WO1998045279A1

WO1998045279A1 - Preparation of thiazoles using 1,3-dihalopropenes

Info

Publication number: WO1998045279A1
Application number: PCT/US1998/007252
Authority: WO
Inventors: Ramiah Murugan; Eric F. V. Scriven
Original assignee: Reilly Industries, Inc.
Priority date: 1997-04-07
Filing date: 1998-04-07
Publication date: 1998-10-15
Also published as: AU6965398A

Abstract

Described are improved processes for preparing thiazoles utilizing a 1,3-dihalopropene as an effective starting material. Especially preferred are such processes for preparing 2-chloro-5-chloromethyl-thiazole utilizing 1,3-dichloropropene as a starting material.

Description

PREPARATION OF THIAZOLES USING 1 ,3-DIHALOPROPENES

Reference to Related Application

This application claims priority upon United States Patent Application No. 60/042,785 filed April 7, 1997, which is hereby incorporated herein by reference in its entirety.

Background of the Invention

The present invention relates generally to the preparation of thiazoles, and in particular to improved preparations of 2-halo-5-halomethyl-thiazoles utilizing a

1,3-dihalopropene such as 1,3-dichloropropene as a starting material.

As further background, thiazoles enjoy a wide range of utilities including serving as actives and intermediates in the fields of pesticidal, and medicinal compounds. As an example, 2-halo-5-halomethyl-thiazoles are known to be useful as intermediates for insecticides and medicines. The specific compound 2-chloro-5-chloromethyl-thiazole is one such intermediate which is attracting significant commercial attention at present. Consequently, a number of routes to 2-chloro-5-chloromethyl-thiazoles have been proposed.

One such route is proposed in U.S. Patent No. 4,748,243 issued on May 31, 1988 to Beck et al. and assigned to Bayer Aktiengesellschaft . In the '243 patent. chlorine is reacted with an allyl isothyocyanate of the formula CH₂=CH-CH₂-NCS at temperatures from 0°C to 150°C to form the 2-chloro-5-chloromethyl-thiazole. Another route to 2-chloro-5-chloromethyl-thiazole is described in U.S. Patent 5,180,833 issued January 19, 1993 to Uneme et al. and assigned to Takeda Chemical Industries, Ltd. In the '833 patent process, an allyl isothiocyanate of the formula CH₂=CX-CH₂-NCS, wherein X is a leaving group, is reacted with a chlorinating agent to prepare the subject compound.

In light of this background the applicants have undertaken an investigation to discover new and useful routes to 2-halo-5-halomethyl-thiazoles which employ readily-available starting material, which can be conveniently conducted in standard laboratory or commercial equipment, and which provide advantageous rates of production for the thiazoles and useful intermediates thereto. In so doing the applicants have discovered that 1, 3-dihalopropenes provide useful starting materials for the production of such thiazoles, and that improved reactions to prepare the thiazoles and intermediates can be attained if certain measures are taken.

Summary of the Invention

Accordingly, aspects of the invention provide for the improved use of a 1,3-dihalopropene in the production of a thiazole compound. In one embodiment, a process is provided for preparing a 2-halo-5-halomethyl-thiazole which includes the steps of reacting a 1,3-dihalopropene with an alkali or alkaline earth metal thiocyanate such as sodium thiocyanate to form a 3-halo-2-propenyl-thiocyanate; rearranging such thiocyanate to form a corresponding isothiocyanate; and reacting the isothiocyanate with a halogenating agent, in the absence of solvent, to form a 2- halo-5-halomethyl-thiazole .

Other embodiments of the invention provide processes for preparing a 2-halo-5-methyl-thiazole which comprise reacting a halogenating agent with a l-(3- substituted)propenyl to form a corresponding 2-halo-5- (substituted) methyl-thiazole. In accordance with one aspect of the invention, such process is conducted in the absence of solvent. In accordance with another aspect of the invention, such process is conducted by feeding gaseous molecular halogen to a heated reaction mixture including the isothiocyanate and an organic solvent, preferably at a temperature of at least about 60°C. In specific embodiments, a 1- (3-halopropenyl) -isothiocyanate is so reacted to form a 2-halo-5-halomethyl-thiazole, or a l-(3- trialkylaminopropenyl or 3-N-pyridinylpropenyl) - isothiocyanate is reacted to form, respectively, a 2-halo- 5-trialkylaminomethyl-thiazole or 2-halo-5-N- pyridinylmethyl-thiazole. For example, preferred processes of the invention involve reacting a halogenating agent with a 1-propenyl-isothiocyanate of the formula

