3-chloro-4-((6-methylpyridin-3-yl)oxy)aniline synthesis

Yield:848482-82-6 83%

Reaction Conditions:

Stage #1: 5-(2-chloro-4-nitro-phenoxy)-2-methyl-pyridinewith sodium tetrahydroborate;nickel dichloride in methanol at 0 - 25; for 1 h;
Stage #2: with hydrogenchloride;water in methanol;
Stage #3: with ammonia in methanol;water; pH=8;

Steps:

80

NiCl₂-OH₂O (14.0 g, 59.0 mmol) was added to a solution of Compound 80c (7.8 g, 29.5 mmol) in MeOH (220 mL). The green solution was cooled to 0⁰C and then NaBH₄ (4.5 g, 118.0 mmol) was added in portions over 30 min. The black solution was stirred an additional 30 min at 0⁰C and then warmed to 25 ⁰C. The reaction was concentrated and then dissolved into 6N HCl. The reaction was adjusted to pH 8 using ammonium hydroxide and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, then filtered and concentrated to yield (5.7 g, 83 %) 3-chloro-4-(6-methyl-pyridin-3-yloxy)- phenylamine Compound 8Od. MS 233 (M-). Using the procedure of Example 1, Compound 8Od was used in place of Compound Ie to prepare 4-chloro-6-[3-chloro-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-pyrimidine-5-carbonitrile Compound 80e. MS 370 (M-). Compound 80e was used in place of 4-chloro-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile Compound If to provide 5-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-4-oxo-4,5-dihydro- 3H-l-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid, Compound 8Of. MS 452 (M-). Using the procedure of Example 1, Compound 8Of was used in place of Compound 1 and 4- morpholin-4-ylmethyl-phenylamine Compound 3e was used in place of Compound Ik to give Compound 129. MS 626 (MT).

References:

WO2006/118749,2006,A1 Location in patent:Page/Page column 124