IL43690A - Preparation of 4-chloro-2-hydroxybenzothiazole - Google Patents

Description

The acid referred to as and esters and salts thereof are used widely as Typical salts are alkali metal for example sodium salts and amine salts for example triethylamine or amine dimethylamine Typical esters are alk l esters for example isopropyl ethyl Benazolin and its esters and salts was originally described in British Patent Specification The method described therein for its production comprised condensing known as with a compound yielding the acetic acid for example ethyl process in that Specification comprised chlorinating or brominatihg The former process was generally the most satisfactory commercially but did suffer from the fact it was rather difficult to obtain the necessary starting material in adequately high yields and had been described in a paper by Elderfield and Short as being prepared by a process involving diazotisation of in a mixture of bromine and hydrobromic acid to give followed by hydrolysis of this to give the required The yields obtained were for the first stage and the making an overall yield of for the synthesis of from The process was not very satisfactory for commercial In British Specification processes were described by which could be converted to in yield and this in turn could be converted to in high yield fairly satisfactory giving overall yield for the entire reaction of at least process comprised diazotising in hydrochloric acid followed by hydrolysing the dichloro It was described that the reaction could be facilitated by the presence of a water miscible solvent and that particularly desirable conditions are obtained if benzene or toluene is benzene giving the most satisfactory The duration of the diazotisation was above 16 ho A modification of this process has been used commercially on a large In this modified process hydrobromide is converted to a mixture of 2 and and the mixture hydrolysed to give Overall yields 70 80 such as are obtained by this are much better than the prior yields of but the process still leaves much to be desired Thus long reaction times are needed to achieve these the benzothiazole is contaminated with significant amounts unacceptable that have to be generally at a later stage in the overall process for making benazolin or its esters or This involves an extra purification step which is clearly consuming and costly and which it desirable to the formation of these unwanted products represent a waste of starting The purpose of the invention has therefore been to devise a method of making thiazole in a higher degree of purity and in better yield shorter reaction time than has obtainable previously on a commercial scale as an intermediate in the preparation of benazolin and its esters and It has now surprisingly been found that improved purity and improved yield shorter reaction time ca in fact be obtained by the use of particular immiscible solvents for the Thus it is now possible to make benazolin and its esters and salts to such a high degree of purity that any impurities that are present are in such small amounts and are such that it is no longer essential to conduct the above mentioned purification Also it is now possible to obtain yields in the same reaction times as were used in the prior are better than were obtainable previously or to obtain satisfactory yields in much shorter reaction times than could be used previously to obtain satisfactory reduce the wastage in starting According to the invention a process for i preparing comprises diazotising hydrohalide and hydrolysing the the diazotisation being carried out in the presence of a halogenated aliphatic hydrocarbon in which the major products of the diazotisation reaction are soluble to the extent of at least at The major product of the diazotisation reaction are When the is in the preferred form of the the major product is is also usually Preferred halogenated aliphatic hydrocarbons for use in the invention are chlorinated example ethylene dichloride which is particularly methylene carbon Other hydrocarbons include for example ethylene It is preferred that the solvent is one which has a boiling point between preferably The diazotising reaction is preferably carried out at a temperature below at usually in hydrochloric acid having a concentration greater than preferably between and The reaction is also preferably carried out in the presence of acetic The quantity of organic solvent is not critical but is preferably at least by volume of the total reaction for example by The diazotisation reaction is generally continued for at least 2 but often less than or even 5 It is generally continued until there is substantially no solid material left suspended in aqueous The organic phase is then separated is preferably evaporated to dryness before being The hydrolysis may be carried out by reacting with a mineral for example concentrated hydrochloric preferably in the presence of a water for example methanolj ethanol or industrial methylated The hydrolysis is suitably carried out at a temperature of and preferably under The product can be isolated by conventional means and if convert to for example by the method described in British Patent Specification The method described in this comprises condensing the with a compound selected from wherein A is a halogen B is carboxyl group or the amide or nitrile thereof and is an alkanesulphonyl or arenesulphonyl in the presence of an alkaline agent to give a compound of formula and if necessary converting B to give a desired group selected from carboxyl or the salts or esters as those described In addition giving the advantages of producing high yields and faster reaction times than have been possible using solvents previously the use of the halogenated aliphatic hydrocarbons as solvents in the invention has a further important This is that the hydrohalide may be made by cyclising thiourea in the same organic solvent system as that used for the subsequent diazotisation reaction with the result that the hydrohalide can be produced and reacted in the same organic solvent without any necessity for isolatin it before the diazotisation As a result of avoiding having to separate the compound before diazotisation the overall yield and the overall time required for carrying out the production of from is improved still Preferred conditions for cyclising the to make thiazole hydrohalide comprise reacting the thiourea with a source of chlorine or bromine atoms in a halogenated aliphatic hydrocarbon such as those discussed The preferred source of chlorine atoms is sulphuryl chloride while the source of bromine atoms is The reaction temperature is preferably to invention is illustrated in the following Examples in The yields are of pure so that the apparent yields impure are slightly higher than EXAMPLE 1 hydrobroraide and ethylene dichloride were to a mixture of concentrated hydrochloric acid glacial acetic acid and water in a 1 litre The whole mixture was stirred and maintained at with water cooling whilst a solution of sodium nitrite in water added at a constant rate over 2 The mixture was stirred for a further 2 Water was added and the lower layer separated and evaporated to The residue was dissolved in hot industrial lated spirits and the solution was maintained at a brisk reflux and stirred whilst concentrated hydrochloric acid was added Stirring and heating were continued for a further 2 The mixture was then cooled below and water The solid was washed free of acid and dried vacuo at The so obtained was shown by titration with tetrabutylammonium hydroxide in acetone to have a purity of Yield EXAMPLE 2 Example 1 was repeated replacing the ethylene dichloride with an equivalent volume of methylene The so obtained shown to have a purity of 9 Yield EXAMPLE hiourea was added to a mixture of glacial acetic acid and ethylene dichloride in a 1 litre The mixture was stirred vigorously and bromine was added in one When the temperature had stopped the mixture was boiled under reflux for 4 hours It was then cooled to between and and a mixture of concentrated chloric acid and water was The temperature was maintained at to whilst a solution of sodium nitrite i water was added over 2 The experiment was then continued as in Example to give which was shown to have a purity of 9 Yield EXAMPLE Example 1 was repeated replacing ethylene dichloride with in turn equivalent volumes of chloroform tetrachloroethylene ethylene dibromide and double the equivalent volume o tetrachloride The obtained in each of these examples had a purity in the range to and gave yields respectively and Higher yields may be obtained conducting the diazotisation for a longer EXAMPLE 10 A slurry of in a mixture of glacial acetic acid and ethylene dichloride was slowly added to a stirred solution of bromine ethylene dichloride whilst keeping the temperature below with water The mixture was carefully heated to reflux and maintained at that temperature for 4 It was then cooled to between and C and the experiment continued as in Example 3 to give having a purity of Yield 8 EXAMPLE 11 obtained from Example 1 was mixed with anhydrous potassium carbonate sodium iodide and methyl ethyl ketone The mixture was stirred and refluxed during the addition of ethyl chloroacetate The mixture was allowed to reflux for a further 4 water added and the mixture cooled to aqueous layer was discarded and the organic layer evaporated to give an oil which was dissolved in refluxing industrial methylated spirits Aqueous sodium hydroxide 440 was added and refluxing continued for The solution was then cooled and acidified to pH 1 to 2 with hydrochloric The resulting product was washed with water and dried to give 18 EXAMPLE In a similar manner to that described in Example benazolin was obtained in turn the prepared as in Examples 2 to COMPARATIVE EXAMPLE Example 1 was repeated except that benzene was used instead of ethylene the sodium nitrite addition took 5 hours instead of 2 and the stirring was continued for 16 hours instead of 2 The was obtained in yield and was only pure and was contaminated inter alia with of which was difficult to separate at this When the product was converted into benazolin as described in Example 11 it was necessary to remove this impurity an by carrying with methylene chloride 1 after the hydrolysis with sodium insufficientOCRQuality

