合成路线1

The reaction of gamma-butyrolactone (I) with Br2 and PBr3 at 100 C followed by a treatment with SOCl2 gives 2,4-dibromobutanoyl chloride (II), which is condensed with O-methylhydroxylamine by means of NaOH in CHCl3 yielding N-methoxy-3-bromopyrrolidin-2-one (III). The reaction of (III) with triphenylphosphine (IV) in hot THF affords the triphenylphosphonium salt (V), which is finally condensed with 3,5-di(tert-butyl)-4-hydroxybenzaldehyde (VI) by means of triethylamine in hot ethanol.

合成路线2

The condensation of gamma-butyrolactone (I) with phenethyl amine (II) at high temperatures afforded phenethylpyrrolidinone (III). This was alkylated with isobutyl iodide (IV) in the presence of lithium diisopropylamide in cold THF yielding the 3-isobutyl pyrrolidinone (V), and further alkylated with tert-butyl bromoacetate (VI) to give (VII). Subsequent alkylation of (VII) at the alpha-position of carboxylate group with allyl bromide provided (VIII). Ozonolysis of the double bond of (VIII), followed by reductive treatment with NaBH4 produced alcohol (IX), which was coupled with dibenzyl iminodicarboxylate (X) under Mitsunobu conditions giving (XI). The biscarbamate (XI) was deprotected by hydrogenolysis over Pd/C, and the resulting primary amine (XII) was condensed with 3,4-difluorobenzoyl chloride (XIII) to furnish amide (XIV). Then, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XIV) provided the corresponding carboxylic acid, which was finally coupled with hydroxylamine by means of EDC and HOBt to afford the target hydroxamic acid

合成路线3

Reaction of 4-chloroaniline (I) with gamma-butyrolactone (II) in a refluxing solution of HCl afforded pyrrolidinone (III). Subsequent carboxylation of (III) with diethyl carbonate in the presence of NaH gave ketoester (IV), which was reduced to alcohol (V) using calcium borohydride in MeOH. Further treatment of (V) with methanesulfonyl chloride and Et3N provided the corresponding mesylate (VI). Methoxyethylpiperazine (IX) was prepared by alkylation of formylpiperazine (VII) with 2-methoxyethyl bromide, followed by acid deprotection of the alkylated formylpiperazine (VIII). Then, condensation of mesylate (VI) with piperazine (IX) provided racemic (X). Finally, resolution with D-tartaric acid in EtOH yielded the target (R)-isomer.

合成路线4

Coupling of ethyl phenylsulfinylfluoro acetate (I) with bromo derivative (II) by means of NaH in DMF yields ethyl hexenoate (III), which is then oxidized by means of Jones reagent in acetone to provide 5-carboxy pentenoate derivative (IV). Alternatively, compound (IV) can be obtained as follows: eduction of gamma-butyrolactone (V) in THF with aluminum diisobutylhydride in toluene affords gamma-butyrolactol (VI), which is treated with ethyl (diethoxyphosphoryl)fluoroacetate (VII) and sodium bis(trimethylsilyl)amide in THF to provide an isomeric mixture of hexenoates (VIII). O-Protection of (VIII) by means of tert-butyldiphenylchlorosilane and imidazole in DMF followed by chromatographic separation of the geometrical isomers furnishes hexenoate (Z)-(IX), which is finally oxidized with Jones reagent in acetone. Conversion of carboxylic acid (IV) into bicycle (±)-(X) is then performed by first reaction with oxalyl chloride in refluxing hexane to form the corresponding acid chloride, followed by treatment with diazomethane in ether and subsequent reaction with cooper(II) bis(N-tert-butylsalicylaldiimidate) in refluxing benzene. Treatment of oxobicycle (±)-(X) with LiHMDS and chlorotrimethylsilane in THF followed by reaction with palladium acetate in acetonitrile gives 6-fluoro-2-oxobicyclo[3.1.0]hex-3-en-6-carboxylate (±)-(XI), from which epoxide (±)-(XII) is obtained by reaction in toluene with tert-butyl hydroxyperoxide (TBHP) and benzyltrimethylammoniumhydroxide (Triton B) in MeOH or EtOH. Epoxide reduction of (±)-(XII) using diphenyl diselenide (PhSe)2 and sodium borohydride in the presence of HOAc in EtOH, or by means of (PhSe)2, N-acetyl-L-cysteine and sodium tetraborate decahydrate in H2O:EtOH, yields hydroxy derivative (±)-(XIII), which is converted into ethylenedithio derivative (±)-(XV) by first protection of the hydroxyl group with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole, followed by thioketalization with 1,2-ethanedithiol (XIV) and boron trifluoride-diethylether complex in CHCl3 (with subsequent TBS group removal during work-up). Oxidation of the hydroxyl group of (±)-(XV) with DMSO and dicyclohexylcarbodiimide (DCC) in the presence of pyridine and TFA gives ketone (±)-(XVI), which is then hydrolyzed with NaOH in EtOH and subjected to reaction with KCN and ammonium carbonate (Bucherer-Bergs conditions) to yield hydantoin (±)-(XVII). Coupling of (±)-(XVII) with (R)-(+)-1-phenylethylamine using EDC-HCl and HOBt followed by chromatographic separation of the two resulting diastereomers furnishes (1R,2S,5R,6S)-(XIX), which is finally converted into the desired product after hydrolysis with H2SO4.

合成路线5

Acetophenone (I) is condensed with gamma-butyrolactone (II) in the presence of NaOMe to afford compound (III), which is finally treated with BF3·Et2O and amine (IV) in dichloromethane/ether. Alternatively, the target compound can be synthesized by regioselective bromination of (III) with PBr3 in dichloromethane to yield bromo derivative (V) followed by heating with primary amine (IV) in MeOH. (Under forceful conditions (V) can be converted into intermediate (VI), which by heating in MeOH in the presence of primary amine (IV) can also lead to the desired product).

合成路线6

Treatment of gamma-butyrolactone (I) with N,O-dimethylhydroxylamine in the presence of dimethylaluminium chloride afforded the corresponding Weinreb amide (II), which was converted to the keto-alcohol (III) by addition of pentylmagnesium bromide. Swern oxidation of alcohol (III), followed by Wittig reaction of the resultant aldehyde (IV) with (methoxycarbonylmethylene)triphenylphosphorane (V), provided the unsaturated keto ester (VI). Subsequent scandium triflate-mediated peroxyhemiacetalyzation of ketone (VI) gave rise to (VII). Then, intramolecular Michael addition of the hydroperoxy ester (VII) in the presence of diethylamine generated the target cyclic peroxide.

合成路线7

Dimethylaluminium chloride-catalyzed ring opening of butyrolactone (I) with N,O-dimethylhydroxylamine furnishes the N-methoxy amide (II). Subsequent condensation of the Weinreb amide (II) with pentylmagnesium bromide (III) gives rise to the hydroxy ketone (IV). Further oxidation of the primary alcohol function of (IV) under Swern conditions leads to keto aldehyde (V). Then, Wittig condensation of aldehyde (V) with (methoxycarbonylmethylene) triphenylphosphorane (VI) affords the unsaturated ester (VII). Treatment of (VII) with urea-hydrogen peroxide in the presence of scandium triflate generates the hydroperoxide compound (VIII), which undergoes further intramolecular ring closure in the presence of triethylamine, leading to the 1,2-dioxane (IX). Enzymatic hydrolysis of ester (IX) employing pig liver esterase gives acid (X). After activation of (X) as the corresponding pentafluorophenyl ester (XI), condensation with propylamine in pyridine provides the title N-propyl amide

合成路线8

合成路线9

合成路线10