BE701764A - - Google Patents

Description

       

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    PATENT OF INVENTION "Improved process for the manufacture of substituted isothiazoles"
The present invention relates to a new and improved process for the synthesis of substituted isothiazoles. in particular 3,4,5-substituted isothiazoles which are useful as chemical intermediates for the subsequent synthesis of biologically active compounds such as isothiazole penicillins and cephalosporins.



   Recent research for the development of new and improved antibacterial agents such as synthetic penicillins has led to the synthesis of a series of substituted isothiazoles derived from the acid

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 6-aminopenicillanic acid (6-APA). These penicillins are useful as antibacterial agents; as a feed supplement for animals, as agents for the treatment of mastitis in cattle, as therapeutic agents for poultry and animals including humans, for the treatment of infectious diseases caused by gram-positive bacteria} particularly Staphylococcus aureus and other penicillinase producing bacteria and sometimes for infections caused by gram-negative bacteria.



   The superior efficacy exhibited by the isothiazole penicillins necessitates the development of a new and more efficient synthetic process for the manufacture. cation of large quantities of 3,4,5-substituted isothiazoles corresponding to the formula
 EMI2.1
 where R and R2, which are the same or different, each represent a lower alkyl radical or R, R being a group of the formula
 EMI2.2
 where A, B and C represent hydrogen, a fluoro, chloro, bromo, iodo, trifluoromethyl, methylsulfonyl nitro, lower alkyl or lower alkoxy radical.

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   Certain of the isothiazoles prepared by the process described herein are compounds which have been previously prepared by processes giving low yields and of little value from an industrial point of view.



   Belgian Patent No. 681,505 leads to yields which are generally well below 10% in the synthesis of these types of isothiazoles. In addition, these methods involve numerous, long and tedious operating stages. The novel process of the invention solves these problems by leading to high product yields by virtue of a more direct and efficient process.



   The present invention provides a process for the synthesis of isothiazoles corresponding to the formula:
 EMI3.1
 where R and R2 which are the same or different each represent a lower alkyl radical or R-, R- being a group of formula!
 EMI3.2
 

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   or. A, B and 0 represent hydrogen, fluoro, chloro, bromo iodo, trifluoromethyl, methylsulphonyl, nitro, lower alkyl or lower alkoxy radicals This process comprises the following operating steps: a) reaction, at a temperature between 50 C and 300 C of an imino compound of formula:

   
 EMI4.1
      with a dithio compound of formula
 EMI4.2
 where R and R2 are as defined above) R1 represents:
 EMI4.3
 
 EMI4.4
 are identical or different and each represent a lower alkyl radical or
R-, and R3 represents a lower alkyl radical or a radical of formula - CnH2nCH2COOH,
 EMI4.5
 each represents an integer of zero and six inclusive. b) oxidation of the intermediate product resulting from the first stage at a temperature between 0 and 100 C using a moderately oxidizing agent chosen from the following:

   2,3-dichloro-5,6-dicyanc-1,4-benzc-quinone, oxygen, air, halogen in the presence of an acid acceptor I2, Br2, Cl2, H2O2, sulfur, FeCl3,

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 Na2S2O8 or chloranil; and R1 represents a radical other than the -COOH radical ,. c) hydrolysis of the intermediate product resulting from the second stage with an acid or a base to obtain the desired compound of formula
 EMI5.1
 
In stadium (a). the imino compound and the dithio compound are heated together to form the first intermediate "Z" and a byproduct, mercaptan, as the following equation shows:

   
 EMI5.2
 The intermediate product Z exists as a mixture of several tautomeric forms for example,
 EMI5.3
 

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For the purposes of description, the tautomeric forms of intermediate Z and their mixtures are represented by the formula
 EMI6.1
 
Intermediate compound Z can, if desired, be isolated from the reaction mixture. For simplicity and convenience, however, it is possible to process it without isolating it from a mild oxidizing agent as described or step (b) above.



   Although one of the starting substances has been called an imine, those skilled in the art will understand very well that the imine is in reality a tautomer of the corresponding unsaturated amine as indicated below:
 EMI6.2
 
This starting compound can be represented either by its structural formula or by designating it under the name of imino or under the name of unsaturated amine * Thus the corresponding starting compound for example 1 exists under the following tautomeric tons and can be
 EMI6.3
 called 3-imino-3-phenylpropionitrile bta.3.mino bta.

   phenylpropionitrile) or 3 - aminacinnamonâ.triZc (bttaaminocirana.mon.tr3.J.e),

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 EMI7.1
 imino amine
It should be noted however that it is a unique compound which can exist either in the tautomeric form or under the firm of a mixture of the two forms in equilibrium.



   The imino compound and the dithio compound can be heated together in various molar proportions, but it is preferable to apply a substantially equimolar ratio. The compounds can be reacted in the absence of a solvent or in the presence of an inert solvent such as benzene, toluene, xylene, dioxanc, tetrahydrofuran, dimethylformamide, dimethyl -acetamide or ether. . When a solvent is used, it is preferable that the reaction be carried out at reflux temperature.



   When the reaction is carried out in the presence of a solvent (and when R 'represents a radical other than --COOH), it is possible, if desired, to apply the imino compound in the form of its salt of a metal alkaline. The alkali metal salt can be prepared, for example, by adding a strong base such as an alkali metal hydride or an alkali metal alcoholate to a solution of the ininocompound. The dithio compound can be added to the resulting solution after evolution of hydrogen has ceased.

   Metal soil formation

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 alkali of the imino compound can be represented as follows:
 EMI8.1
 
It is obvious to those skilled in the art that if R 'is the free carboxyl group, the resulting salt will be the alkali metal salt of the carboxylic acid rather than the desired salt as set out above.



   When the reaction is carried out in the absence of a solvent, it is preferable but not necessary that the reaction be carried out under reduced pressure, for example between 0.1 and 50 mm Hg, at a temperature between 50 C and 300 C The temperature of the vessel is determined by the decomposition temperature of the starting materials and the distillation temperature of the mercaptan by-product. The residual melt is then used for the oxidation stage (b).



   The moderate oxidation step (b) is carried out using a molar ratio of at least one mole of oxidizing agent per mole of intermediate "Z" from the first step. The reaction is carried out in an inert solvent such as benzene, toluene, xylene, dioxane, ether, tetrahydrofuran, dimethylformamide, dimethylacetamide, methylene chloride, chloroform or tetrachloroethane.

   While the reaction temperature can vary between 0 and IGLOO) it is preferable to carry out the oxidation near room temperature, that is to say between

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 20 and 35 ° C. The preferred oxidizing agent is iodine in the presence of an acid acceptor such as for example an inorganic base such as K2CO3 or a tertiary amine such as pyridine.



   The oxidation stage is illustrated by the following equation:
 EMI9.1
 where R, R1 and R2 have the meaning given above.



