合成路线1

The reaction of 2,6-dimethylphenol (I) with hexamethylenetetramine (HMT) and sulfuric acid in ethyleneglycol at 130 C gives 4-hydroxy-3,5-dimethylbenzaldehyde (II), which is finally condensed with 2-(4-fluorophenyl)acetic acid (III) by means of piperidine in dichloromethane at 130 C.

合成路线2

The condensation of 4-(methylsulfanyl)benzaldehyde (I) with 4-fluorophenylacetic acid (II) in refluxing acetic anhydride containing one equivalent of triethylamine, followed by aqueous hydrolysis, provided the diarylpropenoic acid (III). Curtius rearrangement of acid (III) by treatment with diphenylphosphoryl azide in cold toluene, and subsequent hydrolysis of the intermediate isocyanate afforded diarylethanone (IV), which was then brominated in a solution of HBr in acetic acid to give bromoketone (V). The cyclization of this bromoketone with 2-chlorothiobenzamide (VI) in refluxing acetonitrile gave rise to thiazole (VII), and then, oxidation with meta-chloroperbenzoic acid in dichloromethane provided the target sulfone.

合成路线3

The precursor deoxybenzoin (V) was prepared via Perkin condensation of 4-fluorophenylacetic acid (I) with 4-(methylsulfanyl)benzaldehyde (II) to yield the alpha-phenylcinnamic acid derivative (III), followed by Curtius rearrangement of the corresponding acylazide, and further hydrolysis of the intermediate isocyanate (IV) with HCl in t-BuOH. Alternatively, Friedel-Crafts acylation of fluorobenzene with acid chloride (VI) yielded deoxyenzoin (V). Bromoketone (VII) was then obtained by bromination of (V) in the presence of HBr and AcOH. Subsequent condensation of (VII) with 2-chlorothiobenzamide (VIII) formed thiazole (IX). Finally, the sulfide group of (IX) was oxidized to sulfone using m-chloroperbenzoic acid.

合成路线4

Synthesis of morpholine intermediate (I): Treatment of 4-fluorophenyl acetic acid (X) with trimethylacetyl chloride (XI) and Et3N in Et2O followed by reaction with 4-(S)-benzyl-2-oxazolidinone (XII) in THF and n-BuLi in hexane affords oxazolidinone derivative (XIII). Conversion of (XIII) into azido derivative (XV) is achieved by first treatment of (XIII) in THF with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (XIV) in THF. Hydrolysis of azido-oxazolidinone derivative (XV) by means of LiOH in THF/H2O yields azido acetic acid derivative (XVI), which is then hydrogenated over Pd/C in H2O/HOAc to afford (S)-(4-fluorophenyl)glycine (XVII). Treatment of (S)-(4-fluorophenyl)glycine (XVII) with benzaldehyde (XVIII), NaOH and NaBH4 in MeOH yields N-benzyl (S)-(4-fluorophenyl)glycine (XIX), which is then cyclized with 1,2-dibromoethane (XX) in the presence of DIEA in DMF to furnish morpholine intermediate (I).

合成路线5

Alternatively (XVII) can be obtained as follows: Reaction of 4-fluorophenyl acetic (X) with thionyl chloride in toluene in the presence of DMF provides 4-fluorophenyl acetyl chloride (XXII), which is treated with bromine and light irradiation followed by reaction with methanol to furnish methyl bromoacetate derivative (XXIII). Treatment of (XXIII) with benzyl triethylammonium chloride (XXIV) and NaN3 in MeOH followed by hydrogenation over Pd/C in MeOH gives methyl glycine derivative (XXV) in a racemic mixture, from which (XVII) is obtained by crystallization of the corresponding dibenzoyl tartaric (DBT) salts followed by salt hydrolysis by means of refluxing HCl.

合成路线6

The first method required the chiral building block (S)-(4-fluorophenyl)glycine (VI), which was prepared from 4-fluorophenyl acetic acid (I) by two routes. Condensation of (I) with (S)-4-benzyl-2-oxazolidinone (II), via activation as the corresponding mixed anhydride with pivaloyl chloride, furnished the N-acyl oxazolidinone (III). The potassium enolate of (III) was then reacted with 2,4,6-triisopropylphenylsulfonyl azide, producing stereoselectively azide (IV). Hydrolytic removal of the chiral auxiliary of (IV) gave (S)-azido-(4-fluorophenyl)acetic acid (V), which was then reduced to the desired amino acid (VI) by catalytic hydrogenation over Pd/C. Alternatively, 4-fluorophenyl acetic acid (I) was converted to the corresponding acid chloride (VII) with SOCl2. Bromination of (VII) under Hell-Volhard-Zelinskii conditions, followed by quenching with MeOH, afforded the racemic alpha-bromo ester (VIII). Displacement of the bromide of (VIII) with NaN3 using a phase-transfer catalyst produced the azido ester (IX). Catalytic hydrogenation of the azido group of (IX) gave the racemic amino ester, which was resolved via formation of the diastereomeric salts with (+)-dibenzoyltartaric acid. The desired (S)-amino ester (X) was then hydrolyzed to (VI) under acidic conditions.

合成路线7

4-Fluorophenylacetic acid (I) is chlorinated by means of SOCl2 in refluxing benzene. The resultant acid chloride (II) is then reacted with butylamine (III) to produce the target amide

合成路线8