WO1998040367A1

WO1998040367A1 - Novel thiazole derivatives and their preparation

Info

Publication number: WO1998040367A1
Application number: PCT/US1998/004602
Authority: WO
Inventors: Venkataraman Ramachandran; Arcelio J. Malcolm
Original assignee: Albemarle Corporation
Priority date: 1997-03-11
Filing date: 1998-03-10
Publication date: 1998-09-17

Abstract

1-(4-Bromomethyl-2-thiazolyl)guanidine, and its acid addition salts, especially 1-(4-bromomethyl-2-thiazolyl)guanidine hydrobromide are novel compounds useful as starting materials for the synthesis of famotidine. These compounds can be produced without need for prolonged reaction periods at extremely low temperatures by mixing 1,3-dibromoacetone and 2-imino-4-thiobiuret in a suitable reaction medium. Moreover, the novel compounds can be selectively synthesized in good yield and purity from a raw material containing a combination of structurally similar analogs of 1,3-dibromoacetone.

Description

NOVEL THIAZOLE DERIVATIVES AND THEIR PREPARATION

TECHNICAL FIELD This invention relates to a novel compound which is eminently useful as a new intermediate for the efficient synthesis of the pharmaceutical, famotidine, and to the synthesis of this novel compound.

BACKGROUND

Famotidine is a well-known histamine H2-receptor antagonist and gastric acid secretion inhibitor. To prepare this compound U.S. Pat. No. 4,347,370 to D. J. Gilman, J. M. Wardleworth and T. O. Yellin describes a synthesis route in which 2-guanidino-4- chloromethylthiazole hydrochloride is used as a starting material. However, U.S. Pat. No. 4,609,737 to Y. Hirata and I. Yanagisawa points out that 2-guanidino-4- chloromethylthiazole hydrochloride is undesirable in that handling the compound is complicated since it has unfavorable properties such as an irritative odor, and it causes contact dermatitis.

To circumvent these problems U.S. Pat. Nos. 4,562,261 and 4,609,737 describe the synthesis of famotidine using N"-[4-(chloromethyl)-4,5-dihydro-4-hydroxy-2- thiazolyl]-guanidine hydrochloride as the starting material. However, to prepare this starting material, (aminoiminomethyl)thiourea was added portionwise to dichloroacetone in acetone at temperatures of -5 to -7°C and the resultant mixture was then stirred for 5 days at below O°C.

THE INVENTION

A novel compound has now been found which is eminently suited for use as a starting material for the synthesis of famotidine, and which can be produced without need for prolonged reaction periods at extremely low temperatures. Moreover, the novel compound of this invention can be selectively synthesized in good yield and purity from a raw material containing a combination of structurally similar analogs, only one of which produces the compound of this invention.

Thus one embodiment of this invention is the new compound, l-(4-bromomethyl- 2-thiazolyl)guanidine, and its acid addition salts, especially l-(4-bromomethyl-2- thiazoly 1)] -guanidine hydrobromide .

Another embodiment of this invention is a process for the preparation of l-(4- bromomethyl-2-thiazolyl)guanidine and/or the hydrobromide salt thereof which comprises mixing 1,3-dibromoacetone and 2-imino-4-thiobiuret in a suitable organic solvent (or in a water medium) and maintaining the resultant reaction mixture at one or more temperatures in the range of from 0 to 100°C. Solvents such as esters, hydrocarbons, and ketones such as acetone, methyl ethyl ketone, 2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone, or cyclohexanone, including mixtures of two or more of the foregoing, and mixtures with water, are suitable for use as the liquid reaction medium, with acetone being a preferred solvent for the reaction.

Among the advantages of this invention is that it is unnecessary to perform the reaction at temperatures of 0°C and below, and indeed it is preferable to conduct the reaction at temperatures in the range of 20 to 80 °C for at least 50 percent of the total reaction period. Moreover, the reaction is relatively rapid under these conditions, and usually involves reaction periods in the range of 1 to 10 hours. To assist is temperature control, it is desirable to pre-cool at least the ketone reaction medium (which may contain either reactant, preferably the 1,3-dibromoacetone) to a temperature in the range of 0 to 10 °C before initiating the feed of the two reactants, or the feed of the second reactant to be fed. Upon initiation of the reaction, the exotherm will heat up the reaction mixture to desirable reaction temperatures. As the end of the reaction period approaches, it is desirable, but not necessary, to apply heat to the reaction mixture. The reaction mixture should be agitated as by use of a mechanical stirrer to ensure thorough mixing of the reactants within the reaction mixture. Another advantage of this invention is the discovery that the 1,3-dibromoacetone used as the raw material for producing the compound of this invention need not be of high purity. Indeed, the 1,3-dibromoacetone can contain significant amounts of monobromo- acetone and 1,1,3-tribromoacetone without these analogous compounds affecting the purity of the desired product to any significant extent in the reaction. This in turn has a favorable effect upon raw material costs and process economics. Accordingly, the 1,3- dibromoacetone used in the process can contain monobromacetone or 1,1,3- tribromoacetone, or both, in an amount of up to 0.3 mole per mole 1,3-dibromoacetone.