   When R1 represents a radical other than the radical -COOH, the isothiazole obtained after the oxidation stage (b) is hydrolyzed in a stage (c) by means of an acid or a base to give the isothiazolo carboxylic acid desired. The hydrolysis agent is preferably a strong mineral acid or a base of an alkali metal. The reaction is preferably carried out with heating and preferably in a polar solvent such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, propylene glycol or dimethyl ether. ethylene glycol or aqueous solutions of these solvents.

   When a base is applied as a hydrolysis agent, the resulting saponified product is converted to the desired acid by simple acidification.



   The hydrolysis stage is illustrated by the following equa- tion
 EMI9.2
 

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 EMI10.1
 ............- where R, Ret R2 have the meaning given above.



   The starting materials suitable for the process of the invention can be prepared by several known processes. The imino compound can be readily prepared by any of the following general methods:
 EMI10.2
 A can be an -O-alkyl or halogen radical.

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   (1) Beilstein, 10, 681; E I 10, 322; E II 10, 469; Holzwart, J. Prakt. Chem. (2), 39, 242; E. Von Mayer, J. Prakt.Chem. (2), 92, 1? 4.



   (2) M. S. Reich, Bull. Soc, Chim., France, (4) 21, 217 (1917).



   (3) J.M. Straley and A. C. Adams, Organic Synthesis Collective Vol. 4, 415 (1963).



   (4) cf. S.A. Glickman et al., J. Am. Chem.



  Soc., 67, 1017 (1945).



   (5) R. Lukes and J. Kloubek, Czechoslovak Chemical Communications Collections, 25, 607 (1960); R. Lukes and J. Kovar, Chemicke Listy, 50, 272 (1956).



   (6) C. Korschum, Ber., 38, 1129 (1905).



   The dithio compound can also be readily prepared by any of the following general methods.
 EMI11.1
 

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 EMI12.1
 



     (1) O.S. Marvel, et al., J. Am. Chemo Soc., 77,5997 (1955).



     (2) Jensen and Pedersen, Acta Chem. Scand., 15, 1087 (1961) (3) H. Eilingsfeld, et al., Chemische Berichte, 96 2671 (1963),
In the preferred embodiments of the present invention R is R as defined above and in particular phenyl, halophenyl and dihalophenyl, R 'represents - COOH, - ON or -COOR4 where R4 is as defined above, R2 represents a lower alkyl radical and in particular methyl, R3 is a radical

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 lower alkyl or a radical of class -
 EMI13.1
 Ù% CEja00E $ * CnHCH2C00CaïGiS or - nH2n HaCN where n and m are whole numbers from zero to six inclusive but in particular - OH2000il - oH2cH200ORe - Ch E3> - CH20000OH ?, ... Zon or - CH2CH2CN.



   The following examples are given by way of illustration and in no way limit the invention.



   EXAMPLE 1
 EMI13.2
 Preparation of 5-metUl-3 = phen: .71-4-isoth: 3iraino-3rphn.y3.pronionitrile Lazolecarboxylic A sodium dispersion is suspended
 EMI13.3
 50% in paruffinic oil (72.5 g) in a mixture of 300 ml of benzene and 250 ml of toluene. A mixture of benzonitrile (81.5 g) and acetonitrile (64.5 g) is added to the slurry, taking precautions for heating, after which a gentle reflux is started which is maintained by the heating. addition of nitriles. When the addition is complete, the reaction is refluxed for 18 hours.



   The mixture is cooled to 5 ° C and filtered. The gum solids are suspended in 1500 ml of pentane and filtered to remove the paraffinic oil. The solids are stirred with one liter of water for one hour, the solids are filtered off and dried by suction on the filter.
 EMI13.4
 



  The solid is recrystallized twice in boiling petroleum ether between 60 and 6800 $, essentially consisting of n-hexane (Skellysolve L),

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 and 48.0 g (42%) of a product melted at 79-80 ° C. were obtained, which was the desired product.



   B. N-thioacethylpiperidine
36.5 g of phosphorus pentasulfide are suspended in 45 ml of pyridine. 42.3 g of N-acetylpiperidine in 45 ml of pyridine is added to the suspension while cooling, then the yellow suspension is heated and refluxed for 2 hours.



   After reflux, the black mixture is concentrated in vacuo to almost dryness and the resulting residue is treated with 150 ml of 3N HCl. The resulting black liquid and the tar are extracted twice with ether. The dark red ethereal solution is washed with water and with an aqueous solution of NaCl, then it is dried over NaSO 3. After filtration, evaporation of the ether leaves 23.5 g (48%) of a red crystalline solid melting between 50 and 52 C,
C. S-carboxymethyl-1-ethylthiopiperidium bromide
23.57 g of N-thioacetylpiperidine are dissolved in 150 ml of anhydrous benzene.

   25.2 g of bromoacetic acid in 44 ml of benzene are added and the resulting mixture is allowed to stir at room temperature for 22 hours. It forms a precipitate several minutes after the addition of the bromoacetic acid.



   The reaction mixture is diluted with 550 ml of anhydrous ether and filtered. A pale pink solid is collected, triturated with anhydrous ether, filtered and dried under vacuum over P2O5, to give 43.3 g of pale pink crystals melting between 159 and 160 C.

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   D. Methyl S-carboxydithioacetate
S-carboxymethyl-1-thioethylpiperidium bromide (20.0 g) is mixed with absolute ethanol (90 ml), cooled to 0 C and hydrogen sulfide is bubbled through the suspension. The suspension turns to a dark red solution after one hour.



  After bubbling H2S through the solution for a total of 4 hours, the solution is left at 4 ° C. for 17 1/2 hours.



   The red solution containing a quantity of a yellow precipitate is concentrated in vacuo, to almost dryness, and the residue is extracted several times using ethor. The ethereal solution is dried over Na2SO4, filtered and evaporated to dryness in vacuo. The red oil crystallizes and gives 11.60 g of red crystals. The crystals were extracted with boiling "Skellysolve B" to give 7.68 g (72%) of crystals which, after cooling, melt at 79-81 C.



   E. 4-cyano-5-methyl-3-phenylisothiazole
Stirred between 105 and 109 C under a pressure of 0.3 mm Hg for 28 minutes, a mixture of 3-iminc-3-phenylpropionitrile (5.00 g, 0.0347 mol) ot S-carbo-xydithioacetate Methyl (5.20 g, 0.0347 mol). The mercaptcacetic acid is distilled from the reaction mixture. After cooling under nitrogen, the molten residual mass is dissolved in benzene (60 ml). Potassium carbonate (7.20 g, 0.052 mol) is added and then a solution of iodine (13.20 g, 0.052 mol) in 160 ml of benzene is added.