wherein Y is a halo, trialkylamino or N-pyridinyl group and R₂ and R₃ are each H or a lower alkyl or benzyl group, to form a thiazole compound of the formula

wherein X is halo and Y, R₂ and R₃ are as defined above,

Another preferred embodiment of the invention provides a multistep process for preparing a 2-halo-5-halomethyl- thiazole, which includes the steps of reacting a 1,3- dihalopropene with an alkali or alkaline earth metal thiocyanate such as sodium thiocyanate in a heterogeneous reaction mixture containing water, a water-immiscible organic solvent and a phase transfer catalyst, to form a 3- halo-2-propenyl-thiocyanate; rearranging such thiocyanate to form a corresponding isothiocyanate; and reacting the isothiocyanate with a halogenating agent to form a 2-halo- 5-halomethyl-thiazole. In preferred modes, the organic solvent is a halogenated alkane solvent, especially a chloroalkane solvent, and most preferably 1,1,2- trichloroethane. The organic solvent is desirably included in at least a 1:1 weight ratio with respect to water, more desirably at least about 1.5:1. Such reactions have been found to proceed very rapidly, enabling improved, practicable commercial production of the desired 2-halo-5- halomethyl-thiazole .

If desired, 2-halo-5-halomethyl-thiazoles produced as described above can be reacted with a carboxylic acid salt, e.g. of the formula M⁺ RiCOO^" wherein M is an alkali or alkaline earth metal and Ri is an H or an alkyl, aryl or aralkyl group having up to about 10 carbon atoms, to form a corresponding 2-halo-5-ester-substituted-thiazole, which can itself be hydrolysed and dehalogenated to form a corresponding hydroxymethyl-thiazole .

Preferred reactions of the invention are advantageously characterized by the use of the readily- available 1,3-dihalopropene starting material, and the rapid formation of intermediate compounds which are readily converted to the final thiazole compound under relatively mild conditions. Additionally, the 1,3-dihalopropene can be substituted with other hydrocarbon groups, for example alkyl groups, to result in further substituted thiazoles, as described further below.

The invention thus provides improved processes for preparing important thiazole compounds utilizing readily- available 1, 3-dihalopropenes as starting materials. The preferred reactions are rapid, and can be conducted in standard equipment under relatively mild conditions. In addition, processes of the invention involve starting materials which are relatively easy to transport, store and manipulate .

Additional objects, features and advantages of the invention will be apparent from the following description and appended claims .

Description of the Preferred Embodiments

For the purpose of promoting an understanding of the principles of the invention, reference will now be made to certain preferred embodiments thereof and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations, further modifications and applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art to which the invention relates.

As indicated above, the present invention provides for the improved production of thiazoles utilizing a 1,3- dihalopropene starting material. Thus, in one preferred aspect, the invention provides processes for preparing thiazoles encompassed by the formula (I)

wherein X is halo such as chloro, bromo or iodo, and R₂ and R₃ are lower alkyl (Ci to C₆ alkyl, preferably straight- chained) or benzyl. Preferred multistep processes of the invention generally include the steps of first reacting a compound of the formula R₂ H

X-C- C=C(X)(R₃) I H

with a thiocyanate salt of the formula M^{+ "}SCN wherein M is an alkali or alkaline earth metal such as sodium, potassium or lithium, to form a 3-halo-2-propenyl-thiocyanate compound of the formula

In this reaction, as well as other reactions described herein, the 1,3-dihalopropene starting material can be a cis- or trans- isomer, or a mixture of such isomers, and intermediates formed can likewise have cis- or trans- configurations, or a mixture thereof. The wave-line

( ) is used herein to encompass such possibilities, and denotes a bond in which no particular stereochemistry is intended.

In one preferred embodiment of the present invention, this reaction of the 1,3-dihalopropene compound with the thiocyanate salt is conducted in a heterogeneous water/organic reaction mixture in the presence of a phase transfer catalyst. Suitable solvents for such processes generally include aprotic solvents, with illustrative solvents including cyclic or acyclic ethers, including dioxanes, cyanoalkanes, e.g. acetonitrile and proprionitrile, ethyl acetate, haloalkanes, e.g. chloroform, trichloroethanes including 1,1,1- trichloroethane and 1, 1, 2-trichloroethane, and the like. More preferred solvents are immiscible with water, and absorb essentially no water. Further, preferred solvents have boiling points (at atmospheric pressure) above about 60°C, more preferably above about 80°C, and desirably falling in the range of about 80°C to about 150°C. To date, 1, 1, 2-trichloroethane is the most preferred solvent, being immiscible with water, absorbing essentially no water, and providing particularly advantageous rates of production for the 3-halo-2-propenyl-thiocyanate compound.

