Synthesis of the key intermediate of ramelteon

S.B. Yu et al. / Chinese Chemical Letters 22 (2011) 264–267 2673.39 (m, 1H), 3.88 (s, 3H), 4.18 (m, 2H), 6.91 (m, 2H), 7.67 (t, 1H, J = 4.6 Hz). 13 C NMR (100 MHz, CDCl 3 ): d 203.7, 170.9, 165.4, 160.5,130.0, 125.4, 115.5, 108.9, 62.6, 55.7, 43.1, 35.3, 34.7, 20.9. EI-MS: 248 ([M] + ); HR-MS 248.1047 ([M] + ,C 14 H 26 O 4 ; Calcd. 248.1049). 11:20[a] D 15.0 (c, 1.0, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ): d 1.70 (m, 2H), 2.05 (s, 1H), 2.13 (m, 1H), 2.32 (m, 1H), 2.76 (m, 1H), 2.85 (m,1H), 3.21 (m, 1H), 3.78 (s, 3H), 3.80 (m, 2H), 6.71 (d, 1H, J = 8.2 Hz), 6.77 (s, 1H), 7.26 (d, 1H, J = 8.2 Hz). 13 C NMR (100 MHz, CDCl 3 ): d158.7, 148.6, 135.8, 124.9, 112.1, 109.3, 61.5, 55.4, 41.7, 37.8, 32.7, 30.6. EI-MS: 192 ([M] + ); HR-MS 215.1040 ([M+Na] + ,C 12 H 16 NaO 2 ;Calcd. 215.1043). 12: 1 H NMR (500 MHz, CDCl 3 ): d 1.83 (m, 2H), 2.24 (s, 1H), 2.41 (m, 1H), 2.78 (m, 1H), 2.86 (m, 1H), 3.11 (m, 1H), 3.77 (s,3H), 3.81 (m, 2H), 6.68 (dd, 1H, J = 1.8 Hz, 8.2 Hz), 6.79 (s, 1H), 7.08 (d, 1H, J = 8.2 Hz), 7.71 (m, 2H), 7.84 (m, 2H). 13 C NMR (100 MHz,20CDCl 3 ): d 168.4, 158.7, 147.8, 135.8, 133.9, 132.2, 124.9, 123.2, 112.6, 108.9, 55.4, 42.6, 36.5, 33.4, 32.4, 30.6. 13: [a] D 27.0 (c, 0.20,H 2 O); mp 174–175 8C; 1 H NMR (500 MHz, DMSO–d 6 ): d 1.66 (m, 2H), 2.09 (m, 1H), 2.24 (m, 1H), 2.70 (m, 1H), 2.80 (m, 3H), 3.12 (m, 1H),3.71 (s, 3H), 6.71 (d, 1H, J = 8.2 Hz), 6.76 (s, 1H), 7.11 (d, 1H, J = 8.2 Hz), 8.18 (s, 3H). 13 C NMR (100 MHz, DMSO–d 6 ): d 158.3, 147.4,20135.0, 124.9, 112.2, 109.1, 55.1, 41.6, 37.1, 31.9, 31.7, 29.9. 1: [a] D 10.0 (c, 0.20, EtOH); mp 76–77 8C; 1 H NMR (500 MHz, CDCl 3 ): d1.15 (t, 3H, J = 7.5 Hz), 1.60 (m, 1H), 1.70 (m, 1H), 2.02 (m, 1H), 2.19 (q, 2H, J = 7.5 Hz), 2.32 (m, 1H), 2.76 (m, 1H), 2.85 (m, 1H), 3.11 (m,1H), 3.41 (m, 2H), 3.79 (s, 3H), 5.48 (s, 1H), 6.71 (dd, 1H, J = 2.0 Hz, 8.5 Hz), 6.75 (s, 1H), 7.11 (d, 1H, J = 8.0 Hz). 13 C NMR (100 MHz,DMSO–d 6 ): d 173.7, 158.7, 148.1, 135.8, 124.9, 112.3, 109.2, 55.5, 42.7, 37.9, 34.8, 32.5, 30.6, 29.8, 9.9. EI-MS: 247 ([M] + ); HR-MS 247.1572([M] + ,C 15 H 21 NO 2 ; Calcd. 247.1571). The enantiomeric excess of (S)-1 was determined by HPLC as >99.9% [column, CHIRALPAK AS-H(4.6 mm 250 mm), room temperature; eluent, hexane-2-propanol-trifluoroacetic acid (90:10:0.1); flow rate, 1.0 mL/min; detect, 290 nm; t Rof (S)-1, 30.7 min; t R of (R)-1 (enantiomer of (S)-1), 37.1 min].