合成路线1

Treatment of carboxy polystyrene resin (I) with oxalyl chloride in dichloromethane, followed by reaction with Bu4NNCS in THF/DCM, affords isothiocyanate resin (II), to which 2-amino-4,5-dimethoxybenzonitrile (III) is attached by means of NMP to provide derivative (IV). Treatment of resin (IV) with 1-(2-furoyl)-piperazine (V) and EDC in chloroform in the presence of DIEA furnishes resin-bound guanidine (VI), from which prazosin is obtained as its trifluoroacetic acid salt (VII) by acidolysis with TFA/H2O at 80 C. Finally, the hydrochloride salt of prazosin can be obtained by treatment with HCl.

合成路线2

The reaction ot S-(2-aminothiazol-4-ylmethyl)isothiourea (I) with 3-chloropropionitrile (II) by means of NaOH in ethanol - water gives 3-(2-aminothiazol-4-ylmethylthio)propionitrile (III), which is condensed with benzoyl isothiocyanate (IV) in refluxing acetone to afford 3-[2-(3-benzoylthioureido)thiazol-4-ylmethylthio]propionitrile (V). The hydrolysis of (V) with K2CO3 in acetone - methanol - water yields 3-(2-thioureidothiazonl-4-ylmethylthio)propionitrile (VI), which by methylation with methyl iodide in refluxing ethanol is converted into 3-[2-(S-methylisothioureido)thiazol-4-ylmethylthio]propionitrile hydroiodide (VII). The reaction of (VII) with NH3 and NH4Cl in methanol at 90 C in a pressure vessel affords 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile (VIII), which by partial alcoholysis with methanol by means of dry HCl in CHCl3 is converted into methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate (IX). Finally, this compound is treated with sulfamide in refluxing methanol.

合成路线3

Condensation of benzoil isothiocyanate (I) with 6-amino-m-cresol in refluxing acetone gives N-benzoyl-N'-(2-hydroxy-4-methylphenyl)thiourea (II), which is hydrolyzed with sodium hydroxide to afford N-(2-hydroxy-4-methyl(phenyl)thiourea (III). Thiazolyl ring closure is obtained by addition of chloroacetaldehyde diethylacetal in refluxing ethanol catalyzed by p-toluenesulfonic acid. 2-(2-Hydroxy-4-methylphenyl)aminothiazole is then converted to its hydrochloride sait by bubbling gaseous hydrochloric acid.

合成路线4

The acylation of 5-methyl-6-[3-nitro-4-(piperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone (I) with benzoyl isothiocyanate gives the benzoylthiourea (II), which is cleaved by alkaline hydrolysis with potassium carbonate and methylated with methyl iodide to the isothiouronium salt (III). This compound is condensed with 3-(1H-imidazol-4-yl)propylamine (homohistamine, IV) to yield title compound.

合成路线5

The cyclization of N-[5-(2-chloroacetyl)furan-2-ylmethylacetamide (I) with thiourea (II) in ethanol gives the thiazole (III), which is condensed with benzoyl isothiocyanate (IV) in acetone to yield the benzoylthiourea (V). The hydrolysis of (V) with NaOH in aqueous methanol affords the thiourea (VI), which is treated with methyl iodide in methanol to give the S-methylisothiourea (VII). Finally, this compound is condensed with 2-ethoxybenzylamine (VIII) in EtOH/AcOH.

合成路线6

Condensation between aminomalononitrile (I) and benzyl isocyanate (II) produces imidazole (III). This is then cyclized with benzoyl isothiocyanate (IV) in the presence of NaOH to furnish the mercaptopurine derivative (V). Finally, alkylation of thiol (V) with 2-bromoethanol (VI) gives rise to the target hydroxyethyl sulfide.

合成路线7

3-Acetylbenzonitrile (I) was protected as the ethylene ketal (II) employing ethylene glycol and boron trifluoride etherate. Reduction of the cyano group of (II) with LiAlH4 gave amine (III), and further ketal hydrolysis provided 3-acetylbenzylamine (IV). This was acetylated using acetyl chloride and Et3N to yield the intermediate amide (V). Alternatively, intermediate (V) was obtained by addition of methylmagnesium bromide to N-(3-cyanobenzyl)acetamide (VI). Bromination of (V) in dioxan furnished the bromoacetophenone (VII). This was cyclized to the aminothiazole (IX) by treatment with thiourea (VIII) in refluxing ethanol. Condensation of (IX) with benzoyl isothiocyanate (X) provided the benzoyl thiourea (XI). After selective hydrolysis of the benzoyl group of (XI) with NaOH in MeOH-H2O at 60 C, the resulting thiourea (XII) was methylated with iodomethane yielding S-methylisothiourea (XIII). Finally, displacement of the methylthio group with 2-methoxyetylamine (XIV) furnished the title guanidinothiazole.

合成路线8

Synthesis of intermediate (VII): Conversion of 3-fluoroaniline (I) into 2-amino-5-fluorobenzothiazole (III) can be achieved by first coupling with isocyanate (II) followed by hydrolysis with NaOH, reaction with Br2 and finally heating treatment. Dimerization of substituted benzothiazole (III) by means of refluxing aqueous KOH yields disulfide derivative (IV), which is then condensed with substituted benzoyl chloride (V) in refluxing pyridine to afford derivative (VI). Finally, (VI) is converted into intermediate (VII) by treatment with SnCl2 dihydrate in refluxing HCl/EtOH. Alternatively, intermediate (VII) can be synthesized as follows: substituted aniline (VIII) is first brominated via a Sandmeyer reaction with NaNO2 in HBr and CuBr, and then the nitro group is reduced with SnCl2 in refluxing EtOH to provide derivative (IX). Condensation of (IX) with substituted benzoyl chloride (V) in refluxing pyridine yields amide (X), which is then first treated with Lawesson's reagent and HMPA and then with NaH in NMP to afford benzothiazole derivative (XI). Finally, the nitro group of (XI) is reduced with SnCl2 in refluxing EtOH to yield intermediate (VII). Synthesis of EN 295753: The desired compound can finally be obtained by coupling of intermediate (VII) with Boc-Lys(Boc)-OH (XII) by means of carbodiimide WSC.HCl and HOBt in CH2Cl2, followed by Boc removal with HCl (gas) in CH2Cl2.

合成路线9

4-Amiomoindan (I) is reacted with benzoylisothiocyanate (II) to give the benzoylthiourea (III), which after hydrolysis of 4-indanyltiourea (IV) is methylated with iodomethane to (V). The free base (VI) is cyclized with ethyldiamine (A) and p-toluenesulfonic acid to indanazoline

合成路线10

Condensation of benzoyl chloride (I) with ammonium thiocyanate in boiling acetone produces benzoyl isothiocyanate (II). This is then coupled with the known 3-amino-5-phenyl-1,2,4-thiadiazole (III) to afford the N-benzoyl thiourea (IV) (1). Finally, hydrolysis of (IV) under alkaline conditions gives rise to the target thiadiazolyl thiourea

合成路线11