WO1994021617A1

WO1994021617A1 - A process for preparing halogenated isothiazoles

Info

Publication number: WO1994021617A1
Application number: PCT/US1994/002667
Authority: WO
Inventors: Hegde B. Vidyadhar
Original assignee: Dowelanco
Priority date: 1993-03-19
Filing date: 1994-03-10
Publication date: 1994-09-29
Also published as: AU6518694A

Abstract

The present invention is related to a process for making isothiazoles, wherein a thioamide is converted directly to the isothiazole by reacting the thioamide with a halogen in a solvent. The reaction results in the precipitation of the halogen salt. The resulting isothiazole compound can be represented by formula (II).

Description

A PROCESS FOR PREPARING HALOGENATED ISOTHIAZOLES

Field of the inventiςn

The invention relates to method of making halogenated isothiazoles, by reacting a thioamide with a halogen in the presence of a solvent.

Background of the Invention

Isothiazoles are useful as intermediates in the manufacture of a wide variety of chemical products, including, for example pharmaceuticals, agricultural chemicals, such as herbicides, fungicides, insecticides, and the like. In making these isothiazoles, the typical starting material is a thioamide. Hydrogen peroxide is used to oxidize the thioamide to produce an isothiazole. The isothiazole intermediate is then halogenated. Typically the reaction is the following:

where R is ethyl or t-butyl. Ada s et al. lOG-Heterocyclic Compounds 11410 discloses a method of preparing 5-amino-3-methylisothiazole by oxidative ring closure of β-iminothiobutyramide. The β- iminothiobutyramide is treated with potassium persulfate in sodium hydroxide and water, or the β-iminothiobutyramide is treated with hydrogen peroxide and hydrochloric acid to give the ethylisothiazole. Adams et al. lOG-Heterocyclic Compounds 1657 discloses preparation of 5-benz-amino-3- methylisothiazoles by oxidizing β-iminothioamides with hydrogen peroxide, ammonium chloride, potassium sulfate or chloramine. Adams et al. lOG-Heterocyclic Compounds 1381 discloses a method of preparing 4 (or 5)-p- aminobenzosulfonamidoisothiazole by adding slowly 4 (or 5)- aminoisothiazole to NHC6H4SO2CI.

All of the methods described above use hydrogen peroxide for the oxidation of thioamide to an isothiazole. The isothiazole has to be then halogenated. The difficulty with the processes described above is that the hydrogen peroxide is readily combustible. Hydrogen peroxide solutions may explode being concentrated in vacuo.

Therefore, extreme caution must be used when trying to concentrate the hydrogen peroxide solution to isolate the desired product. Another difficulty with the processes is that the overall yield is not very good. The yield is relatively low, typically about 55% just for the oxidative step.

Thus, it is highly desirable to have a process that does not use hydrogen peroxide, does not have the tedious work-up associated with it, is easily isolated and has good yields, where the halogenated isothiazoles are produced from readily available starting materials or materials that can be easily made. Summarv of the Invention

The present invention is related to a process for making halogenated isothiazoles, wherein a thioamide is converted directly to the isothiazole by reacting the thioamide with a halogen in a solvent. The reaction results in the precipitation of the halogen salt. The halogen salt can be easily separated from solution. Thus, the isolation of the desired isothiazole is simple and efficient.

The present invention concerns the process for preparation of making isothiazoles of the following formula(II) :

where, R¹ is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, substituted phenoxy, pyridyl, furyl or thienyl;

R² is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, or substituted phenoxy; and

X is Cl, Br, or I. The isothiazoles described above are prepared by halogenating a thioamide of the formula below.

(I) (II)

wherein,

R1, R² and X are the same as described above.

Detailed Description of the Invention

As used herein, the terms C1-C10 alkyl is refers to straight or branched hydrocarbon groups with up to ten carbon atoms. The alkyl may be substituted, provided that the all substituents are "sterically compatible" with each other.

The phrase "sterically compatible "is employed to designate substituent groups which are not affected by steric hindrance. Steric hindrance is defined in The

Condensed Chemical Dictionary 7th Ed. p.893 (1966) as "A characteristic of a molecular structure in which the molecules have a spatial arrangement of their atoms such that a given reaction with another molecule is prevented or retarded in rate." Sterically compatible may be further defined as reacting compounds having substituents whose physical bulk does not require confinement within volumes insufficient for the exercise of their normal behavior as discussed in Cramend Or^ganic Chemistry 2nd Ed. p. 215 (1964) .

