合成路线1

Reduction of morpholinone (I) with L-Selectride in THF at -78 C produced the intermediate lactol (II), which was condensed at low temperature with 3,5-bis(trifluoromethyl)benzoyl chloride (III) to afford acyl acetal (IV). Further reaction with dimethyl titanocene in THF-toluene at 80 C provided enol ether (V). Catalytic hydrogenation of the double bond, with concomitant N-benzyl group hydrogenolysis, yielded a 8:1 mixture of diastereomers, from which the major isomer (VI) was isolated by column chromatography. Alkylation of morpholine (VI) with N-methoxycarbonyl-2-chloroacetamidrazone (VII) (obtained by reaction of chloroacetonitrile (IX) with NaOMe and methyl carbazate in MeOH) in the presence of N-ethyl diisopropylamine (DIEA) in acetonitrile gave the intermediate (VIII), which was finally cyclized to the desired triazolone in refluxing xylene.

合成路线2

Synthesis of 250157: Alternatively, the final compound can be obtained by direct condensation of (VI) with chlorotriazolinone (XXVI) in DMF/H2O in the presence of K2CO3 or DIEA. For the obtention of (XXVI), two routes can be followed: 1. Reaction of semicarbazide (XXVII) with orthoester (XXVIII) in MeOH; and 2. Condensation of semicarbazide (XXVII) with benzyloxyacetyl chloride (XXIX) in THF/H2O in the presence of NaOH to provide adduct (XXX), which is then cyclized by means of refluxing NaOH to afford triazolinone (XXXI). Debenzylation of (XXXI) by hydrogenation over Pd/C in MeOH/H2O yields alcohol (XXXII), which is finally treated with thionyl chloride.

合成路线3

Reductive alkylation of (S)-(4-fluorophenyl)glycine (VI) with benzaldehyde and NaBH4 generated the N-benzyl amino acid (XI). This was cyclized with 1,2-dibromoethane (XII) to yield the morpholinone (XIII). Reduction of the lactone function of (XIII) with L-Selectride at -70 C, followed by acylation of the intermediate lactol (XIV) with 3,5-bis(trifluoromethyl)benzoyl chloride (XV), furnished the aroyloxy morpholine (XVI) as the main isomer. Ester (XVI) was converted to the enol ether (XVII) upon treatment with dimethyltitanocene, generated from titanocene dichloride and methyllithium. Catalytic hydrogenation of the enol ether double bond of (XVII) with simultaneous benzyl group hydrogenolysis generated the desired morpholine (XVIII) along with its diastereoisomer (XIX); these were separated by flash chromatography.

合成路线4

In an alternative route to morpholine (XVIII), bromination of 1,3-bis(trifluoromethyl)benzene (XX) by means of 1,3-dibromo-5,5-dimethylhydantoin (XXI) yielded bromide (XXII). The Grignard reagent prepared from aryl bromide (XXII) was acylated with acetic anhydride at -15 C to produce acetophenone (XXIII). Enantioselective reduction of ketone (XXIII) with ruthenium(II) chloride in the presence of (1S,2R)-cis-1-amino-2-indanol furnished the (R)-alcohol (XXIV). N-Benzyl ethanolamine (XXV) was condensed with glyoxylic acid (XXVI) to give the hydroxy oxazinone (XXVII). This was coupled with the chiral alcohol (XXIV) using trifluoroacetic anhydride and boron trifluoride etherate to afford the target (R,R)-adduct (XXVIII) as the main diastereoisomer. Addition of 4-fluorophenylmagnesium bromide (XXIX) to the lactam function of (XXVIII), followed by catalytic hydrogenation of the intermediate (XXX), provided the required disubstituted morpholine (XVIII).

合成路线5

From the intermediate morpholine (XVIII) the title compound was obtained by several routes. Alkylation of (XVIII) with propargyl bromide (XXXI) gave the N-propargyl morpholine (XXXII). Palladium-catalyzed addition of N,N-dimethylcarbamoyl chloride to the propargyl group of (XXXII) produced the butynamide derivative (XXXIII). The target triazole system (XXXIV) was obtained by dipolar cycloaddition of NaN3 to the acetylenic triple bond of (XXXIII) in hot DMSO. Finally, amide reduction in (XXXIV) with LiAlH4 led to the title dimethylaminomethyl triazole, which was isolated as the hydrochloride salt.

合成路线6

Alternatively, morpholine (XVIII) was alkylated with 1,4-dichloro-2-butyne (XXXV) in the presence of K2CO3 to afford the propargyl chloride (XXXVI). Displacement of the chloride of (XXXVI) with sodium azide in DMSO gave the propargylic azide (XXXVII). The title triazole was then produced via isomerization and cyclization of azide (XXXVII) upon heating with dimethylamine in a sealed tube.

合成路线7

In a further method, the acetylide resulting from N,N-dimethyl propargylamine (XXXVIII) and either BuLi or ethylmagnesium chloride was formylated by means of N-methyl formanilide (XXXIX), producing the unstable acetylenic aldehyde (XL), which was immediately subjected to dipolar cycloaddition with sodium azide to furnish 4-(dimethylaminomethyl)-5-formyl-1,2,3-triazole (XLI). The title compound was then obtained by reductive condensation of morpholine (XVIII) with aldehyde (XLI) in the presence of sodium triacetoxyborohydride.

合成路线8