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   After stirring at 28 ° C. for 15 hours, the supernatant solution is washed successively with an aqueous solution of sodium thiosulfate, with an aqueous solution of sodium hydroxide and then with water. Drying and subsequent disposal
 EMI16.1
 solvent leaving a crystalline solid (2.5µ g, 34%) t Recrystallization from "Skellysolve B" gives a substance having a melting point between 76 and 78 C.
 EMI16.2
 



  F. Acid -met 1- - hèn 1-4-isothiazolecarbo li ue A mixture of 4-cyano-5-methyl-3-phenylisothiazole (1.45 g) of ethylene is heated under reflux for 48 1/2 hours. glycol (8.9 ml), water (1.8 ml) and potassium hydroxide (0.885 g).
 EMI16.3
 



  The mixture is poured over ice (30 g).



    Acidification with hydrochloric acid gives a crystalline solid which is washed with water and dried. The yield is 1.45 g (91%); melting point 148-151 C. Recrystallization from a mixture of benzene and "Skellysolve B" gives 1.19 g of a product melting between 151 and 153 C.



   The acid prepared according to the process described in (F) above is used to prepare the corresponding penicillin as shown in steps (G) and (H) below.
 EMI16.4
 



  G. 5-Methyl-3-ph'-nZlisothiazole-4-carbonyl chloride,
A mixture of 3.2 g (0.0147 mol) is heated on a water bath between 70 and 80 C for one hour.
 EMI16.5
 5-methyx-3-phenylisothiazolc-.l.-caxboxy7.ic acid and

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 of 5 ml of thionyl chloride. The excess thionyl chloride was distilled off under reduced pressure to give an oil which was distilled in vacuo.

   The yield is 3.2 g (95%) of chloride of
 EMI17.1
 5-metllyl-3-phenylisothiazole-4-carbonylee with a boiling point between 122 and 125 C / 0.6 mm. liquid max 1770, 1490, 1450, 1400, 1360, 1230, 1105 cm-1.
 EMI17.2
 H 6- (5-methyl-5-phé¯nylisothiazole-4-carboxamiào) - sodium penicillanate A solution is added over the course of 2 minutes
 EMI17.3
 from 3 s2 g (0.0136 mole) of 5-methyl.-3..phenyz isothiazol-4-carbonyl chloride in 5 ml of methylene chloride, to a rapidly stirred solution of 3 g (0.0138 mole ) 6-aminopenicillanic acid and 3.0 g (0.03 mole) of
 EMI17.4
 triethyl # mine in 50 ml of methylene chloride at between 5 and 10 ° C. The reaction mixture is stirred for one hour at 15 ° C. and extracted with 3 x 50 ml portions of water.

   The extracts are combined and washed with gentle portions of 50 ml of ether, the phases are separated with 100 ml of ethyl acetate and the pH is adjusted to 2 with. 10% hydrochloric acid. The ethyl acetate layer is separated and the aqueous layer is again extracted with two portions of do. 100 ml of ethyl acetate.



   The ethyl acetate extracts are combined and washed with 50 ml of water, dried over sodium sulphate, filtered (an additional 50 ml of ethyl acetate is used. to wash the flask and the filter) and treated with 4 ml of a solution of sodium 2-ethylhexanoate in methyl

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 isobutyl ketone. The clear solution is evaporated to a volume of about 200 ml and collected, by
 EMI18.1
 filtration, the fine needles of sodium 6- (5-methyl-3-phenyl-isothiazol-4-carboxamido) -penicillanate separate (Crop A). A second crop (Crop B) is obtained from the filtrate by the addition of anhydrous ether.

   Yield, (A) 1.97 g (33%); (B) 0.38 g (6%), melting point (A) 184-190 C (decomposition), (B)
 EMI18.2
 180-19010 (H2C decomposition 266.5 m}. 1 Ct "11.200), nax H20 1780, 1665, 1615, 154q, 1410, 1330 cm-1.



  Max Analysis for 19H1aN304S2Na'B20: Calculated; C, 49.88; II, 4.11; N, 9.19
 EMI18.3
 Found s C, 50.31; 49.69; H 4.91.4.61; N, 9.02, J 92
This compound, exhibited in vitro, at minimum inhibitory concentrations of 0.4-0.8 mcg / ml against Smith's Staphylococcus aureus and 0.8 mcg / ml against.
 EMI18.4
 against Staphylococcus aurcus & .- t633--22 resistant to benzylpenicillin and in mice against S, aureus BX-1633-2 and it presents a CD50 of approximately 1.56 mg / kg after an intramuscular injection. This compound is also very stable in an aqueous acidic medium and has a half life of 4 hours at pH 2.0.
 EMI18.5
 



  EX "L..1-1PLE 2 Preferred Carboxylic Acid A. Ethyl thioimidoacetate hydrochloride A solution of ethanethiol (5c) is cooled in an ice bath. , g) in 11: \ ketoni sort (33.2 g) then bubbled hydrochloric gas (30 g)

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 in the stirred solution for 1 1/2 hours. The addition of hydrochloric gas is continued for about another 10 minutes, after which the solution crystallizes. The solid is allowed to stand at 25 ° for 3 days.



   The light yellow solid is triturated with ether, separation is carried out by filtration, washed well with an additional quantity of ether and then dried under vacuum over P2O5 and KOH flakes, which gives 100.7 g (90%) of a white crystalline solid.



   B. Ethyl dithioacetate
One saturates 100 ml of pyridine with hydrogen sulfide at 0 C for 75 minutes. Ethyl thioimidoacetate hydrochloride (45 g) was added and the mixture was stirred in a salt and ice bath while bubbling an additional amount of hydrogen sulfide through the mixture for an additional 7 hours.



   50 ml of water at 0 C is added to this mixture, After stirring at 0 C for 5 minutes, the solution is poured onto a mixture of concentrated hydrochloric acid (150 ml) H2O (50 ml) and ice (150 g). ).



     The mixture is immediately extracted with 2 portions of ether. The ethereal extracts are combined and washed with a cold solution of 10 ml of concentrated hydrochloric acid in 30 ml of water and then dried over anhydrous K2CO3.



   Evaporation of the ether leaves a yellow oil which is distilled through a 203 mm Vigreux column to give a deep yellow oil. melting between 49 and 50 C / 14 mm, with a yield of 30.8 g (80%).

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 EMI20.1
 



  C. ethyl 3-aminooinnamate
To a stirred suspension of 600 ml of anhydrous ether and 16.9 g of magnesium turnings, 5 ml of bromobenzene are added. The reaction is started using 2 ml of iodomethane and a crystal of iodine and the reaction rate is maintained by the addition of bromobenzene until the total addition of 103.0 g. The reaction mixture is refluxed for one hour after the addition is complete.



   Ethyl cyanoacetate 30.0 g is added dropwise over 30 minutes and the reaction mixture is refluxed for 20 hours, cooled and carefully decomposed with the addition of 180 ml of 3.5N sulfuric acid while cooling and stirring rapidly. The ethereal layer separates, it is dried over sodium sulfate, evaporated to dryness in vacuo and distilled under reduced Prussian, which gives 37.3 g (73%) of a
 EMI20.2
 yellow oil boiling between 128 and 128.5 a / lmn.



