Condensation of the piperidone (I) with 2-fluoroaniline (II), followed by reduction of the Schiff base with sodium borohydride afforded 1-benzyl-3-methyl-4-phenylaminopiperidine (III). Intermediate (III) was produced in an approximate 7:3 (cis/trans) isomeric ratio. Acylation of (III) with methoxyacetyl chloride gave compound (IV) and subsequent catalytic debenzylation gave the compound (V), which was N-alkylated in acetonitrile with 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one (VI). Brifentanil is the cis-isomer obtained by the chromatographic separation of the isomeric mixture.

Condensation of the piperidone (I) with 2-fluoroaniline (II), followed by reduction of the Schiff base with sodium borohydride afforded 1-benzyl-3-methyl-4-phenylaminopiperidine (III). Intermediate (III) was produced in an approximate 7:3 (cis/trans) isomeric ratio. Acylation of (III) with methoxyacetyl chloride gave compound (IV) and subsequent catalytic debenzylation gave the compound (V), which was N-alkylated in acetonitrile with 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one (VI). Brifentanil is the cis-isomer obtained by the chromatographic separation of the isomeric mixture.

Condensation of the piperidone (I) with 2-fluoroaniline (II), followed by reduction of the Schiff base with sodium borohydride afforded 1-benzyl-3-methyl-4-phenylaminopiperidine (III). Intermediate (III) was produced in an approximate 7:3 (cis/trans) isomeric ratio. Acylation of (III) with methoxyacetyl chloride gave compound (IV) and subsequent catalytic debenzylation gave the compound (V), which was N-alkylated in acetonitrile with 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one (VI). Brifentanil is the cis-isomer obtained by the chromatographic separation of the isomeric mixture.

The synthesis of tritium-labeled brifentanil has been described: The hydrogenolysis of 1-benzyl-3-methylpiperidin-4-one (I) with H2 over Pd/C in ethanol gives the free piperidone (II), which is condensed with 1-(2-bromoethyl)-4-ethyl-4,5-dihydro-1H-tetrazol-5-one (III) by means of NaI and Na2CO3 in acetonitrile, yielding the condensation product (IV). The reductocondensation of (IV) with 4-bromo-2-fluoroaniline by means of NaBH3CN and HCl in methanol affords the substituted aniline (VI), which is acylated with 2-methoxyacetyl chloride (VII) and submitted to chromatographic (HPLC) separation to obtain the cis-isomer of bromobrifentanil (VIII). Finally, this compound is submitted to debromination with tritium gas and Pd/C in ethanol to afford [3H]-brifentanil.