Suitable phase transfer catalysts for such reactions include, for example, quaternary salt catalysts such as butylpyridinium bromide, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium fluoride, hexadecyltriethylammonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, heptylpyridinium bromide, hexyltriethylammonium bromide, dodecylpyridinium bromide, dodecyltriethylammonium bromide, methyltrinonylammonium chloride, methyltriphenylammonium bromide, octyltriethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium chloride, trioctylmethylammonium chloride, trioctylpropylammonium chloride, tetrapropylammonium bromide, and the like. Given the teachings herein, it will be within the purview of those skilled in the art to select and utilize a suitable phase transfer catalyst in the formation of the 3-halo-2-propenyl-thiocyanate.

The temperature of this first reaction can vary, but is generally conducted in the range of about

-20°C up to about 150°C, more preferably in the range of about 0°C up to about 120°C, and most preferably in the range of about 80°C to about 120°C. Advantageously, when using a heterogeneous reaction mixture as disclosed above, the salt formed in the reaction (M⁺X^") , is taken up in the water layer, thus avoiding the need to filter the reaction to remove the salt at this point. Instead, the organics layer can be separated from the aqueous layer, and optionally then washed with water to remove any remaining salt.

After its preparation, the 3-halo-2-propenyl- thiocyanate can then be caused to rearrange to form a corresponding 3-halo-l-propenyl-isothiocyanate of the formula

The rearrangement is desirably conducted in an organic solvent such as those previously described, under heated conditions (e.g. at reflux) at any suitable temperature which causes the rearrangement, preferably not exceeding about 150°C, more preferably not exceeding about 120°C. Optionally, this rearrangement can be conducted in the presence of a metal salt which facilitates the formation of the trans isomer of the 3-halo-2-propenyl-isothiocyanate, such as a salt of magnesium, calcium, barium, manganese, iron, ruthenium, cobalt, rhodium, nickel, palladium, platinum, copper, silver, gold and the like. The salt can be an organic or inorganic salt, including for examplee halides such as bromides or chlorides, sulfates, nitrates, phosphates, hydroxides, carbonates, acetates, benzoates, acetylacetonates, oxides, and the like.

After the rearrangement, the isothiocyanate is reacted with a halogenating agent in the absence of solvent, or in an organic solvent, e.g. an aprotic solvent such as a polyhalogenated lower alkane solvent such as methylene chloride, 1, 2-dichloroethane, 1, 1, 1-trichloroethane, 1,1,2- trichloroethane, or chloroform, to form the 2-halo-5- halomethyl thiazole of formula (I) . The reaction with halogenating agent is preferably conducted at a temperature from about 0°C to about 150°C, more preferably about 20°C to about 130°C.

As disclosed above, in one preferred mode, the reaction with the halogenating agent is conducted in the absence of solvent and has been found nonetheless to proceed efficiently to the desired thiazole compound. In such reactions, the preferred halogenating agent is gaseous molecular halogen. In another preferred mode, gaseous molecular halogen, e.g. gaseous molecular chlorine, is fed to and reacted with a heated, for example refluxing, reaction mixture containing the isothiocyanate and an organic solvent, desirably at an elevated temperature in the range of about 60°C to 150°C, more desirably about 80°C to 150°C. Halogenated alkane solvents such as those disclosed above, especially 1, 1, 2-trichloroethane, are preferred for use in such processes.

In other aspects of the invention, the halogen X in the above-described isothiocyanate may be replaced with a group Y, which can be X or tertiary amino group such as a trialkylamino (e.g. trimethylamino) or N-pyridinyl group, to result upon cyclization in a corresponding 2-halo-5- halomethyl-thiazole or 2-halo-5-tertiaryaminomethyl- thiazole quaternary compound.

Each of the reactions involved in the syntheses described herein can be conducted for any suitable time to yield the desired product, typically up to about 20 hours, more preferably up to about 10 hours, and in most preferred processes the reactions are essentially complete in less than about 2 or 3 hours .

