrrolidino-6-(2,2,2-trifluoroethoxy) pyrimidine-5-sulfonamide; N-[(4,6-dimethoxylpyrimid-2-yl)aminocarbonyl]-4-

amino-6-difluoromethoxypyrimidine-5-sulfonamide; N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino - carbonyl]-4-ethoxy-6-ethylthiopyrimidine-5- sulfonamide; N-[(4 methoxy-6-methyl-1,3,5-triazin-2-yl)amino- carbonyl]-4-(4-methylphenylthio)-6-(2,2,2-trifluo- ethoxy)pyrimidine-5-sulfonamide; N-[4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino- carbonyl]-4-ethyl-6-(2,2,2-trifluoroethoxy)- pyrimidine-5-sulfornamide;

N-[(4,6-dimethoxypyrimid-2-yl)aminocarbonyl]-4- ethoxy-6-ethoxyamino-pyrimidine-5-sulfonamide; and N-[(4-methoxy-6-methylpyrimid-2-yl)amino¬ carbonyl]-4-ethoxy-6-(2,2- dimethylhydrazino) pyrimidine-5-sulfonamide.

Specific examples of the compounds of the invention include the compounds listed in Table 1.

TABLE 1

S0 ₂ NHCONH

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

Comp¬ ound No. X

136 C ₃ CH ₂ 0 NH(i-C ₃ H _? ) ^CH 3° ^CH 3°* CH 137 CF ₃ CH ₂ 0 NH(i-C ₃ H _? ) ^CH 3° CH ₃ Ci CH 138 CF ₃ CH ₂ 0 NH(i-C ₃ H _? ) CH ₃ 0 ^CH 3 N 139 CF ₃ CH ₂ 0 NH(i-C ₃ H _? ) Cl CH ₃ O; CH

140 C ₂ H ₅ 0 NH(i-C ₃ H _? ) ^CH 3° CH ₃ 0| CH 141 CF ₃ CH ₂ 0 NH(i-C ₃ H _? ) ^CH 3° ^CH 3 CH 142 CF ₃ CH ₂ 0 NH(i-C ₃ H ₇ ) CH ₃ 0 CH, N 143 CF ₃ CH ₂ 0 NH(i-C ₃ H _? ) Cl CH ₃ 0| CH

144 CF ₃ CH ₂ 0 NCH ₃ (C ₂ H ₅ ) ^CH 3° CH ₃ 0| CH 145 CF ₃ CH ₂ 0 NCH ₃ (C ₂ H ₅ ) ^CH 3° ^CH 3 CH 146 CF ₃ CH ₂ 0 NCH ₃ (C ₂ H ₅ ) CH ₃ 0 ^CH 3 N 147 CF ₃ CH ₂ 0 NCH ₃ (C ₂ H ₅ ) Cl CH ₃ (j CH

48 C ₂ H ₅ 0 JCH ₃ (C ₂ H ₅ ) CH3O CH3O; CH 9 C ₂ H ₅ 0 rcH ₃ (c ₂ H ₅ ) CH ₃ 0 CH, CH 0 ^C 2 ^H 5° *CH ₃ (C ₂ H ₅ ) CH ₃ 0 CH ₃ 0| N 1 C ₂ H ₅ 0 MCH ₃ (C ₂ H ₅ ) Cl CH3OI N

TABLE 1 (Continued)

I

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

Comp¬ ound No. X

274 CH ₂ =CHCH ₂ S CH ₂ =CHCH ₂ 0 CH ₃ 0| CH ₃ 0| CH 275 CH ₂ =CHCH ₂ S CH ₂ =CHCH ₂ 0 CH, CH ₃ 0| N

276 ^CH 3 ^S CgH ₅ 0 CH ₃ 0| CH ₃ 0| CH 277 CH ₃ S CgH ₅ 0 CH, CH ₃ 0| N

278 CH ₃ CH ₂ S CgH ₅ 0 CH ₃ O! CH ₃ O| CH 279 CH ₃ CH ₂ S CgH ₅ 0 CH, CH,0i N

280 CH ₃ 0 ₂ CCH ₂ S CF ₃ CH ₂ 0 CH ₃ 0| CH ₃ O| CH 281 CH ₃ 0 ₂ CCH ₂ S CF ₃ CH ₂ 0 CH, CH ₃ 0| N

282 CH ₃ CH ₂ 0 ₂ CCH ₂ S CF ₃ CH ₂ 0 CH ₃ 0l CH ₃ 0i CH 283 CH ₃ CH ₂ 0 ₂ CCH ₂ S CF ₃ CH ₂ 0 CH, CH ₃ d N

284 CH ₃ CH ₂ O ₂ CCH ₂ S0| CF ₃ CH ₂ 0 CH ₃ 0| CH ₃ 0| CH 285 CH ₃ CH ₂ 0 ₂ CCH ₂ SO| CF ₃ CH ₂ 0 CH, CH ₃ 0| N

286 CH ₃ CH ₂ S0 ₂ CF ₃ CH ₂ 0 CH ₃ CJ CH ₃ 0| CH 287 CH ₃ CH ₂ S0 ₂ CF ₃ CH ₂ 0 CH, CH ₃ 0| N

288 CH ₃ CH ₂ S0 ₂ CH ₃ CH ₂ 0 CH ₃ d CH ₃ 0| CH 289 CH ₃ CH ₂ S0 ₂ CH ₃ CH ₂ 0 CH, CH ₃ 0| N

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

TABLE 1 (Continued)

The compounds of the invention may be prepared by a variety of methods and in a further aspect the invention provides methods for the preparation of compounds of formula I.

Conveniently the preparation of the compounds of the invention can be considered in three parts.

Part A involves the preparation of 5-pyrimidine-sulfonamides of the formula II

wherein X and Y are as defined above for formula I. The sulfonamides of formula II cannot be prepared by the traditional chlorosulfonation/ aminolysis approach commencing with compound III,

but may be obtained via the following method in which a sulfonamide of formula IV is treated with the nucleophile X and optionally a second nucleophile Y~ , wherein X and Y are as defined above for formula 1.

SUBSTITUTESHEET

Groups A and B are leaving groups which may be selected from such groups as alkoxy groups such as those defined for X = OR in formula I, or A and B may be aryloxy or halogen substituents. The groups A and B are preferably chosen from phenoxy, methoxy, 2,2,2-trifluoroethoxy and halogen moieties selected from chlorine, bromine, iodine and fluorine. More preferably the halogen moiety is chlorine. The reactants X ^~ or Y~ are alkali metal salts, preferably the sodium or potassium salts of the corresponding thiols or alcohols, typically but not necessarily employed in substantially equimolar proportions. The reaction may be carried out in a suitable organic solvent. Examples of suitable organic solvents include ethers, alkyl nitriles, dimethylformamide, and the like.

The sulfonamides of formula IV may be formed via the 5-mercaptopyrimidyl derivatives of formula V.

SUBSTITUTE SHEET

wherein A and B are as defined for X=0R in formula I, and R is selected from hydrogen, cyano, benzyl or a suitable alkyl or substituted alkyl group. Thus, treatment of the mercaptopyri_midyl compounds V with aqueous chlorine leads to the corresponding 5-chlorosulfonylpyrimidines of formula VI:

and treatment of the sulfonyl chlorides VI with either anhydrous or aqueous ammonia results in compounds of formula IV.

The chlorinolysis reaction is preferably carried out in the presence of a suitable organic solvent, such as a water miscible co-solvent, for example acetic acid, or a lower alcohol may be employed. Furthermore two-phase systems utilising suitable solvents such as the hydrocarbons, halocarbons or ethers may be employed. Preferably the reaction is carried out at or below ambient temperature. A typical temperature range lies from -5°C to about 25°C.

The conversion of the sulfonyl chlorides of formula VI into the sulfonamides IV may conveniently be carried out in a suitable organic solvent, for example a solvent selected from diethyl ether, acetonitrile, tetrahydrofuran or methylene chloride.

The reaction is preferably carried out at low temperatures, for example, within the range of from -20°C to + 10°C, and the amount of ammonia used may need to be controlled to avoid further reaction of the products.

The 5-mercaptopyrimidyl derivatives of formula V may be prepared by a number of methods including those described in the sections (i) to (iv) below.

(i) By condensing formamidine or two moles of formamide, with suitable mercapto derivatives of alkyl malonates to give 4,6-dihydroxy-5- mercaptopyrimidines of formula VII,

2 HCONH,

and then treatment of the dihydroxy compound of formula VII with phosphorous oxychloride to give the 4,6-dichloro compounds of formula VIII,

VII VIII

which may then be converted to the compounds of formula V by reaction with the appropriate nucleophiles A~ and B .

(ii) By the reaction of 5-halo-4,6-dihydroxy- pyrimidines of formula IX with suitable sulfur nucleophiles RSH to give the 4,6-dihydroxy-5-mercaptopyrimidines of formula VII

IX VII

which can be converted to the compounds of formula V by the general method outlined in section (i) above.

(iii) By the reaction of 4,6-dihydroxypyrimidine with suitable sulfenyl chlorides RSCl to give the 4,6-dihydroxy-5-mercaptopyrimidines of formula VII,

VII

which can be converted to the compounds of formula V by the general approach given in section (i) above.

(iv) Treatment of the 4,6-dihydroxy-5-mercapto derivatives of formula VII with certain difluorohalomethanes or various polyhaloethylene and propylene derivatives to give certain compounds of formula V

VII

wherein for example A and B are difluoromethoxy, 1,1,2,2-tetrafluoroethoxy or 2-chloro-1,1,2-trifluoroethoxy.

In section (i) above R is alkyl or benzyl and in sections (ii) and (iii) above, the definition of the group R in formula VII is the same as defined for formula V above.

In section (i) the group R' represents C. to C. alkyl and in section (ii) the group X' denotes a halogen atom preferably chlorine or bromine.

Part B of the preparation of the compounds of the invention involves the preparation of various 2-amino-pyrimidines and -s-triazines.

The heterocyciic amines of Formula X can be prepared by methods known in the literature, or simple modifications thereof, by one skilled in the art.

x

For a review of the synthesis and reactions of 2-amino- and 2-methylaminopyrimidines (X, E=CH) see The Chemistry of Heterocyciic Compounds. Vol. 16, Wiley Interscience, New York (1962). For a review of the synthesis and reactions of 2-amino- and 2-methylamino-s-triazines (X, E*=N) see The Chemistry of Ifeterocyc c Compounds, Vpj. 13, Wiley-Interscience, New York (1959), and F C Schaefer and K R Huffman, J. Orσ. Chem.. 28. 1812 (1963).

Part C of the preparation of the compounds of the invention (formula I) involves the coupling of the sulfonamides of formula II with the heterocyciic amines of formula X. The compounds of formula I can be prepared by one or more of the methods described below.

a) Many of the compounds of formula I can be prepared by reacting a sulfonylisocyanate or a sulfonylisothiocyanate of formula XI with a heterocyciic a ine of formula X.

W

J-S0 ₂ N=C=W + HN-A > JS0 ₂ NHCN-A

^R l ^R l

XI X I

where J represents the system

and A represents the system

The reaction is carried out at 25° to 100°C in an inert, aprotic solvent such as methylene chloride or xylene for 0.5 to 24 hours as taught in U.S. Patent, 4,127,405.

5 The intermediate sulfonylisocyanates (XI, W=0) and isothiocyanates (XI, W=S) are prepared by a variety of methods which are well known in the art and are described for example in European Patent Application 0 212 10 779 and the references cited therein.

b) Many of the compounds of formula I, where W is oxygen, can be prepared by reacting a phenyl carbamate of formula XII with a suitable amine of formula X.

15

J-S0 ₂ NHC-OCgH ₅ + HN-A > JSO _j NHCN-A

XII X la

The reaction is carried out at 50° to 100°C 20 in a solvent such as dioxane for 0.5 to 24 hours. The required carbamates XII are prepared by reacting the corresponding sulfonamides II with diphenylcarbonate in the presence of a strong base.

c) Compounds of formula la can also be made by reacting a heterocyciic carbamate of formula XIII with a suitable sulfonamide of formula II.

J-S0 ₂ NH ₂ + CgH ₅ 0C-N-A > JSO _j NHCN-A

^R l ^R l

II XIII la

The reaction is carried out at 0° to 100°C in a solvent such as acetonitrile, dioxane, or N,N-dimethyl forma ide in the presence of a non-nucleophilic base such as DBU for 0.2 to 24 hours. The required phenylcarbamates XIII are prepared by reacting the corresponding heterocyciic amines X with diphenylcarbonate or phenylchloroformate in the presence of a strong base.

d) Some of the compounds of the invention of formula lb can be prepared by reacting a sulfonamide II with a heterocyciic isocyanate or isothiocyanate of formula XIV.

