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2) Hexadeuteroethyl alcohol (IX) is treated with red phosphorus and I2 at reflux temperature to give pentadeuteroethyl iodide (X), which is condensed with potassium phthalimide (XI) in DMF, yielding N-(pentadeuteroethyl)phthalimide (XII). The hydrolysis of (XII) with hydrazine and HCl affords pentadeuteroethylamine (XIII), which is condensed with 1-methylpiperidin-4-one (III) and formaldehyde (XIV) in a Mannich reaction to give 3-methyl-7-(pentadeuteroethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (XV). The reduction of (XV) with NaBH4 as before yields the diastereomeric mixture (XVI + XVII). Finally, the alpha-isomer (XVI) is condensed with 4-chlorobenzoyl chloride (VIII) as before to give the pentadeuterium-labeled bisaramil.

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1) The mesylation of 5'-O-tritylthymidine with mesyl chloride gives the corresponding 3'-O-mesyl derivative (II), which is cyclized by means of potassium phthalimide (III) in hot DMF water, yielding 5'-O-trityl-2,3'-anhydrothymidine (IV). The reaction of (IV) with sodium azide in refluxing DMF - water affords 5'-O-trityl-3'-azido-3'-deoxy thymidine (V), which is finally deprotected with 80% aqueous acetic acid at 100 C.

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A new synthesis for Y-26611 has been reported: The reaction of 4-benzyl-2-(chloromethyl)morpholine (I) with potassium phthalimide (II) in refluxing DMF gives 4-benzyl-2-(phthalimidomethyl)morpholine (III), which is treated with hydrazine hydrate in refluxing ethanol yielding 2-(aminomethyl)-4-benzylmorpholine (IV). The acetylation of (IV) with acetic anhydride in cool toluene affords 2-(acetamidomethyl)-4-benzylmorpholine (V), which is debenzylated by hydrogenation with hydrazine hydrate over Pd/C in isopropanol to give 2-(acetamidomethyl)morpholine (VI). The condensation of (VI) with 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) by means of triethylamine in refluxing acetonitrile yields 7-[2-(acetamidomethyl)morpholin-4-yl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VIII), which is finally deacetylated with refluxing aqueous HCl.

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Reaction of 1,4-dibromopentane (XI) with potassium phthalimide (XII) gives N-(4-bromopentyl)phthalimide (XIII), which is then treated with NaI in refluxing acetone.

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The starting compound phthalimido derivative (I) could be obtained as follows: The condensation of 2-[2-(2-chloroethoxy)ethoxy]ethanol (VI) with potassium phthalimide (VII) in refluxing DMF gives the expected phthalimido derivative (VIII), which is oxidized with the Jones reagent in acetone yielding 2-[2-(2-phthalimidoethoxy)ethoxy]acetic acid (IX). The condensation of (IX) with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (X) by means of carbonyldiimidazole (CDI) and pyridine in dichloromethane affords 2,2-dimethyl-5-[2-[2-(2-phthalimidoethoxy)ethoxy]acetyl]-1,3-dioxane-4,6-dione (XI), which is finally treated with refluxing ethanol to obtain the phthalimido derivative (I) used as starting material.

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Substitution on dibromobutene (I) by potassium phthalimide (II) provided bromobutenyl phthalimide (III). Further treatment with sodium acetate afforded acetate (IV) which, after hydrolysis, gave phthalimidobutenol (V). Reaction with refluxing ethyl orthoacetate in the presence of a trace of butyric acid generated the intermediate ketene acetal (VI), which experienced a Claisen rearrangement to give pentenoate ester (VII). Ozonolysis of the olefinic double bond of (VII) yielded aldehyde (VIII). Then, Wittig reaction of aldehyde (VIII) with (isopropylidene)triphenylphosphorane in cold THF provided olefin (IX), which was hydrogenated in the presence of Pd/C to give the isobutyl compound (X). Finally, hydrolysis of both ester and phthalimide groups in refluxing 6 N HCl provided the GABA analogue.