  D. 5 4 "," ho rcr "rbonyl - m.t'r¯yl-, phen; tl.isothiazolo A solution of ethyl 3-iaoc s ... r.araatc is added dropwise. (78 g) in 5 ml of dameti'ra.? Qrma: 3.dC: apart from sodium hydride (0.4 g of a 56% dispersion) in dimethylformamide (5 ml) while stirring the mixture and cooling it at the
 EMI20.3
 Using an ice and salt bath * After stirring for 30 minutes, at 0 C the mixture is stirred for 20 minutes at room temperature, after which the NaH appears to have been consumed.



   A solution of ethyl dithioacetate (1.12 g) dissolved in 10 ml of

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 benzene) which gives a dark red solution with release of a certain amount of heat. The reaction mixture is stirred for 4 1/2 hours at room temperature, after which it is heated to 40 ° C., to remove the ethanethiol.



   10 ml of the mixture is diluted with ether and the latter is neutralized with 55 ml of cold 0.126N hydrochloric acid, washed with aqueous NaCl solution, dried over Na2SO4 and it is evaporated under vacuum to give a red oil. This is dissolved in anhydrous ether and divided into 2 equal parts.



     (1) The first part is treated with 20 ml of absolute ethanol containing 0.4 ml of 30% H2O2.



  After stirring for 16 hours the solution, evaporated to dryness in vacuo, the residue is dissolved in ether, washed with 0.1N HCl, an aqueous solution of NaCl and water , and again taken to dryness to give 0.7 g of a dark red oil which contains the desired isothiazole as determined by vapor phase chromatography (VPC).



   (2) The second part is stirred with potassium carbonate while slowly adding a solution of 0.92 g of iodine in 20 ml of ether. The reaction mixture is stirred at room temperature, laying
12 hours. The solution is washed with 0.1N HCl, an aqueous solution of Na2S2O3, an aqueous solution of NaCl and water, dried over NaSO, and evaporated in vacuo until the mixture is obtained. 0.97 grams of an eraser. The presence of the desired isothiazole is confirmed by CPV analysis.

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 EMI22.1
 



  E. 5-Methyl-3-Phenyl-4-isothiazolocarboxylic acid The 4 - ethoxycarbonyl-5-nethyl-3-phenylisothiazole prepared according to the process described in paragraph (D2) above is hydrolyzed by means of 5% KOH in a aqueous alcoholic solution at reflux temperature) is poured onto ice and acidified to give the desired acid melting between 148 and 151 C.



   EXAMPLE 3
 EMI22.2
 Preparation of ..e cno -met 7 .. - hénisothiazole ar application of various oxidizing agents
5.0 g of 3-imino-3-phenylpropionitrile and 5.2 g of methyl S-carboxydithioacetate are dissolved in ether. The solvent is evaporated, leaving an oil
 EMI22.3
 homogeneous and heated to about 105-109 C for 35 minutes to sort, 3 ml. The residue is cooled to 2000 under nitrogen and diluted to 54 ml with benzene. The resulting solution is divided into 4 aliquots of 12 ml and one part of 5 ml which is subjected to different oxidation techniques.
 EMI22.4
 



  (1) Treat a 12 ml aliquot with 2.94 g of iodine in benzene then 1.6 g of carbonate
 EMI22.5
 of potassium as previously described in Example 1, which gives 0.75 g of an oil determined by CPV as being mainly constituted by the desired isothiazal.



   (2) Treatment of a second aliquot of 12 ml using 1.6 g of potassium carbonate then 2.94 g of iodine in benzene and the procedure is carried out as described in Example 1, this which gives 0.82 g of a red oil determined by CPV to be main
 EMI22.6
 mainly consisting of the desired isothiazolc.

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   (3) Treatment of a third aliquot of 12 ml with 1.97 g of iodine in benzene and in the manner indicated in Example 1, to give 0.77 g of a reddish brown oil which is determined by CPV to be approximately 90% of the desired isothiazolo.



   (4) Add to an aliquot of 12 ml
 EMI23.1
 a solution of 1.2 ml of 30% aqueous Ilg0g in 20 mil of ethylene glycol dimethyl ether. The solution was stirred at 28 µl for 16 hours. The mixture was washed with Naflü, 5N Na 2 O 3 P, water and NACI in aqueous solution. Evaporation leaves 0.85 g of an orange oil which CPV analysis gives as being about 50% of the desired isothiazole.



   (5) Oxygen is bubbled through the .5 ml aliquot for 20 minutes and
 EMI23.2
 let the solution evaporate. After alkali.ization and washing with water, it is determined by CPV analysis that the 0.3 g of the semi-solid residue consists of approximately
 EMI23.3
 20% of the desired isothiazolo. Further study shows that yields do not increase following longer exposure to oxygen.



    EXAMPLE 4
 EMI23.4
 Pi repetition of? ' 5-Nethyl-3-ph61yl-4-isothiazolçz carbpmlic acid A. t-.nmeth, y.-3-thf n ,, rlisothiazoLr Cn add a solution of .3.mino-3-phen.yâ.pro pianitri .. c (1.0 g) in 10 ml of anhydrous dimethylformamide to a cold suspension of 0.3 g of sodium hydride in 10 ml of anhydrous dimethylformanido. The mixture, which releases hydrogen is left with stirring, while

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 6 minutes with cooling then for an additional 38 minutes at room temperature.



   A solution of 0.835 g of ethyl dithioacetate (0.835 g) in 10 ml of dry benzene is added to the reaction mixture. After several minutes of stirring, the mixture deviating from a reddish solution darkens. The solution is heated for one hour at about 55 ° C, cooled and oxidized using
 EMI24.1
 2.62 g of iodine in 35 ml of benzene with 1 # 30 of X20030 After stirring at room temperature for 16 hours, the mixture is washed with water using
 EMI24.2
 of an aqueous solution of NS203 'z dilute hydrochloric acid? with water using an IN solution of naos ot in water, then dried over NS04.

   Evaporation left 0.56 g of a dark oil which was determined by VPC to be about 40% of the desired isothiazole.
 EMI24.3
 



  5-Meth yl Acid - Rhênvl-4-isothîazolecarboMlique
Hydrolysis of the oil from the treatment according to A above in aqueous sulfuric acid at reflux temperature gives the desired acid which, after recrystallization from a mixture of benzene and "Skellysolve B", melts between 151 and 153 C.