W

J-S0 ₂ NH ₂ + W = C = N - A > JS0 ₂ NHCNH-A

II XIV lb

The reaction is carried out at 25° to 80°C in an inert, aprotic solvent such as acetone or acetonitrile in the presence of a base such as potassium carbonate for 0.5 to 24 hours. The required heterocyciic isocyanates and iso-thiocyanates XIV are prepared from the corresponding amines H ₂ N which would be known to one skilled in the art as taught in European Patent Application 0 035 893.

In each of parts b), c) and d) above the groups J, W, A and R« are as previously described.

Certain of the intermediate compounds of formulae II, IV, V, VI, VII and VIII are novel compounds and therefore in further embodiments the invention provides novel compounds of formulae II, IV, V, VI, VII and VIII and processes for the preparation thereof.

Certain 4-halo-6-substituted-5-pyrmidylsulfonylureas which show some herbicidal activity, may be used as intermediates for the preparation of the highly active 5-pyrimidylsulfonylurea herbicides of the invention. Thus intermediate compounds of formula I in which Y is chosen from the halogens chloro, bromo and iodo and X, W, E, R 1, R2 and R3 are as hereinbefore defined may be used in the preparation of compounds of the invention of formula I in which X, Y, W, E, R 1, R2 and R3 are as hereinbefore defined. Accordingly, in a further aspect the invention provides intermediate compounds of formula

I and salts thereof in which Y is chosen from the halogens chloro, bromo and iodo and X, W, E, R 1, R2

3 and R are as hereinbefore defined with the proviso that if Y is chloro and X is OR then R is not methyl.

Specific examples of the intermediate compounds of invention include those compounds listed in Table 2 below.

Agriculturally suitable salts of compounds of Formula I are also useful herbicides and can be prepared in a number of ways known to the art. For example, metal salts can be made by contacting compounds of formula I with a solution of an alkali or alkaline earth metal salt having a sufficiently basic anion (e.g. hydroxide, alkoxide or carbonate). Quaternary amine salts can be made by similar techniques.

TAB E 2

/f l) — SO-NHCONH —/f y

TABLE 2 (Continued)

TABLE 2 (Continued)

TABLE 2 (Continued)

TAB E 2 (Continued)

TA E 2 (Continued)

Salts of compounds of Formula I can also be prepared by exchange of one cation for another. Cationic exchange can be effected by direct treatment of an aqueous solution of a salt of a compound of Formula I, (e.g, alkali metal or quaternary amine salt) with a solution containing the cation to be exchanged. This method is most effective when the desired salt containing the exchanged cation is insoluble in water, e.g., a copper salt, and can be separated by filtration.

Exchange may also be effected by passing an aqueous solution of a salt of a compound of Formula I, (e.g., an alkali metal or quaternary amine salt) through a column packed with a cation exchange resin containing the cation to be exchanged. In this method, the cation of the resin is exchanged for that of the original salt and the desired product is eluted from the column. This method is particularly useful when the desired salt is water-soluble, e.g., a potassium, sodium or calcium salt.

Acid addition salts, useful in this invention, can be obtained by reacting a compound of Formula I, with a suitable acid, e.g., P.-toluenesulfonic acid, trichloroacetic acid or the like.

The compounds of Formula I are active as herbicides and therefore, in a further embodiment the invention provides a process for severely damaging or killing unwanted plants which process comprises applying to the plant, or to the growth medium of the plants, an effective amount of a compound of Formula I as hereinabove defined.

The compounds of Formula I may be applied directly to the plant (post-emergence application) or to the soil before the emergence of the plant (pre-emergence application). The compounds of Formula I are active against a broad range of weed species including monocotyledonous and dicotyledonous species. Some of the compound show selectivity towards certain crop species. A number show selectivity towards cereals, a particularly commercially valuable trait.

The compounds of Formula I may be used on their own to inhibit the growth of, severely damage, or kill plants but are preferably used in the form of a composition comprising a compound of the invention in admixture with a carrier comprising a solid or liquid diluent. Therefore, in yet a further aspect the invention provides growth inhibiting, plant damaging, or plant killing compositions comprising a compound of Formula I as hereinbefore defined and an inert carrier therefor. Certain of the compounds of Formula I exhibit useful plant growth regulating activity.

Plant growth regulating effects may be manifested in a number of ways. For example, suppression of apical dominance, stimulation of auxiliary bud growth, stimulation of early flowering and seed formation, enhancement of flowering and increase in seed yield, stem thickenings, stem shortening and tillering.

Accordingly in a still further embodiment the invention provides a process for regulating the growth of a plant which process comprises applying to the plant, to the seed of the plant, or to the growth medium of the plant, an effective amount of a compound of Formula I, as hereinbefore defined.

To effect the plant growth regulating process of the present invention the compounds of Formula I may be applied directly to the plant (post-emergence application) or to the seed or soil before the emergence of the plant (pre-emergence) application.

The compounds of Formula I may be used on their own to regulate the growth of plants but in general are preferably used in the form of a composition comprising a compound of the invention in admixture with a carrier comprising a solid or liquid diluent. Therefore, in a still further aspect the invention provides plant growth regulating compositions comprising a compound of Formula I as hereinbefore defined and an inert carrier therefor.

Compositions according to the invention include both dilute compositions, which are ready for immediate use, and concentrated compositions, which require to be diluted before use, usually with water. Preferably the compositions contain from 1 pp to 2% of active ingredient, while concentrated compositions may contain from 20 to 99% of active ingredient, although from 20 to 70% is usually preferred.

The solid compositions may be in the form of granules, or dusting powders wherein the active ingredient is mixed with a finely divided solid diluent, eg kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth and gypsum. They may also be in the form of dispersible powders or grains, comprising a wetting agent to facilitate the dispersion of the powder or grains in liquid. Solid compositions in the form of a powder may be applied as foliar dusts.

Liquid compositions may comprise a solution or dispersion or an active ingredient in water optionally containing a surface-active agent, or may comprise a solution or dispersion of an active ingredient in a water-immiscible organic solvent which is dispersed as droplets in water.

The rate of application of the compounds of the invention will depend on a number of factors including, for example, the compound chosen for use, the identity of the plants to be treated, the formulations selected for use and whether the compound is to be applied for foliage or root uptake. As a general guide, however, an application rate of from 0.001 to 10 kilograms, per hectare is suitable while from 0.01 to 5 kilograms per hectare may be preferred.

The compositions of the invention may comprise, in addition to one or more compounds of the invention, one or more compounds not of the invention but which possess biological activity. In certain applications it may be preferred to use a herbicidal composition comprising a mixture of at least one herbicidal compound of formula I as hereinbefore defined and at least one other herbicide.

The compounds of this invention and their preparation are further illustrated by the following examples.

Example 1

N-T 14-Methoxv-6-methγl-l.3.5-triazin-2-vl .amino- carbonvl1-6-ethoxv-4- 12-methoxvethvlamino \ pyrimidine-5-sulfonamide (42)

(i) 4,6-Dihydroxy-5-benzylthiopyrimidine

Benzylmercaptan (6 ml, 0.05 mole) was added to a stirred and heated (90°) suspension of 5-bromo-4,6-dihydroxypyrimidine (9.5g, 0.05 mole) and potassium carbonate (7.5g, 0.055 mole) in dimethylformamide (25 ml). The reaction mixture was stirred and heated at 95-105°C under an atmosphere of dry nitrogen for 3.5 hours. The mixture was poured into ice cold water (400 ml) with vigorous stirring and then acidified to pH 1 with hydrochloric acid. After stirring for 0.5 hours the suspension was filtered and the solid which was collected was rinsed several times with n-hexane and diethyl ether. The remaining brown solid was air dried to give 4,6-dihydroxy-5-benzylthiopyrimidine (5.5g 50%) (PHR spectrum: (d _g DMSO) 3.96 (s, 2H); 7.2 (m, 5H); 8.11 (s, IH); 12.2 (bs, 2H) .

(ii) 4,6-Dichloro-5-benzylthiopyrimidine

A mixture of phosphorus oxychloride (40 ml) and 4,6-dihydroxy-5-benzylthiopyrimidine (5 g) was stirred and heated under reflux for 3 hours. Excess phosphorous oxychloride was removed by distillation under reduced pressure and the residue was cooled, dissolved in chloroform (200 ml) and the chloroform solution was washed with water (3 x 200 ml). The chloroform layer was separated, dried (MgS0 ₄ ) and then concentrated to give a brown oil (4.1 g) which was purified by column chromatography (silica gel, hexane-chloroform (1:1)) to give the dichloropyrimidine as a nearly colourless low-melting point solid (3.3 g). P r spectrum: (CDC1 ₃ ) 4.18 (8, 2H; 7.2 (m, 5H); 8.60 (s, IH).

(iii) 4-Chloro-6-ethoxy-5-benzylthiopyrimidine

Sodium metal (0.37 g) was dissolved in ethanol (20 ml) and the solution slowly added to 4,6-dichloro-5-benzylthiopyrimidine (4.0 g) in ethanol (20 ml). The mixture was stirred at room temperature for 18 hours and then concentrated on a rotary evaporator. The residue was partitioned between aqueous 5% citric acid solution and ethyl acetate. The ethyl acetate layer was washed with water dried (MgS0 ₄ ) and evaporated to give the title chloropyrimidine as a yellow oil (4.5 g). Pmr spectrum: (CDC1-.) 1.43 (t, 3H); 4.10 (s,

2H) ; 4.46 (q, 2H) ; 7.20 (m, 5H) ; 8.37 ( s , lH) .

(iv) 6-Ethoxy-4-(2-methoxyethylamino)-5-benzyl- thiopyrimidine

2-Methoxyethylamine (3.6 ml) was added to a solution of 4-chloro-6-ethoxy-5-benzyl- thiopyrimidine (2.0 g) in tetrahydrofuran (10 ml) and the mixture heated at 50°C for 16 hours. The mixture was concentrated on a rotary evaporator and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was washed with water, dried (HgS0 ₄ ) and evaporated to give the title pyrimidine as an oil (2.4 g) . Pmr spectrum: (CDC1 ₃ ) 1.37 (t, 3H); 3.46 (m, 4H); 3.55 (s, 3H); 3.82 (s, 2H); 4.39 (q,

2H); 6.13 (br s, IH); 7.19 (m, 5H); 8.18 (s, IH).

(v) 6-Ethoxy-4-(2-methoxyethylamino)pyrimidine- 5-sulfonamide

A suspension of 6-ethoxy-4-(2-methoxyethyl- amino)-5-benzylthiopyrimidine (2.4 g) in acetic acid (30 ml) and water (30 ml) was cooled to below 5°C. Chlorine gas was bubbled into the stirred suspension for approximately 0.5 hour. After stirring at room temperature for a further 0.5 hour it was poured into ice water (100 ml) and extracted with ethyl acetate (2 x 30 ml) . The combined extracts were washed with brine (30 ml), dried (HgS0 ₄ ), and concentrated to give a clear oil. This was dissolved in

acetonitrile (50 ml), cooled to below 5°C and treated with ammonia gas for 0.5 hours. After further stirring for 0.5 hours the acetonitrile and excess ammonia were removed on a rotary evaporator and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was dried and concentrated to give an oil. This was dissolved in IH sodium hydroxide solution (15 ml) and washed with ether (20 ml). The aqueous layer was then acidified with 1M hydrochloric acid and extracted with ethyl acetate (30 ml). The ethyl acetate layer was dried and concentrated to give an oil. Trituration with ether gave the title sulfonamide as a pale brown solid (0.15 g) . Pmr spectrum: (d _g -Acetone) 1.38 (t, 3H); 3.33 (s, 3H); 3.57 (m, 4H); 4.55 (q, 2H); 6.51 (br s, IH); 6.84 (br s, 2H); 8.22 (s, IH).

(vi) N-[(4-Methoxy-6-methyl-l,3,5-triazin-2-yl)- amino carbonyl]-6-ethoxy-4-(2-methoxyethyl- amino)pyrimidine-5-sulfonamide (42)

N-(4-Methoxy-6-methyl-l,3,5-triazin-2-yl)- phenyl carbamate (170 mg) and 6-ethθ3^-4- (2-methoxyethylamino)pyrimidine-5- sulfonamide (150 mg) were dissolved in dimethyl formamide (5 ml). The solution was cooled in ice and 1,8-diazabicyclo[5.4.0]- undec-7-ene (DBU) (102 mg) was added with stirring. After 0.5 hours at ice temperature and a further 1 hour without cooling the

reaction mixture was poured into cold aqueous 5% citric acid solution (20 ml) and extracted into ethyl acetate (20 ml). The extract was dried and concentrated to give an oil which was dissolved in aqueous 5% potassium carbonate solution. The carbonate solution was washed with ether, acidified to pH 3 and extracted with ethyl acetate. The ethyl acetate layer was dried, concentrated and triturated with ether to give compound No. 42 as a white solid (89 mg) .