The invention is related to a process for making isothiazoles, wherein a thioamide is converted directly to the isothiazole by reacting the thioamide with a halogen in the presence of a solvent. The reaction results in the precipitation of the halogen isothiazole salt. The halogen salt can be easily separated from solution. Thus, the isolation of the desired isothiazole is simple and efficient.

The isothiazoles of the present invention encompasses compounds of the following formula:

(II) where R^ and R² are defined below. In order to prepare the resulting isothiazole product in Formula II, the process comprises :

( I ) ( II )

wherein, R¹ is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, substituted phenoxy, pyridyl, furyl or thienyl;

X is Cl, Br, or I. Preferably R¹ is methyl, ethyl, t-butyl or phenyl, R² is preferably substituted phenyls and X is bromine. More preferably, the resulting compound is 5-amino (or substituted amino) 3-alkyl (or aryl) -4-halogenated isothiazole. Most preferably the resulting product is 5- amino-3-alkyl-4-bromo isothiazole.

When the thioamide R² is substituted with hydrogen, then the thioamide can be made by reacting acetonitrile and ethyl propionate in the presence of a suitable base such as sodium hydride, triethylamine, potassium t-butoxide, sodium, or lithium diisopropylamide at a temperature of between about -78°C to about 100°C. The resulting intermediate pivaloylacetonitrile or 3-oxoalkyl or aryl nitrile is further reacted with ammonium nitrate, where gaseous ammonia is bubbled through the reaction to give 3- aminoalkyl or aryl nitrile at a temperature of between about -20°C to about 50°C, preferably between about -5°C to about 25°C. The 3-aminoalkyl or aryl nitrile can be further reacted, at a temperature of between about -20°C to about 50°C, with hydrogen sulfide to make the thioamide starting material. hen R² is ethyl or phenyl, furyl or thienyl, to make 3-amino alkyl or aryl nitrile, ammonia is bubbled through the solution, but it is not necessary to use ammonium nitrate. The ammonium nitrate is usually only used when the reaction is performed under atmospheric pressure.

When R² is hydrogen, the resulting halogenated isothiazole many be further reacted with any of the other substituents defined as R². An example of further modifying the isothiazoles would be to react 5-amino-3- methyl isothiazole with phenyl or substituted phenyl chloroformate to form the corresponding carbamate, see U.S. Patent 4,196,126, which is incorporated herein by reference. Another example would be to reflux 4-amino isothiazole with acetic anhydride to give an N-acyl compound, see Liebiσs Ann. Chem. (1979), p. 1534-46 which is incorporated herein by reference. Still yet another example would be to reflux 5-amino-3-alkyl isothiazoles with acid chlorides to give the corresponding amide, which is further illustrated in PCT Application US92/10331, which is also incorporated by reference. Clearly using standard chemical techniques known in the art one could modify the resulting isothiazole.

When the thioamide R² is not substituted with hydrogen, then the thioamide can be made by reacting a substituted enamine and a N-substituted thiocyanate. The enamine and thiocyanate may be substituted with the substituents described as R¹ and R². The substituted enamine and a N-substituted thiocyanate is typically stirred in an aprotic solvent at a temperature between about -80°C to about 100°C. Solvents that can be used include ether, THF, dioxane and the like. The reaction mixture is stirred between one and 24 hours, with a standard work-up following to obtain the desired thioamide.

The thioamide starting material, such as pivaloylacetonitrile, is generally available for purchase from Aldrich Chemical Co. in Milwaukee, Wisconsin U.S.A.. Furthermore, examples of methods of preparation of the thioamide defined as Formula I can be found herein, see Example 1, Parts A through E.

The thioamide is converted to an isothiazole by oxidative-cyclization and halogenation. It is thought that this is accomplished by the nucleophilic attack on bromine by either the amino substituent closest to R! ^{or tne} thio substituent of the thioamide followed by the ring closure to isothiazole_ The halogenation can be accomplished with an elemental halogen directly or with BrCl, which can be generated in situ from HBr and Cl2, or other similar techniques. Other halogenating agents such as sodium bromate/HBr and N-bromosuccinimide, N-chloro succinitride, N-itodo succinimide and the like may also be used. Optionally the bromination could be conducted in the presence of an electrophilic aromatic substitution catalyst such as, FeCl3, in the presence a buffer such as NAOAc.