The halogenating agent can include any suitable source of halogen, including for example molecular halogen and compounds which dehalogenate under the reaction conditions, e.g. a sulfuryl halide which dehalogenates to produce molecular halogen. Preferred halogenating agents include those which provide molecular chlorine, molecular bromine and/or molecular iodine, most preferably molecular chlorine. In the one preferred form, gaseous chlorine can be fed to and reacted with a liquid reaction mixture including the 3-halo-2-propenyl-isothiocyanate so as to form the desired thiazole compound of formula (I) . In one specific preferred thiazole synthesis of the invention, sodium thiocyanate is reacted with 1,3- dichloropropene to form 3-chloro-2-propenyl-thiocyanate, which is rearranged to form the corresponding 3-chloro-l- propenyl-isothiocyanate. This isothiocyanate is then reacted with a chlorinating agent to form 2-chloro-5- chloromethyl-thiazole. In one advantageous mode of carrying out this synthesis, the reaction of the chlorinating agent with the isothiocyanate is performed in the absence of solvent, yet proceeds smoothly to the thiazole product. In another advantageous mode, the reaction of the sodium thiocyanate with 1,3-dichloropropene is conducted in a heterogeneous water/organic reaction mixture, in the presence of a phase transfer catalyst, which results in the rapid production of 3-chloro-2- propenyl-thiocyanate. After separation from the aqueous layer, the organic portion can be washed, e.g. with water, to remove remaining salts, dried and then heated (preferably to reflux) to cause the rearrangement to the 3- chloro-1-propenyl-isothiocyanate. Chlorine gas can then be passed through the reaction mixture under heat (e.g. at reflux) to form 2-chloro-5-chloromethyl-thiazole. In its most preferred form, each of these steps is conducted in the presence of the same organic solvent, and isolation of intermediates from the organic solvent is not necessary.

In such cases the organic solvent is desirably a haloalkane solvent, most preferably 1, 1, 2-trichloroethane.

2-halo-5-halomethyl-thiazoles prepared in accordance with the invention are useful as intermediates in the production of insecticidal or medicinal compounds. In the medicinal area, it is often desirable to convert a 2-halo- 5-halomethyl-thiazole such as 2-chloro-5-chloromethyl- thiazole to 5-hydroxy-thiazole . Generally, this can be achieved by reacting the 2-halo-5-halomethyl-thiazole with a carboxylic acid salt to form an ester of a 2-halo-5- hydroxymethyl-thiazole, hydrolyzing the ester to form the corresponding 2-halo-5-hydroxymethyl-thiazole, and dehalogenating the latter to form 5-hydroxymethyl-thiazole. Preferred carboxylic acid salts for use in this conversion include those having the formula RιCOO^~M⁺ wherein R_x can be hydrogen, alkyl, aryl such as phenyl, or aralkyl such as benzyl, with R₁ preferably having up to about ten carbon atoms; and M is an alkali or alkaline earth metal such as sodium, potassium, lithium or the like. For example, in preferred such reactions involving a 2-halo-5-halomethyl- thiazole, the corresponding ester will have the formula

wherein X is halogen, especially chloro, and Ri is as defined above for the preferred carboxylic acid reactants. The ester-forming reaction is desirably conducted at a temperature from about 20°C up to about 120°C, and the carboxylic acid salt is more preferably a formic acid salt such as sodium formate, potassium formate or lithium formate. Generally speaking, the carboxylic acid salt is desirably used in an amount of from about 1.0 to about 5.0 mole equivalents (based on 2-chloro-5- chloromethylthiazole) , more preferably from about 2.5 to about 3.5 mole equivalents. The ester-forming reaction is also desirably conducted in the presence of a phase transfer catalyst such as a quaternary ammonium phase transfer catalyst, neat or in the presence of a solvent. Illustrative solvents for these purposes include aprotic, polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, or hydrocarbon solvents such as heptane, octane, decane, benzene, toluene, xylene, cumene or similar solvents. When present, the phase transfer catalyst is used in an amount from about 0.01 to about 0.1 mole equivalents (based on 2- chloro-5-chloromethylthiazole) , preferably from about 0.01 to about 0.02 mole equivalents.

The hydrolysis step is conducted in the presence of a hydrolyzing agent, which can be added to the crude ester- containing reaction mixture. Preferred hydrolyzing agents include aqueous solutions of strong bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide. When ester hydrolysis is accomplished with aqueous strong base, the strong base is preferably used in about 1 to about 2 mole equivalents (based on 2-chloro-5-chloromethyl- thiazole) at a concentration of from about 5% to about 50%, preferably from about 20% to about 30% (w/w) .

As to the dechlorination step, it can be conducted by catalytic hydrogenation, reaction with zinc/acetic acid or reaction with magnesium/methyl or magnesium/isopropenol or the like.