Pmr spectrum: (d _g -DMS0) 1.26 (t, 3H); 2.52 (s, 3H); 3.36 (s, 3H); 3.64 (m, 4H); 4.04 (ε, 3H); 4.46 (q, 2H); 8.05 (br s, IH); 8.25 (s, IH); 9.68 (br s, IH); 12.53 (br s, IH) .

Example 2

N-r(4-Methoxy-6-methyl-1.3,5-triazin-2-yl )amino- carbonyl1-6-ethγlamino-4-(2.2,2-trifluoroethoxy)- pyrlπHfHτιe-5-sulfonamide (11)

(i) 4,6-Bis(2,2,2-trifluoroethoxy)-5-benzyl- thiopyrimidine

Sodium hydride (60% dispersion in oil) (1.8 g) was added to a solution of 2,2,2- trifluoroethanol (3.25 ml) in dioxan (30 ml) and the mixture stirred for 30 minutes.

4,6-Dichloro-5-benzylthiopyrimidine (3.0 g) in dioxan (20 ml) was added over 15 minutes and the mixture stirred at 50°C for 3 hours. The mixture was then concentrated and the

residue partitioned between ethyl acetate and aqueous 5% citric acid. The organic phase was washed with water, dried and evaporated to give the title pyrimidine (4.3 g) as a yellow oil which crystallised on standing. Pmr spectrum: (dg-DMSO) 4.09 (s, 2H); 5.09 (q, 4H); 7.18 ( , 5H); 8.49 (s, IH) .

(ii) 4,6-Bis(2,2,2-trifluoroethoxy)pyrimidine- 5-sulfonamide

A suspension of 4,6-bis(2,2,2-trifluoro¬ ethoxy)-5-benzylthiopyrimidine (4.3 g) in acetic acid (50 ml) and water (50 ml) was vigorously stirred and cooled to 5°C. Chlorine gas was bubbled into the stirred suspension for approximately 30 minutes.

After 30 minutes further stirring below 10°C the reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (2 x 50 ml). The dichloromethane extracts were washed with water, dried and evaporated to give an oily solid. This was dissolved in acetonitrile (100 ml), and the solution cooled in ice and treated with ammonia gas for several minutes. After 30 minutes stirring the acetontrile and excess ammonia were removed on a rotary evaporator and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to give an oily residue. Trituration with ether/light petroleum and filtration allowed

isolation of the title sulfonamide as a white solid (1.92 g).

Pmr spectrum: (dg-Acetone) 5.21 (q, 4H); 6.68 (br s, 2H); 8.62 (8, IH).

(iii) 6-Ethylamino-4-(2,2,2-trifluoroethox )- pyrimidine-5-sulfonamide

Ethylamine (33% in ethanol) (4 ml) was added to a solution of 4,6-bis(2,2,2-trifluoro¬ ethoxy)pyrimidine-5-sulfonamide (400 mg) in ethanol (6 ml). The mixture was stirred at room temperature for 2 hours and then evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was dried and evaporated to give the title sulfonamide as an off-white solid (260 mg).

Pmr spectrum: (d _g -DMS0) 1.14 (t, 3H); 3.46 (m, 2H); 5.14 (q, 2H); 7.41 (br s, IH); 7.86 (m, IH); 8.33 (8, IH).

(iv) N-[(4-Methoxy-6-methyl-l,3,5-triazin-2-yl)- aminocarbonyl]-6-ethylamino-4-(2,2,2- trifluoroethoxy)pyrimidine-5-sulfonamide

(11)

6-Ethylamino-4-(2,2,2-trifluoroethoxy) pyrimidine-5-sulfonamide (120 mg) was dissolved in dimethylformamide (2 ml) and cooled in ice. 1,8-Oiazabicyclo[5.4.0]undec- 7-ene (67 mg) was added with stirring and after 5 minutes N-(4-methoxy-6-methyl-l,3,5-

triazin-2-yl)phenyl carbamate (115 mg) was also added to the mixture. After 0.5 hours at ice temperature and a further 1 hour without cooling the reaction mixture was poured into an ice cold aqueous 5% citric acid solution (15 ml) and stirred for 1 hour. The white precipitate was collected by filtration and air dried to give compound No. 11 as a white powder (175 mg) which was identified by its proton magnetic resonance spectrum: (dg-DMSO) 1.16 (t, 3H); 2.45 (s, 3H); 3.54 (m, 2H); 3.97 (s, 3H); 5.09 (q, 2H); 7.95 (t, IH); 8.39 (s, IH) ; 11.19 (br s, IH); 12.70 (br s, IH) .

Example 3

Compounds Nos. 2, 4, 9, 16, 18, 20, 22, 28, 29, 30, 31, 32, 34, 36, 38, 40, 44, 46, 48, 50, 52, 55, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 90, 92, 100, 102, 104, 108, 110 , 128, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 174 and 175 were each prepared starting from 4,6-dihydroxy-5- benzylthiopyrimidine and proceeding via the appropriate 4,6-disubstituted-5-sulfonamido pyrimidine following methods similar to those described in Example 1, parts (i) to (vi) and Example 2, part (i) to (iv).

Each compound was characterised in part by its proton magnetic resonance spectrum and details are recorded in Table 3 below.

TABLE 3

TABLE 3 ( Continued )

Compound Proton Chemical Shift δ in ppm No. (dg DMSO unless noted)

34 (dg-Acetone) 1.27 (t, 3H); 2.53 (s, 3H); 4.04 (s, 3H); 4.24 (m, 2H); 4.44 (q, 2H); 5.09 (m, IH); 5.39 (m, IH); 6.04 ( , IH); 7.94 (br ε, IH); 8.24 (s, IH); 9.67 (br s, IH); 12.57 (br s, IH).

44 3.90 (s, 6H); 5.07 (q, 2H); 6.00 (s,

IH); 7.44 (br s, IH); 8.29 (br s,

2H); 10.72 (br s, IH); 12.89 (br s, IH).

46 2.45 (s, 3H); 3.97 (s, 3H); 5.07 (q, 2H); 7.42 (br s, IH); 8.30 (8, IH); 8.34 (br s, IH); 11.18 (br s, IH); 12.67 (br 8, IH) .

50 2.45 (s, 3H); 3.01 (d, 3H); 3.97 (8,

3H); 5.09 (q, 2H); 7.94 (br s, IH);

8.41 (s, IH); 11.18 (br s, IH); 12.68 (br 8, IH).

52 3.19 (s, 6H); 3.90 (s, 6H); 5.03 (q, 2H); 5.98 (8, IH); 8.28 (s, IH); 10.48 (br s, IH); 12.76 (br s, IH) .

2ABLE_2(Continued)

TABLE 3(Continued)

Compound Proton Chemical Shift δ in ppm No. (dg DMSO unless noted)

70 1.88 (m, 4H); 2.45 (s, 3H); 3.65 ( ,

4H); 3.97 (8, 3H); 5.05 (q, 2H); 8.27

(s, IH); 10.94 (br s, IH); 12.52 (br s, IH).

72 3.72 (m, 8H); 3.90 (s, 6H); 5.05 (q, 2H); 5.99 (s, IH); 8.35 (8, IH); 10.53 (br s, IH); 12.81 (br s, IH) .

74 2.45 (s, 3H); 3.71 (m, 8H); 3.97 (s, 3H); 5.08 (q, 2H); 8.36 (8, IH); 10.97 (br s, IH); 12.56 (br s, IH) .

92 2.91 (d, 6H); 3.91 (s, 6H); 6.00 (s, IH); 7.20 (m, 2H); 8.12 (s, IH); 10.58 (br β, IH); 12.26 (br s, IH) .

100 1.10 (t, 6H); 3.47 ( , 4H); 3.91 (s, 6H); 5.99 (8, IH); 7.24 (br 8, 2H); 8.10 (s, IH); 10.55 (s, IH); 12.48 (s, IH).

102 (dg-Acetone) 1.18 (t, 6H); 2.52 (8, 3H); 3.53 ( , 4H); 4.02 (s, 3H); 7.25 (br s, 2H); 8.05 (s, IH); 9.62 (s, IH); 12.68 (s, IH).

TABLE 3 ( Continued )

TABLE 3 ( Continued )

Compound Proton Chemical Shift δ in ppm No. (dg DMSO unless noted)

(CDC1 ₃ ) 1.21 (t, 3H); 1.27(t, 3H) ; 3.57 (m, 2H); 3.97 (s, 6H) ; 4.43 (q, 2H); 5.80 (s, IH) ; 7.16 (br s, IH) ; 7.79 (br s, IH); 8.24 (s, IH) ; 12.63 (br s, IH)

16 (CHC1 ₃ ) 1.21 (t, 3H); 3.08 (d, 3H) ; 3.97 (s 6H); 4.43 (q, 2H) ; 5.80 (s, IH); 7.20 (br s, IH); 7.76 (br s IH); 8.27 (s, IH); 12.66 (br s, IH)

20 (dg-Acetone) 1.17 (t, 3H) ; 3.23 (s, 6H); 3.98 (s, 6H) ; 4.40 (q, 2H) ; 5.86 (s, IH); 8.13 (s, IH); 9.05 (br s, IH); 12.57 (br s, IH)

28 (dg-Acetone) 0.99 (t, 3H); 1.18 (t, 3H); 1.65 ( , 2H); 3.54 (m, 2H) , 3.98 (s, 6H); 4.44 (q, 2H) ; 5.89 (8, IH) 7.91 (br s, IH); 8.23 (8, IH); 9.34 (br β, IH); 12.79 (br s, IH)

29 (dg-Acetone) 0.99 (t, 3H); 1.19 (t, 3H); 1.65 (m, 2H) ; 2.44 (s, 3H) ; 3.54 (m, 2H); 3.96 (s, 3H) ; 4.41 (q, 2H) ; 6.48 (s, IH); 7.91 (br 8, IH); 8.22 (s, IH); 9.25 (br 8, IH); 13.14 (br s, Liq

TABLE 3 ( Continued )

TABLE 3 ( Continued )

Compound Proton Chemical Shift δ in ppm No. (dg DMSO unless noted)

48 (CDCL ₃ ) 3.11 (d, 3H); 3.95 (s 6H); 4.80 (q, 2H); 5.80 (s, IH); 7.16 (br m, IH); 7.88 (br s IH); 8.27 (s, IH); 12.79 (br s, IH)

55 (dg-Acetone) 3.19 (s, 6H); 3.97 (s, 3H); 6.86 (s, IH); 8.28 (8, IH); 10.78 (br s, IH); 12.13 (br s, IH)

58 (dg-Acetone) 1.26 (t,6H); 2.50 (8, 3H); 3.76 (q, 4H); 4.02 (s, 3H); 5.03 (q, 2H); 8.19 (s, IH); 9.53 (br s, IH); 12.53 (br s, IH)

64 (CDC1 ₃ ) 3.95 (s, 6H); 4.24 (m, IH); 4.81 (q, 2H); 5.19 (m, IH); 5.37 (m, IH); 5.79 (s, IH); 5.92 (m, IH); 7.18 (br s, IH); 8.05 (br s, IH); 8.25 (s, IH); 12.78 (br s, IH)

90 (dg-Acetone) 1.27 (t, 3H); 2.26 (s, 3H); 3.65 (m, 2H); 3.92 (s, 3H); 7.0- 7.3 (m, 5H); 7.94 (br s, IH); 8.16 (s, IH); 9.74 (br s, IH); 12.89 (br s, IH)

TABLE 3 (Continued)

TABLE 3 ( Continued )

Compound Proton Chemical Shift δ in ppm No. (dg DMSO unless noted)

144 (CDC1 ₃ ) 1.27 (t, 3H); 3.26 (s, 3H); 3.78 (q, 2H); 3.95 (s, 6H); 4.80 (q, 3H); 5.78 (s, IH); 7.16 (br s, IH); 8.02 (br s, IH); 8.14 (s, IH); 12.70 (br s, IH)

146 (dg-Acetone) 1.26 (t, 3H); 2.50 (s, 3H); 3.24 (s, 3H); 3.79 (q, 2H); 4.02 (s, 3H); 5.04 (q, 2H); 8.18 (s, IH); 9.58 (br s, IH); 12.58 (br s, IH)

