5-CHLORO-4-FLUORO-2,3-DIHYDROBENZOFURAN-3-AMINE HCL synthesis

Yield:1294003-39-6 90%

Reaction Conditions:

Stage #1: 3-azido-5-chloro-4-fluoro-2,3-dihydro-1-benzofuranwith water in tetrahydrofuran;n-heptane at 20 - 57;
Stage #2: with hydrogenchloride in water;

Steps:

5.3

Step 3. Synthesis of 5-chloro-4-fluoro-2,3-dihydro-1 -benzofuran-3-amine(P5). Polymer-supported triphenylphosphine (100 g, 1 .48 mmol / g loading) was added to a solution of 3-azido-5-chloro-4-fluoro-2,3-dihydrobenzofuran (1 1 .8 g, 55.3 mmol) in heptane (5.76 mL), THF (1 .3 L), and water (30.0 mL) in a 3-neck flask equipped with a mechanical stirrer. The reaction was heated to 50 °C, and after 10 min an exotherm was noted (internal reaction temperature of 57 °C). The reaction was cooled to room temperature and was stirred for an additional 2 h. Et₂0 (500 mL) was added to the reaction, followed by MgS0₄ (250 g), and the reaction was stirred at room temperature for 0.5 h. The reaction mixture was filtered through Celite, and the solids were washed with Et₂0. The filtrate was concentrated to a minimal volume, and aqueous 4 M HCI (20 mL) was added. The resulting precipitate was isolated by filtration and dried under reduced pressure to afford the title compound as its HCI salt (1 1.1 g, 90%). H NMR (400 MHz, DMSO-d₆) 4.80-4.71 (m, 2H), 5.26 (dd , J=7.2, 2.9 Hz, 1 H), 6.87 (d, J=8.6 Hz, 1 H), 7.56 (dd, J=8.6, 8.2 Hz, 1 H), 8.90 (br s, 3H). This material was taken up in CH₂CI₂ and washed once with aqueous 1 M NaOH . The aqueous layer was extracted twice with CH₂CI₂. The combined organic layers were dried (Na₂S0₄), filtered, and concentrated under reduced pressure to provide title compound as the free amine. This material was used without further purification.

References:

WO2011/48525,2011,A1 Location in patent:Page/Page column 46-47