Reaktion #48539
ord-cbfb36e6a50f43289751dc4a8914185a
Reaktionsgleichung
Edukte
Reagenzien
Reaktionsbedingungen
Vorschrift
In a fourteenth embodiment of the present invention there is provided a process for the preparation of a compound according to formula 2 which process comprises the steps of: (a) contacting 3,5-dibromo-fluoro-benzene (25) with iso-propyl magnesium chloride to afford a 3-bromo-5-fluoro-phenylmagnesium halide (26); (b) contacting 26 with DMF followed by aqueous acid and MTBE to afford 3-bromo-5-fluoro-benzaldehyde (28); (c) contacting 28 with DEOXO-FLUOR and DCM to a afford 3-fluoro-5-difluoromethyl-1-bromo-benzene (30); (d) contacting 30 with p-methoxy-benzyl alcohol and potassium tert-butoxide in THF to afford 1-bromo-3-difluoromethyl-5-(4-methoxy-benzyloxy)-benzene (32); (e) contacting a solution of 32 and NMP with potassium ferrocyanide, Na2CO3, Pd(OAc)2 and DPPF at about 130° C. to afford 34; (f) treating a solution of 34 and anisole with TFA at temperatures sufficient to cleave the O-benzyl linkage and afford 36; (g) treating a solution of 36 and THF with 1,2,3-trifluoro-4-nitrobenzene (37) and K2CO3 to afford 3-difluoromethyl-5-(2,3-difluoro-6-nitro-phenoxy)-benzonitrile (38); (h) contacting 4 with a strong base in an inert solvent said strong base capable of forming the conjugate base of 4 and contacting said conjugate base with 6 to afford 8; (i) exposing 8 to reaction conditions which are capable of hydrolyzing the ester and decarboxylating the resulting carboxylic acid 8a, (j) contacting 2 with a reducing agent capable of selective reduction of the nitro group to afford 12; (k) contacting 12 with a diazotizing reagent and either Cu(I)Br/LiBr or Cu(I)Cl/LiCl to afford 14, (1) exposing 14 to an oxidizing agent capable of oxidation of the sulfide to a sulfone 18; and (m) contacting 18 with acetic acid/acetic anhydride under conditions which result in cleavage of the S-heteroaryl bond and hydrolysis of the resulting acetate to afford 20 wherein R2 is bromo and chloro respectively, Ar is phenyl substituted with 2 or 3 groups independently selected from halogen, cyano and C1-6 haloalkyl, and R1 and R3 are C1-10 alkyl.