148 (dg-Acetone) 1.19 (m, 6H); 3.20 (8, 3H); 3.74 (m, 2H); 3.97 (s, 6H); 4.39 (m, 2H); 5.87 (s, IH); 8.13 (s, IH); 9.24 (br s, IH); 12.61 (br s, IH)

150 (dg-Acetone) 1.22 ( , 6H); 2.52 (s, 3H); 3.21 (s, 3H); 3.74 (q, 2H); 4.03 (s, 3H); 4.41 (q, 3H); 8.13 (s, IH)

152 (dg-Acetone) 0.93 (t, 3H); 1.73 (m, 2H); 3.26 (s, 3H); 3.74 (m, 2H); 3.96 (s, 6H); 5.02 (q, 2H); 5.89 (8, IH); 8.18 (s, IH); 9.20 (br s, IH); 12.74 (br s, IH)

TABLE 3 ( Continued )

TABLE 3 ( Continued )

Compound Proton Chemical Shift δ n ppm No. (dg DMSO unless noted)

164 1.02 (t, 3H); 1.67 (m, 2H); 3.57 (m, 2H); 3.93 (s, 3H); 4.03 (s, 6H); 6.12 (s, IH); 7.92 (br ε, IH);) 8.43 (8, IH); 10.70 (br s, IH); 12.90 (br s, IH)

166 1.02 (t, 3H); 1.66 (m, 2H); 2.57 (s, 3H); 3.56 (m, 2H); 3.97 (s, 3H); 4.08 (s, 3H); 7.89 (br s, IH); 8.43 (s, IH); 11.11 (br s, IH); 12.60 (br s, IH)

168 (CDC1 ₃ ) 1.92 (m, 4H); 3.77 (m, 4H); 3.83 (s, 3H); 3.98 (s, 3H); 5.81 (s, IH); 7.18 (br s, IH); 8.17 (s, IH); 12.66 (br s, IH)

170 1.96 (m, 4H); 2.59 (s, 3H); 3.71 (m,

4H); 3.85 (s, 3H); 4.07 (8, 3H); 8.32

(8, IH); 11.04 (br s, IH); 12.51 (br 8, IH)

175 CDC1 ₃ 2.56 (8, 3H); 3.41 (8, 3H); 3.59 (m, 2H); 3.77 (m, 2H); 4.04 (s. 3H); 4.80 (q, 2H); 8.11 (br s, IH); 8.24 (s, IH); 12.48 (br s, IH)

TABLE 3 ( Continued )

SUBSTITUTE SHEET

Example 4

pyrimidine-5-sulfonamide (2171

(ia) 4,6-Dihydroxy-5-benzylthiopyrimidine

Benzylmercaptan (6 ml, 0.05 mole) was added to a stirred and heated (90 ) suspension of 5-bromo-4,6-dihydroxypyrimidine (9.5g, 0.05 mole) and potassium carbonate (7.5g, 0.055 mole) in dimethylformamide (25 ml). The reaction mixture was stirred and heated at 95-105°C under an atmosphere of dry nitrogen for 3.5 hours. The mixture was poured into ice cold water (400 ml) with vigorous stirring and then acidified to pH 1 with hydrochloric acid. After stirring for 0.5 hours the suspension was filtered and the solid which was collected was rinsed several times with n-hexane and diethyl ether. The remaining brown solid was air dried to give 4,6-dihydroxy-5-benzylthiopyri idine (5.5g 50%), ¹ HNMR (dg-DMSO) δ 3.96 (s, 2H); 7.2 (m, 5H); 8.11 (s, IH); 12.2 (bs, 2H) .

An alternative method for the preparation of the 4,6-dihydroxy-5-benzylthiopyrimidine is described as follows:

(ib) Sulfuryl chloride (3.5 ml, 43 mmol) was added to a stirred suεpension of dibenzyl disulfide (10.35 g, 42 mmol) in carbon tetrachloride (55 ml) containing three drops of triethylamine. The orange solution was stirred for 30 minutes at room temperature before being added dropwise to a stirred suspension of

4,6-dihydroxypyrimidine (8.6 g, 77 mmol) in dimethylformamide (120 ml). The resulting mixture was stirred at room temperature for three and half hours after which time the precipitate was filtered, washed several times with water followed by diethyl ether, then air dried to give the desired 4,6-dihydroxy-5-benzylthiopyrimidine as a pale yellow powder (15.35 g, 85%).

(ii) 4,6-Dichloro-5-benzylthiopyrimidine

A mixture of phosphorous oxychloride (40 ml) and 4,6-dihydroxy-5-benzylthiopyrimidine (5g) was stirred and heated under reflux for 3 hourβ. Excess phosphorous oxychloride was removed by distillation under reduced pressure and the residue was cooled, dissolved in chloroform (200 ml) and the chloroform solution was washed with water (3 x 200 ml). The chloroform layer was separated, dried (MgSO.) and then

concentrated to give a brown oil (4.1g) which was purified by column chromatography (silica gel, hexane-chloroform (1:1) to give the dichloropyrimidine as a nearly colourless low-melting point solid (3.3g). 'H NMR (CDC1 ₃ ) δ ppm 4.18 (s, 2H); 7.2 (m, 5H); 8.60 (s, IH).

(iii) 4,6-Bis(2,2,2-trifluoroethoxy)-5-benzylthio¬ pyrimidine

Sodium hydride (60% dispersion in oil) (1.8 g) was added to a solution of 2,2,2-tri- fluoroethanol (3.25 ml) in dioxan (30 ml) and the mixture stirred for 30 minutes. 4,6-Dichloro-5-benzylthiopyrimidine (3.0 g) in dioxan (20 ml) was added over 15 minutes and the resulting mixture stirred at 50°C for 3 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate and aqueous 5% citric acid. The organic phase was washed with water, brine, dried (MgS0 ₄ ) and evaporated off to give the title product (4.3 g) as a yellow oil which crystallised on standing.

^~ H NMR (dg-DMSO) δ 4.09 (s, 2H); 5.09 (q, 4H); 7.18 (m, 5H); 8.49 (s, IH) .

(iv) 4 ,6-Bis-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonyl chloride

A suspension of 4,6-bis-(2,2,2-trifluoro¬ ethoxy)-5-benzyl thiopyrimidine (18.5 g, 47 mmol) in acetic acid (270 ml) and water (65 ml) was vigorously stirred and cooled to 5 C. Chlorine gas was bubbled through the cooled reaction mixture for approximately 10 minutes. Af er 15 minutes further stirring below 5 C, the reaction mixture was poured into ice water (600 ml), and the product 4,6-bis-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonyl chloride separated out as a cream coloured solid which was filtered and dried (15.9 g, 91%).

^~ Ε NMR (dg-DMSO) δ (ppm) 5.00 (q, 4H); 8.58 (s, IH).

(v) 4,6-Bis-(2,2,2-trifluoroethox ) yrimidine-5- sulfonamide

4,6-Bis-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonyl chloride (15.9 g) was dissolved in acetonitrile (160 ml) and the solution cooled in ice and treated with ammonia gas for 10 minutes. The resulting mixture was stirred at ice temperature for a further 15 minutes before the acetonitrile and excess ammonia were removed on a rotary evaporator. The residue was then diluted with water, and the desired sulfonamide separated out as a creamy coloured solid. Trituration with

SUBSTITUTESHEET

ethyl acetate:petroleum spirits mixtures afforded the pure product as a colourless solid (10.6 g, 71%).

^Η NMR (dg-DMSO) δ (ppm) 5.20 (q, 4H); 7.44 (br s, 2H); 8.70 (8, IH) .

(vi) 4-Methylthio-6-(2,2,2-trifluoroethoxy)- pyrimidine-5-sulfonamide

4,6-Bis(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonamide (710 mg, 2 mmol) was added to a stirred suspension of sodium thiomethoxide

(140 mg, 2 mmol) in dimethylformamide (4 ml). After stirring at room temperature for 4 hours, the reaction mixture was then diluted with water, and acidified to pH 3-4 with stirring. The precipitate was collected by filtration and air dried to give the title sulfonamide as a slightly off-white solid (440 mg, 73%). ^~ H NMR (dg-DMSO) δ (ppm) 2.48 (s, 3H); 5.23 (q, 2H); 7.56 (br s, 2H); 8.77 (s, IH) .

(vii) N-[(4-methoxy-6-methyl-l,3,5-triazin-2-yl)- aminocarbonyl]-4-methylthio-6-(2,2,2-tri- fluoroethoxy)pyrimidine-5-sulfonamide (217)

N-(4-Methoxy-6-methyl-l,3,5-triazin-2-yl) phenylcarbamate (260 mg, 1.0 mmol) and 4-methylthio-6-(2,2,2-trifluoroethoxy)- pyrimidine-5-sulfonamide (303 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (2 ml) . The solution was cooled in ice and

l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (152 mg, 1.0 mmol) was added with stirring. After one hour at ice temperature, the reaction mixture was poured into ice-water (50 ml) and the aqueous solution acidified to pH 3-4 with stirring. The white precipitate was collected by filtration and air dried to give compound No. 217 as a colourless powder (280 mg) which was identified by its proton magnetic resonance spectrum.

-R NMR (dg-DMSO) δ 2.46 (s, 3H); 2.54 (s, 3H); 3.98 (s, 3H); 5.19 (q, 2H); 8.85 (s, IH); 11.11 (broad s, IH); 12.80 (broad s, IH) .

Example 5

N-f f4-Methoxγ-6-methyl-l.3.5-triazin-2-yl)amino- carbonyl"}-4-ethoxγ-6-ethylthiopyrimidine-5- εulfonamide (229)

(i) 4-Chloro-6-ethoxy-5-benzylthipyrimidine

Sodium metal (1.67 g) was dissolved in ethanol (55 ml) and the solution slowly added to 4,6-dichloro-5-benzylthiopyrimidine (17.9 g) in ethanol (150 ml). The mixture was stirred at room temperature for 18 hours and then concentrated on a rotary evaporator. The residue was partitioned between aqueous 5% citric acid solution and ethyl acetate. The organic layer was washed with water, dried (MgS0 ₄ ) and evaporated to give the title product as a yellow oil (17.8 g) . ^X H NMR (CDC1 ₃ ) δ (ppm) 1.43 (t, 3H); 4.10 (s, 2H); 4.46 (q, 2H); 7.20 (m, 5H); 8.37 (s, IH).

(ii) 4-Ethoxy-6-(2,2,2-trifluoroethoxy)-5-benzyl- thiopyrimidine

Sodium hydride (60% dispersion in oil) (8.63 g) was added to a solution of 2,2,2-tri- fluoroethanol (23.5 ml) in dioxan (200 ml), and the mixture stirred at room temperature for 30 minutes. 4-Chloro-6-ethoxy-5-benzyl- thiopyrimidine (30.13 g) in dioxan (150 ml) was added over 15 minutes, and the mixture was heated at 50-60°C for 2.5 hours. The mixture was then concentrated and the residue partitioned between ethyl acetate and aqueous citric acid. The combined organic layers were washed with water, brine, dried and evaporated to give the title compound as an oil.

^~ H NMR (dg-Acetone) δ (ppm) 1.36 (t, 3H), 4.09 (s, 2H); 4.42 (q, 2H); 4.98 (q, 2H); 7.18-7.23 (m, 5H); 8.31 (s, IH) .

(iii) 4-Ethoxy-6-(2,2,2-trifluoroethoxy)pyrimidine- 5-sulfonamide

A suspension of 4-ethoxy-6-(2,2,2-trifluoro¬ ethoxy)-5-benzylthiopyrimidine (9.16 g, 26.7 mmol) in acetic acid (150 ml) and water (100 ml) was vigorously stirred and cooled to 5°C. Chlorine gas was gently bubbled into the stirred suspension for approximately 30 minutes. After 30 minutes further stirring below 5°C the reaction mixture was diluted with ice water and extracted three times

with dichloromethane. The combined organic layers were washed with water, brine and dried (MgS0 ₄ ). Removal of the solvent gave a yellow oil which was immediately dissolved in acetonitrile (50 ml) and the solution cooled in an ice bath. Ammonia gas was bubbled through the mixture for approximately 5 minutes which was then stirred for a further 30 minutes. The solvent was removed and the residue partitioned between ethyl acetate and water. The combined ethyl acetate layer was dried and concentrated to give an oil which crystallised out on standing (2.53 g) . ^~ H NMR (dg-cetone) δ (ppm) 1.43 (t, 3H), 4.62 (q, 2H); 5.12 (q, 2H); 6.64 (br ε, 2H); 8.54 (s, IH).