A preferred product, which can be formed from 2- chloro-5-chloromethyl-thiazole by the above ester-forming, hydrolysis, and dehalogenation steps, is 5-hydroxymethyl- thiazole, having the formula

As to additional details of the above-described ester- formation, hydrolysis and dehalogenation steps, suitable quaternary ammonium phase transfer catalysts for use in the invention include for example those disclosed in International Publication No. WO96/16050 published on 30 May 1996 and entitled process for preparation of 5- hydroxymethyl-thiazole. Briefly, these include the phase transfer catalysts disclosed in (1) "Phase-Transfer Catalysis, New chemistry, Catalysts and Applications", ACS Symposium Series 326, American Chemical Society, Wash.,

D.C., 1987, Charles M. Starks (editor); (2) "Phase-Transfer Reactions", Fluka-Compendium, Volume 1, Georg Thieme Verlag, New York, 1986, Walter E. Keller (editor) and (3) "Phase-Transfer Reactions", Fluka-Compendium, Volume 2, Georg Thieme Verlag, New York, 1987, Walter E. Keller (editor) . Suitable quaternary ammonium phase transfer catalysts include, for example, butylpyridinium bromide, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium fluoride, hexadecyltriethylammonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, heptylpyridinium bromide, hexyltriethylammonium bromide, dodecylpyridinium bromide, dodecyltriethylammonium bromide, methyltrinonylammonium chloride, methyltriphenylammonium bromide, octyltriethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium chloride, trioctylmethylammonium chloride, trioctylpropylammonium chloride, tetrapropylammonium bromide, or the like.

Catalytic hydrogenation is a preferred method for dechlorination. The catalytic hydrogenation of 2-chloro-5- hydroxymethylthiazole can be accomplished using hydrogen at a pressure of from about 1 atmosphere to about 10 atmospheres, and a hydrogenation catalyst (e.g., Pd/C, RaNi, and the like) in the amount of from about 1% to about 25% by weight in an inert solvent such as an alcohol, e.g. methanol, ethanol, and the like.

The thiazole products of the invention are generally useful as active agents or as intermediates to active agents employed in pesticidal and/or medicinal compositions. As specific examples, 2-choro-2- chloromethyl-thiazole is a commonly used intermediate to the compound Ritonavir, a peptidomimetic HIV-1 protease inhibitor used in the treatment of AIDS.

For the purposes of promoting a further understanding and appreciation of the invention and its various advantages, the following specific Examples are given. It will be understood, however, that these Examples are illustrative, and not limiting, in nature.

EXAMPLE 1 Preparation of 2-Chloro-5-Chloromethyl-Thiazole In the Absence of Solvent

3-chloro-l-propenyl-isothiocyanate (45g) is charged to a 200 mL 3-neck flask with gas inlet, mechanical stirrer, condenser and gas outlet with appropriate traps including backflow traps and a caustic trap to neutralize HC1 produced and excess chlorine. Chlorine gas (26 g, 1.4 equivalents) is passed through the reaction, while applying no external heat. The reaction is then heated to 60°C for 2 hours. The yield of 2-chloro-5-chloromethyl-thiazole from this chlorination step is approximately 76%.

EXAMPLE 2 Multi-Step Preparation of

2-Chloro-5-Chloromethγl-Thiazole

A 500 mL flask equipped with mechanical stirrer, heating mantle thermometer and condenser, was charged with 44.6 g (0.55 moles) sodium thiocyanate (finely ground up), 218 ml 1, 1, 2-trichloroethane, 83 ml water, 55.5 g (0.50 moles) 1,3-dichloropropene (mixed cis and trans), and 0.55 g (0.002 moles) tetrabutylammonium bromide. The reaction was heated at reflux (90°C) for 90 minutes. After this reaction, the organics layer was separated from the aqueous layer, washed with water, and dried over sodium sulfate, and filtered. The resulting mixture was heated to reflux (115°C) for 4 hours, upon which the rearrangement was complete. Chlorine gas was then passed through the reaction mixture while maintaining reflux, to yield 2- chloro-5-chloromethylthiazole. Sodium bicarbonate was then added to the reaction mixture, which was then distilled to recover the 2-chloro-5-chloromethylthiazole. EXAMPLE 3 Preparation of 3-Chloro-l-Propenyl-Thiocyanate

A 3-liter, 3-neck flask equipped with mechanical stirrer, heating mantle thermometer and condenser, was charged with 368g (4.54 moles) sodium thiocyanate (finely ground up), 2000 ml acetonitrile, and 459g (4.136 moles 1,3-dichloropropene (mixed cis and trans). The slurry was stirred overnight at 25°C, then heated up to 83°C over about 30 minutes, cooled to 25°C and the pasty white solid filtered off. The filtrate was stripped off using a rotary evaporator to remove acetonitrile. The concentrate obtained was washed 2 X 300 ml water and the separated organic layer dried using Na₂S0₄, filtered, and 500-600 ml 1,4-dioxane added. The mixture was then heated with stirring at reflux (100°C) for about 9 hours. The reaction was followed by gas chromatography to verify the disappearance of the thiocyanates. After acceptable conversion to corresponding isothiocyanate, the mixture was cooled to room temperature and filtered. The filtrate was topped off on a rotary evaporator to remove dioxane. This gave a concentrate of 428.4 g containing mixed thiocyanate and isothiocyanate.

