4-Methoxybenzyl alcohol → 1-Bromo-3-difluoromethyl-5-(4-methoxy-benzyloxy)-benzene

HRID 20261

反応式

HRID 20261 の反応式
COCCN(S(F)(F)F)CCOC.F[C:15]1[CH:16]=[C:17]([Br:24])[CH:18]=[C:19]([CH:21]([F:23])[F:22])[CH:20]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[Br:24][C:17]1[CH:16]=[C:15]([O:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:20]=[C:19]([CH:21]([F:23])[F:22])[CH:18]=1

参加物

7

反応物 4

HCID 77384-Methoxybenzyl alcoholHCID 2734690(Bis(2-methoxyethyl)amino)sulfur trifluorideHCID 222402791-Bromo-3-(difluoromethyl)-5-fluorobenzeneHCID 23665647Potassium tert-butoxide

生成物 1

HCID 669380551-Bromo-3-difluoromethyl-5-(4-methoxy-benzyloxy)-benzene

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

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.

出典と根拠

ORDレコード
ord-cbfb36e6a50f43289751dc4a8914185a
出典データセット
uspto-grants-2010_06
特許番号
US07745634B2

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