合成路线1

Compound can be prepared in three different related ways: 1) The reaction of 5-(o-clorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine-2-one (I) with P2S5 in pyridine at 80 C gives the corresponding thioketone (II), which by reaction with hydrazine hydrate (A) in methanol yields 2-hydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (III). Finally, this compound is cyclized with acetic anhydride acetic acid in refluxing benzene. This cyclization can also be carried out with refluxing ethyl orthoacetate (E) and H2SO4, with acetimino ethyl ether (G) in refluxing chloroform, with acetamidine hydrochloride (C) and 2-methylimidazole (D) at 160 C or thioacetamide (F) and H2SO4 at 190 C. 2) The condensation of thioketone (II) with acetohydrazide (B) in refluxing chloroform gives 2-acetylhydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (IV), which is then cyclized with acetic acid in refluxing benzene or by heating at 205 C. 3) The acetylated compound (IV) can also be obtained by acetylation of (III) with acetic anhydride and triethylamine at room temperature.

合成路线2

The reduction of potassium hexachloroplatinate (I) with hydrazine dihydrochloride (II) in hot water gives potassium tetrachloroplatinate (III), which is finally treated with NH4Cl or NH4OAc and aqueous ammonia.

合成路线3

The reaction of 2,3-dichlorobenzoic acid (I) with oxalyl chloride in dichloromethane gives the acyl chloride (II), which is condensed with labeled copper cyanide (III) by means of KI in refluxing xylene to yield the 2,3-dichlorobenzoyl cyanide (IV). The condensation of (IV) with labeled aminoguanidine (V) by means of sulfuric acid in acetonitrile/water affords adduct (VI), which is finally cyclized by refluxing under the conditions of the preceding reaction to provide the target labeled diaminotriazine. The intermediate labeled copper cyanide (III) has been obtained by reaction of CuSO4 with labeled potassium cyanide (VII) and Na2S2O5 in hot water. The intermediate labeled aminoguanidine (V) has been obtained by methylation of thiourea (VIII) with dimethyl sulfate in boiling water to give S-methylisothiourea (IX), which is finally treated with hydrazine (X) and NaOH in water.

合成路线4

Hydrazine hydrate (I) is added dropwise under stirring to ethyl acetoacetate (II), which has been heated to 140 C, water and ethanol formed in the reaction are distilled off, and the mixture is heated at reflux. Upon completion of the reaction, the mixture is allowed to stand at room temperature, and the solid thus separated is collected and recrystallized from ethanol to obtain the title compound.

合成路线5

Diazotization of the known aniline (I), followed by Sandmeyer reaction with CuCN and KCN afforded nitrile (II). Addition of hydrogen sulfide to (II) in the presence of Et3N in hot DMF led to the thioamide (III). Subsequent alkylation of (III) with methyl triflate gave the intermediate thioimidate (IV), and a further treatment of (IV) with hydrogen sulfide and pyridine provided dithioester (V). Displacement of the methylthio group of (V) by hydrazine yielded thiohydrazide (VI). Finally, cyclization of (VI) to the target thiadiazole was achieved upon refluxing in formic acid.

合成路线6

Diazotization of the known aniline (I), followed by Sandmeyer reaction with CuCN and KCN afforded nitrile (II). Addition of hydrogen sulfide to (II) in the presence of Et3N in hot DMF led to the thioamide (III). Subsequent alkylation of (III) with methyl triflate gave the intermediate thioimidate (IV), and a further treatment of (IV) with hydrogen sulfide and pyridine provided dithioester (V). Displacement of the methylthio group of (V) by hydrazine yielded thiohydrazide (VI). This was cyclized to the required thiadiazole (VII) upon treatment with 3-carbomethoxypropionyl chloride (A) in refluxing THF. Aminolysis of the ester group of (VII) with methanolic ammonia at 100 C in a sealed vessel provided amide (VIII). This was finally dehydrated to the title nitrile using trifluoroacetic anhydride and pyridine.

合成路线7

The reaction of 2,6-dichloro-4-methoxybenzyl chloride (I) with tetraethylammonium cyanide in refluxing dichloromethane gives 2-(2,6-dichloro-4-methoxyphenyl)acetonitrile (II), which is condensed with ethyl acetate (III) by means of sodium ethoxide in refluxing ethanol to yield the 3-oxobutyronitrile (IV). The cyclization of (IV) with hydrazine (V) by means of HOAc in refluxing benzene affords the aminopyrazole (VI), which is further cyclized with ethyl acetoacetate (VII) in refluxing acetic acid to provide 3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (VIII). The reaction of (VIII) with refluxing POCl3 furnishes the corresponding chloro derivative (IX), which is allowed to react with ethylenediamine (X) in hot acetonitrile to give 7-(2-aminoethylamino)-3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (XI). Finally, this compound is reductocondensed with tetrahydropyran-4-one (XII) by means of sodium cyanoborohydride in methanol/HOAc to yield the target CP-671906-01.

合成路线8

The reaction of 5(R)-(azidomethyl)-3-phenyloxazolidin-2-one (I) with Ac2O and MsOH gives the 4-acetylphenyl derivative (II), which is cyclized with glyoxylic acid (III) and hydrazine (IV) in hot acetic acid to yield the pyridazinone derivative (V). The reduction of the azido group of (V) by means of PPh3 in THF/water affords the aminomethyl compound (VI), which is finally condensed with ethyl dithioacetate (VII) by means of TEA in DMF to provide the target thioacetamide.

合成路线9

The reaction of 5(R)-(azidomethyl)-3-phenyloxazolidin-2-one (I) with Ac2O and MsOH gives the 4-acetylphenyl derivative (II), which is cyclized with glyoxylic acid (III) and hydrazine (IV) in hot acetic acid to yield the pyridazinone derivative (V). The reduction of the azido group of (V) by means of PPh3 in THF/water affords the aminomethyl compound (VI), which is condensed with acetic anhydride and pyridine to provide the acetamide (VII). Finally, this compound is treated with Lawesson's reagent in hot dioxane to furnish the target pyridazinethione.

合成路线10

The cyclization of 4-(benzyloxycarbonylamino)acetophenone (I) with glyoxylic acid (II) and hydrazine (III) in hot acetic acid gives the pyridazinone (IV), which is treated first with Lawesson's reagent in hot dioxane and then with MeI and TEA in DMF to yield the methylsulfanyl pyridazine (V). The cyclization of (V) with acetamide (VI) by means of t-BuOLi in methanol/DMF affords the oxazolidinone (VII), which is finally treated with Lawesson's reagent in hot dioxane to provide the target thioacetamide.

合成路线11

The cyclization of 4-(benzyloxycarbonylamino)acetophenone (I) with glyoxylic acid (II) and hydrazine (III) in hot acetic acid gives the pyridazinone (IV), which is treated first with Lawesson's reagent in hot dioxane and then with MeI and TEA in DMF to yield the methylsulfanyl pyridazine (V). The cyclization of (V) with acetamide (VI) by means of t-BuOLi in methanol/DMF affords the oxazolidinone (VII), which is finally treated with Lawesson's reagent in hot dioxane to provide the target thioacetamide.

合成路线12

合成路线13