EXAMPLE 4 Cyclization to Thiazole

A 1-liter, 4-neck flask equipped with mechanical stirrer, heating mantle, thermometer, gas inlet tube, and a condenser with an outlet vented into an aqueous sodium hydroxide trap to remove chlorine, was charged with the 428.4g concentrate of mixed thiocyanates and isothiocyanates from Example 3 and 500 ml chloroform. After heating to reflux, chlorine gas was introduced under the surface, through the gas inlet tube. The chlorine was bubbled in over a period of 13 hours. Conversion was followed by gas chromatography until little or none of the starting material remains and over-chlorination was not excessive. The mixture was then cooled to room temperature and filtered off. The filtrate was concentrated using the rotary evaporator to remove chloroform. Concentrate weight was 563.4g and gas chromatographic analysis shows 74.8% 2- chloro-5-chloromethyl-thiazole, representing a 61% yield from 1,3-dichloropropene in two steps. 50g of sodium bicarbonate were added to the concentrate and it was distilled at 5-10 mm using a vacuum pump. This gave 260.4g of 2-chloro-5-chloromethyl-thiazole in 86.3% purity (32% yield) at about a 100°C vapor temperature. An additional 61g of 78% purity was taken after the main batch.

In later runs similarly performed, up to 70% recovery was obtained, and 91% purity was obtained in other distillations. Purity was also enhanced by treating concentrates with saturated sodium bicarbonate solutions (10%), drying with sodium sulfate, filtering and distilling.

EXAMPLE 5 Preparation of 2-Chloro-5-Hydroxymethγl-Thiazole

A 1-liter, 3-neck flask was charged with 127g (1.86 moles) sodium formate, 45 Aliquat 336 (tricaprylmethyl ammonium chloride) phase transfer catalyst and 131 ml heptane. With mechanical stirring and heating at reflux with a heating mantle, llOg of 91% purity chloromethylchlorothiazole (100. lg - 0.596 mole actual) were dripped in over a 2 hour period. A slight exotherm was noted. After the addition, the mixture was refluxed overnight. At this point, a sample was taken while still hot, off the top heptane layer. On cooling, this sample separated into two layers . A gas chromatograph was taken on the small bottom layer, showing 40% solvent, 43% 2- chloro-5-chloromethyl-thiazole, and 7% formate intermediate (2-chloro-5-formylmethyl-thiazole) . At this point the starting material was recovered by cooling the mixture, adding methyl t-butyl ether, filtering off the solid (with washing in ether) and topping off the ether and heptane using a rotary evaporator. This gave 88. lg containing 76.9% chlorochloromethylthiazole and 11.8% formate intermediate. Recovery was about 78%. The reaction procedure described above was repeated in a 1-liter, 3-neck flask using 85.8g sodium formate and 2.6g Aliquat 336 with 95 ml heptane. The concentrate (88. lg from above) was dripped into the slurry again and refluxed overnight. This time gas chromatography analysis showed 68% formate intermediate in the bottom oil layer and no 2-chloro-5- chloromethyl-thiazole. The mixture was then cooled to 10- 20°C and 50 ml of 25% NaOH added dropwise keeping the temperature below 25°C. After the NaOH addition was complete, the mixture was stirred at 25°C for 30 minutes and about 100 ml methyl t-butyl ether added. Gas chromatographic analysis of the top layer showed no formate intermediate and all 2-chloro-5-hydroxymethyl-thiazole.

The reaction mix was then filtered off and the salt thoroughly washed with ether. A small bottom water layer was then separated from the filtrate. The top layer of the filtrate was then dried over sodium sulfate, filtered, treated with decolorizing carbon and silica gel (stirred 30 minutes and filtered using filter aid) , and concentrated using a rotary evaporator. A 74.7g concentrate was obtained which was 83.0% (62.0g) 2-chloro-5-hydroxymethyl- thiazole. This was distilled at 15 mm vacuum at a vapor temperature of 141-143°C and pot temperature of 149-210°C using a short vigreux column. A small front end cut was discarded and a small amount of residue remained behind in the pot. The main cut weighed 56.9g and was 98.4% 2- chloro-5-hydroxymethyl-thiazole, representing a 62.8% yield from 2-chloro-5-chloromethyl-thiazole .