The halogenation is performed in the presence of a solvent which is resistant or inert to the reaction conditions. A wide variety of solvents may be used, but preferably a protic solvent is employed. The protic solvents that are the most preferred are methanol, ethanol, isopropanol, and n-butanol and the like. More preferably, the protic solvents are methanol and ethanol. Even more preferred are the halogenated solvents such as chloroform, carbon tetra chloride, dichloroethane and the like. Most preferably, the halogenated solvents are methylene chloride and chloroform. The solvents may be mixed with water. If the solvents are mixed with water, generally the range of the ratio of polar solvent to water is between about 10:1 to about 10:4, preferably between about 10:2 to about 10:3.

Although not necessary, buffers could be added to the reaction mixture. The buffer will assist in maintaining the pH of the reaction and will assist the reaction in going to completion. The amount of buffer is typically enough to maintain a pH between about 2 to about 5.

Halogenation is typically conducted below ambient temperature, preferably under agitation. Preferably, the temperature is between about 5°C and about -50°C, more preferably between about 0°C and about -50°C. The halogen is slowly added to a mixture containing the solvent and the thioamide. The weight ratio of the solvent to the thioamide is between about 5:1 to about 25:1, preferably between about 10:1 to about 15:1. More preferable, the halogen is combined with solvent as a first mixture and is added to a second mixture of solvent and thioamide. The weight ratio of halogen to solvent in the first mixture is between about 1:25 to about 1:75, preferably between about 1:40 to about 1:60. To obtain the desired yields of about 50 percent to about 99 percent, preferably between about 70 percent to about 95 percent of halogenated isothiazole, preferably at least two equivalents of halogen are reacted with the thioamide. Of course the halogen and thioamide may be reacted in an amount of a one to one ratio, but the halogenated isothiazole yield will be typically between about 50 percent to about 70 percent.

Generally, the solvent and thioamide mixture is cooled prior to the halogen addition. The halogenating agent is introduced to the solvent and thioamide at a rate that is commensurate in scope with the reaction and cooling. As the resulting product precipitates, additional reactants and/or solvent may be added. Of course additional solvent may be used, particularly in order to keep the slurry flowable. The pH of the reaction is typically between about 1 to about 6, preferably between about 2 to about 3.

The resulting salt of the desired product may be isolated using standard filtration techniques. Typically the salt of the resulting product is basified and separated from solution with a halogenated or protic solvent. The salt can be basified with ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like. The salt is basified such that the pH is between about 8 to about 13. Preferably, the salt is basified so that the pH is between about 9 to about 10. The preferred halogenated or protic solvents are described above.

The following examples are presented to illustrate the invention and should not be construed as limiting the scope of the invention.

Exampl s

Example 1

Preparation of the thioamide having the following formula:

(ID

where R^ is either ethyl or t-butyl and R² is hydrogen. The synthesis of the above compound may be completed by reactions described below.

( ID

Part A

s. Preparation o_f 3 -Q?cppentane nitrile

Sodium hydride (60%, 32.0 g, 0.8 mole) was suspended in dry THF (250 m ) and heated to reflux (70°C) with vigorous stirring. To this suspension was added a mixture of ethyl propionate (30.7 g, 0.3 mole) and acetonitrile (27.0 g, 0.6 mole) over a 2.0 hour period and further refluxed for 9.0 hours. After cooling to 25°C, ethanol (15.0 mL) followed by water (350 mL) was added to the reaction mixture. To the resulting yellowish-brown solution was added hexane (500 mL) and vigorously stirred. The aqueous layer obtained was washed with hexane/ethyl ether (2:1, 400 mL) , acidified with 5N HCl (about 130 L) and then extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 28.0 g of 3-oxopentane nitrile (96%).

