合成路线1

Thiosemicarbazide (I) is refluxed for 1 h with one equivalent of formic acid (II) in a water solution. It may be recrystallized from water to give needles.

合成路线2

This compound can be obtained by two related ways: 1) The cyclization of 3-cyclohexylpropionitrile (I) with thiosemicarbazide (II) by means of trifluoroacetic acid gives 5-(2-cyclohexylethyl)-1,3,4-thiadiazol-2-amino (III), which is submitted to a new cyclization process with bis(2,4,6-trichlorophenyl)malonate (IV) in refluxing xylene yielding 2-(2-cyclohexylethyl)-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (V) (1-3). The nitration of (V) with fuming nitric acid in acetic acid affords the corresponding 7-hydroxy-6-nitro derivative (VI), which is treated with POCl3 and tripropylamine to afford the 7-chloro-6-nitro derivative (VII). The reaction of (VII) with concentrated aqueous NH4OH in ethanol gives the corresponding 7-amino-6-nitro compound (VIII), which is reduced with Sn-HCl in dioxane-water to afford the 6,7-diamino derivative (IX). Finally, this compound is dissolved in aqueous HCl and treated with NaNO2. 2) The cyclization of 3-cyclohexylpropionic acid (X) with thiosemicarbazide (II) by means of hot H2SO4 gives the thiadiazole (III), which is cyclized again with malonic acid (XI) by means of POCl3 in hot toluene to afford the previously obtained thiadiazolopyrimidine (V).

合成路线3

The synthesis of LY-217896 and its [5-14C]- and uniformly labeled [UL-13C]-isotopomers has been described: The cyclization of thiosemicarbazide (I) with formic acid (II) at 80-90 C gives 2-amino-1,3,4-thiadiazole (III), which is protected with benzyl chloride in refluxing isopropanol to yield 3-benzyl-1,3,4-thiadiazol-2(3H)-imine (IV). The reaction of (IV) with cyanogen bromide by means of NaHCO3 in methanol - water affords N-(3-benzyl-1,3,4-thiadiazol-2(3H)-ylidene)cyanamide (V), which is finally deprotected with AlCl3 in dichloromethane. The [5-14C]-isotopomer is obtained using [14C]-labeled formic acid in the first step of the synthesis, and the [UL-13C]-isotopomer is obtained using [13C]-labeled thiosemicarbazide (I) and [13C]-formic acid. [13C]-Labeled (I) is synthesized by reaction of potassium cyanide-[13C] with sulfur, yielding potassium thiocyanate-[13C], which is reacted with hydrazine to give [13C]-thiosemicarbazide.

合成路线4

The title compound has been obtained by several related ways: The reaction of 2-chloro-3-nitropyridine (I) with methylboronic acid by means of Pd(PPh3)4 and K2CO3 in hot dioxane gives 2-methyl-3-nitropyridine (III), which is condensed with dimethylformamide dimethylacetal (IV) to yield 2-[2-(dimethylamino)vinyl]-3-nitropyridine (V). The oxidation of (V) by means of NaIO4 affords 3-nitropyridine-2-carbaldehyde (VI), which is condensed with semicarbazide (VII) to provide the corresponding semicarbazone (VIII). Finally, the nitro group of (VIII) is reduced with SnCl2 or Na2S to furnish the target 3-aminopyridine-2-carbaldehyde semicarbazone. 2-Methyl-3-nitropyridine (III) can also be obtained by condensation of 2-chloro-3-nitropyridine (I) with diethyl malonate (II) by means of Na, followed by decarboxylative hydrolysis with H2SO4 at 125 C. The direct oxidation of 2-methyl-3-nitropyridine (III) with SeO2 in dioxane gives carbaldehyde (VI), which is treated with ethyleneglycol (IX) and Ts-OH to yield the cyclic acetal (X). The reduction of (X) with H2 over Pd/C in ethanol affords 3-aminopyridine-2-carbaldehyde ethylene ketal (XI), which is treated with semicarbazide (VI) and HCl to afford the target 3-aminopyridine-2-carbaldehyde semicarbazone. The condensation of 2-chloro-3-nitropyridine (I) with tributyl vinyl tin (XII) Pd(PPh3)4 and PPH3 in refluxing toluene gives 3-nitro-2-vinylpyridine (XIII), which is oxidized with O3 and Me2S in methanol to yield 3-nitropyridine-2-carbaldehyde (VI). This compound is condensed with semicarbazide (VII) and reduced to the target compound as already described.