EXAMPLE 6 Dechlorination of 2-Chloro-5-Hydroxymethyl-Thiazole

To Form Hydroxymethyl-Thiazole

A 1.4 liter Parr hydrogenation shaker bomb was loaded with 57.25g (0.38 moles) 99.3% purity 2-chloro-5- hydroxymethylthiazole, 19. Og 50% water wet 5% Pd/C DeGussa catalyst, 36. Og sodium acetate and 600 ml ACS MeOH. It was found to be expedient to thoroughly pre-mix or wet the Pd/C with the chlorohydroxymethylthiazole first, under N₂, and then add MeOH, to avoid fire. The shaker bomb was sealed, pressurized to 150-200 psi with hydrogen, and heated with shaking at 65°C for 19 hours. Hydrogen uptake occurred rapidly the first two hours and then stopped. After cooling and venting the contents of the bomb were poured out. The Pd/catalyst was filtered off using filter aid and a medium fritted glass funnel. The filtrate was topped on a rotary evaporator, 100 ml of toluene added to slurry and the salts filtered off and washed with toluene. This filtrate was then topped and the concentrate which weighed 50.5g (87.6% finished hydroxymethyl-thiazole by gas chromatography) was distilled at 1.5 mm on a short vigreux column. Three small front end cuts were taken up to 114°C vapor temperature and 125°C liquid temperature. Cut 2 (2.1g) contained 97.9% hydroxymethyl-thiazole (1.0% AcOH) . Cut 3 (4.3g) contained 99.9% hydroxymethyl-thiazole and cut 4 (28. lg) contained 99.9% hydroxymethyl-thiazole. The yield of finished hydroxymethyl-thiazole (cuts 3 and 4) was therefore 32.3g or 76.8%. If cut 2 was considered, yield was be over 80%.

The invention has been described above with reference to preferred embodiments thereof. It will be understood that various modifications and additions can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention, and all such modifications and additions are contemplated as being a part of the present invention. In addition, all publications cited herein are indicative of the level of skill in the art, and are hereby incorporated by reference as if each had been individually incorporated by reference and fully set forth.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a thiazole compound, comprising reacting a halogenating agent with a 1-propenyl- isothiocyanate of the formula

wherein Y is a halo, trialkylamino or N-pyridinyl group and R₂ and R₃ are each a lower alkyl or benzyl group, in the absence of solvent, to form a thiazole compound of the formula

wherein Y, R₂ and R₃ are as defined above.

2. A process for preparing a thiazole compound, comprising feeding gaseous molecular halogen to a heated reaction mixture containing an organic solvent and a 1- propenyl-isothiocyanate of the formula

wherein Y is halo or a trialkylamino or N-pyridinyl group and R₂ and R₃ are each a lower alkyl or benzyl group, to form a thiazole compound of the formula

wherein Y, R₂ and R₃ are as defined above

3. The process of claim 1 or 2, wherein Y is halo

4. The process of claim 1 or 2 wherein the 1- propenyl-isothiocyanate is a 3-trialkylamino-l-propenyl- isothiocyanate and the thiazole is a 2-halo-5- triakylaminomethyl-thiazole

5. The process of claim 4 wherein the 1-propenyl- isothiocyanate is 3-trimethylamino-l-propenyl- isothiocyanate and the thiazole is 2-halo-5- trimethylaminomethyl-thiazole.

6. The process of claim 1 or 2 wherein the 1-propenyl- isothiocyanate is 3-chloro-l-propenyl-isothiocyanate, and the thiazole is 2-chloro-5-chloromethyl-thiazole.

