合成路线1

The intermediate pyrimidine (IV) has been obtained as follows: The reaction of 2,4,6-trichloropyrimidine (I) with pyrrolidine in THF gives 6-chloro-2,4-bis(1-pyrrolidinyl) pyrimidine (II), which is condensed with piperazine (III) in pyridine to yield 6-(1-piperazinyl)-2,4-bis(1-pyrrolidinyl)pyrimidine (IV). The methylation of 21-acetoxy-pregna-1,4,9(11),16-tetraene-3,20-dione (V) with methylmagnesium chloride catalyzed by copper propionate, followed by hydrolysis of the acetate group with NaOMe in methanol, gives the 16-alpha-methyl steroid (VI), which is condensed with piperazine intermediate (IV) by means of MeSO2Cl and TEA in acetonitrile, affording the precursor (VII). Finally, this compound is treated with methanesulfonic acid to afford the target compound.

合成路线2

合成路线3

Cyclization of morpholine-4-carboximidamide hydrobromide (I) with diethyl malonate (II) by means of naoEt in refluxing EtoH gives 2-(morpholin-4-yl)pyrimidine-4,6-diol (III), which by chlorination with PoCl3 at 120 °C affords 4,6-dichloro-2-(morpholin-4-yl)pyrimidine (IV). nucleophilic substitution of the dichloropyrimidine (IV) with morpholine (V) in the presence of Et3n in refluxing N-methyl-2-pyrrolidone provides 2,4-di(morpholin-4-yl)-6-chloropyrimidine (VI) . Alternatively, dimorpholinopyrimidine (VI) is prepared by reaction of 2,4,6-trichloropyrimidine (VII) with morpholine (V) in THF, followed by chromatographic separation . Finally, chloropyrimidine derivative (VI) is submitted to a Suzuki cross-coupling reaction with boronate ester (VIII) in the presence of Pd(dppf)2Cl2·CH2Cl2 or Pd(dppf)2Cl2 and na2Co3 in 1,2-dimethoxyethane at 90-95 °C .
Alternatively, iodination of chloride (VI) with HI and naI yields the corresponding iodide (IX) , which is also coupled with boronate (VIII) in the presence of Pd(dppf)Cl2·CH2Cl2 and K2Co3 in 1,4-dioxane/H2o at 100 °C .
Boronate ester (VIII) is obtained by bromination of 4-(trifluoromethyl) pyridin-2-amine (X) with nBS in CHCl3 or CH2Cl2 to afford 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine (XI), which is finally condensed with bis(pinacolato)diboron (XII) in the presence of Pd(dppf)2Cl2·CH2Cl2 and KoAc in refluxing dioxane or DMSO .