   EXAMPLE 5
 EMI24.4
 Preparation of 5-mothl3-phnyl-4-isothiazole- acid. cl.3.rboxyliau ± Ae S-methoxycarbonithioacett of methyl <3 A solution is refluxed for 1/2 hour.
 EMI24.5
 tion of ethyl dithioacetate (25.42 g, 0.212 mol) and methyl acetate mercapte (22.56 g, 0.212 months) in pyridine (80 ml). We then hunt the

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 pyridine by distillation (760 mm). Distillation of the residue in vacuo gives the dithioacetate; yield
 EMI25.1
 15.36 g (45%); boiling point 100-109 '/ 8 mm.



  Analysis for 5H802S2: Calculated for: C, 36.56; H, 4.91; S, 39.04 Found: C, 36.6? H, 4.98; S, 38.46.
 EMI25.2
 



  B. 4-cyano-5-methyl-3-phenylisothiazole A solution of 2 g of 3-imino-3-phenylpropionitrile in 20 ml of dimethylformnmidc is added to a dispersion of 6.0 g of sodium hydride in 20 ml of dimethylformamido while stirring at room temperature. After 30 minutes, a solution of 2.3 g of methyl S-m, thoxycarbonyldithioacetate in 20 ml of benzene is added. The reaction mixture is stirred for 30 minutes at room temperature and then heated for one hour between 49 and 50 C.



   The mixture was cooled to room temperature then K2CO3 (2.9 g) and iodine (5.3 g) dissolved in 70 ml of benzene were added. The mixture is stirred at 28 ° C. for 16 hours, then washed with water at the mo-
 EMI25.3
 There is an aqueous solution of Na2S203 and an aqueous solution of NaOl. The solution was dried over NSO4 and evaporated to a black oil (3.75 g) in vacuo. Analysis by vapor phase chromatography shows that the oil is 65% iso-. thiazole desired.
 EMI25.4
 



  This Acid "-net 1-- he 1-4-isothiazolecarbovliaue
The oil prepared according to the method indicated in paragraph B above is hydrolyzed by means of a 5% solution of NaOH in aqueous ethanol, which gives

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 the desired acid melting between 148 and 151 C.



   EXAMPLE 6
 EMI26.1
 Preparation of 5-methyl-3-phenyl-4-isothiazolecarboxylic acid A. 4-ethoxycarbonyl-5-methyl-3-phenylisothiazole Cn refluxes for one hour a solution of ethyl beta-aminocinnamate (158.1 mg, 0.826 mol) and methyl S-carboxydithioacetate (124.0 mg
 EMI26.2
 0.826 mol) in diiaethyl ether tallow (10 mL). After cooling, a solution of iodine (320 mg, 1.26 moles) in benzene (6 ml) is added and then potassium carbonate (180 mg, 1.3 moles) is added.



   After stirring for 16 hours at 28 ° C., the mixture is diluted with benzene and the solution washed with an aqueous solution of sodium thiosulfate, an aqueous solution of sodium hydroxide and the water. Drying and subsequent solvent removal leaves 50 mg (25%) of the contaminated acetophenone ester
 EMI26.3
 had of ethyl btta-D.I! lino-cinn # natc. The ester was purified by vapor phase chromatography and found to be identical to an authentic sample prepared from
 EMI26.4
 shot of 5-methyl-µ-phenyl-4-isothiazolccarboXylic acid.



   The ester can even be prepared from
 EMI26.5
 sodium salt of ethyl bata-aminocinnamata and ethyl dithioacetate.



  B. Acid -meth, yl-3-phEryl - 4-.isoth.iazolecarbocYliaue
The desired acid is prepared from the above ester by hydrolysis using 5% NaOH in aqueous alcohol; melting point between 151 and 153 C.

 <Desc / Clms Page number 27>

 



  EXAMPLE 2
 EMI27.1
 Preparation of acid - 2-chloro hèn 1 -met 1-4 isothiazolecarbo li ue A. --imino- - 2-chloro hén 1 ro ionitrile
A 50% dispersion of sodium in paraffin oil (36 g) is suspended in a solution of 146 ml of benzene and 120 ml of toluene and a solution of acetonitrile (34 g) of toluene is carefully added. o-chlorobenzonitrile (52 g) and benzene (25 ml).



  The reaction is started by heating and then the mixture is maintained at the reflux temperature by adding the nitriles. When addition is complete, the reaction mixture is refluxed for 6 hours, cooled to 5 ° C. and filtered. The resulting filter cake is resuspended in benzene, filtered again and washed thoroughly to remove all traces of paraffinic oil.



   Cn suspends the solids with an excess of an aqueous solution of NH4Cl for 30 minutes then. The product obtained is collected by filtration, which gives 53.7 g (79.5%) of product melting between 90 and 95 ° C. .



   The solids are dissolved in ethanol, partially decolorized with decolorizing charcoal and recrystallized from a mixture of ethanol and water, to give 24 g (35.5%) of light orange crystals melting between 101 and 104 C.
 EMI27.2
 



  B, - 2-chloro hn 1 - -met 1-4-isothiazolecar-. bonitrile
A mixture of 3- (2-chloro-phenyl) -3-iminopropionitrile (5.00 g, 0.028 mol) is heated between 116 and 125 C under a pressure of 7 mm for 36 minutes).

 <Desc / Clms Page number 28>

 and methyl S-carboxydithioacetate (4.20 g, 0.28 mol). After cooling under nitrogen, the residue is dissolved in benzene (100 ml). Potassium carbonate (5.8 g, 0.042 mole) and then a solution of iodine (10.70 g, 0.042 mole) in benzene (120 ml) are added.



   After stirring at 28 ° C. for 16 hours, the mixture is treated as described above, which gives a mixture (3.1 g) of the desired nitrile and the starting iminonitrile. The mixture is separated by chromatography on alumina, which gives the nitrile (1.32 g, 20%); recrystallization from ethanol gives a product melting between 86 and 87 C.



  Analysis for C11H7C1N2S:
Calculated: C, 56.28H, 3.00; cl, 15.11
 EMI28.1
 Found t C, 56.10; xi, 3.1; Ci, 14.91 C. 9 Carboxylic acid - 2-chloro hen 3. -.-Met l.t-isoth3.azo.e
3- (2-Chlorophenyl) -5-methyl-4-isothiazolecarbonitrile (1.02 g) is hydrolyzed with a 5% solution of NaOH in aqueous ethanol at reflux temperature. ; the acid yield was 1.04 g (94%). Recrystallization from a mixture of benzene and "Skellysolve B" gives a product having a melting point between 185.5 and 186.5 C.



   The acid prepared as described in paragraph (C) above is used to prepare the corresponding penicillin as illustrated in paragraphs (D) and (E) below.

 <Desc / Clms Page number 29>

 
 EMI29.1
 



  D. 3 - '(2-Chlorcphenyl) -5-methylisothiazole-4-carbonyl chloride
A mixture of 2.7 g (0.0107 mol) of 3- (2-chlorophenyl) -5-methylisothiazole-4-carboxylic acid and 3 ml of sodium chloride is heated on a water bath at 80 ° C. for 30 minutes. thionyl. The excess thionyl chloride is removed by distillation under reduced pressure and the residue is distilled off under vacuum. The yield is
 EMI29.2
 2.55 g (88%) of 3- (2-chlorophenyl) -5-methyl-isothiazole-4-carbonyl chloride including boiling point
 EMI29.3
 between 130 and 135 C / 3 mm. Liquid 1760 cm-1.