7. The process of claim 2 wherein the gaseous molecular halogen is gaseous molecular chlorine.

8. The process of claim 2 or 7 wherein the heated reaction mixture is at a temperature of at least about 60°C.

9. The process of claim 2, 7 or 8 wherein the heated reaction mixture is at reflux.

10. The process of claim 2, 7, 8 or 9 wherein the organic solvent is a polyhalogenated lower alkane solvent.

11. The process of claim 2, 7, 8 or 9 wherein the organic solvent is a polyhalogenated ethane solvent.

12. The process of claim 11, wherein the polyhalogenated ethane solvent is 1, 1, 2-trichloroethane.

13. A process for preparing a thiazole, comprising the steps of:

(a) reacting an alkali or alkaline earth metal thiocyanate with a 1,3-dihalopropene of the formula

wherein X is halo and R₂ and R₃ are each H or a lower alkyl or benzyl group, in a heterogeneous reaction medium containing water, a water-immiscible organic solvent, and a phase transfer catalyst, so as to form a thiocyanate of the formula

(b) rearranging the thiocyanate to form an isothiocyanate of the formula

wherein X, R₂ and R₃ are defined as above, and

(c) reacting the isothiocyanate with a halogenating agent to form a thiazole of the formula

wherein X, R₂ and R₃ are as defined above,

14. A process for preparing 2-chloro-5-chloromethyl- thiazole, comprising the steps of:

(a) reacting an alkali or alkaline earth metal thiocyanate with 1,3-dichloropropene in a heterogeneous reaction medium containing water, 1, 1, 2-trichloroethane and a phase transfer catalyst to form 3-chloro-2-propenyl- thiocyanate;

(b) rearranging the 3-chloro-2-propenyl-thiocyanate to form 3-chloro-l-propenyl-isothiocyanate; and

(c) reacting the 3-chloro-l-propenyl-isothiocyanate with a chlorinating agent to form 2-chloro-5-chloromethyl- thiazole.

15. The process of claim 13, wherein said 1,3- dihalopropene is 1,3-dichloropropene, said thiocyanate is 3-chloro-2-propenyl-thiocyanate, said isothiocyanate is 3- chloro-1-propenyl-isothiocyanate, and said thiazole is 2- chloro-5-chloromethyl-thiazole .

16. The process of claim 13 or 15, wherein said water-immiscible organic solvent absorbs essentially no water.

17. The process of claim 13 or 15, wherein the polyhalogenated alkane solvent is a trichloroethane solvent .

18. The process of claim 17, wherein the trichloroethane solvent is 1, 1, 2-trichloroethane.

19. The process of any of claims 13-18, wherein said phase transfer catalyst is a quaternary ammonium phase transfer catalyst.

20. The process of any of claims 13-19, wherein said steps (a) , (b) and (c) are each conducted in the presence of the same organic solvent.

21. The process of claim 13, wherein the trichloroethane solvent is 1, 1, 2-trichloroethane.

22. The process of any of claims 13-21 and also comprising the steps of:

(d) reacting the thiazole with a carboxylic acid salt to form an ester of a corresponding 2-halo-5-hydroxymethyl- thiazole; and

(e) hydrolyzing said ester to form a corresponding 2- halo-5-hydroxymethyl-thiazole .

23. The process of claim 22 wherein the carboxylic acid salt is of the formula R_!COO^~M⁺ wherein R_λ is hydrogen, alkyl or phenyl, and M is Na, K or Li.

24. The process of claim 22 and also comprising the step of: (f) dehalogenating the 2-halo-5-hydroxymethyl-thiazole to form a corresponding 5-hydroxymethyl-thiazole.

25. The process of claim 24 wherein the thiazole is a 2-halo-5-hydroxymethyl-thiazole.

26. The process of claim 25 wherein the thiazole is 2-chloro-5-hydroxymethyl-thiazole.

27. The process of claim 26 wherein said dehalogenating is conducted in the presence of a palladium catalyst.

28. A process for preparing a thiocyanate of the formula :

wherein X is halo and R₂ and R₃ are each H or a lower alkyl or benzyl group, comprising reacting an alkali or alkaline earth metal thiocyanate with a 1,3-dihalopropene of the formula

R₂ H

^■C-C=C(X)(R₃) I H

wherein X, R₂ and R₃ are as defined above, in a heterogeneous reaction medium containing water, a water- immiscible organic solvent and a phase transfer catalyst, so as to form said thiocyanate.

29. The process of claim 28, wherein the 1,3- diahlopropene is 1,3-dichloropropene, and the thiocyanate is 3-chloro-2-propenyl-thiocyanate .

30. The process of claim 29, wherein the water- immiscible organic solvent is a polyhalogenated alkane solvent.

31. The process of claim 30, wherein the organic solvent is 1, 1, 2-trichloroethane .

32. A process for preparing a thiazole compound, comprising reacting a halogenating agent with a 1-propenyl- isothiocyanate of the formula

wherein Y is a trialkylamino or N-pyridinyl group and R₂ and R₃ are each a lower alkyl or benzyl group, to form a thiazole compound of the formula

wherein Y, R₂ and R₃ are as defined above.