(iv) 4-Ethoxy-6-ethylthiopyrimidine-5-sulfonamide

To a stirred suspension of sodium hydride (60% dispersion in oil) (88 mg) and ethanethiol (163 ul) in DMF (5 ml) was added 4-ethoxy-6-(2,2,2-trifluoroethoxyJpyrimidine- 5-sulfonamide (0.6 g) . The resulting mixture was stirred at room temperature overnight. The mixture was then poured slowly into a cold aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried and evaporated to give the title sulfonamide as a solid (0.35 g). ^~ K NMR (dg-Acetone) δ (ppm) 1.30 (t, 3H); 1.43 (t, 3H); 3.13 (q, 2H); 4.64 (q, 2H); 6.60 (br s, 2H), 8.58 (8, IH).

(v) N-[(4-Methoxy-6-methyl-l,3,5-triazin-2-yl)- aminocarbonyl-4-ethoxy-6-ethylthiopyrimidine- 5-sulfonamide (229)

4-Ethoxy-6-ethylthiopyrimidine-5-sulfonamide (350 mg) and N-(4-methoxy-6-methyl-1,3,5- triazin-2-yl) phenyl carbamate (380 mg) were dissolved in DMF (5 ml). The solution was cooled in ice and DBU (0.24 ml) was added with stirring. After 30 minutes at ice temperature followed by one hour without cooling, the reaction mixture was poured into ice cold aqueous citric acid. The solid product (Compound No. 229) was filtered and dried (376 mg) and identified by its proton magnetic resonance spectrum (dg-DMSO) δ (ppm) 1.18 (t, 3H); 1.29 (t, 3H); 2.47 (s, 3H); 3.15 (q, 2H); 3.98 (s, 3H); 4.46 (q, 2H); 8.74 (s, IH); 11.04 (br s, IH); 12.56 (br 8, IH).

Example 6

N- T ( 4-Methoxy-6-methyl-l .3.5-triazin-2-yl . amino- carbonvl 1 -4.6-dimethvlthiopvrimidine-5-sulf onamide

X222X

(i) 4,6-Dimethylthiopyrimidine-5-sulfonamide

4,6-Biβ-(2,2,2-trifluoroethoxy)pyrimidine-

5-sulfonamide (355 g, 1 mmol) [as described in Example 4 part (v)] was added to a stirred suspension of sodium thiomethoxide (160 mg, 2.2 mmol) in dimethylformamide (2 ml) at

room temperature. Stirring was maintained for 4 hours before the reaction mixture was poured into citric acid solution (10%, 50 ml) . A creamy coloured precipitate was collected by filtration (156 mg, 62%). ^X H NMR (dg-DMSO) δ (ppm) 2.49 (s, 6H); 7.78 (broad s, 2H); 8.81 (s, IH) .

(ii) N-[(4-Methoxy-6-methyl-1,3,5-triazin-2-yl)- aminocarbonyl-4,6-dimethylthiopyrimidine- 5-sulfonamide (292)

N-(4-Methoxy-6-methyl-l,3,5-triazin-2-yl) phenylcarbamate (168 mg, 0.62 mmol) and 4,6-dimethylthiopyrimidine-5-εulfonamide (155 mg, 0.62 mmol) was dissolved in dimethyl- formamide (2 ml) . The solution was cooled in ice and l,8-diazabicyclo[5.4.0]undec-7-ene (98 mg, 0.62 mmol) was added with stirring. After 80 minutes at ice temperature, the reaction mixture was poured into cooled citric acid solution (10%). The white precipitate was collected by filtration and air dried to give compound no. 92 as a colourless powder (160 mg, 62%). H NMR (dg-DMSO) δ (ppm) 2.47 (s, 6H); 2.52 (8, 3H); 3.99 (8, 3H); 8.87 (s, IH); 11.03 (s, IH) .

Example 7

N-T (4-Methoxv-6-methvl-l.3.5-triazin-2-vl amino- carbonvl1-4-ethoxv-6-ethvlsulfonvlpvrimidine-5- sulfonamide r289ϊ

The sulfonylurea compound no. 229 (described in Example 6) was converted to the title compound by treatment with two molar equivalents of m-chloroperbenzoic acid (mCPBA) in dichloromethane at room temperature. After two hours stirring, the product was obtained by removing the dichloromethane solvent on a rotary evaporator. The reaction mixture was washed several times with diethyl ether to remove by-product, m-chlorobenzoic acid. H NMR (dg-acetone) δ (ppm) 0.91 (t, 3H); 1.26 (t, 3H); 2.47 (s, 3H); 3.38 (q, 2H); 3.99 (s, 3H); 4.60 (q, 2H); 9.14 (s, IH); 11.05 (br s, IH) .

Example 8

Compounds Nos. 201,203, 209, 211, 215, 218, 221, 223, 227, 232, 234, 259, 261, 280, 281, 282, 283, 284, 285, 287, 289, 290, 292, 294, 295, 297 and 322 were each prepared starting from 4,6-dihydroxy-5- benzylthio-pyrimidine and proceeding via the appropriate 4,6-disubstituted-5-sulfonamido pyrimidine following methods similar to those described in Examples 4-7.

Each compound was characterised in part by its proton nuclear magnetic resonance spectra and the details thereof recorded in Table 4 below.

TAgfcg

JE&B E_i(Continued)

Compound Proton Chemical Shift δ in ppm No. (dg-DMSO unless noted)

223 1.28 (t, 3H); 2.47 (s, 3H); 3.15 (q,

2H); 3.95 (s, 3H); 3.98 (s, 3H); 8.75

(s, IH); 10.93 (br s, IH); 12.63 (br s, IH).

TABLE 4 ( Continued )

aa_ELE_ ( Continued)

Compound Proton Chemical Shift δ in ppm No. (dg-DMSO unless noted)

287 (dg-Acetone): 1.11 (t, 3H); 2.52 (s, 3H); 3.41 (q, 2H); 4.04 (s, 3H); 5.27 ( , 2H); 9.16 (8, IH); 13.05 (br 8, IH).

290 2.53 (s, 6H); 3.94 (s, 6H), 6.03 (s, IH); 8.87 (s, IH), 10.69 (s, IH); 13.12 (br s, IH) .

294 2.53 (8, 6H); 4.01 (s, 3H); 6.88 (s, IH); 8.87 (8, IH); 10.82 (s, IH); 12.30 (br s, IH).

295 1.22 (t, 6H); 3.17 (q, 4H); 3.94 (s, 6H); 6.02 (s, IH); 8.82 (s, IH); 10.68 (br 8, IH); 13.10 (br s, IH) .

297 1.26 (t, 6H); 2.47 (s, 3H); 3.17 (q, 4H); 3.99 (s, 3H); 8.82 (s, IH); 11.02 (br s, IH); 12.90 (very br s, IH).

2£BLE_A( Continued)

Example 9

N-r (4-Methoxy-6-methyl-l.3.5-triazin-2-yl \amino- carbonyl1-4- ( 2 .2-dimethylhvdrazino.-6- 12.2.2-tri- fluoroethoxvϊPvrimidine-5-εulfonamide (4Q9)

(i) 4,6-Dihydroxy-5-benzylthiopyrimidine

Benzylmercaptan (6 ml, 0.05 mole) was added to a stirred and heated (90 ) suspension of 5-bromo-4,6-dihydroxypyrimidine (9.5g, 0.05 mole) and potassium carbonate (7.5g, 0.055 mole) in dimethylformamide (25 ml). The reaction mixture was stirred and heated at 95-105°C under an atmosphere of dry nitrogen for 3.5 hours. The mixture was poured into ice cold water (400 ml) with vigorous stirring and then acidified to pH 1 with hydrochloric acid. After stirring for 0.5 hours the suspension was filtered and the solid which was collected was rinsed several times with n-hexane and diethyl ether. The remaining brown solid was air dried to give 4,6-dihydroxy-5-benzylthiopyrimidine (5.5g 50%), Pmr spectrum: (dg-DMSO) 3.96 (8, 2H); 7.2 (bm, 5H); 8.11 (8, IH); 12.2 (bs, 2H) .

(ii) 4,6-Dichloro-5-benzylthiopyrimidine

A mixture of phosphorous oxychloride (40 ml) and 4,6-dihydroxy-5-benzylthiopyrimidine (5g) was stirred and heated under reflux for 3 hours. Excess phosphorous oxychloride was removed by distillation under reduced pressure and the residue was cooled, dissolved in chloroform (200 ml) and the chloroform solution was washed with water (3 x 200 ml). The chloroform layer was separated, dried (MgS0 ₄ ) and then concentrated to give a brown oil (4.1g) which was purified by column chromatography (silica gel, hexane-chloroform (1:1)) to give the dichloropyrimidine as a nearly colourless low-melting point solid (3.3g). Pmr spectrum (CDC1 ₃ ) 4.18 (s, 2H); 7.2 (b , 5H); 8.60 (8, IH).

(iii) 4,6-Bis(2,2,2-trifluoroethoxy)-5-benzylthio- pyrimidine

Sodium hydride (60% dispersion in oil) (1.8 g) was added to a solution of 2,2,2-tri- fluoroethanol (3.25 ml) in dioxane (30 ml) and the mixture stirred for 30 minutes. 4,6-Dichloro-5-benzylthiopyrimidine (3.0 g) in dioxane (20 ml) was added over 15 minutes and the mixture stirred at 50°C for 3 hours. The mixture was then concentrated and the residue partitioned between ethyl acetate

and aqueous 5% citric acid. The organic phase was washed with water, dried and evaporated to give the title pyrimidine (4.3 g) as a yellow oil which crystallised on standing.

Pmr spectrum: (dg-DMSO) 4.09 (8, 2H); 5.09 (q, 4H); 7.18 ( , 5H); 8.49 (8, IH) .

(iv) 4,6-Bis-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonamide

A suspension of 4,6-biβ-(2,2,2-trifluoro¬ ethoxy)-5-benzylthiopyrimidine (4.3 g) in acetic acid (50 ml) and water (50 ml) was vigorously stirred and cooled to 5°C. Chlorine gas was bubbled into the stirred suspension for approximately 30 minutes.

After 30 minutes further stirring below 10°C the reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (2 x 50 ml). The dichloromethane extracts were washed with water, dried and evaporated to give an oily solid. This was dissolved in acetonitrile (100 ml), and the solution cooled in ice and treated with ammonia gas for several minutes. After 30 minutes stirring the acetonitrile and excess ammonia were removed on a rotary evaporator and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried and concentrated to give an oily residue. Trituration with

ether/light petroleum and filtration allowed isolation of the title sulfonamide as a white solid (1.92 g).

Pmr spectrum: (dg-Acetone) 5.21 (q, 4H); 6.68 (br 8, 2H); 8.62 (8, IH) .

(v) 4-(2,2-Dimethylhydrazino)-6-(2,2,2-trifluoro¬ ethoxy)pyrimidine-5-sulfonamide.

A solution of 4,6-Bis(2,2,2-trifluoroethoxy) pyrimidine-5-sulfonamide (0.50g, 1.5 mmol) in neat 1,1-dimethylhydrazine (5 ml) was stirred with warming to 50°C for 20 hours. The reaction mixture was then concentrated leaving an off white solid (0.40g). Pmr spectrum: (CDC1 ₃ ) 3.23 (s, 6H); 4.96 (q, 2H); 8.15 (8, IH).

(vi) N-[(4-Methoxy-6-methyl-l,3,5-triazin-2-yl) aminocarbonyl]-4-(2,2-dimethylhydrazino)-6- (2,2,2-trifluoroethoxy)pyrimidine-5- sulfonamide(409) .

N-(4-methoxy-6-methyl-l,3,5-triazin-2-yl) phenylcarbamate (0.40g, 1.5 mmol) and 4-(2,2- dimethylhydrazino)-6-(2,2,2-trifluoroethoxy) pyrimidine-5-sulfonamide (0.44g, 1.4 mmol) were dissolved in N,N-dimethylformamide (5 ml). The solution was cooled in ice and l,8-diazabicyclo[5.4.0] undec-7-ene (DBU) (0.26g, 1.6 mmol) was added with stirring.

After five hours stirring at ice temperature the reaction mixture was poured into ice cold 5% citric acid solution (30 ml) with stirring. The white precipitate was collected by filtration and air dried to give compound no. 409 as a colourless powder (0.40g).

Pmr spectxnim: (CDC1-.) 2.56 (s, 3H); 3.28 (s, 6H); 4.04 (s, 3H); 4.83 (q, 2H); 8.16 (s, IH); 12.38 (br s, IH) .