Part P

T s. ^p epara ion o_f 3-amino- , 4-flimethvl-2-pentene nitrile

Ammonium nitrate (28.8 g, 0.36 mole) was added to solution of pivaloyl acetonitrile (90.0 g, 0.72 mole), which is available from Aldrich Chemical Co. at 1001 West Saint Paul Ave. Milwaukee, WI 53233, U.S.A., in absolute ethanol (500 mL) . Gaseous ammonia was bubbled through the reaction mixture (83°C) under reflux for 1 6.0 hours. After cooling to 25°C, water (100 mL) was added to the mixture and ethanol was evaporated under vacuum. The resulting aqueous solution was basified with 0.1 N NaOH (100 mL) and extracted with ether. The organic extracts was dried over sodium sulfate, filtered and concentrated to yield yellow oil. Crystallized from hexane to give 85.0 g of 3-amino-4,4-dimethyl-2-pentene nitrile (95%) as white crystals, mp 48°-49°C.

Part c Ui_£ Preparation oj. 3-aminopentene nitrile Ammonia (about 3.5 g) was bubbled at a steady rate over a 5.0 mm period through a solution of 3-oxopentane nitrile (7.09, 72.2 mmol ) in absolute ethanol (130 mL) in a heavy wall tube (Ace Glass Inc.) and immediately sealed with a teflon plug. The sealed tube was then placed in an oven and heated at 110°C for 16 hours. After cooling to 2°C, the solvent was removed under vacuum to give 6.39 of 3-aminopentene nitrile (91%) as red oil.

Part D

τ_h£ Preparat on o_ι 3-amino-4,4-dimethyl-2-pentene thioamide

H2S was bubbled at a steady rate over a 5.0 min period through a solution of 3-amino-4, 4-dimethyl-2-pentene nitrile (8.0 g, 64.5 mmol) in THF (40 mL) , ethyl alcohol (30 mL) and triethylamine (2.0 mL) in a heavy wall tube and immediately sealed with a teflon plug. The sealed tube was then placed in an oven and heated at 120°C for 6.0 hours. Upon cooling and removal of solvent under vacuum, 3-amino- 4,4-dimethyl-2-pentene thioamide was obtained as thick yellow oil (10.1 g, 89%) which solidified on standing.

part E

1 Preparation o_£ 3-amino-2-pentene thioamide

H2Ξ (7.2 g) was bubbled at a steady rate over a 4.5 min period through a solution of 3-aminopentene nitrile (11.1 g, 115.6 mmol) in THF (35 mL) and ethyl alcohol (25 mL) at 0°C in a heavy wall tube and immediately sealed with a teflon plug. After the reaction mixture was allowed to warm to 25°C, the sealed tube was placed in an oven and heated 90°C for 3 hours. The sealed tube was allowed to stand at 25°C for 48.0 hours and then removal of solvent under vacuum gave 3-amino-2-pentene thioamide 14.5 g of lb (96% yield) as thick red oil.

Example 2

Preparation of the thioamide having the following formula:

NH, s R .¹i^^' ^NHR÷

where P.¹ is previously defined and P.² is as previously defined except that P.² is not hydrogen. The synthesis of the above compound may be completed by reactions described below.

(I)

The preparation of the thioamide above is as follows:

The substituted enamine above and N-substituted thiocyanate are stirred in an aprotic solvent such as ether, THF, dioxane at a temperature range of -80°C to 100°C in an equal-molar or excess quantity between 1 to 24 hours. Standard work-up procedures will lead to the desired thioamide

Example 3

Bromine (0.44g, 2.8 mmol) in dichloromethane (25.0 ml) was added drop-wise to a solution of 3-amino-4,4-dimethyl- 2-pentene thioamide (0.22g, 1.4 mmol) in dichloromethane (25.0 mL) at 25°C over a 15 min period. The resulting reddish-brown solution was stirred at ambient temperature for 3.0 hrs. After the removal of dichloromethane in vacuo, the residue was triturated with ethyl acetate. The white solid obtained was filtered to give halogenated isothiazole bromine salt. An additional 0.130 g of halogenated isothiazole bromine salt was obtained from the filtrate upon further cooling. The halogenated isothiazole bromine salt was basified with ammonium hydroxide (pH of between 9 to 10) and extracted with dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated to give the halogenated isothiazole (0.315 g, 96%) as a yellow solid. The yellow solid was recrystalized from methylene chloride/hexane with a mp 68- 69°C. The analytical calculations were determined as follows:

Calculated: C=35.74; H=4.71; N=11.96; S=13 , 63 Found: C=35.88; H=4.99; N=11.79; S=13.48.