The acid addition salts of l-(4-bromomethyl-2-thiazolyl)]guanidine provided by this invention include the salts of inorganic acids such as sulfuric acid, hydrobromic acid, orthophosphoric acid, metaphosphoric acid, pyrophosphoric acid, orthophosphorous acid, and thiophosphoric acid, and salts of organic acids such as oxalic acid, malonic acid, bromoacetic acid, and salicylic acid. The preferred salt is l-(4-bromomethyl-2- thiazoly 1)] guanidine hydrobromide .

The following examples, wherein all percentages are by weight, illustrate the practice and advantages of this invention, and are not to be construed as constituting limitations on the invention.

EXAMPLE 1 l-(4-Bromomethyl-2-thiazolyl)guanidine 1,3-Dibromoacetone (50.7 g of 92% purity and thus equivalent to 46.6 g, 0.216 mol) was dissolved in acetone (150 mL) and cooled to 5°C. 2-Imino-4-thiobiuret (28.3 g, 0.24 mol) was added (exotherm to 45 °C), and the reaction was stirred (with a mechanical stirrer) for 1 hr at ambient temperature, and 1 hr at 50-55 °C. After cooling to room temperature, the product was collected via filtration, washed with acetone (35 mL), and dried under high vacuum, affording 66.5 g (98%) of a white powdery solid. HPLC showed the purity to be 91 % . The product has the formula:

It will be appreciated that the guanidine moiety is capable of undergoing tautomerization to a terminal -NH-C(-NH₂)(=NH) moiety.

Examples 2 through 4 illustrate the usefulness of the compound of this invention as a starting material in a three-step synthesis of famotidine. EXAMPLE 2 l-[4-(Cyanoethylthiomethyl)-2-thiazolyl]guanidine Thiourea (30.4 g, 0.40 mol) was dissolved in water (440 mL), product formed as in Example 1 above (124.5 g, 0.394 mol) was added, and the reaction mixture was stirred for 1 hr at 50-55 °C. After cooling to 5°C, chloropropionitrile (41.2g, 0.46 mol) and 2- propanol (215 mL) were added, and NaOH (65 g) in water (240 mL) was added over 1 hr (temperature kept below 10°C). The reaction mixture was stirred 2 hr at 0°C, filtered, and the solid product washed with water (120 mL). The slightly tan product was dried overnight under high vacuum, affording 84.4 g of product (89% yield). This product has the formula

EXAMPLE 3

Methyl 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]- thiojpropionimidate

In a 5.0-liter jacketed flask under inert atmosphere was added 1.0 liter of anhydrous dimethylformamide, (502 g, 2.08 moles) of l-[4-(cyanoethylthiomethyl)-2-thiazolyl]- guanidine, and 1.0 liter of anhydrous methanol (dried over NaH). The reaction mixture was cooled to -20 °C and 1.04 kg of anhydrous HC1 was added over a period of eight hours (maintaining the temperature below 5 °C). After stirring the reaction mixture for two days

(0-5 °C), the reaction mixture was transferred (with the use of a 0.25" canula) under nitrogen to a cooled (-10°C) solution of 4375 g ofK₂CO₃ in 12.1 Hters ofwater and 519 mL of ethyl acetate in a 22-liter round bottomed flask equipped with an overhead stirrer. The mixture is stirred for two hours at 0 to 5° C. The resultant precipitate is collected by filtration and enough cold water is added to make a stirrable slurry, and the mixture is stirred for 30 minutes to remove KC1. The precipitate is collected, and dried under vacuum to yield 463 g (yield 82%) of the above-named imidate ester (about 94% purity by HPLC). This product has the formula

EXAMPLE 4

3-[[[2-[(Diaminomethylene)amino]-4-thiazolyl]methyl]-thio]-N- sulfamoylpropionamidine (Generic name, Famotidine)¹

In 1.5 liters of anhydrous methanol was added 396 g (4.125 moles) of sulfamide. The mixture was heated to 55 °C to dissolve the sulfamide. The solution was cooled to 30 °C, and 512 g of imidate ester (1.875 moles) prepared according to Example 3 was added and stirred at room temperature for 2 days. The crystalline product formed was collected by filtration, washed with 400 mL of cooled methanol, and air dried at room temperature to afford 310 g (49%> yield) of the desired product, which can be represented by the formula

O

Examples 5 and 6 illustrate the fact that relatively impure 1,3-dibromoacetone contaminated with 1-bromoacetone and/or 1,1,3-tribromoacetone can be effectively used in forming the compound of this invention without any appreciable adverse effect, due to the surprising high selectivity of the reaction with 2-imino-4-thiobiuret.