Example 10

N-T (4-Methoxv-6-methvl-l.3.5-triazin-2-vl \ aminocarbonyl"|-4- (2.2-dimethylhydrazino)-6- thiomethoxvpvrimidine-5-sulfonamide (425.

(i) 4-(2,2-dimethylhydrazino)-6-thiomethoxy- pyrimidine-5-sulfonamide.

Sodium thiomethoxide (0.71g, 10.1 mmol) was added to a solution of 4-(2,2-dimethyl hydrazino)-6-(2,2,2-trifluoroethoxy)- pyrimidine-5-sulfonamide (0.53g, 1.7 mmol) in dimethylformamide (3 ml). The reaction mixture was heated to 90°C for 24 hours with stirring then partitioned between 5% citric acid solution and ethyl acetate. The ethyl acetate layer was washed thoroughly with water, dried (MgS0 ₄ ) and concentrated to give the required product as an off white solid.

Pmr spectrum: (CDC1 ₃ ) 2.65 (8, 3H); 3.21 (8, 6H) 5.42 (br s, 2H); 8.23 (s,l H).

(ii) N-[(4-Methoxy-6-methyl-l,3,5-triazin-2-yl) aminocarbonyl]-4-(2,2-dimethylhydrazino)-6- thiomethoxypyrimidine-5-sulfonamide (425).

N-(4-Methoxy-6-methyl-1,3,5-triazin-2-yl) phenyl carbamate (0.16g, 0.61 mmol) and 4-(2,2-dimethylhydrazino)-6-thiomethoxy- pyrimidine-5-sulfonamide (0.15g, 0.57 mmol) were coupled in a manner similar to that described in Example 9 (vi) above to give the required sulfonyl urea as a colourless solid

(0.15g).

Pmr spectrum: (CDC1 ₃ ) 2.50 (s, 3H); 2.58 (s, 3H); 3.26 (s, 6H); 4.06 (s, 3H); 8.22 (s, IH); 12.5 (br s, IH) .

Example 11

N-r(4-Methoxv-6-methvl-l.3.5-triazin-2-vl . aminocarbonvl .-4-(propvloxvamino)-6- (2.2.2-trifluoroethoxylPyrimidine-5-sulfonamide (4611.

(i) 4-(propyloxyamino)-6-(2,2,2-trifluoroethoxy) pyrimidine-5-sulfonamide.

A solution of O-propylhydroxylamine hydrochloride (0.59g, 5.3 mmol) and sodium acetate (0.43g, 5.3 mmol) in water (10 ml) was added to a solution of 4-chloro-6-(2, 2,2-trifluoroethyoxy)pyrimidine-5-

sulfonamide (0.51g, 1.8 mmol) in ethanol (5 ml). The reaction mixture was stirred at 20° to 25°C for four hours then left to stand for three days. After removal of the ethanol in vacuo the residue was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (MgSO.) and concentrated to give the required product as a pale yellow solid (0.37g). Pmr spectrum: (dg-Acetone) 0.98 (m, 3H); 1.68 (m, 2H); 3.97 (m, 2H); 5.16 (q, 2H); 6.72 (br s, 2H); 8.40 (s, IH); 10.02 (br 8, IH) .

(ii) N-T(4-Methoxv-6-methvl-l.3.5-triazin-2-vl1 aminocarbonvn-4-(propvloxvaminol-6-(2.2.2- triflu9r?gthp^γ)pγgimJ, ting-5-8ulfp wBi4g

(461) ,

N- [ ( 4 -Methoxy-6 -methyl- 1 , 3 , 5-triazin-2-yl ) phenyl carbamate (0.28g, 1.0 mmol) and

4-(propyloxyamino)-6-(2,2,2-trifluoroethoxy)- pyrimidine-5-sulfonamide (0.30 g, 0.91 mmol) were coupled in a manner similar to that described in Example 9 (vi) above to give the required sulfonyl urea as a pale brown solid (0.33 g). Pmr spectrum: (CDC1 ₃ ) 1.01 (t, 3H); 1.78 (m, 2H); 2.57 (8, 3H); 4.01 (t, 2H); 4.05 (8, 3H); 4.83 (q, 2H); 7.67 (br 8, IH); 8.39 (8, IH); 9.95 (br 8, IH); 12.61 (br 8, IH).

Example 12

N- r ( 4.6-Dimethoxv-l .3-pvrimidin-2-vl 1 aminocarbonyl 1 -4- ( 2.2-dimethvlhvdrazino ) -6-propvlaminopvrimidine- 5-sulf onamide (418)

(i) N-[(4,6-Dimethoxy-l,3-pyrimidin-2-yl) aminocarbonyl]-4-(2,2-dimethylhydrazino)- 6-propylaminopyrimidine-5-sulfonamide (418) .

1,1-Dimethylhydrazine (0.20g, 3.3 mmol) was added to a solution of N-[(4,6-dimethoxy

-1,3-pyrimidin-2-yl)aminocarbony]-4-chloro- 6-propylamino-pyrimidine-5-sulfonamide (0.33g, 0.77 mmol) in dimethylformamide (3 ml) . The reaction was stirred at 20° to 25°C for six hours then left to stand for 18 hours before adding the reaction to a solution of citric acid (0.15g, 0.78 mmol) in water (20 ml). Filtration of the precipitate gave the required sulfonyl urea (41 mg) .

Pmr spectrum: (CDC1 ₃ ) 0.99 (t, 3H); 1.65 (m, 2H); 3.20 (s,6H); 3.50 (m, 2H); 3.95 (s,6H); 5.79 (s, IH); 7.28 (br s, IH); 7.72 (br t, IH); 8.02 (br s, IH); 8.05 (8, IH); 12.43 (br s, IH).

Example 13

Compounds Nos. 76, 78, 172, 173, 401, 403, 433, 434, 441, 473 and 485 were each prepared starting from 4,6-dihydroxy-5-benzylthiopyrimidine and proceeding via 25 modifications of the methods described in Examples 9 to 12 above.

Each compound was characterized in part by its proton magnetic resonance spectrum and details are recorded in Table 5 below.

TABLE 5

Compound Proton Chemical Shift δ in ppm No.

401 (dg-Acetone) 1.22 (t, 3H); 2.52 (8, 3H); 3.23 (8, 6H); 4.04 (s, 3H); 4.41 (q, 2H); 8.14 (s, IH) .

403 (CDC1 ₃ ) 1.19 (t, 3H); 2.43 (s, 3H); 3.27 (s, 6H); 3.96 (s, 3H); 4.38 (q, 2H); 6.30 (s, IH); 8.03 (br s, IH); 8.15 (s, IH); 12.90 (br s, IH).

404 (CDC1 ₃ ) 1.24 (t, 3H); 3.27 (s, 6H); 4.03 (s, 3H); 4.42 (q, 2H); 6.50 (s, IH); 7.29 (br s, IH); 8.17 (s, IH); 11.92 (br s, IH) .

433 (dg-DMSO) 1.21 (t, 3H); 2.45 (s, 3H); 3.97 (8, 3H); 3.99 (q, 2H); 5.10 (q, 2H); 8.49 (s, IH); 10.33 (br 8, IH); 11.20 (br 8, IH); 12.76 (br 8, IH).

434 (dg-DMSO) 1.22 (t, 3H); 3.90 (s, 6H); 3.99 (q, 2H); 5.11 (q, 2H); 6.02 (s, IH); 8.49 (s, IH); 10.32 (br 8, IH); 10.78 (br s, IH); 12.99 (br 8, IH) .

441 (dg-Acetone) 1.28 (t, 6H); 2.53 (8, 3H); 4.04 (s, 3H); 4.07 (q, 2H); 4.47 (q, 2H); 8.36 (s, IH); 9.75 (br 8, IH); 9.96 (br s, IH); 12.64 (br s, IH).

Example 14

N-r(4-Methoxv-6-methvl-l.3.5-triazin-2-vl1 amino carbonvl1-4-ethvl-6-(2.2.2-trifluoroethoxy1 pyrimidine-5-sulfonomide (176.

i) Methyl α-chloropropionylacetate

Sulfuryl chloride (5.2g) was added dropwise over a 10 minute period to a stirred solution of methyl propionylacetate (5.0g) in carbon tetrachloride (20ml) warmed to 45°C. Heating and stirring was continued for 1.5 hours after the additon was complete. The mixture was allowed to cool, washed three times with water (50ml), dried (MgS0 ₄ ) and the solvent removed to give the -chloro ester as a colourless liquid (6.1g). Pmr spectrum (CDC1-) 1.13 (t, 3H); 2.75 (q, 2H); 3.84 (s, 3H); 4.82 (s, IH)

ii) 4-Ethyl-6-hydroxy-5-benzylthiopyrimidine

Benzyl mercaptan (7.5g) was added to a solution of methyl α-chloropropionylacetate (lOg) in tetrahydrofuran (200ml) under a nitrogen atomosphere. After the addition was complete triethylamine (6.1g) was added to the stirred solution, the mixture became warm and a large amount of precipitate formed. Stirring was continued for 3 hours and the mixture then evaporated. The residue was taken into dichloromethane (100ml) and water (200ml) and the organic phase separated, dried (MgSO.) and evaporated to leave crude methyl o-(benzylthio)propionylacetate as an oil (15.5g).

This was taken into methanol (150ml) and treated with trimethyl orthoformate (7g) and p-toluenesulfonic acid monohydrate (500mg). The mixture was refluxed for 40 hours then concentrated. The concentrate was added to a mixture of formamidine acetate (6.2g) in methanolic sodium methoxide (2.75g sodium metal in 50ml of methanol) and stirred overnight. After being boiled for 2 hours the mixture was evaporated to near dryness and the solid residue dissolved in water and then acidified with an aqueous 10% citirc acid solution. The oily solid which separated on cooling was isolated by decantation and triturated with ether to give after filtration 4-ethyl-6-hydroxy-5-benzyl- thiopyrimidine (4.5g) as a fawn solid. P.m.r. spectrum (dg-DMSO) 0.81 (t, 3H); 2.48 (q, 2H); 4.07 (s, 2H); 7.1-7.3 (m, 5H); 8.08 (s, IH); 12.55 (br s, IH)

(iϋ) 4-Ethyl-6-chloro-5-benzylthiopyrimidine

A mixture of phosphorus oxychloride (25ml) and 4-ethyl-6-hydroxy-5-benzylthiopyrimidine (4.0g) was stirred and heated under reflux for 20 minutes. The mixture was cooled, poured into iced water (300ml), and extracted into ethyl acetate (3x50ml). The combined extracts were washed with water (3x50ml), dried (MgSO,) and evaporated to give the chloropyrimidine as a brown oil (3.8g). P.m.r. spectrum (CDC1 ₃ 1.07 (t, 3H); 2.79 (q, 2H) ; 4.06 (s, 2H); 7.0-7.3 (m, 5H); 8.75 (s, IH) .

SUBSTITUTESHEET

(iv) 4-Ethyl-6-(2,2,2,-trifluoroethoxy)-5-benzyl- thiopyrimidine

Sodium hydride (60% dispersion in oil) (0.49g) was added to a solution of 2,2,2,-trifluoroethanol (1.84g) in dioxane (5ml) and the mixture stirred for 10 minutes. 6-chloro-4-ethyl-5-benzylthiopyrimidine (1.62g) in dioxane (5ml) was added and the mixture stirred at 50°C for 3 hours. The mixture was then concentrated and the residue partitioned between ethyl acetate and aqueous 5% citric acid. The organic phase was washed with water, dried and evaporated to give the title pyrimidine (1.93g) as a tan solid. P.m.r. spectrum (CDCl,) 1.03 (t, 3H); 2,81 (q, 2H); 4.02 (s, 2H); 4.89 (q, 2H); 7.08-7.26 ( , 5H); 8.57 (s, IH).

(v) 4-Ethyl-6-(2,2,2-trifluoroethoxy)-pyri idine- 5-sulfonamide.

A mixture of 4-ethyl-6-(2,2,2-trifluoroethoxy)-5- benzylthiopyrimidine (1.93g) dissolved in chloroform (30ml) and water (20ml) was stirred and cooled to 5°C. Chlorine gas was bubbled into the stirred mixture for about 10 minutes. After a further 20 minutes stirring the organic phase was isolated and dried (MgSO.). The solution was cooled in ice and treated with ammonia gas for several minutes. After 30 minutes stirring the mixture was concentrated and the residue partioned between ethyl acetate and water. The ethyl acetate layer was dried and evaporated to give an oil residue. Trituration with ether/light petroleum and filtration allowed isolation of the title sulfonamide as a while solid

SUBSTITUTESHEET

(0.5g). P.m.r. spectrum (CDC1 ₃ ) 1.31 (t, 3H) ; 3.29 (q, 2H); 5.01 (q, 2H); 5.25 (br s, 2H) ; 8.77 (s, IH) .

