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With hydrogenchloride; In diethyl ether; isopropyl alcohol;pH 1.0; |
Following the procedure outlined in Example 4 above, 4-chlorocatechol was reacted to yield a mixture of (2S)-C-(7-Chloro-2,3-dihydro- benzo[1 ,4]dioxin-2-yl)-methylamine and (2S)-C-(6-Chloro-2,3-dihydro- benzo[1 ,4]dioxin-2-yl)-methylamine (ca. 3:1 ratio of 6-chloro:7-chloro isomers by RP HPLC).The mixture was dissolved in 2-propanol (100 mL) and 1 N HCI in diethyl ether was added until pH = 1.0 was attained. The hydrochloride salt that precipitated was filtered (2.65 g) and re-crystallized from methanol/IPA to yield white crystals. The white crystals were partitioned between DCM and dilute <n="40"/>NaOH. The DCM was dried and evaporated in vacuo to yield purified (2S)-C- (6-Chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-methylamine as an oil.[alpha]D = -67.8 (c = 1.51 , CHCI3)The oil (7.75 mmol) and sulfamide (1.50 g, 15.5 mmol) were combined in dioxane (50 mL) and refluxed for 2.0 h, cooled to room temperature and evaporated in vacuo to yield a solid. The product was purified via flash column using DCM/methanol 20:1 to yield the title compound as a white solid.MS 277 (M"1)[alpha]D = -59.9 (c = 1.1 1 , M) 1H NMR (CDCI3) delta 6.90 (d, J = 2.2 Hz, 1 H), 6.81 (m, 2H), 4.76 (m, 1 H),4.55 (s, 2H), 4.40 (m, 1 H), 4.29 (dd, J = 2.4, 1 1 .5 Hz, 1 H), 4.05 (dd, J = 7.1 , 1 1.5 Hz, 1 H), 3.45 (m, 2H)Elemental Analysis:Anal CaIc: C, 38.78; H, 3.98; N, 10.05 Anal Found: C, 38.80; H, 3.67; N, 9.99.The filtrates of the crystallized hydrochloride salt of (2S)-C-(6-Chloro- 2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-methylamine prepared above were recovered (ca. 1 :1 of 6-chloro:7-chloro isomers) and evaporated in vacuo to yield a solid, which was partitioned between DCM (200 mL) and dilute NaOH (0.5 M, 50 mL). The DCM solution was washed once with brine, dried (Na2SO4) and evaporated in vacuo to yield an oil, which was purified via reverse phase HPLC (10 - 50% ACN with 0.16% TFA in water with 0.20% TFA) to yield (2S)-C-(7-Chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-methylamine as a residue. The residue was combined with sulfamide (0.90 g, 9.4 mmol) in dioxane(25 mL) and refluxed for 2.5 h, cooled to room temperature and evaporated in vacuo to yield an oil. The oil was purified by flash column chromatography using DCM/methanol - 10:1 to yield (2S)-(-)-N-(7-Chloro-2,3-dihydro- benzo[1 ,4]dioxin-2-ylmethyl)-sulfamide as a white solid. MS 277 (M"1)1H NMR (CDCI3/CD3OD) delta 6.88 (d, J = 0.7 Hz, 1 H), 6.81 (m, 2H), 4.37 (m, 1 H), 4.30 (dd, J = 2.3, 1 1 .6 Hz, 1 H), 4.04 (dd, J = 7.0, 1 1 .6 Hz, 1 H), 3.38 (m, 2H). |