合成路线5

The alkylation of thiosemicarbazide (I) with methyl iodide in hot ethanol gives the corresponding S-methyl derivative (II), which is treated with pentylamine (III) in refluxing methanol to yield N1-amino-N3-pentylguanidine hydroiodide (IV). Finally, this compound is condensed with 5-methoxy-1H-indole-3-carbaldehyde (V) by means of HCl in methanol.

合成路线6

Treatment of thiosemicarbazide hydrobromide (I) with ethyl bromide (II) in refluxing EtOH affords S-ethylthiosemicarbazide (III), which is then condensed with N-acetyl-ethylenediamine (IV) in refluxing EtOH to provide N1-(2-acetamidoethyl)-N3-aminoguanidine (V). Finally, the desired product is obtained by the formation of the corresponding hydrochloride salt by treatment of (V) with HCl in methanol. Alternatively the target compound can be obtained by reaction of N-acetylethylenediamine (IV) with cyanogen chloride in 2-propanol followed by treatment with anhydrous hydrazine.

合成路线7

Triazinoindole thione (III) was obtained by condensation of isatin (I) with thiosemicarbazide (II). Subsequent S-alkylation of (III) with dipropylaminoethyl chloride (IV) furnished the title thioether derivative.

合成路线8

Oxidation of 2-fluoro-4-nitrotoluene (I) by means of Jones reagent afforded the benzoic acid (II). After activation of (II) as the corresponding acid chloride with SOCl2, reaction with lithium tert-butoxide furnished the tert-butyl ester (III). Reduction of the nitro group of (III) by means of iron powder gave amine (IV), which was further converted into the carbamate (V) upon treatment with benzyl chloroformate. The chiral oxazolidinone (VII) was prepared by condensation of the lithium salt of carbamate (V) with (R)-glycidyl butyrate (VI) at -78 C. After activation of the primary hydroxyl of (VII) as the corresponding mesylate, displacement with NaN3 in hot DMF provided the alkyl azide (VIII). Tert-Butyl ester cleavage in (VIII) employing trifluoroacetic acid afforded the carboxylic acid (IX), which was cyclized to the thiadiazole (XI) by condensation with thiosemicarbazide (X) in the presence of POCl3. Reduction of the azido group of (XI) to the primary amine (XII) was accomplished by treatment with triphenylphosphine followed by aqueous hydrolysis. Finally, acylation of the aliphatic amino group of (XII) with ethyl dithioacetate gave rise to the title thioacetamide.

合成路线9

The title thiosemicarbazone is prepared by condensation of 1-acetyladamantane (I) with thiosemicarbazide (II) in refluxing MeOH.

合成路线10

The title thio semicarbazone is prepared by condensation of 3-bromopropiophenone (I) with thio semicarbazide (II) in MeOH in the presence of a catalytic amount of HOAc. (1,2)

合成路线11

Alkylation of phenothiazine (I) by ethyl chloroacetate (II) in the presence of K2CO3 affords the ester (III). Subsequent condensation of (III) with thiosemicarbazide (IV) gives the acyl thiosemicarbazide (V), which is cyclized to the thiadiazole derivative (VI) in concentrated H2SO4. Finally, Mannich condensation of aminothiadiazole (VI) with thiobarbituric acid (VII) and formaldehyde furnishes the desired compound.

合成路线12