Ceftriaxone, 7-[[(2-amino-4-thiazolyl)-2-(Z)-(methyoximino)acetyl]amino]-8- oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio]methyl]-5-thia-1- azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.72), is synthesized by acylating 7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-1,2,4-triazin-5-on-3-yl)thio]methyl]3-cefem- 4-carboxylic acid (32.1.2.70), by the 2-(4-thiazolyl)-2-methoxyiminoacetic acid chloride, which is protected at the amino group by a chloroacetyl group, namely with 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetylchloride (32.1.2.67). The last is synthesized from ethyl ester of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (32.1.2.52), the amino group of which is protected by the acylation with chloracetic acid chloride in dimethylacetamide, giving ethyl ester of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid (32.1.2.65). Hydrolysis of the ester group of this compound by potassium hydroxide to an acid (32.1.2.66), and its subsequent reaction with phosphorous pentachloride in the presence of trimethylamine gives 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetylchloride (32.1.2.67). The synthesis of 7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-1,2,4-triazin-5- on-3-yl)thio]methyl]-3-cefem-4-carboxylic acid (32.1.2.70) is done in parallel.
In order to do this, methylhydrazine is reacted with potassium thiocyanate to give 1-amino-1-methylthiourea (32.1.2.68), which is reacted with dimethyloxalate in the presence of sodium methoxide to form a heterocyclization product, 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-1,2,4-triazin- 5-on (32.1.2.69). Reacting this with 7-aminocephalosporanic acid replaces the acetoxy group giving 7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-1,2,4-triazin-5-on-3-yl)thio]methyl]-3- cefem-4-carboxylic acid (32.1.2.70). Acylating this with the acid chloride synthesized earlier (32.1.2.67) in tetrahydrofuran in the presence of sodium hydroxide gives the desired product (32.1.2.71). Removal of the chloroacetyl protection in this molecule is accomplished in the following manner. Subsequent reaction of the product (32.1.2.71) with thiourea in the presence of sodium bicarbonate results in the formation of a new thiazole derivative. Subsequent cleaving of the resulting secondary heteroaromatic amine with formic acid gives ceftriaxone (32.1.2.72).