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A new synthesis of S-4661 has been reported: The esterification of trans-4-hydroxy-L-proline (I) with methanol/HCl gives the corresponding methyl ester (II), which is N-protected as trans-N-(4-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester (III). The mesylation of (III) with methanesulfonyl chloride and triethylamine in dichloromethane affords the 4-O-mesylate (IV), which is treated with sodium triphenylmethylsulfide giving cis-N-(4-methoxybenzyloxycarbonyl)-4-(triphenylmethylsulfanyl)-L-prolin e methyl ester (V). The reduction of (V) with LiBH4 in THF yields the corresponding methanol (VI), which is mesylated as before affording (VII). The reaction of (VII) with potassium phthalimide (VIII) gives the adduct (IX), which is cleaved with hydrazine yielding (2S,4S)-2-(aminomethyl)-1-(4-methoxybenzyloxycarbonyl)-4-(triphenylmeth ylsulfanyl)pyrrolidine (X). The condensation of (X) with N-(4-methoxybenzyl)sulfamoyl chloride (XI) by means of triethylamine affords the corresponding protected sulfamide (XII). Deprotection of the trityl group of (XII) by treatment with silver nitrate and pyridine affords compound (XIII) with a free SH group. The reaction of (XIII) with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-methoxybenzyl ester (XIV) by means of diisopropylethylamine yields the protected final product (XV), which is finally treated with AlCl3 in anisole to eliminate the protecting groups.

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2) The chiral intermediates the amine (I) and the acid (II) have been obtained as follows: 2a) The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

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2a) The chiral intermediate amine (I) has been obtained as follows: The bromination of 1-tetralone (IV) with Br2 in methanol gives the 2-bromotetralone (V), which is treated with hydroxylamine yielding the corresponding oximae (VI). The isomerization of (V) with polyphosphoric acid (PPA) at 80 C affords the benzazepinone (VII), which is treated with potassium phthalimide (VIII) in DMF to give the corresponding phthalimido derivative (IX). The reaction of (IX) with tert-butyl bromoacetate (X) by means of potassium tert-butoxide in DMF yields the benzazepinoacetic ester (XI), which is treated with hot ethanolamine to eliminate the phthalimido group yielding racemic (I). Finally, this racemate is submitted to optical resolution with L-(+)-tartaric acid to afford the chiral (S)-intermediate (I).

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Alkylation of potassium phthalimide (I) with an excess of 1,8-dibromooctane (II) in refluxing acetone afforded N-(8-bromooctyl)phthalimide (III). This was condensed with 6-O-demethylgalanthamine (IV) in the presence of Et3N in boiling acetonitrile to give phthalimidooctyl compound (V). Finally, reaction with N-bromosuccinimide in the presence of azobisisobutyronitrile provided the iminium bromide.

合成路线11

After bromination of the methyl group of (XII) with N-bromosuccinimide in the presence of 2,2'-azobis(isobutyro-nitrile) to give (XIII), the aminomethyl derivative (XVI) was obtained by condensation with potassium phthalimide (XIV) in DMF and subsequent hydrazinolysis of the resulting (XV). Treatment with methanesulfonyl chloride and triethylamine then provided sulfonamide (XVII), and the ester function was finally hydrolyzed to the target carboxylic acid with NaOH in a mixture of H2O/MeOH/THF.

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Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.

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Lithiation of 1-(N-N-dimethylsulfamoyl)imidazole (I) followed by reaction with tert-butyldimethylsilyl chloride produced the 2-silyl protected imidazole (II). Further lithiation of (II) allowed the introduction of a bromohexyl group at position 5 upon treatment with 1,6-dibromohexane yielding (III). Bromide (III) was subsequently converted into primary amine (VI) through a Gabriel synthesis involving condensation with potassium phthalimide (IV) with concomitant desilylation, and then hydrazinolysis of the resulting alkylated phthalimide (V). Condensation of amine (VI) with naphthalene-2-sulfonyl chloride (VII) furnished sulfonamide (VIII). The sulfamoyl protecting group of (VIII) was finally removed by hydrolysis with HCl.

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