(vi) N-f( -Methoxy-6-methyl-l.3.5-triazin-2-yl - amino carbonyl]-4-ethyl-6-(2.2.2,-trifluoro¬ ethoxy) pyrimidine-5-sulonamide (1761

4-Ethyl-6-(2,2,2-trifluorethoxy)pyrimidine-5-sulfon¬ amide (300mg) was dissolved in dimethylformamide (4ml) and cooled in ice. 1,8-Diazabicyclo[5.4.0] undec-7-ene (190mg) was added with stirring and after 5 minutes

N-(4-methoxy-6-methyl-l,3,5-triazin-2-yl)phenyl carbonate (300mg) was also added to the mixture. After 0.5 hurs at ice temperature and a further 1 hour without cooling the reaction mixture was poured into ice aqueous 5% citric acid solution (15ml) and stirred for 1 hour. The off-white precipitate was collected by filtration and air-dried to give compound No. 176 as a white powder (523mg) . P.m.r. spectrum (CDC1 ₃ ) 1.39 (t, 3H) ; 2.58 (s, 3H); 3.42 (q, 2H); 4.06 (s, 3H); 4.88 (q, 2H); 7.42 (br s, IH); 8.79 (s,lH); 12.61 (b s, IH).

SUBSTITUTESHEET

Exam le 5

chloro-6-(2.2.2-trifluoroethoxy1pvrimidine-5- suIfonamide (607)

(ia) 4,6-Dihydroxy-5-benzylthiopyrimidine

Benzylmercaptan (6 ml, 0.05 mole) was added to a stirred and heated (90°C) suspension of 5-bromo-4,6-dihydroxypyrimidine (9.5g, 0.05 mole) and potassium carbonate (7.5g, 0.055 mole) in dimethylformamide (25 ml). The reaction mixture was stirred and heated at 95-105°C under an atmosphere of dry nitrogen for 3.5 hours. The mixture was poured into ice cold water (400 ml) with vigorous stirring and then acidified to pH 1 with hydrochloric acid. After stirring for 0.5 hour the suspension was filtered and the solid collected and rinsed several times with n-hexane and diethyl ether and air dried to give 4,6-dihydroxy-5-benzylthiopyrimidine as a brown solid (5.5g 50%), ^~ H NMR (dg-DMSO) 3.96 (s, 2H); 7.2 ( , 5H); 8.11 (s, IH); 12.2 (bs, 2H).

An alternative method for the preparation of the 4,6-dihydroxy-5-benzylthiopyrimidine is described as follows:

(ib) Sulfuryl chloride (3.5 ml, 43 mmol) was added to a stirred suspension of dibenzyl disulfide (10.35 g, 42 mmol) in carbon tetrachloride (55 ml) containing three drops of triethylamine. The orange solution was stirred for 30 minutes at room temperature before being added dropwise to a stirred suspension of

4,6-dihydroxypyrimidine (8.6 g, 77 mmol) in dimethylformamide (120 ml). The resulting mixture was stirred at room temperature for three and half hours after which time the precipitate was filtered, washed several times with water followed by diethyl ether, then air dried to give the desired 4,6-dihydroxy-5-benzylthiopyrimidine as a pale yellow powder (15.35 g, 85%).

(ii) 4,6-Dichloro-5-benzylthiopyrimidine

A mixture of phosphorous oxychloride (40 ml) and 4,6-dihydroxy-5-benzylthiopyrimidine (5g) was stirred and heated under reflux for 3 hours. Excess phosphorous oxychloride was removed by distillation under reduced pressure and the residue was cooled, dissolved in chloroform (200 ml) and the chloroform solution was washed with water (3 x 200 ml). The chloroform layer was separated, dried (MgS0 ₄ ) and then

concentrated to give a brown oil (4.1g) which was purified by column chromatography (silica gel, hexane-chloroform (1:1) to give the dichloropyrimidine as a nearly colourless low-melting point solid (3.3g). 'H NMR (CDC1 ₃ ) 4.18 (s, 2H); 7.2 (m, 5H); 8.60 (8, IH).

(iii) 4,6-Bis(2,2,2-trifluoroethoxy)-5-benzylthio¬ pyrimidine

Sodium hydride (60% dispersion in oil) (1.8 g) was added to a solution of 2,2,2-tri- fluoroethanol (3.25 ml) in dioxan (30 ml) and the mixture stirred for 30 minutes. 4,6-Dichloro-5-benzylthiopyrimidine (3.0 g) in dioxan (20 ml) was added over 15 minutes and the resulting mixture stirred at 50°C for 3 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate and aqueous 5% citric acid. The organic phase was washed with water, brine, dried (MgS0 ₄ ) and evaporated off to give the title product (4.3 g) as a yellow oil which crystallised on standing. H NMR (dg-DMSO) 4.09 (s, 2H); 5.09 (q, 4H); 7.18 (m, 5H); 8.49 (8, IH) .

(iv) 4,6-Bis-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonyl chloride

A suspension of 4,6-bis-(2,2,2-trifluoro¬ ethoxy)-5-benzyl thiopyrimidine (18.5 g, 47 mmol) in acetic acid (270 ml) and water (65 ml) was vigorously stirred and cooled to 5°C. Chlorine gas was bubbled through the cooled reaction mixture for approximately 10 minutes. After 15 minutes further stirring below 5°C, the reaction mixture was poured into ice water (600 ml), and the product 4,6-biε-(2,2,2-trifluoroethoxy)pyrimidine-5- εulfonyl chloride separated out as a cream coloured solid which was filtered and dried (15.9 g, 91%). hi NMR (dg-DMSO) 5.00 (q, 4H); 8.58 (s, IH) .

(v) 4,6-Bis-(2,2,2-trifluoroethox )pyrimidine-5- sulfonamide

4,6-Biε-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonyl chloride (15.9 g) was dissolved in acetonitrile (160 ml) and the solution cooled in ice and treated with ammonia gas for 10 minutes. The resulting mixture was stirred at ice temperature for a further 15 minutes before the acetonitrile and excess ammonia were removed on a rotary evaporator. The residue was then diluted with water, and the desired sulfonamide separated out as a creamy coloured solid. Trituration with

ethyl acetate: etroleum spirits mixtures afforded the pure product as a colourless solid (10.6 g, 71%).

~H NMR (dg-DMSO) 5.20 (q, 4H); 7.44 (br s, 2H); 8.70 (s, IH) .

(vi) 4-Hydroxy-6-(2,2,2-trifluoroethoxy) pyrimidine-5-sulfonamide

A solution of sodium hydroxide (0.91 g) in water (12 ml) was added to 4,6-bis(2,2,2- trifluoroethoxy)pyrimidine-5-sulfonamide

(2.01 g) . The stirred suspension was heated to "90 C and formed a solution. After 2 hours the mixture was allowed to cool, acidified to pH 6 with concentrated hydrochloric acid, and chilled in ice. The white precipitate was collected by filtration and air-dried to give the title sulfonamide (1.33 g). Pmr spectrum: (dg-Acetone) 5.08 (q, 2H); 6.92 (s, 2H); 8.40 (s, IH); 13.41 (br s, IH).

(viia) 4-Chloro-6-(2,2,2-trifluoroethoxy)pyrimidine- 5-sulfonamide

A mixture of phosphorus oxychloride (10 ml), diethylaniline (0.05 ml) and 4-hydroxy-6- (2,2,2-trifluoroethoxy)pyrimidine-5- sulfonamide (800 mg) were heated under reflux for 4 hours. The yellow solution was cooled, added to ice-cooled water (150 ml) and stirred for 30 minutes. The mixture was

extracted with ethyl acetate (2 x 30 ml), the combined extracts washed with water (40 ml), dried and evaporated to give the title chloro sulfonamide as an off-white solid (520 mg) .

Pmr spectrum: (dg-Acetone) 5.26 (q, 2H); 7.01 (br s, 2H); 8.75 (s, IH) .

An alternative method for the preparation of 4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine-5- sulfonamide can be achieved via the direct chlorination and aminolysis of 4-chloro-6-(2,2,2- trifluoroethoxy)-5-benzylthiopyrimidine via the following procedure:

(viib) 4-Chloro-6-(2,2,2-trifluoroethoxy)-5- benzylthiopyrimidine

Sodium hydride (1.3 g, 60% dispersion in oil) was added to a stirred solution of 2,2,2-tri- fluoroethanol (3.25 g) in 1,2-dimethoxyethane (DME, 40 ml). The resulting mixture was stirred at room temperature for 10 minutes before addition of 4, -dichloro-5-benzyl¬ thiopyrimidine (8.0 g) in DME (40 ml). The reaction was then stirred at room temperature for 24 hours before removal of solvent in vacuo. The residue was diluted with water and the product precipitated out and filtered as a pale brown solid (8.6 g, 86%). hi NMR (dg-DMSO) 4.19 (s, 2H); 5.17 (q, 2H); 7.22 (m, 5H); 8.61 (8, IH).

- Ill -

4-Chloro-6-(2,2,2-trifluoroethoxy)pyrimidine- 5-sulfonamide

A suspension of 4-chloro-6-(2,2,2-trifluoro¬ ethoxy)-5-benzylthiopyrimidine (3.0 g) and 5 sodium acetate (2.0 g) in acetic acid (40 ml) and water (5 ml) was vigorously stirred and cooled to 5 C. Chlorine gas was bubbled into the stirred suspension for about 20 minutes. After 30 minutes further stirring at below

10 5°C the resulting yellow solution was poured into ice-water and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were then washed with water, brine, dried (Na ₂ S0 ₄ ) and concentrated to give the

15 crude 4-chloro-6-(2,2,2-trifluoroethoxy)- pyrimidine-5-sulfonyl chloride as a yellow oil. The sulfonyl chloride was not fully characterized, but was immediately dissolved in acetonitrile (40 ml) and the solution

20 cooled in ice and treated with ammonia gas for a period of 10 minutes. The resulting mixture was stirred at ice temperature for 45 minutes, after which the solvent and excess ammonia were removed on a rotary evaporator,

25 the residue was diluted with water and the sulfonamide precipitated out, and filtered as a tan coloured solid (1.1 g, 42% yield from the benzylthio ether) . ^~ R NMR (dg-DMSO) 5.24 (q, 2H); 8.23 (br 8,

30 2H); 8.82 (s, IH) .

(viii) N-[(4,6-Dimethoxypvrimidin-2-yl)amino¬ carbonyl]-4-chloro-6-(2,2,2-trifluoro¬ ethoxy)pyrimidine-5-sulfonamide

4-Chloro-6-(2,2,2-trifluoroethoxy)pyrimidine- 5-sulfonamide (180 mg) and N-(4,6-dimethoxy- pyrimidin-2-yl) phenyl carbamate (187 mg) were dissolved in dimethylformamide (1 ml) and cooled in ice. 1,8-Diazabicyclo[5.4.0]- undec-7-ene (103 mg) was added and the mixture stirred with cooling for 2 hours and for a further 1 hour without cooling. It was then added to aqueous 10% citric acid solution (20 ml) and stirred with cooling for 1 hour. The white precipiate was collected by filtration and air dried to give the title compound (254 mg) as a cream powder. Pmr spectrum (dg-Acetone) 3.97 (s, 6H); 5.23 (q, 2h); 5.90 (s, IH); 8.83 (s, IH); 9.50 (br s, IH); 13.20 (br s, IH) .

Example 16

N-f(4-Methoxy-6-methyl-l.3.5-triazin-2-yl .amino¬ carbonyl1-4-chloro-6-ethoxypyrimidine-5-8ulfonamide (6Q3)

(i) 4-Chloro-6-ethoxy-5-benzylthiopyrimidine

Sodium metal (1.67 g) was dissolved in ethanol (55 ml) and the solution slowly added to 4,6-dichloro-5-benzylthiopyrimidine (17.9 g) in ethanol (150 ml). The mixture was stirred at room temperature for 18 hours and then concentrated on a rotary evaporator.

The residue was partitioned between aqueous 5% citric acid solution and ethyl acetate. The organic layer was washed with water, dried (MgS0 ₄ ) and evaporated to give the title product as a yellow oil (17.8 g) . NMR (CDC1 ₃ ) 1.43 (t, 3H); 4.10 (s, 2H); 4.46 (q, 2H); 7.20 (m, 5H); 8.37 (s, IH) .

