6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid synthesis

Yield:145739-56-6 78.4%

Reaction Conditions:

Stage #1: 2-(2-chloroacetyl)-6-pyridine carboxylic acid;3,4-diethoxybenzthioamide in 1,2-dimethoxyethane;water; for 2 h;Heating / reflux;
Stage #2: with potassium hydroxide in water;Product distribution / selectivity;

Steps:

1.6

20 g of 2- (2-chloroacetyl) -6-pyridine carboxylic acid and 22.6 g of 3, 4-diethoxythiobenzamide were dissolved in a solution consisting of 100 ml of water and 200 ml of dimethoxyethane . The obtained solution was heated to reflux for 2 hours while stirring, and the reaction solution was then cooled to 5°C or lower, so as to obtain a yellow-brown precipitate by filtration. [0169]Subsequently, the above precipitated crystal was dissolved in a solution formed by dissolving 6.18 g of potassium hydroxide in 372 ml of water. The obtained solution was extracted with ethyl acetate twice (186 ml x 2) . Thereafter, 1 g of activated carbon was added to the separated water layer, and the obtained solution was then stirred at approximately 3O⁰C for 30 minutes. Thereafter, the activated carbon was removed by filtration, and 372 ml of acetone and 11.2 g of concentrated hydrochloric acid were then added to the obtained filtrate, so as to obtain a suspension (a mixture consisting of a tetomilast hydrate crystal and an anhydrous tetomilast type B crystal) . In order to transfer the mixture consisting of a tetomilast hydrate crystal and an anhydrous tetomilast type B crystal to an anhydrous tetomilast type A crystal, the above suspension was heated at 60⁰C for 30 minutes, and it was then cooled to room temperature, so as to obtain a crystal by filtration, thereby obtaining an anhydrous tetomilast type A crude crystal (34.82 g; wet state). [01701 8.67 g of the crude crystal was dissolved in a solution consisting of 213 ml of acetone and 53 ml of water by heating at 60⁰C without drying it, followed by filtration during a hot state. Subsequently, the obtained filtrate was heated again, and dissolution of the crystal was then confirmed. Thereafter, the filtrate was cooled to 50⁰C. 79 mg of an anhydrous tetomilast type A crystal was added as a seed crystal to the cooled filtrate, and the obtained mixture was .61 then stirred at a temperature between 42°C and 5O⁰C (internal temperature) for 2 hours. Thereafter, the obtained solution was cooled to 20°C over approximately 20 minutes, and it was then stirred at a temperature between 19⁰C and 25⁰C for 2 hours. Thereafter, the solution was cooled to 5°C over 35 minutes, and it was then stirred at a temperature between 4°C and 5°C for 2 hours, so as to obtain the precipitated crystal by filtration. The above precipitated crystal was dried at 80⁰C overnight, so as to obtain 7.25 g of an anhydrous tetomilast type A crystal (whose yield was 78.4% when 6-chloroacetyl-2-pyridine carboxylic acid was used as a reference) . The HPLC purity of the obtained anhydrous tetomilast type A crystal was 99.9%. [0171]A part of the obtained anhydrous tetomilast type A crystal melted around 175°C, and it was changed to a needle crystal. Thereafter, the above crystal completely melted (decomposed) at a temperature between 187°C and 190⁰C. [0172]The obtained anhydrous tetomilast type A crystal was subjected to thermogravimetry/differential thermal analysis. As a result, it was found that the same endothermic peak as that shown in Fig. 3 was observed. [0173]The powder X-ray diffraction spectrum of the .68 obtained anhydrous tetomilast type A crystal was measured. As a result, it was found that the same spectrum as that shown in Fig. 4 was observed. [0174] The IR(KBr) spectrum of the obtained anhydrous tetomilast type A crystal was measured. As a result, it was found that the obtained anhydrous tetomilast type A crystal had significant infrared absorption bands at 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758, and 704 cm^"1 in the IR (KBr) spectrum thereof. [0175]The obtained anhydrous tetomilast type A crystal was crushed with an atomizer, so as to obtain powders having a mean particle size of 30.4 μm and a 90% cumulative particle size of 57 μm.

References:

WO2007/119496,2007,A1 Location in patent:Page/Page column 65-68