| 66% |
|
EXAMPLE 5A compound of formula (XI) was prepared as described in Scheme 6 above. A solution of 5-aminopentyltriphenylphosphonium bromide hydrogen bromide (McAllister, P. R.; Dotson, M. J.; Grim, S. O.; Hillman, G. R. Journal of Medicinal Chemistry 1980, 23, pp 862-5) (467 mg, 0.917 mmol) and triethylamine (136 muL, 0.920 mmol) in dichloromethane (10 mL) was stirred for 5 min after which time a solution of N-(2,2-Dimethyl-4-oxo-thietan- 3-yl)-acetamide (Moynihan, H. A., Roberts, S. M. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) 1994, pp 797-805) (157 mg, 0.917 mmol) in dichloromethane (20 mL) was added in one aliquot and the reaction mixture was stirred for a further 4 h. After the mixture had been washed with a saturated solution of sodium methanesulfonate (3 x 20 mL), the organic fraction was collected, dried (MgSO4), filtered and the solvents removed in vacuo to give pale yellow oil. The oil was dissolved in minimal dichloromethane (2 mL) and then excess diethyl ether (70 mL) was added. After the resultant precipitate had settled, the solvents were decanted and the residue was dried in vacuo (0.1 rnmHg) for 2 h to give a thiol as a cream powder (374 mg, 0.607 mmol, 66%). HRPI ESMS (CE) calculated for C30H38N2O2PS+: 521.2386, found: 521.2397. Analysis calculated for C3IH41N2O5PS2: C 60.4, H 6.7, N 4.5, S 10.4%; found C 59.8, H 6.9, N 4.8, S 10.2%. UV-vis: 2.7 mg in 10 mL ethanol, epsilon268 2660 Lmol'W1, epsilon275 2292 Lmor'cm" '. 1H NMR (chloroform-di) delta 7.94 (IH, t, J= 5 Hz, CH2-NH), 7.82-7.62 (16H, m, ArH, CH- NH), 4.67 (IH, d, J= 10 Hz, CH), 3.58-3.47 (2H, m, CH2-P+), 3.42-3.27 (IH, m, CHH-NH), 3.27-3.14 (IH, m, CHH-NH), 2.76 (3H, s, SO3-CH3), 2.69 (IH, s, SH), 2.13 (3H, s, CO- CH3), 1.55 (3H, s, CH3), 1.43 (3H, s, CH3), 1.80-1.52 (6H, m, CH2) ppm. 13C NMR (chloroform-d], 125 MHz) 5170.7, (CO), 170.3, (CO), 135.1 (d, J= 3 Hz^alphara-Ph), 133.6 (d, J- 10 Hz, meta-?h), 130.6 (d, J= 13 Hz, ortho-?h), 118.5 (d, J= 86 Hz, ipso-?h), 62.3 (CH), 46.5 (C), 39.8 (CH3-SO3'), 38.2 (CH2-NH), 30.7 (CH3), 30.6, (CH3), 27.6 (CH2-CH2-NH), 27.1 (d, J= 17 Hz, CH2-CH2-P+), 23.4 (CH3), 22.0 (d, J= 53 Hz, CH2-P+), 21.9 (d, J= 5 Hz, CH2-CH2-CH2-P+) ppm. 31P NMR (chloroform-d iota) delta 25.4 ppm. HPLC: mobile phase 50% acetonitrile, 50% water (0.1% trifluoroacetic acid); Prodigy 5mu OD53 HA 250x4 mm, detection 275 nm, flow rate 1.00 mL/min; retention time 4.76 min, one peak. |
| 66% |
|
EXAMPLE 5A compound of formula (XI) was prepared as described in Scheme 6 above.A solution of 5-aminopentyltriphenylphosphonium bromide hydrogen bromide (McAllister, P. R.; Dotson, M. J.; Grim, S. O.; Hillman, G. R. Journal of Medicinal Chemistry 1980, 23, pp 862-5) (467 mg, 0.917 mmol) and triethylamine (136 muL, 0.920 mmol) in dichloromethane(10 mL) was stirred for 5 min after which time a solution of N-(2,2-Dimethyl-4-oxo-thietan-3-yl)-acetamide (Moynihan, H. A., Roberts, S. M. Journal of the Chemical Society, PerkinTransactions 1: Organic and Bio-Organic Chemistry (1972-1999) 1994, pp 797-805) (157 mg, 0.917 mmol) in dichloromethane (20 mL) was added in one aliquot and the reaction mixture was stirred for a further 4 h. After the mixture had been washed with a saturated <n="43"/>solution of sodium methanesulfonate (3 x 20 mL), the organic fraction was collected, dried (MgSO4), filtered and the solvents removed in vacuo to give pale yellow oil. The oil was dissolved in minimal dichloromethane (2 mL) and then excess diethyl ether (70 mL) was added. After the resultant precipitate had settled, the solvents were decanted and the residue was dried in vacuo (0.1 ramHg) for 2 h to give a thiol as a cream powder (374 mg, 0.607 mmol, 66%). HRPI ESMS (CE) calculated for C30H38N2O2PS+: 521.2386, found: 521.2397. Analysis calculated for C3iH41N2O5PS2: C 60.4, H 6.7, N 4.5, S 10.4%; found C 59.8, H 6.9, N 4.8, S 10.2%. UV-vis: 2.7 mg in 10 mL ethanol, epsilon268 2660 Lmol'W, epsilon275 2292 LmorW '. 1H NMR (chloroform-d,) delta 7.94 (IH, t, J = 5 Hz, CH2-NH), 7.82-7.62 (16H, m, ArH, CH- NH), 4.67 (IH, d, J = 10 Hz, CH), 3.58-3.47 (2H, m, CH2-P+), 3.42-3.27 (IH, m, CHH-NH), 3.27-3.14 (IH, m, CHH-NH), 2.76 (3H, s, SO3-CH3), 2.69 (IH, s, SH), 2.13 (3H, s, CO- CH3), 1.55 (3H, s, CH3), 1.43 (3H, s, CH3), 1.80-1.52 (6H, m, CH2) ppm. 13C NMR (chloroform-d,, 125 MHz) 6170.7, (CO), 170.3, (CO), 135.1 (d, J = 3 Hz,para-Ph), 133.6 (d, J= 10 Hz, meta-Ph), 130.6 (d, J= 13 Hz, ortho-?h), 118.5 (d, J= 86 Hz, ipso-?h), 62.3 (CH), 46.5 (C), 39.8 (CH3-SO3"), 38.2 (CH2-NH), 30.7 (CH3), 30.6, (CH3), 27.6 (CH2-CH2-NH), 27.1 (d, J= 17 Hz, CH2-CH2-P+), 23.4 (CH3), 22.0 (d, J= 53 Hz, CH2-P+), 21.9 (d, J= 5 Hz, CH2-CH2-CH2-P+) ppm. 31P NMR (chloroform-d ,) delta 25.4 ppm. HPLC: mobile phase 50% acetonitrile, 50% water (0.1% trifluoroacetic acid); Prodigy 5mu OD53 HA 250x4 mm, detection 275 nm, flow rate 1.00 mL/min; retention time 4.76 min, one peak. |
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