  <max E. 6 -. [3- (2-chlorophenyl) -5-methylisothia2oJ.e-4- sodium carboxamidopenicillanate
To a stirred mixture of 2.5 g (0.0115 mole) of 6-APA, 2.9 g (0.034 mole) of sodium bicarbonate, 80 ml of water and 50 ml of acetone is added, dropwise. by drop, a solution of 2.55 g (0.0094 mol)
 EMI29.4
 of 3 '- (2-chloropheny3) -5-methylisothiazol-4-carbonyl chloride in 30 ml of anhydrous acetone at 5 C and stirring continued for 30 minutes at 10 to 15 C.



  The reaction mixture is washed twice with 100 ml portions of ether, the phases are separated with 100 ml of ethyl acetate and the pH is adjusted to 2.0 using. of hydrochloric acid diluted to 5 ° C. The ethyl acetate layer is separated and the aqueous layer is extracted with two 50 ml portions of ethyl acetate. The ethyl acetate extracts are combined and washed with water, dried over anhydrous sodium sulfate and evaporated to 3/4 of its volume.



  The concentrate is treated with a 35% aqueous solution of sodium 2-ethylhexanoate to give a

 <Desc / Clms Page number 30>

 
 EMI30.1
 crystalline precipitate of 6-3w (.chlorophény7.) .- 5-methyl, 1 isothiazole-4-oarboxamidoJ sodium penicillanato which is collected by filtration. When the precipitate is washed with acetone, it has a tendency to dissolve in the solvent. The remaining precipitate "B" (1.3 g) is washed with ethyl acetate. On the other hand, to the acetone solution containing part of the sample, 5 volumes of ethyl acetate are added.

   The resulting solution is moderately concentrated to obtain 1.6 g of
 EMI30.2
 6- [µ- (2-chlorophenyl) -5-methylisothiazolo-4-carboxmido] penicill: sodium matl which are crystals designated by "A"). Crystalline forms "A" and "B" are different from each other with reference to the infrared spectrum, but have practically the same microbiological activities. "B" is also recrystallized from acetone and acetone. ethyl acetate to give 0.6 g of crystals having an infrared spectrum identical to that of "A". The total yield is 2.2 g (50%). "B" t melting point 182-188 C (decomposition) 1760,
 EMI30.3
 1650, 1595 1530, 1405 cm 'H2p 258 Mil ((9.100). Max "A":

  melting point 182-188 C. (decomposition) max 3530, 3370, 1765, 1650, 1600, 1510, 1480, 1410 cm-1;
 EMI30.4
 ) 257 m 9.400). kn.alysis for ClgH7C1N3048Na H2O; Calculated! : C, 45.55; H, 4.02; N, 8.39
 EMI30.5
 Found C, 45.31; 45.66;

   H,;, 83,, 4.16;
N, 8.45, 8.95
The crystalline form "A" of this penicillin exhibits in vitro minimum inhibitory concentrations of about 0.4 ncg / ml against S. aureus do.

 <Desc / Clms Page number 31>

 Smith and approximately 0.4 mcg / ml against S. aureus
 EMI31.1
 X..i633 -'- resistant to benzylpenicillin and in mice, after intramuscular injection, it pre-
 EMI31.2
 shows an OD50 of about 72 mg / kg against S. aux, Smith's and about 200 mg / kg against S. aureus HK-1633-2. This penicillin is also very stable in acidic aqueous solution, exhibiting a duration up to half its weight of 3.3-3.7 hours at pH 2 and 37 C.



   EXAMPLE 8
 EMI31.3
 Preparation of - 2 6-dichlorohe 1 -meth, Y 4-iaothiazolecarboxylic acid A. 3- (2., 6-dichlorophenyl) -5-methyl-4-isothiazole- carbonitrile
A mixture of 3- (2,6-dichlorophenyl) -3-imino-propionitrilo (10.14 g, 0.0476 mole) and S is heated between 145 and 162 C under 7 mm of pressure for 20 minutes -Methyl c & rboxydithioacetate (7.50 g, 0.050 mol). A distillate of the mixture of mercaptoacetic acid.



  After cooling under nitrogen, the residue is dissolved in benzene (180 ml). Potassium carbonate (10.32 g, 0.075 mol) is added followed by a solution of iodine (18.90 g, 0.075 mol) in 230 ml of benzene.



   After stirring at 28 ° C. for 15 hours, the supernatant solution is washed successively with an aqueous solution of sodium thiosulfate, an aqueous solution of sodium hydroxide and water. Drying and subsequent removal of the solvent left 3.48 g of a starting iminonitrile and isothiazole mixture. Cn chromatography the substance on alumina

 <Desc / Clms Page number 32>

   (elution by means of a mixture of benzene and "Skelly-solve B") which gives the pure isothiazole nitrile Recrystallization (ethanol) gives a substance with a melting point between 125 and 126 C: max 255 (E 8.200).



  Analysis for C11H6Cl2N2S: Calculated; : C, 49.09; H, 2.25; Cl, 26.35; N, 10.41;
S, 11.91.
 EMI32.1
 



  Found C, 49.06H, 2.31; Cl, 25.99 Np 10.3; Se 12.00.



  B. Acid - 2 6-diohlorohe 1 - -met 1-4-isoth3.a.



  , zoleçarbozzlégue A mixture of 3- (2,6-dichlorophenyl) -5-methyl-4-isothiazole carbonitrile (729.5 mg), ethylene glycol (3.3 ml) is refluxed for 49 hours. and water (0.66 ml) and potassium hydroxide (0.33 g) then this mixture is poured over ice (11 g). Acidification with hydrochloric acid (6N) gives a crystalline solid which is washed with water and dried; the yield is 670.0 ng (86%) of a product melting between 210 and 212 C. Recrystallization from a mixture of benzene and "Skellysolve B" gives 550 mg, melting point
 EMI32.2
 213.5-2150C. At: 253 h (±? .550).



  Analysis for C11H7Cl2NO2S:
Calculated: C, 45.85; H, 2.45; Cl, 24.61;
N, 4.86; S, he, 13.



   Found: C, 46.10; H, 2.57; Cl, 24.56;
N, 4.76.

 <Desc / Clms Page number 33>

 



  EXAMPLE
 EMI33.1
 Preparation of 3 -d3.meth 1. 4..isothiazole-carboxylic acid A. 4-cyano-3,5-dinethylisothiazolē
We put in. 200 ml of benzene, 3-iminobutyronitrile (10 g) and methyl S-carboxydithioaoétate (18.3 g) and reflux for 65 minutes. The dark solution is cooled to room temperature, after which K2CO3 (25.3 g) and iodine (46.4 g) dissolved in 560 ml of benzene are added to the solution with stirring.