Example 4

Bromine (2.72g, 17.0 mmol) in dichloromethane (50.0 ml) was added dropwise to a solution of 3-amino-2-pentene thioamide (l.lg, 8.5 mmol), in dichloromethane (50.0 mL) at 5°C over a 30 min period. The resulting reddish-brown solution was stirred at ambient temperature for 2 hours. After the removal of dichloromethane in vacuo, the residue was triturated with ethyl acetate. The white solid obtained was filtered to give and basified, pH between 9 to 10, with ammonium hydroxide and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 5- amino-4-bromo-3-ethylisothiazole (1.30g, 74%) as a yellow oil. -E NMR (CDCI3): 4.70 (s, 2H, NH₂), 2.75 (q, 2H, CH₂) 1.25 (t, 3H, CH₃) . Of course it should be understood that a wide range of changes and modifications can be made of the preferred embodiments described above. The temperatures may be altered provided the cyclization and halogenation is not disrupted. The process of this invention is not limited to the use of the solvents listed above, but can include solvents that facilitate the cyclization and halogenation of the starting material. It is therefore intended that the foregoing description be regarded as illustrative rather than limiting, and that it be understood that it is the following claims, including all equivalents, which are intended to define the scope of this invention.

Claims

We claim:

1. A process for preparing an isothiazole, having the formula:

where, R^ is H, C1-C10 branched or unbranched alkyl that may be substituted or unsubstituted, cyclo-alkyl or aralkyl, cyclohexylmethyl phenyl, substituted phenyl, phenoxy, substituted phenoxy, pyridyl, furyl or thienyl;

X is Cl, Br, or I;

wherein the process comprises reacting a thioamide of the formula (I) :

where, Rl and R2 are as previously defined,with a halogen selected from the group consisting of bromine, chlorine, and iodine.

2. The process of Claim 1, wherein the R² substituent on the isothiazole (I) is hydrogen and the isothiazole is reacted with acetic anhydride, phenyl or substituted phenylchloroformate, or acid chloride.

3. The process of Claim 1, wherein the thioamide is a 3-amimo nitrile or 3-amino aryl nitrile.

4. The process of Claim 1, wherein a buffer is added to the reaction to maintain a reaction pH of between about 2 to about 5.

5. The process of Claim 1, wherein the solvent is a protic solvent.

6. The process of Claim 1 wherein the solvent is methanol, ethanol, isopropanol, n-butanol, chloroform, carbon tetra chloride, dichlorethane, methylene chloride, or chloroform.

7. The process of Claim 5, wherein the solvent is methylene chloride or chloroform.

8. The process of Claim 1, wherein the solvent is mixed with water in the range between about 10:1 to about

10:4.

9. The process of Claim 8, wherein the solvent is mixed with water in the range between about 10:2 to about 10:3.

10. The process of Claim 1, wherein the weight ratio of halogen to solvent is between about 1:25 to about 1:75.

11. The process of Claim 10, wherein the weight ratio of halogen to solvent is between about 1:40 to about 1:60.

12. The process of Claim 1, wherein the weight ratio of solvent to thioamide is between about 5:1 to about 25:1.

13. The process of Claim 12, wherein the weight ratio of solvent to thioamide is between about 10:1 to about 15:1.

14. The process of Claim 1, wherein about two weight equivalents of halogen is reacted with the thioamide (I) .

15. The process of Claim 1, wherein R¹ is methyl, ethyl, t-butyl or phenyl.

16. The process of Claim 1, wherein R² is a phenyl.

17. The process of Claim 1, wherein X is bromine.

18. The process of Claim 1, wherein R¹ is methyl, ethyl, t-butyl or phenyl; R² is phenyl; and X is bromine.

19. The process of Claim 1, wherein the isothiazole is 5- amino-3-alkyl-4 halogenated is isothiazole, or 5-amino- aryl-4-halogenated isothiazole.

20. The process of claim 19, wherein the isothiazole is 5- amino-3-alkyl-4-bromo isothiazole.