Processes to prepare 5-amino-3-methylisothiazole are disclosed by Adam and Slack, J. Chem. Soc., (1959), 3061; and Goerdeler and Pohland, Chem. Ber., (1961), 94,2950; and in BE629580.

Processes to prepare 5-amino-4-chloro-3-methylisothiazole are disclosed in W09531448 and by Skotsch and Breitmaier, Synthesis, (1979), 370.

In one aspect the present invention provides a process for the preparation of a compound of formula (D : wherein R is C16 alkyl ; or an acid addition salt derived therefrom; the process comprising oxidising a compound of formula (IT) : with hydrogen peroxide with a continuous phase comprising a chlorinated alkane (such as dichloromethane, 1,2-dichloroethane or 1,1,2,2-tetrachloroethane), an aromatic liquid (for example benzene, toluene, chlorobenzene, fluorobenzene, perfluorobenzene, iso-butyl benzene or mesitylene or a xylene), an ester (for example ethyl acetate or iso-propyl acetate), tert-butyl alcohol, acetic acid, trifluoroacetic acid, sulfuric acid, propionitrile, butyronitrile or benzonitrile.

It is preferred that the continuous phase for the oxidation step comprises toluene, chlorobenzene, fluorobenzene, acetic acid, trifluoroacetic acid, sulfuric acid, tert-butylalcohol, ethyl acetate, iso-propyl acetate, dichloromethane or 1,2-dichloroethane.

More preferably the continuous phase for the oxidation step comprises toluene, fluorobenzene, ethyl acetate, iso-propyl acetate or dichloromethane.

Most preferably the continuous phase for the oxidation step comprises ethyl acetate or iso-propyl acetate.

The continuous phase for the oxidation step may comprise a mixture of the liquids recited above.

The oxidation step is preferably performed at a temperature below 40°C, such as in the range 20 to 35°C, preferably in the range 24 to 26°C.

It is preferred that R is C14 alkyl, more preferably R is Cl 2 alkyl and most preferably R is ethyl.

Suitable acid addition salts include the hydrochloric acid salt.

In another aspect the present invention provides a process for the preparation of a compound of formula (IR) : wherein R is Cul-6 alkyl ; the process comprising oxidising a compound of formula (In : with hydrogen peroxide with a continuous phase comprising a chlorinated alkane (such as dichloromethane, 1,2-dichloroethane or 1,1,2,2-tetrachloroethane), an aromatic liquid (for example benzene, toluene, chlorobenzene, fluorobenzene, perfluorobenzene, iso-butyl benzene or mesitylene or a xylene), an ester (for example ethyl acetate or iso-propyl acetate), tert-butyl alcohol, acetic acid, trifluoroacetic acid, sulfuric acid, propionitrile, butyronitrile or benzonitrile to prepare a compound of formula (I) : or an acid addition salt derived therefrom; and chlorinating said compound of formula (I) with SO2C12 in the presence of a suitable continuous phase.

The chlorination step is preferably performed at a temperature below 35°C, more preferably in the range 10 to 35°C and even more preferably in the range 20 to 30°C.

The continuous phase for the chlorination step may be a chlorinated alkane (such as dichloromethane, 1, 2-dichloroethane or 1,1,2,2-tetrachloroethane), a saturated straight or branched chain hydrocarbon or a mixture thereof (for example a petroleum fraction, pentane or hexane), an optionally alkyl substituted C5-7 cycloalkane (for example cyclohexane, cyclopentane or methylcyclohexane), an ether (such as tert-butylmethylether, glyme, diglyme, triglyme or tetrahydrofuran), an aromatic liquid (for example benzene, toluene, chlorobenzene, fluorobenzene, perfluorobenzene, iso-butyl benzene or mesitylene or a xylene), acetic acid or a polar aprotic liquid (such as a nitrile (for example propionitrile, butyronitrile, benzonitrile or acetonitrile)).

It is preferred that the continuous phase for the chlorination step is a chlorinated alkane (such as dichloromethane, 1,2-dichloroethane or 1,1,2,2-tetrachloroethane), an ether (such as tert-butylmethylether, glyme, diglyme, triglyme or tetrahydrofuran), an aromatic liquid (for example benzene, toluene, chlorobenzene, fluorobenzene, perfluorobenzene, iso-butyl benzene or mesitylene or a xylene), acetic acid or a polar aprotic liquid (such as a nitrile (for example propionitrile, butyronitrile, benzonitrile or acetonitrile)).

More preferably the continuous phase for the chlorination step is an ether (especially tert-butylmethylether), an aromatic liquid (especially toluene, chlorobenzene or fluorobenzene), acetic acid, dichloromethane or acetonitrile.

Most preferably the continuous phase for the chlorination step is acetic acid, toluene, fluorobenzene, dichloromethane, tert-butylmethylether or acetonitrile.

The continuous phase for the chlorination step may comprise a mixture of the liquids recited above (for example a mixture of tert-butylmethylether and another liquid or a mixture of acetonitrile and dichloromethane).

In a further aspect the present invention provides a process for the preparation of a compound of formula (m) wherein R is Cl-6 alkyl, the process comprising oxidising a compound of formula (It) with hydrogen peroxide to prepare a compound of formula (1) or an acid addition salt derived therefrom; and chlorinating said compound of formula (1) with SO2Cl2 wherein the compound of formula (I) is not isolated prior to chlorination and both the oxidation step and the chlorination step are conducted with a continuous phase which comprises toluene, fluorobenzene, dichloromethane, ethyl acetate, iso-propyl acetate or

acetonitrile, more preferably toluene, fluorobenzene, dichloromethane, ethyl acetate or iso- propyl acetate.

