合成路线1

The reaction of 2-chloro-3,5-dinitrobenzoic acid (I) with thionil chloride, followed by treatment with diethyl ethoxymagnesium malonate gives diethyl 2-chloro-3,5-dinitrobenzoylmalonate (II), which is hydrolyzed and decarboxylated in hot sulfuric acid/propionic acid yielding 2-chloro-3,5-dinitroacetophenone (III). Reaction of (III) with thioglycolic acid by means of NaHCO3 in refluxing isopropanol gives the thioacetic acid compound (IV), which is cyclized in refluxing propionic acid yielding 3-methyl-5,7-dinitrobenzothiophene (V). Partial selective reduction of one of the nitro groups in (V) by means of ammonium sulfide in ethanol leads to 7-amino-3-methyl-5-nitrobenzothiophene (VI), which is diazotied by treatment with NaNO2 in hydrochloric acid. The following reaction with diethylamine in alkaline solution gives the triazene derivative (VII), which is finally fluorinated by reaction with anhydrous HF yielding 7-fluoro-3-methyl-5-nitrobenzothiophene (VIII). Catalytical reduction of (VIII) yields 5-amino-7-fluoro-3-methylbenzothiophene (IX), which is converted to 5-hydrazino-7-fluoro-3-methylbenzothiophene (X) by diazotation and subsequent reduction by means of stannous chloride in hydrochloric acid. The reaction of (X) with N-ethyl-4-piperidone (XI) in refluxing isopropanol gives the corresponding hydrazone, which is cyclized in refluxing isopropanol/HCl yiellding tiflucarbine base. Finally, this compound is converted to the lactate by means of lactic acid in acetone.

合成路线2

Erdosteine (III) can be obtained in a two-step synthesis starting from homocysteine thiolactone (I). (I) is acylated in chloroform with chloroacetyl chloride (A) to the amide (II). Subsequent reaction with thioglycolic acid (B) gives rise to (III).

合成路线3

The protected ligand (IV) was also prepared by a related method. The acylation of thioglycolic acid (V) with benzoyl chloride (VI) under Schotten-Baumann conditions afforded S-benzoyl thioglycolic acid (VII). After activation of (VII) as the corresponding succinimidyl ester (VIII) with N-hydroxysuccinimide and DCC, coupling with triglycine (I) furnished compound (IV).

合成路线4

Other S-protecting groups for mercaptoacetyl triglycine have been reported. The S-benzyl derivative (X) was prepared by condensation of triglycine (I) with (benzylthio)acetyl chloride (IX). Alternatively, the S-benzamidomethyl compound (XII) was prepared as follows. Thioglycolic acid (V) was condensed with benzamidomethanol under acidic conditions to give S-(benzamidomethyl)thioglycolic acid (XI), which was then coupled to triglycine (I) using DCC/HOBt. Deprotection in the presence of 99Tc pertechnetate under the same conditions as above furnished the title Tc complex.

合成路线5

The acylation of 2-butene-1,4-diol (XXII) with butyryl chloride and DMAP in pyridine gives the dibutyrate (XXIII), which is ozonolyzed with O3 in dichloromethane yielding the aldehyde (XXIV). The cyclization of (XXIV) with mercaptoacetic acid (XXV) in refluxing toluene affords 2-(butyryloxymethyl)-1,3-oxathiolane-5-one (XXVI), which is reduced with lithium tri-tert-butoxyaluminum hydride and acetylated with acetic anhydride in THF to give 5-acetoxy-2-(butyryloxymethyl)-1,3-oxathiolane (XXVII). The condensation of (XXVII) with disilylated 5-fluorocytosine (XV) (obtained from cytosine (XVI) as described) by means of SnCl4 in dichloromethane yields the racemic butyryl nucleoside rac-(cis)-(XXVIII). The biological resolution of this racemic mixture has been performed by digestion with the enzyme pig liver esterase (PLE-A) providing a mixture of unreacted (-)-(cis)-(2R,5S)-(XXVIII) butyrate and hydrolyzed (+)-(cis)-(2S,5R)-(XXIX) that are separated by fractional extraction. The desired (-)-(cis)-(2R,5S)-enantiomer is finally hydrolyzed to the target compound with NaOMe in methanol. The biological resolution of rac-(cis)-(XXVIII) can also be performed with the enzyme Amano PS-800 yielding a mixture of unreacted (+)-(cis)-(2S,5R)-(XXVIII) butyrate and the desired (-)-(cis)-(2R,5S) target nuceloside that are separated by fractional extraction.

合成路线6

A new process for the preparation of emtricitabine has been described: The esterification of 2-butene-1,4-diol (I) with butyryl chloride and DMAP in pyridine gives the diester (II), which by ozonolysis with O3 in methanol provides the hemiacetal (III). Cyclization of (III) with 2-mercaptoacetic acid in refluxing toluene affords racemic 2-(butyryloxymethyl)-1,3-oxathiolan-5-one (V), which is submitted to optical resolution to afford the (R)-enantiomer (VI). The reduction of (VI) with Li(t-BuO)3AlH, followed by acetylation with acetic anhydride gives 5-(acetoxy)-2(R)-(butyryloxy)-1,3-oxathiolane (VII), which by treatment with HCl in dichloroethane is converted into 2(R)-(butyryloxy)-5-chloro-1,3-oxathiolane (VIII). Condensation of (VIII) with 5-fluoro-bis(trimethylsilyl)cytosine (IX) ­ obtained by silylation of cytosine (X) with HMDS ­ by means of NaHCO3 in dichloroethane gives a diastereomeric mixture of the butyrate nucleosides (XI), which is hydrolyzed with butylamine in methanol yielding the corresponding diastereomeric mixture of the (2R,5S)-isomer, emtricitabine, and the (2R,5R)-isomer (XII). This mixture is separated by crystallization of the corresponding hydrochlorides obtained by treatment with HCl in methanol/dioxane.

合成路线7

Aldehyde (I) was condensed with 3-aminopropanol (II) in refluxing benzene using a Dean-Stark trap to give imine (III) which, without purification, was in turn condensed with a-mercaptoacetic acid (IV) to afford thiazolidinone (V). Treatment of alcohol (V) with PBr3 gave bromide (VI). Then, reaction of (VI) with amine (VII) in the presence of K2CO3 in refluxing acetone produced the target compound.

合成路线8

Title compound has been prepared by several related ways. Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III), which was brominated in CHCl3 at 0 C to give (IV). Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t. provided (XI). Alternatively, beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI). Thus, protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA, followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX). Then, Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI). In order to avoid b-ketoacid decarboxylation, ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C. This hydroxyester was also prepared by a related route, consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII), followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X). Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI). Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII). Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX). Finally, deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.

合成路线9

The title diaryl thiazolidinone was synthesized by condensation between 2,6-dichlorobenzaldehyde (I), 2-amino-6-methylpyridine (II) and mercaptoacetic acid (III) in refluxing toluene.

合成路线10

The cyclocondensation of N,N'-bis(3,4-dichlorobenzylidene)ethylenediamine (I) with 2-sulfanylacetic acid (II) in refluxing toluene gives a mixture of the meso (R,S)-isomer and the corresponding racemate (R,R)+(S,S), which is easily separated by HPLC on a Chiracel OD column to obtain the target meso (R,S)-isomer.

合成路线11