合成路线1

1) By condensation of 2 chloropyrazine (I) with N-acetylphenylhydroxylamine (II) by means of NaH in DMF (or NaOH in DMF - water; or with K2CO3 in acetone).

合成路线2

2) The condensation of (I) with benzyl-N-hydroxy-N-phenylcarbamate (III) in ethanolic KOH gives 5-[4-(benzyloxycarbonylamino)phenyl]pyrazin-2(1H)-one (IV), which is hydrolyzed witn HBr in acetic acid yielding 5-(4-aminophenyl)pyrazin-2(1H)-one (V). Finally, this compound is acetylated with acetic anhydride.

合成路线3

4-Amino-1-phenethylpiperidine (I) is stirred with chloropyrazine (II) and copper powder in phenyl ether at 170-175 C to obtain 1-phenethyl-4-[N-(pyrazinyl)amino]piperidine (III). Subsequent acylation of (III) with 2-furoyl chloride in 1,2-dichloroethane yields mirfentanil as the hydrochloride salt after cooling and filtration. Further purification is achieved by recrystallization from n-propanol.

合成路线4

Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III), which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF. In a different procedure, bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide, followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII), which was further reduced to (IV) by using LiAlH4 in Et2O.

合成路线5

合成路线6

合成路线7

Reduction of methyl 4-formyl-3-nitrobenzoate (XIII) by means of Fe and HCl in EtOH, followed by Friedländer condensation of the resulting aminoaldehyde with acetophenone (XIV) in the presence of KOH at 95 °C, and treatment with HCl, yields 2-phenylquinoline-7-carboxylic acid hydrochloride (XV). Reduction of acid (XV) with LiAlH4 in THF gives alcohol (XVI), which is then oxidized by means of MnO2 in CHCl3 to give 2-phenylquinoline-7-carbaldehyde (XVII). Coupling of carbaldehyde (XVII) with the metalated derivative of 2-chloropyrazine (XVIII) in the presence LTMP (prepared from BuLi and TMP) in THF yields the diaryl carbinol (XIX), which is then subjected to Mitsunobu reaction with phthalimide (XX) in the presence of PS-PPh3 and DIAD in THF to provide the N-substituted phthalimide (XXI). Hydrazinolysis of phthalimide (XXI) with NH2NH2 in EtOH/CH2Cl2 then affords amine (I).
Alternatively, carbaldehyde (XVII) can be prepared by arylation of 7-methylquinoline (XXII) with phenyl lithium in THF, followed by air oxidation to produce 7-methyl-2-phenylquinoline (XXIII). Side chain oxidation of (XXIII) using SeO2 at 160 °C provides the target aldehyde (XVII) .

合成路线8

Metalation of 2-chloropyrazine (XVIII) with LTMP (prepared from BuLi and TMP) in THF, followed by formylation with DMF and subsequent reduction with NaBH4 yields (3-chloro-2-pyrazinyl)methanol (XXXI). Mitsunobu coupling of alcohol (XXXI) with phthalimide (XX) in the presence of PPh3 and DIAD in THF gives the N-substituted phthalimide (XXXII), which is then subjected to hydrazinolysis with NH2NH2 in CH2Cl2 to provide, after treatment with HCl, (3-chloro-2-pyrazinyl)methylamine dihydrochloride (XXXIII) . Coupling of amine (XXXIII) with succinimidyl ester (XXXIV) (prepared by condensation of 3-oxocyclobutanecarboxylic acid [XXXVI] with N-hydroxysuccinimide [XXXV] using DCC in isopropyl acetate [3]) in the presence of NaHCO3 in THF/H2O produces the 3-oxocyclobutanecarboxamide (XXXVII). Cyclization of amide (XXXVII) in the presence POCl3 and DMF in EtOAc affords 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (XXXVIII), which is then brominated by means of NBS in DMF to yield the 1-bromo derivative (XXXIX) . Addition of CH3MgI to ketone (XXXIX) in THF, followed by chloride substitution with NH3, gives rise to cis-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (XII) .