   After stirring for 15 hours at 28 ° C., the mixture is washed with water, by means of an aqueous solution of Na2S2O3, with water, by means of a 0.5N solution of NaOH, of 0.1N HCl and water. The benzene phase is dried over Na2SO4, filtered and evaporated until a semi-solid (4.97 g, 30%) is obtained under vacuum.



   The substance is chromatographed on alumina, the fraction is eluted with a 1: 1 mixture of benzene and petroleum ether which is the desired product melting between 51 and 54 ° C.



  Analysis: for C6H6N2S;
 EMI33.2
 Calculated s C, 52J7; 3 Ha 4.38; N, S 20.281, 23.17 Found C, 52.00; H, 4.61; N, 19.99; 3 '23.25 B. Acid,.-5 dimst l-.r isothiazolecarbo li ue
The isothiazole produced as described in paragraph (A) above is hydrolyzed with a 5% solution of NaOH in aqueous ethanol to give the desired acid melting after recrystallization from water between 184 and 189 vs.

 <Desc / Clms Page number 34>

 



  EXAMPLE 10
 EMI34.1
 Preparation of the acid. 2-chloro-6-fluoro he 1 - metryl-4-isothiazolecarboxyliQ
A, 2-chloro-6-fluorobenzonitrile
2-chloro-6-fluorobenzal-doxime, prepared from 2-chloro-6-fluorobenzaldehyde, is brought to reflux.
 EMI34.2
 Lc.is. 'Zi, e 3816 Berichte, 6 B, 2253 (1936)] with acetic anhydride, which gives 2-chloro-6-
 EMI34.3
 fluorobenzànitrile by the method of M.S. Reich, Bulle Sot. Chiw. , France, (4) 2, 217 (1917).



  B. -imino.- - 2-.chloro-6-fluoro h 1 ro ionitri3.e The preparation of 3-imino-3- (2-ohloro-6 fi.uoro. Phenyl) -propionitrilc is generally that of Holz- wart, iL. trait. Chem., [2], 22, 242, according to which a mixture of 2-chloro-6-fluorobenzonitrile is added and
 EMI34.4
 of acetonitrile to a metallic sodium suspension) is refluxed and isolated as described in Example 1.
 EMI34.5
 



  0. 3- (2-chlcro-fluorophénl isothîazolacarbo2Mli9uo acid
In the same way as that described in Example 1, cn heating chsemble, in the absence of solvent,
 EMI34.6
 ôquinolar quantities of 3-3 mi.na-3.-2-ahloro..6..fluora phenyl) propionitrile and methyl S-carboxydithioacetate. After cooling and dissolving the residues in benzene, a solution of iodine in benzene is added, followed by solid K2CO3.



   After stirring for 20 hours at room temperature, the mixture is washed with an aqueous solution of sodium thiosulfate, an aqueous solution of sodium hydroxide, water and then dried over Na2SO4.

 <Desc / Clms Page number 35>

 



  After removing the solvent, the residue is hydrolyzed at reflux temperature using methanol, water and sodium hydroxide. The solution was acidified, the crystalline precipitate collected and recrystallized from a mixture of ethanol and water to give an analytically pure product melting between 199 and 201 ° C.



  Analysis for C11H7ClFNO2S:
Calculated: C, 48.53; H, 2.59; S, 11.76
Found: C, 49.30, 48.96; H, 2.89, 2.71;
S, 11.80, 11.88.



   EXAMPLE 11
 EMI35.1
 rú-n1.I'ation of the ucid - 2 6-dichloro-4-met 1 hé 11- 5-methyl-4-isothiazolecarbpxyliquo A. 2,6-dichloro-4-meth, vlbenzonirilc The 2 , 6-dichloro-4-methyl-benzaldoxime prepared from 2,6-dichlorw-4 = n6thyl-benzaldehyde [Beriohte? 69B, 2253 (1936) 1p with acetic anhydride to obtain 2,6-dichloro-4-methylbenzonitrile by the method of 1.5. Roich, Bull.



  Soc. Chim., France, (4) 21, p 217 (1917).



  B. 3-3.mino- - 2,6-.dichloro- -mt 1 hr 1 ro io-. nitrile.



  The preparation of> -ina - 2 ', 6'-dichloro - 4' methylphenyl) propionitrile is generally that given by Holzwart, J. Prakt. Chem. [2], 39, 242 according to the-
 EMI35.2
 which is added a mixture of, 6-d.ehloro-4-raLthylbenzonitrile and acetonitrilo to a suspension of metallic sodiuri, refluxed and isolated in the manner indicated in Example 1,

 <Desc / Clms Page number 36>

 
 EMI36.1
 c,, cide - 2 6-dichloro-4.- et 1 hn 1 - -meth 1-- 4-isothiazolecarboxylic In the process described in Example 1, the imino-3-phenylpropionitrilo which is therein is replaced. used by 3-immo-3- (2,6-dichloro-4-nethylphenyl) propionitrile to obtain 3- (2,6-dichloro-4-methylphenyl) acid

  -5-methyl-4-isothiazolocarboxylic.



     EXAMPLE 12
 EMI36.2
 Preparation of '- 2 4 6-trichloro hén 1 - -met 1- + -3.sothiazolec arbox, yliQue A. 2, 4,6-tnichlonobenzonitrilē acid
Refluxing 2,4,6-trichlorobenzaldo- xime with acetic anhydride to give 2,4,6-triclilorobenzonitrile as described in Example 11.
 EMI36.3
 



  B. -imino- - 2 4 6-trichloro hén 1 ro ionitrile The preparation of 3-imino-3- (2,4,6-trichloroph6nyl) -propionitrile is generally that of Holzvrar 'J. Prakt * Chem.e [2J , 39, 22, according to which a mixture of 2,4,6-trichlorobenzonitrile and acetonitrile is added to a suspension of metallic sodium, brought to reflux and isolated in the same manner as that described above. example 1.
 EMI36.4
 



  C. Àq # Oē¯3-¯ (2, 4, 6-trichlorophenyl) -5-methyl-4 = isothiaz olocarboml igue
In the process described in Example 1, 3-imino-
 EMI36.5
 3-phc: nylpropionitrile 'which is used there is replaced by 3-3.mino-3- (2,4,6-.trichlorophnyl) prop3.onirxl to obtain 3- (2,4,6-tnichlorophenyl acid ) -5-netbyl-4- isothiazolecarboxylic,