¹ Other chemical names for the compound, include 3-[[[2- [(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulfonyl)- propanimidamide and N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4- thiazoyl]methyl]thio]propanimidamide; the compound normally exists as the monohydrochloride . EXAMPLE 5 l-(4-Bromomethyl-2-thiazolyl)guanidine 1,3-Dibromoacetone (108 g, 0.50 mol) of only 83.5% purity was dissolved in acetone (400 mL) and cooled to 0°C. 2-Imino-4-thiobiuret (59 g, 0.50 mol) was added as a solid (the temperature went up to about 40 °C) and the reaction mixture was stirred 30 minutes at 0°C, 45 minutes at 25 °C, and 60 minutes at 55 °C. The reaction mixture was cooled to 10°C, the solid product was collected on a funnel, and the product was washed with acetone (75 mL). This product was used in wetcake form in the process of Example 6. EXAMPLE 6 l-[4-(Cyanoethylthiomethyl)-2-thiazolyl]guanidine

The wetcake from Example 5 was added to thiourea (38 g, 0.51 mol) dissolved in water (350 mL) and the reaction mixture was heated to 50-55 °C for 1 hour. The solution was cooled to 0°C, 3-chloropropionitrile (49.2 g) and 2-propanol (180 mL) were added, and NaOH (81 g) in water (300 mL) was added over 1 hour (keeping the temperature below

10°C). The reaction mixture was stirred 2 hours at 0°C, and product was collected on a filter, washed with water (100 mL), and dried under vacuum, affording 105.5 g (88%>) of offwhite, granular crystals of l-[4-(cyanoethylthiomethyl)-2-thiazolyl] guanidine with a purity of 95% by HPLC. It will be noted that an essentially quantitative yield of 1 - [4-(cyanoethylthiomethyl)-

2-thiazolyl]guanidine based on dibromoacetone was achieved in the reaction sequence of

Examples 5 and 6. Thus, 84%> of the 108 g of the initial crude 1,3 -dibromoacetone was equivalent to 90.7 g or 0.42 mole of 1,3-dibromoacetone. From this was produced 105.5 g of the end product having a purity of 95%>. This is equivalent to 100.2 g or 0.416 mole of l-[4-(cyanoethylthiomethyl)-2-thiazolyl]guanidine.

It is to be understood that the reactants and components referred to by chemical name or formula anywhere in the specification or claims hereof, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g., another reactant, or a solvent). It matters not what preliminary chemical changes, transformations and/or reactions, if any, take place in the resulting mixture or solution or reaction medium as such changes, transformations and/or reactions are the natural result of bringing the specified reactants and/or components together under the conditions called for pursuant to this disclosure. In short, the reactants and components are identified as ingredients to be brought together in connection with performing a desired chemical reaction or in forming a mixture to be used in conducting a desired reaction. Accordingly, even though the claims hereinafter may refer to substances, components and/or ingredients in the present tense ("comprises", or "is" ), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure. Thus the fact that a substance, component or ingredient may have lost its original identity through a chemical reaction or transformation during the course of contacting, blending or mixing operations, if conducted in accordance with this disclosure and with the application of common sense and the ordinary skill of a chemist, is thus wholly immaterial for an accurate understanding and appreciation of the true meaning and substance of this disclosure and the claims thereof.

The structural formulas presented herein are for the purpose of illustrating the molecular makeup of the compounds depicted. However, such formulas do not represent geometric or spatial configurations or isomeric forms of the compounds.

Claims

1. A compound selected from l-(4-bromomethyl-2-thiazolyl)guanidine, and acid addition salts thereof.

2. 1 -(4-Bromomethyl-2-thiazolyl)guanidine, a compound of Claim 1.

3. l-(4-Bromomethyl-2-thiazolyl)guanidine hydrobromide, a compound of

Claim 1.

4. A process for the preparation of l-(4-bromomethyl-2-thiazolyl)guanidine or l-(4-bromomethyl-2-thiazolyl)guanidine hydrobromide, or a mixture thereof, which process comprises mixing 1,3 -dibromoacetone and 2-imino-4-thiobiuret in proportions of 1 to 2 mole of 2-imino-4-thiobiuret per mole of 1,3 -dibromoacetone in a liquid, chlorine- free ketone solvent and maintaining the resultant reaction mixture at one or more temperatures in the range of from -IO C to 100°C, with the proviso that for at least 50 percent of the reaction period, the temperature of the reaction mixture is in the range of 20 to 100°C.

5. A process according to Claim 4 wherein the 2-imino-4-thiobiuret is added to a solution of the 1,3 -dibromoacetone in said ketone solvent which has been pre-cooled to a temperature in the range of 0 to 10°C before initiating the feed of 2-imino-4-thiobiuret thereto.

6. A process according to Claim 4 wherein the 1,3 -dibromoacetone used contains monobromacetone and/or 1,1,3-tribromoacetone in an amount of up to about 0.3 mole per mole 1,3 -dibromoacetone.

7. A process according to Claim 4 wherein the ketone solvent consists essentially of acetone.