(ii) 4-Chloro-6-ethoxypyrimidine-5-sulfonamide

A suspension of 4-chloro-6-ethoxy-5-benzyl- thiopyrimidine (3.1 g) and sodium acetate

(3.7 g) in acetic acid (50 ml) and water (12 ml) was stirred vigorously and cooled to 5°C. Chlorine gas was bubbled into the stirred suspension for a period of 10 minutes. The yellow reaction mixture was stirred at ice temperature for a further 15 minutes before being poured into ice water (400 ml). The aqueous layer was extracted with ethyl acetate (3 x 80 ml) and the combined organic phases washed with brine (200 ml), dried (Na ₂ S0 ₄ ), and concentrated to give the product as a yellow oil, which was immediately dissolved in acetonitrile (40 ml), and the solution cooled in ice and treated with ammonia gas for three periods of 10 minutes over two hours with continuous stirring. The solvent and excess ammonia were then removed in vacuo and the residue diluted with water. The aqueous layer was extracted with ethyl acetate (3 x 60 ml) and the combined organic layers washed with brine, dried (Na ₂ S0 ₄ ), and concentrated to dryness, at which point the product was

precipitated with addition of petroleum spirits and filtered aε a tan coloured solid (0.55 g, 21%).

(iii) N-[(4-Methoxy-6-methyl-1,3,5-triazin-2-yl)- aminocarbonyl]-4-chloro-6-ethoxypyrimidine-5- sulfonamide (603)

4-Chloro-6-ethoxypyrimidine-5-sulfonamide (250 mg) and N-(4-methoxy-6-methyl-1,3,5- triazin-2-yl) phenyl carbamate (287 mg) were dissolved in DMF (4 ml). The solution was cooled in ice and l,8-diazabicyclo[5.4.0]- undec-7-ene (167 mg) added. The reaction mixture was stirred at room temperature for 1.5 hours before being poured into a citric acid solution (5%). The cream coloured precipitate was collected by filtration and air dried to give the title sulfonylurea (603) (310 mg, 73%). hi NMR (dg-DMSO) 1.24 (t, 3H); 2.47 (8, 3H); 3.98 (s, 3H); 4.53 (q, 2H); 8.83 (s, IH); 11.09 (br s, IH); 12.80 (br s, IH) .

Example 17

Compounds Nos. 601, 609, 610, 615, 616, 627 and 695 were each prepared starting from 4,6-dihydroxy-5- benzylthiopyrimidine and proceeding via the appropriate 4-chloro-6- alkoxy-5-sulfonamido, or 4-chloro-6-aryloxy -5-sulfonamido, or 4-chloro-6-alkylamino-5 -sulfonamido pyrimidine following the method similar to that as described in Examples 15 and 16.

Each compound was characterized in part by its proton magnetic resonance spectrum and details are summarized in Table 6.

TABLE 6

Example 18

This non-limiting Example illustrates the preparation of formulations of the compounds of the invention.

a) Emulsifiable Concentrate

Compound No. 1 was dissolved in toluene/DMSO containing 7% v/v "Teric" N13 and 3% v/v "Kemmat" SC15B to give an emulsifiable concentrate which was diluted with water to the required concentration to give an aqueous emulsion which was applied by spraying.

("Teric" is a Trade Mark and "Teric" N13, is a product of ethoxylation of nonylphenol; "Kemmat" is a Trade Mark and "Kemmat" SC15B is a formulation of calcium dodecylbenzene- sulfonate) .

b) Aσueous Suspension

Compound No. 3 (5 parts by weight and "Dyapol" PT (1 part by weight) were added to a 2% aqueous solution (94 parts by weight) of "Teric" N8 and the mixture was ball milled to produce a stable aqueous suspension which may be diluted with water to the required concentration to give an aqueous suspension which may be applied by spraying.

("Dyapol" is a Trade Mark and "Dyapol" PT is an anionic suspending agent; "Teric" N8 is a product of ethoxylation of nonylphenol) .

c) Emulsifiable Concentrate

Compound No. 30 (10 parts by weight), "Teric" N13 (5 parts by weight) and "Kemmat" SC15B (5 parts by weight) were dissolved in "Solvesso" 150 (80 parts by weight) to give an emulsifiable concentrate which may be diluted with water to the required concentration to give an aqueous emulsion which may be applied by spraying.

("Solvesso" is a Trade Mark and "Solvesso" 150 is a high boiling point aromatic petroleum fraction) .

d) Dispersible Powder

.Compound No. 70 (10 parts by weight), "Matexil" DA/AC (3 parts by weight), "Aerosol" OT/B (1 part by weight) and china clay 298 (86 parts by weight) were blended and then milled to give a powder composition having a particle size below 50 microns.

("Matexil" is a Trade Mark and "Matexil" DAAC is the disodium salt of a naphthalenesulfonic acid/formaldehyde condensate; "Aerosol" is a Trade Mark and "Aerosol" OT/B is a formulation of the dioctyl ester of sodium sulfosuccinic acid) .

e) Pμating ?Q ~H V

Compound No. 70 (10 parts by weight), attapulgite (10 parts by weight) and pyrophyllite (80 parts by weight) were thoroughly blended and then ground in a hammer-mill to produce a powder of particle size less than 200 microns.

Emulsifiable concentrates and/or suspensions of the compounds of the invention were prepared essentially as described in part a), b) or c) above and then diluted with water, optionally containing surface active agent and/or oil, to give aqueous compositions of the required concentration which were used, as described in Examples 18 and 19, in the evaluation of the pre-emergence and post-emergence herbicidal activity of the compounds.

Example 19

The pre-emergent herbicidal activity of the compounds of the invention formulated as described in Example 18 was assessed by the following procedure:

The seeds of the test species were sown in rows 2 cm deep in soil contained in seed boxes. The monocotyledonous plants and the dicotyledonous plants were sown in separate boxes and after sowing the two boxes were sprayed with the required quantity of a composition of the invention. Two duplicate seed boxes were prepared in the same

manner but were not sprayed with a composition of the invention and were used for comparison purposes. All the boxes were placed in a glass house, lightly watered with an overhead spray to initiate germination and then sub-irrigated as required for optimum plant growth. After three weeks the boxes were removed from the glass house and the effect of the treatment was visually assessed. The results are presented in Table 7 where the damage to plants is rated on a scale of from 0 to 5 where 0 represents from 0 to 10% damage, 1 represents from 11 to 30% damage, 2 represents from 31 to 60% damage, 3 represents from 61 to 80% damage, 4 represents from 81 to 90% damage and 5 represents 100% kill. A dash (-) means that no experiment was carried out.

The names of the test plants are as follows:

L

TABLE 7 Continued) Pre-emerσent Herbicidal Activity

TABLE 7 (Continued) Pre-emerσent Herbicidal Activity

TABLE 7 Continued Pre-emerσent Herbicidal Activity

Example 2Q

The post-emergent herbicidal activity of the compounds of the invention formulated as described in Example 18 was assessed by the following procedure.

The seeds of the test species were sown in rows 2 cm deep in soil contained in seed boxes. The monocotyledonous plants and the dicotyledonous plants were sown in separate seed boxes in duplicate. The four seed boxes were placed in a glass house, lightly watered with an overhead spray to initiate germination and then sub-irrigated as required for optimum plant growth. After the plants had grown to a height of about 10 to 12.5 cm one box of each of the monocotyledonous plants and the dicotyledonous plants was removed from the glass house and sprayed with the required quantity of a composition of the invention. After spraying the boxes were returned to the glass house for a further 3 weeks and the effect of treatment was visually assessed by comparison with the untreated controls. The results are presented in Table 8 where the damage to plants is rated on a scale of from 0 to 5 where 0 represents from 0 to 10% damage, 1 represents from 11 to 30% damage, 2 represents from 31 to 60% damage, 3 represents from 61 to 80% damage, 4 represents from 81 to 90% damage and 5 represents 100% kill. A dash (-) means that no experiment was carried out.

The names of the test plants are as follows:

Wh Wheat Ot Wild Oats Rg Ryegrass Jm Japanese millet

B Barley P Peas ip Ipomea

Ms Mustard Sf Sunflower Mz Maize

TABLE 8 Post-emerσent Herbicidal Activity

TABLE 8 (Continued) ppgt-e *rg?nt Bert>i?j<foi Activity

TABLE 8 (Continued) Post-emerσent Herbicidal Activity

TABLE 8 (Continued) Post-emerσent Herbicidal Activity

TABLE 8 (Continued) Post-emerσent Herbicidal Activity

Exam le 21

The herbicidal activity of the compounds of the invention was further tested as follows:

Each chemical was formulated by dissolving it in an appropriate amount, dependent on the final spray volume, of a solvent/surfactant blend which comprised 78.2 gm/litre of Tween 20 and 21.8 gm/litre of Span 80 adjusted to 1 litre using methylcyclohex- anone. Tween 20 is a Trade Mark for a surface- active agent comprising a condensate of 20 molar proportions of ethylene oxide with sorbitan laurate.

Span 80 is a Trade Mark for a surface-active agent comprising sorbitan mono-laurate. If the chemical

3 did not dissolve, the volume was made up to 5cm with water, glass beads were added and this mixture was then shaken to effect dissolution or suspension of the chemical, after which the beads were removed.

In all cases, the mixture was then diluted with water to the required spray volume. If sprayed independently, volumes of 25cm 3 and 30cm3 were required for pre-emergence and post-emergence tests respectively; if sprayed together, 45cm was required. The sprayed aqueous emulsion contained 4% of the initial solvent/surf ctant mix and the test chemical at an appropriate concentration.

The spray compositions so prepared were sprayed onto young pot plants (post-emergence test) at a spray volume equivalent to 1000 litres per hectare. Damage to plants was assessed 13 days spraying by comparison with untreated plants, on a scale of 9 to 9 where 0 is 0% damage, 1 is 1-5% damage, 2 is 6-15% damage, 3 is 16-25% damage, 4 is 26-35% damage, 5 is 36-59% damage, 6 is 60-69% damage, 7 is 70-79% damage, 8 is 80-89% damage and

9 is 90-100% damage.

In a test carried out to detect pre- emergence herbicidal activity, crop seeds were sown at 2 cm depth (ie. sugar beet, cotton, rape, winter wheat, maize, rice, soya) and weed seeds at 1cm depth beneath compost and sprayed with the compositions at a spray volume equivalent to 1000 litres per hectare. 20 days after spraying, the seedlings in the sprayed plastic trays were compared with the seedlingε in unεprayed control trays, the damage being assessed on the same scale of 0 to 0.

The results of the tests are given in Tables 9a and 9b below.

TABLE

10

15

20

25

TABLE 9a

Applic- Comp- Pre ation ound or Rate No. Post g/ha BV BN GH GM ZM OS TA PA CA GA AR BP EH

TABLE 9a (Continued)

Applic- Comp- Pre ation ound or Rate No. Post g/ha BV BN GH GM ZM OS TA PA CA GA AR BP EH

TABLE 9a (Continued)

Applic- Comp- Pre ation ound or Rate 5 No. Post g/ha BV BN GH GM ZM OS TA PA CA GA AR BP EH

TABLE 9a (Continued)

Applic- Co p- Pre ation ound or Rate No . Post g/ha BV BN GH GM ZM OS TA PA CA GA AR BP EH

TABLE 9a (Continued)

Applic- Comp- Pre ation ound or Rate No. Post g/ha BV BN GH GM ZM OS TA PA CA GA AR BP EH

TABLE 9 (Continued)

Applic- Comp- Pre ation ound or Rate NO. Poet g/ha BV BN GH GM ZM OS TA PA CA GA AR BP EH

TAB E 9j>

Applic- Comp- Pre ation ound or Rate No. Post g/ha IH IL AT XP XT AF AM AE SH SV DS EC CR CE

TOfrfi 9fc> (Continued)

Applic- Comp- Pre ation ound or Rate No. Post g/ha IH IL AT XP XT AF AM AE SH SV DS EC CR CE

TABLE 9b (Continued)

Applic- Comp- Pre ation ound or Rate No. Post g/ha IH IL AT XP XT AF AM AE SH SV DS EC CR CE

TABLE 9b (Continued)

Applic- Comp- Pre ation ound or Rate NO. Post g/ha IH IL AT XP XT AF AM AE SH SV DS EC CR CE

TABLE 9b (Continued)

Applic- Comp- Pre ation ound or Rate 5 No. Post g/ha IH IL AT XP XT AF AM AE SH SV DS EC CR CE

TABLE 9b (Continued)

Applic- Comp- Pre ation ound or Rate 5 No. Post g/ha IH IL AT XP XT AF AM AE SH SV DS EC CR CE

8