合成路线1

Reaction of the labeled chiral bromoacetylbornanesultam (I) with benzophenone imine (II) and DIEA in hot acetonitrile gives the imine (III), which is enantioselectively alkylated with isopropyl iodide and n-BuLi yielding the L-valine derivative (IV). Treatment of (IV) with HCl in THF in order to eliminate the diphenylmethylene group affords compound (V) with a free amino group that by protection with Boc2O in THF provides the L-valine derivative (VI). The hydrolysis of (VI) with LiOH in THF/water affords labeled N-(tert-butoxycarbonyl)-L-valine (VII), which is condensed with the decapeptide (VIII) by means of BOP and NMM in dichloromethane providing the linear undecapeptide (IX).

合成路线2

The reaction of 14C labeled chiral bromoacetyl sultam (I) with benzophenoneimine (II) in hot acetonitrile gives the substituted benzophenoneimine (III), which is estereoselectively alkylated with isopropyl iodide (IV) and n-BuLi in THF yielding the labeled L-valine derivative (V). The hydrolysis of (V) with HCl in THF affords the valine derivative (VI) with a free amino group that is protected with Boc2O in THF providing the carbamate (VII). The basic hydrolysis of (VII) with LiOH in THF gives the labeled N-(tert-butoxycarbonyl)-L-valine (VIII), which is esterified with Bn-OH, EDC and DMAP in dichloromethane yielding the protected benzyl ester (IX). Treatment of (IX) with TFA in dichloromethane affords L-valine benzyl ester (X), which is condensed with the bromomethylbiphenyl (XI) by means of DIEA in hot DMF to give the N-alkylated valine ester (XII). The acylation of (XII) with pentanoyl chloride (XIII) by means of DIEA in toluene yields the N-disubstituted valine ester (XIV), which is finally deprotected by hydrogenation with H2 over Pd/C in EtOH.

合成路线3

The reaction of the labeled acylated (-)-bornane-10,2-sultam (XI) with benzophenone imine (XII) gives the glycylsultam derivative (XIII), which is alkylated with 4-iodobutyl chloride (XIV) by means of butyllithium and DMPU in THF yielding intermediate (XV). The selective hydrolysis of (XV) with HCl affords the omega-chloro-L-norleucine derivative (XVI), which is cyclized by means of tetrabutylammonium fluoride and DIEA in hot acetonitrile giving the (2S)-piperidyl derivative (XVII). Finally, this compound is hydrolyzed with LiOH in THF/water to the labeled intermediate (II).

合成路线4

The reaction of 3-acetamido-4-methylbenzaldehyde (I) with malonic acid by means of piperidine in hot pyridine gives 3-(3-acetamido-4-methylphenyl)-2(E)-propenoic acid (II), which by reaction first with ethyl chloroformate and then with sodium azide yields the corresponding azide (III). The thermal cyclizaton of (III) affords the isoquinolinone (IV), which is treated with HCl in refluxing ethanol to give 6-amino-7-methylisoquinolin-1(2H)-one (V). The reaction of (V) with refluxing POCl3 yields the 1-chloroisoquinoline (VI), which is protected by reaction with phenzophenoneimine and HCl in methanol to afford 1-chloro-6-(diphenylmethyleneamino)-7-metylisoquinoline (VII). The bromination of (VII) with NBS and benzoyl peroxide in refluxing CCl4 gives the bromomethyl derivative (VIII), which is condensed with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (IX) (obtained by cyclization of the diaminobutyric acid (X) by means of HOBT in THF) by means of NaH in THF/DMF yielding the N-substituted pyrrolidone (XI). The deprotection of (XI) with HCl afford the diamino intermediate (XII), which is selectively acylated with thieno[3,2-b]pyridine-2-sulfonyl chloride (XIII) by means of triethylamine in acetonitrile giving the sulfonamidde (XIV). Finally, this compound is treated with ammonium acetate in hot phenol. The intermediate sulfonyl chloride (XIII) has been obtained as follows: The reaction of 2-ethynylpyridine (XV) with benzylthiol and sodium ethoxide in ethanol gives 2-[2-(benzylsulfanyl)vinyl]pyridine (XVI), which is cyclized at 625 C yielding thieno[3,2-bpyridine (XVII). Finally, this compound is chlorosulfonated by reaction with BuLi, SO2 and SO2Cl2 in THF.

合成路线5

Treatment of methyl 6-bromo-3-amino-2-pyrazinecarboxylate (I) with sodium nitrite (NaNO2) in H2SO4 followed by refluxing in MeOH yields methoxy derivative (II), whose Br group is converted into an amino functionality by treatment with benzophenone-imine, tris(dibenzylidene-acetone)dipalladium, (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and sodium tert-butoxide in toluene; a final treatment with HCl in THF affords amino compound (III). Treatment of methyl carboxylate of (III) with NH3(g) in MeOH gives carboxamide (IV), which is then treated with pyridine hydrofluoride and NaNO2 to furnish fluoro derivative (V). Finally, the target product is obtained by conversion of the methoxy group of (V) into a hydroxy group by reaction with NaI and trimethylsilyl chloride (TMSCl) in acetonitrile.

合成路线6