Laboratory Synthesis Of Famotidine

Famotidine Synthesis

Use: ulcer therapeutic, H2-receptor antagonist

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The reaction ot S-(2-aminothiazol-4-ylmethyl)isothiourea (I) with 3-chloropropionitrile (II) by means of NaOH in ethanol - water gives 3-(2-aminothiazol-4-ylmethylthio)propionitrile (III), which is condensed with benzoyl isothiocyanate (IV) in refluxing acetone to afford 3-[2-(3-benzoylthioureido)thiazol-4-ylmethylthio]propionitrile (V). The hydrolysis of (V) with K2CO3 in acetone - methanol - water yields 3-(2-thioureidothiazonl-4-ylmethylthio)propionitrile (VI), which by methylation with methyl iodide in refluxing ethanol is converted into 3-[2-(S-methylisothioureido)thiazol-4-ylmethylthio]propionitrile hydroiodide (VII). The reaction of (VII) with NH3 and NH4Cl in methanol at 90 C in a pressure vessel affords 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile (VIII), which by partial alcoholysis with methanol by means of dry HCl in CHCl3 is converted into methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate (IX). Finally, this compound is treated with sulfamide in refluxing methanol.

 

SYNTHESIS REFERENCE

Drugs Fut 1983, 8, 1, 14

US 4283408

DOS 2 951 675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979).

DOS 3 008 056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979).

GB 2 052 478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979).

GB 2 055 800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979).

synthesis of S-[2-aminothiazol-4-ylmethyl]isothiourea:

Spragne, J.M.; Lund, A.H.; Ziegler, C.: J. Am. Chem. Soc. (JACSAT) 68, 2155 (1946).