 <Desc / Clms Page number 37>

   EXAMPLE 13
 EMI37.1
 Preparation of 3- (2-Chlono-6-fluoro-4-methozzr phenyl) -5-methyl-4-isothiazolecarboxylic acid i1. 2-chloro-6-fluoro-4-methoxybenzonitrile
2-Chloro-6-fluoro-4-methoxybenzaldoxime is refluxed with acetic anhydride to give 2-chloro-6-fluoro-4-methoxybenzonitrile as described in Example 11.
 EMI37.2
 



  B. 3-inino-3- (2-chloro-6-fluoro-4-methoxyphenyl) ¯ propionitrile
The preparation of 3-imino-3- (2-chloro-6-fluoro-4-nethoxyphenyl) propionitrile is generally that of Holzwart, J. Prakt. Chem., [2], 39,242 according to which a mixture of 2-chloro-6-fluoro-4-methoxybenzonitrile and acetonitrile is added to a suspension of metallic sodium brought to reflux and isolated in the same manner as that described in Example 1.
 EMI37.3
 



  C. 3- (Chloro-6-fluoro-4-mthoxyphenyl) -5-meth, yl-4-isothiazolecarboxylic acid In the process described in Example 1, the 3-mmo-3-phenylpropionitrile which is therein is replaced. used by 3-imīno-3 -. (2-chloro-6-fluoro-4-methocyphenyl) propionitrile to obtain 3- (2-chloro-6-fluoro-4-methoxyphenyl) -5-methyl acid -4-isothiazolecarboxylic.



   EXAMPLE 14
 EMI37.4
 5-Methyl-3- (4-trifluoroLiethylphenyl) -4-iEothiazolecarboxylic acid
In the process of Example 1, the
 EMI37.5
 3-imino-3-phenylpropionitrilo which is used there by 3-mmo-3- (4-tn; f: uoronétuyiphényi> propionitriie (prepared

 <Desc / Clms Page number 38>

 
 EMI38.1
 by the reaction of 4trifluoromethylbenzonitrilo with acetonitrile according to the method of Holzwart) to obtain 5-methyl-3- (4-trifluoromethylphenyl) -4-isothiazole-carboxylic acid
EXAMPLE 15
 EMI38.2
 Acid -raiah 1- - 2 6-di trifluoromet 1 hén 1. -4- is othiazolec arboxyliq ue In the process of example 1, the 3-immo-3-ph ± nylpropionitrile which is used therein is replaced by the 3-imino.

   3-L2,6-di (trifluoromthyl) phenyl] propionitrile (prepared by the reaction of 2,6-di (trifluoronethyl) benzonitrile with acetonitrile according to the method of
 EMI38.3
 Holzwart) to obtain 5-r.nthyl-3-2 6-d3. (Tr3 .: fluoronethl) ph4nyl] -4-isothiuzolecarboxylic acid.



  EXL1, LPLE 16 Preparation of the acid -met 1- -nitro hén 1 -4- is othiaz olec arboxyliquo A. -imino -nitrc hén 1 ro ionate d 'et1wl, c
In the process of Example 2, the bromine-benzene which is used therein is replaced by 3-nitro-1-bromo-
 EMI38.4
 benzene for. obtaining ethyl 3-inma-3- (3-nitnaph6nyi) prapionate followed the method of R. Lukos and J. Kloubek, Collections Czechoslovak Chemical Communications) 25, 607 (1960); R. Lukes and J. Kovar, Chomicke Listy, 50,272 (1956).
 EMI38.5
 



  B, 5-m6t! Iyl-â- (3-nitroph6Ml-4-isothiazolccarboxylic).



   In the process of Example 6, the
 EMI38.6
 Ethyl 3-aiainocinnamate which is used therein by 3- * iBino- '3- (3-nitrophenyl) propionate to obtain 5-nethyl-µ- (3-nitrophànyl) -4-isothiazolccarboxyliquo acid

 <Desc / Clms Page number 39>

 melting between 235 and 236 C.



   EXAMPLE 17
 EMI39.1
 5-Methyl? Y1-3- (4..mthoxYhny1) -4-isothiazoleear.bo- xylic acid
In the process of Example 1, the 3-imino-3-phenylpropionitrile used therein is replaced by
 EMI39.2
 3-imino-3- (4-nethoxyphenyl) propionitrilo (prepared by reacting 4-nethoxybenzonitrile with acetonitrilo according to the method of Holzwart) to obtain the acid
 EMI39.3
 5-methyl-3- (4-nethoxyph6nyl) -4-isothiazolecarboxylic, melting between 148 and 150 C.



   It goes without saying, moreover, that the present invention has been described only for explanatory purposes and in no way limiting and that any modification can be made to it without departing from its scope.


    

Claims (1)

ABSTRACT Process for the manufacture of isothiazoles of the formula: EMI39.4 where R and R2 are the same or different and each represents a lower alkyl radical or R, / R being a group of formula: EMI39.5 <Desc / Clms Page number 40> where A, B, and 0 represent hydrogen, fluoro, or chloro, bromo, iodo, trifluoromethyl, methylsulfonylo, nitro, lower alkyl or lower alkoxy radicals, a process characterized by the following points taken alone or in combinations: 1. It includes the following successive stages; a) reaction, at a temperature between 50 and 300 C, of an imino compound of formula EMI40.1 with a dithio composa of formula; 2 EMI40.2 where R and R2 have the meaning above, R1 represents: EMI40.3 EMI40.4 are identical or dif- forinted and each represent a lower alkyl radical or R-, and R3 represent a lower alkyl radical or a radical of formula t EMI40.5 - CnH2nCH2CN where. n and m are whole numbers from zero to six inclusive; b) 1 oxidation of the intermediate product from the first stage at a temperature between <Desc / Clms Page number 41> 0 and 100 C with a moderately oxidizing agent chosen from among the following, 2,3-dichloro-5,6-d-cyano-1,4-benzoquinone, oxygen, air, halogen, in the presence of an acid acceptor I2 , Br2, Cl2, H2O2, sulfur, FeCl3, Na2S2O8 and chloranil; and where R1 is a radical other than -COOH, c) hydrolysis of the intermediate product resulting from the second stage with an acid or a base to obtain the desired compound of the formula: EMI41.1 2. The imino compound and the dithio compound are reacted in a substantially equimolar ratio; the oxidation is carried out at a temperature between 20 and 35 C using a molar ratio of at least one mole of the oxidizing agent per mole of the first intermediate and the hydrolysis is carried out with a solution of a strong mineral acid or an alkali metal hydroxide on heating ,, 3. The inino compound: and the dithio compound are reacted in the absence of solvent under a pressure of between 0.1 mm and 50 mm Hg. 4. The imino compound and the dithio compound are reacted in an inert solvent at reflux temperature. 5. The inino compound is reacted in the form of its alkali metal salt. <Desc / Clms Page number 42> :. . . . . . : 6. R2 represents a lower alkyl radical and R represents R-, R- being as defined above. 7, R represents the methyl group and R is a group of the formula: EMI42.1 where A, B and C represent hydrogen or halogen.