The preparation of a compound of formula (II) is described in, for example, WO 94/21617.

The present invention is illustrated by the following Examples. Selected NMR data and melting point data are presented in the Examples. For NMR data, no attempt has been made to list every absorption. The following abbreviations are used throughout the Examples: mp = melting point (uncorrected) ppm = parts per million s = singlet t = triplet q = quartet b = broad EXAMPLE 1 This Example illustrates the preparation of 5-amino-3-ethylisothiazole hydrochloride.

3-Amino-2-pentenethioamide (498.5g, 3.84mol) and ethyl acetate (1.251itre) were charged to a jacketed reaction vessel. The mixture was stirred, placed under a nitrogen blanket and the thermal control of the reaction vessel was set to maintain an internal temperature of ca. 23-25°C. A solution of hydrogen peroxide (575ml ; 4.98mol) in water (270ml) was carefully added, from a pressure addition bottle using nitrogen pressure and via a PTFE tube, to the reaction mixture, initially at ca. 23°C. There was an exothermic reaction but the temperature of the reaction mixture was maintaind between 22-53°C by the use of cooling means and by controlling the rate of addition of the hydrogen peroxide solution. The addition was performed over 1. 5hours, achieving a final temperature of 26°C. The resultant mixture was stirred for ca. 1. 5hours, maintaining the temperature at 26-33°C. Stirring was then halted and the mixture was allowed to stand for 30minutes. An aliquot was removed from the (upper) organic phase and stirring was restarted. The reaction aliquot was evaporated and the residue was subjected to analytical HPLC, which confirmed that starting material was absent and that product was present.

Excess hydrogen peroxide (nominally 1.14 mol) was destroyed by adding a solution comprising a mixture of sodium metabisulphite (108. 13g) in water (191.36ml) and sodium hydroxide (45.53g) in water (191. 36ml) over 20minutes at 33-43°C, finishing the addition at 41°C.

The reaction mixture was then stirred for 15minutes, while warming to 45-50°C (in order to aid separation). Stirring was halted and the layers were allowed to separate (-90% separation after 20 minutes). The aqueous phase was extracted at ca. 45°C with ethyl acetate (3x250ml) and the combined organic phases were washed at ca. 45°C with brine (4x500ml).

A yellow sulphur-like solid was present at the interface which stayed in the organic phase.

The combined organic phases were treated with magnesium sulfate and decolourising charcoal (SOg) and left to stand overnight at room temperature. The mixture was then filtered and the pad was washed through with ethyl acetate (2x5OOml). The orange-coloured filtrate (3.5litre) was charged to a 51itre 3-necked reaction flask, stirred and cooled to 0-2°C using an external ice/acetone bath. HC1 gas was passed through the stirred and cooled mixture at a rate of ca. l87ml/minute. Precipitation occurred immediately. HC1 gas addition was continued at below 10°C for ca. 3hours, after which stirring was continued whilst the reaction mixture was allowed to warm to room temperature overnight.

Then the reaction mixture (a very thick-semi solid) was stirred vigorously and cooled to 0-2°C. Addition of HC1 gas (at a rate of-290ml/minute) was then continued for a further 3hours, during which the suspension became thinner and more mobile. The mixture was filtered (using some of the filtrate to wash the solid from the flask) and the solid material was then washed with hexane (2x500ml) and sucked dry to give a buff-coloured solid (573.3g; 90% yield).

1H NMR (d6-DMSO) : 6.0-3.0 (bs, NH3+) ; 6.00 (s, lH) ; 2.45 (q, CH2); 1. 00 (t, CH3) ppm.

This material was used in Example 2 without further purification. EXAMPLE 2 This Example illustrates the preparation of 5-amino-4-chloro-3-ethylisothiazole.

Acetonitrile (1000ml) was charged to the reaction vessel and stirred. The thermal control of the vessel was set to maintain ca. 25-27°C (internal temperature). The product from Example 1 (411.25g; 2.5mol) was added and washed-in with acetonitrile (2.31itres), to form a pale cream-coloured slurry.

A solution of sulphuryl chloride (385g ; 231ml ; 2.75mol) in acetonitrile (175ml) was added to the vessel from a pressure addition bottle over 50minutes, commencing the addition at 27°C and controlling the reaction temperature to a maximum of 32°C. The reaction mixture was then stirred at 29 to 30°C for 2hours, after which the reaction mixture was separated in to three equal portions, each of which was added to saturated NaHCO3 (2.61itres) to which more solid NaHCO3 (ca. 83g for each of the three portions) was added, so as to maintain the solution at pH7-8. The three portions were stirred for 20 minutes then each was extracted with ethyl acetate (lx400ml). The aqueous portions were combined and extracted with ethyl acetate (3x600ml). The combined organic phasess were washed with brine (lx750ml) and dried (MgS04) overnight.

The mixture was filtered, the filter pad was washed through with ethyl acetate and the combined filtrate and washing was evaporated under reduced pressure using a rotary evaporator to give a brown oil that started to crystallise on the rotary evaporator as a brown amorphous solid (374.3g; yield 92%); mp: 40-43°C.

1H NMR (CDC13) : 4.7-4.5 (bs, NH2); 2.69 (q, CH2); 1.27 (t, CH3) ppm.