Claims (1)

1. A process- for preparing 4—chloro-2-hydroxybenzothiazole which. comprises diazotising 2-amino- -chlorobenzothiazole hydrohalide and hydrolysing the product, the diazotisation being carried out in the presence of a halogenated aliphatic hydrocarbon solvent in which the major products of the diazotisation reaction are soluble to the extent of at least 10% w/v at 20°C. 2. A process according to claim 1 in which the solvent is a chlorinated hydrocarbon. $. A process according to claim 2 in which the solvent is ethylene dichloride. 4. A process according to claim 1 in which the solvent is selected from methylene chloride, chloroform, carbon tetrachloride, te.trachlorethane,- trichloroethylene, perchloroethylene, 1,1,1-trichloroethane and ethylene dibromide . 5. A process according to any one of the preceding claims in which the diazotisation is carried out in hydrochloric acid. 6. A process according to any one of the preceding claims in which the diazotisation is carried out in the presence of acetic acid. 7. A process according to any one of the preceding claims in which the solution in halogenated aliphatic hydrocarbon solvent resulting from the diazotisation is separated from the reaction medium and is evaporated to dryness before the hydrolysis of the product. 8. A process according to any one of the preceding claims in which the hydrolysis is carried out using a mineral acid. 9. A process according to claim 8 in which the mineral acid is hydrochloric acid. 10. A process according to any one of the preceding claims in which the 2-amino-4—chlorobenzothiazole is obtained by cyclising N-2-chlorophenylthiourea in the same solvent system as that used for the diazotisation reaction and is then subjected to the diazotisation without isolation from the solvent system. 11. A process according to claijm.1 substantially as hereinbefore described. 12. A process according to claim 1 substantially as described in any one of Examples 1 to 3· 13. A process according to claim 1 substantially as described in any one of Examples to 10. 14·. A process according to any one of the preceding claims in which the 4-chloro-2-hydroxybenzothiazole so obtained is condensed with a compound selected from ACH B and R,0CH ClT wherein A is a halogen atom, B is carboxyl group or the- salt¾ ester, amide or nitrile thereof and is an alkanesulphonyl or arenesulphonyl group, in the presence of a alkaline condensing agent to give a compound of formula I * CI and if necessary converting B to give a desired group selected from carboxyl or the salt or ester thereof. 15. A process according to claim 14- substantially as described in Example 11 or 12. 16. 4-Chloro-2-hydroxybenzothiazole when obtained by a process claimed in any one of claims 1 to 13.

1. . 4—Chloro-2-oxobenzothiazolin-3-ylacetic acid , its esters or salts when obtained byj a process claimed in claim 15 or 16» 14 or 15. P, 0. Box 33116 , Te!-Aviv Attorneys f o r Ap p lic a n t